Novel Concepts in Direct Electrochemical C–H Functionalization Dissertation for attaining the academic degree of “Doctor rerum naturalium” (Dr. rer. nat.) in Chemistry submitted in the Department 09 ”Chemistry, Pharmaceutical Sciences, and Geosciences” at the Johannes Gutenberg University Mainz by JOHANNES LUDWIG RÖCKL born in Regensburg Mainz, May 2020 Dean: Univ.-Prof. Dr. Tobias Reich First Reviewer: Univ.-Prof. Dr. Siegfried R. Waldvogel Second Reviewer: Univ.-Prof. Dr. Holger Frey Date of Defense: Declaration The experimental and written elaboration of this thesis was carried out from March 2018 to May 2020 at the Department of Chemistry (FB 09, Johannes Gutenberg University Mainz) under supervision of Prof. Dr. S. R. Waldvogel. Hereby, I, Johannes Ludwig Röckl declare that I wrote the dissertation submitted without any unauthorized external assistance and used only sources acknowledged in the work. All textual passages, which are appropriated verbatim or paraphrased from published and unpublished texts, as well as all information obtained from oral sources are duly indicated and listed in accordance with bibliographical rules. In carrying out this research, I complied with the rules of standard scientific practice as formulated in the statutes of Johannes Gutenberg University Mainz to ensure standard of good scientific practice. “When you know nothing matters, the universe is yours…” - Rick Sanchez Acknowledgements Zunächst möchte ich mich für die Unterstützung bei meinem Doktorvater, Prof. Dr. Siegfried Waldvogel und der Managerin des Studiengangs angewandte organische Chemie, Dr. Birgit Janza, an dem ich teilnehmen durfte, bedanken. Ohne euch wäre ich vermutlich nicht auf die Idee gekommen, eine Promotion zu beginnen. Als ich Ende 2016 fragte, ob mich Sigi bei einer Fast-Track Promotion unterstützt und ein einfaches „Ja!“ erklang, ohne große Bedingungen und ausschweifende Erklärungen, war ich gleichermaßen erstaunt und aufgeregt was die Zukunft so bringen würde. Auch an meine Kollegen in der Forschung der BASF (Dörthe und Marco Naujok, Nadine Vogelgesang, Gerd Molle, Peter Schmitt und Yüksel Battal) möchte ich ein großes Dankeschön aussprechen, der Zuspruch über die vielen Jahre und das Aushalten meiner Launen im Labor waren sicher nicht einfach zu ertragen. Im speziellen habe ich Dr. Martin McLaughlin sehr viel zu verdanken, seine stetige Motivation und sein chemischer Input verhalfen mir zu einer guten Grundlage im Bereich der organischen Chemie, die mir während der Promotion sehr zu Gute kam. Auch meinem Gruppenleiter Dr. Jochen Dietz und meinem Mentor Dr. Peter Eckes gilt mein Dank für eine stetige organisatorische Unterstützung und viele lehrreiche Gespräche. Meine zwei engsten Wegbegleiter und Freunde während meiner Zeit bei BASF, Maximilian Blochberger-Claus und Paul Schneide gilt des Weiteren mein Dank und Anerkennung für reichlich Motivation und auch tolle gemeinsame Erlebnisse. Ohne die tatkräftige Hilfe meiner Laborkollegen innerhalb und neben des Labors, wäre diese Arbeit nicht möglich gewesen. Daher danke ich im speziellen Lars Wesenberg, Silja Hofmann, Dennis Pollok, Dimitrij Ryvlin, meinen Vorgängern Anton Wiebe sowie Yasushi Imada für die Hilfe über die letzten Jahre. Bei meinen beiden Bacheloranden Adrian Hauck und Jonas Rein bedanke ich mich für eure tolle Mitarbeit und wünsche alles Gute für eure Zukunft. Eine sehr große Inspiration während meiner Laufbahn stellte für mich Prof. Dr. Bill Morandi dar, da er mich durch seine Art ein Labor zu führen und Forschung zu betreiben auf die Idee brachte, etwas Ähnliches anzustreben. An dieser Stelle auch ein großer Dank an die ganze Morandi-Gruppe für die herzliche Aufnahme in ihrer Mitte. Zu guter Letzt möchte ich mich bei meinen Eltern und Geschwistern für die Erziehung und Unterstützung bedanken und im ganz Besonderen meiner Partnerin Emma Louise Robertson und ihrer Familie für Support in allen Lebenslagen und viel Verständnis danken. Ohne euch wäre das so nicht möglich gewesen. Abstract The focus of this Ph.D. thesis was to develop novel electro-organic methods in C–H functionalization; in particular to eliminate the need for additional supporting electrolyte by applying a combination of base with acidic HFIP (pKa = 9.3) to form a supporting electrolyte in situ. This avoids the use of salts and simplifies the work-up procedure, facilitating easy removal of the electrolyte by distillation, simplifying downstream processing and recycling of the electrolyte. The thesis covers studies towards various C–H functionalization reactions of different types of C–H bonds. The benzylic C–H functionalization of methyl groups with HFIP and subsequent cross-coupling has been successfully demonstrated, giving access to valuable diarylmethanes. The unique properties of 1,3-benzodioxoles were used to synthesize orthoesters electrochemically. A closer look at the properties of these structures revealed their extraordinary stability towards acids and bases and their high lipophilicity. Successful introduction of the HFIP moiety with further functionalization of purines and arenes was achieved by applying a Design of Experiment (DoE) approach. Moreover, the first successful electrochemical dehydrogenative homo- and cross-coupling reaction of electron-deficient phenols has been developed. Finally, an electrochemically-enabled isodesmic shuttle reaction of halogens is described. This concept was expanded to SPhBr and SPhCl shuttle reactions, which were thus far unprecedented. The reversibility was utilized in various synthetic applications, such as intramolecular bromine shuttle reactions or the protection and deprotection of double bonds. Kurzzusammenfassung Der Schwerpunkt dieser Dissertation lag auf der Entwicklung neuartiger elektro- organischer Methoden zur C–H Funktionalisierung; insbesondere sollte der Bedarf an zusätzlichem Leitsalz durch die Kombination von Base mit HFIP (pKs = 9,3) eliminiert werden. Dies vermeidet die Verwendung von Salzen und vereinfacht die Aufarbeitung, da der Elektrolyt leicht destillativ abgetrennt werden kann und das Recycling des Elektrolyten dadurch vereinfacht wird. Die Arbeit umfasst Studien zu verschiedenen C–H Funktionalisierungsreaktionen an verschiedenen Arten von C-H-Bindungen. Die benzylische C–H Funktionalisierung von Methylgruppen mit HFIP und anschließender Kreuzkupplung wurde erfolgreich demonstriert, wodurch der Zugang zu wertvollen Diarylmethanen ermöglicht wird. Die einzigartigen Eigenschaften von 1,3- Benzodioxolen wurden genutzt, um Orthoester elektrochemisch zu synthetisieren. Ein genauerer Blick auf die Eigenschaften dieser Strukturen zeigte ihre außerordentliche Stabilität gegenüber Säuren und Basen und ihre hohe Lipophilie. Die erfolgreiche Einführung der HFIP-Einheit mit weiterer Funktionalisierung von Purinen und Arenen wurde durch Anwendung eines Design of Experiment (DoE)-Ansatzes erreicht. Darüber hinaus wurde die erste erfolgreiche elektrochemische dehydrierende Homo- und Kreuzkupplungsreaktion von elektronenarmen Phenolen entwickelt. Zuletzt wurde eine elektrochemische isodesmische Shuttle-Reaktion von Halogenen beschrieben. Dieses Konzept wurde auf SPhBr- und SPhCl-Shuttle-Reaktionen ausgeweitet, die bisher noch nicht beschrieben waren. Die Reversibilität wurde in verschiedenen synthetischen Anwendungen genutzt, wie z.B. bei intramolekularen Brom-Shuttle- Reaktionen oder zur Schützung und der Entschützung von Doppelbindungen. Table of Contents 1 INTRODUCTION ...................................................................................................................... 17 1.1 ORGANIC ELECTROCHEMISTRY ............................................................................................ 17 1.2 C–H FUNCTIONALIZATION ..................................................................................................... 20 1.2.1 Electrochemical C–H Functionalization ....................................................................................... 22 1.2.1.1 Benzylic C–H Functionalization ...................................................................................................................................... 23 1.2.1.2 Aromatic C–H Functionalization ..................................................................................................................................... 25 1.2.2 Aryl-Aryl C-C Bond Formation ........................................................................................................... 26 1.3 1,1,1,3,3,3-HEXAFLUOROPROPAN-2-OL (HFIP)/ BASE SYSTEM AS A UNIQUE ELECTROLYTE .................................................................................................................................. 28 2 OBJECTIVE .............................................................................................................................. 29 3 RESULTS AND DISCUSSION ..................................................................................................... 31 3.1 BENZYL-ARYL CROSS-COUPLING VIA ANODIC C–H FUNCTIONALIZATION WITH HFIP ..... 31 3.2 BENZYLIC ANODIC C–H FUNCTIONALIZATION WITH HFIP AND SUBSEQUENT CYANATION TO GENERATE 2-PHENYLACETONITRILES ....................................................................................... 35 3.3 ANODIC C–H FUNCTIONALIZATION TOWARDS FLUORINATED ORTHOESTERS FROM 1,3- BENZODIOXOLES .............................................................................................................................. 38 3.4 ANODIC C–H FUNCTIONALIZATION OF PURINE DERIVATES AND SUBSEQUENT CROSS- COUPLING ......................................................................................................................................... 42 3.5 DEHYDROGENATIVE ANODIC C–C COUPLING OF PHENOLS BEARING ELECTRON- WITHDRAWING GROUPS ................................................................................................................... 46 3.6 ELECTROCHEMISTRY-ENABLED ISODESMIC SHUTTLE REACTION ...................................... 49 4 CONCLUSION .......................................................................................................................... 55 5 OUTLOOK ............................................................................................................................... 59 6 REFERENCES ........................................................................................................................... 62 7 APPENDIX ............................................................................................................................... 67 7.1 PUBLICATIONS ....................................................................................................................... 67 7.2 SUPERVISED WORK ............................................................................................................... 68 7.3 CURRICULUM VITAE .................................................................................................................... 69 7.4 ATTACHED PUBLICATIONS ............................................................................................................ 71 1 Introduction 1.1 Organic Electrochemistry Global energy consumption has increased enormously over the last few decades. In the context of global warming, this has become a major topic of social and political discussion. Fossil resources are in limited supply and this will no doubt have a significant impact on the organic synthesis of chemicals in years to come. With the advent of green chemistry,[1] current research efforts are focused on not only improving efficiency of industrial reactions and processes, but also on the development of sustainable synthetic approaches. Cutbacks on ecological footprint, carbon dioxide emissions and waste generation will become increasingly important for industry. With this shift in focus, electro-organic synthesis is experiencing a renaissance after being overlooked for several decades.[2,3] The use of electric current to induce oxidation and reduction in lieu of conventional chemical agents poses several advantages from an environmental and economical perspective (Figure 1).[4] Inexpensive and readily accessible electric current from renewable resources can be harnessed as an inherently safe reagent. This in turn leads to transformations with high atom economy and minimal reagent waste. Electrochemical reactions have already demonstrated robustness across a broad range of current densities, allowing for short reaction times at high current densities without any significant loss in yield versus conventional synthetic routes.[5,6] Furthermore, an electrochemical approach may open up novel synthetic avenues or enable facile alternatives to otherwise challenging reactions.[7] Significant progress has been made in electro-organic synthesis over the past two decades, as outlined in reviews by Waldvogel et al., Baran et al., and Kärkäs [3,8–11] Figure 1. Comparison classical organic synthesis and electro-organic synthesis. 17 Introduction The general principles of organic electrochemistry are based on either cathodic reduction (single electron transfer from electrode to substrate or mediator) or anodic oxidation (single electron transfer from substrate to electrode or mediator). The substrate is dissolved in an ion conductive reaction mixture (electrolyte) and the electrode is usually composed of an electroconductive solid material such as graphite. There are several reaction parameters which require optimization prior to establishing a novel electro-synthetic method. These include current density, which has direct influence onto the concentration of reactive intermediates; applied charge, which equals the amount of reagent added; temperature, and supporting electrolyte to ensure conductivity (Figure 2).[8] Single electron transfer occurs at the electrode. For subsequent reactions, these highly reactive intermediates need to diffuse into the bulk, therefore ionic strength and solvation are important factors for the electrolyte system. substrate product intermediate intermediate' intermediate'' electrode-controlled: electrolyte-controlled: electrocatalysis ionic strength inert solvation potential convection over-potential general parameters: current density temperature supporting electrolyte applied charge Figure 2. Common parameters in electro-organic synthesis. The material characteristics of the electrodes must also be considered, as these influence their mode of operation (Figure 3). Inert electrodes are involved exclusively in the electron transfer process, and the selectivity of this process is proportional to the electrode potential. Common inert electrode materials are platinum or carbon-based systems, such as graphite, glassy carbon, or boron-doped diamond (BDD), which share several advantages including simple application and relatively low maintenance.[9–12] If higher selectivity is needed, active electrodes and mediated electrolysis can be used. Active electrodes generate a non-soluble electrocatalytic 18 species which forms a layer on the electrode surface and acts as an immobilized redox mediator.[13] This redox mediator is formed and regenerated in situ, serving as a redox filter. Examples for these electrodes are active Mo,[14] Ni/NiOOH[15] or Pb/PbO [16]2. Dependence of conversions on the applied electrode potential is reduced compared to that of inert electrode systems. Mediated electrolysis represents a further approach, using a soluble active mediator which converts the substrate and is electrochemically regenerated. A stepwise approach can be taken for even more sensitive substrates, in which a reagent is converted into an active species electrochemically, and the substrate is added in a separate step ex-cell, after complete electrolysis.[17] In general, oxidized or reduced intermediates generated in situ at the electrode are highly reactive and prone to further reactions.[18] Figure 3. Modes of operation for electrodes in electro-organic synthesis. There are several different modes of operations in electro-organic synthesis. The galvanostatic protocol operates at constant current, facilitating rapid transformations at low cost (Figure 4). The setup is simple, requiring two electrodes in electrolyte and in a preferentially undivided cell supplied with a source of constant current. Simple direct current power sources which are readily commercially available can be used. The reaction mixture is composed of solvent, and if necessary, an additional supporting electrolyte to facilitate the conductivity. The supporting electrolyte is typically a salt, a strong acid or base. Alternatively, a divided cell setup with an additional semipermeable or porous membrane between the catholyte and anolyte can be used. This is useful for reversible redox reactions or to prevent instability towards the counter electrode.[3] An alternative setup is required for potentiostatic electrolysis. An additional reference electrode is needed to control the potential, enhancing the selectivity but prolonging reaction time and increasing the associated setup costs.[19] 19 Introduction Figure 4. Modes of operation in electro-organic synthesis. User-friendly setups, such as the ElectraSyn designed by Baran et al.,[20] screening cells,[21] and electro-organic continuous flow setups developed in the Waldvogel lab are also commercially available.[22,23] Regardless of the setup used, electrodes should be arranged in parallel to give a homogeneous electric field without local potential peaks which could lower reaction selectivity due to uncontrolled side reactions.[19] Additionally, the cells should also ensure effective mixing, which was found to be a crucial parameter during this work. 1.2 C–H Functionalization The terms C–H activation and C–H functionalization are often used interchangeably. C–H activation refers to the cleavage of the C–H bond by a transition metal, forming an organometallic complex.[24–26] This complex can then undergo subsequent reactions leading to C–H functionalization (Scheme 1). For the purposes of the work described in this thesis, C–H functionalization is better defined as any organic transformation of the relatively inert C–H bond into a C–X bond (where X is usually carbon, oxygen or nitrogen), irrespective of the mechanism. Scheme 1. General equation for metal-catalyzed C–H functionalization. 20 A notably successful example of C–H functionalization is the Shilov system (Scheme 2).[27] This system enables direct conversion of methane into methanol in a high-yielding reaction catalyzed by metal salts in solution. This transformation has huge significance for industry, as methanol is the feedstock for many processes including manufacturing of plastics and paints,[28] and is used as a solvent, antifreeze in pipelines,[29] and as an efficient energy carrier due to its high energy density.[30] Direct conversion from methane opens up access to renewable sources such as biogas for industrial processes. The Shilov reaction was first discovered on observation of a hydrogen-deuterium exchange in deuterated solution using a platinum tetrachloride anion.[31] Shilov was able to catalytically convert methane into methanol or methyl chloride using a Pt(IV) salt as a stoichiometric oxidant. The process involves three main steps: (a) C–H activation; (b) a redox reaction to form an octahedral complex; followed by (c) attack of water for the formation of the carbon-oxygen bond towards methanol. Scheme 2. Catalytic cycle of the platinum catalyzed C–H functionalization of methane to methanol. Although C–H bonds are ubiquitous in organic molecules, selective C–H functionalization has yet to be fully exploited.[32] While transition metal-catalyzed C–H functionalization represents a major breakthrough in organic synthesis, it has its limitations which have led to increasing efforts to develop metal-free alternatives.[33] C−H functionalization is associated with high cost, due to the need for expensive catalysts and non-commercial ligands. A stoichiometric amount of oxidant is often required, leading to a decrease in atom economy and generation of waste. Toxicity is a further issue, particularly in the production of pharmaceutical products, where certain 21 Introduction threshold values of metals cannot be exceeded.[34] Sensitivity to air and moisture is a further factor affecting the robustness and ease of setup of metal-catalyzed C–H functionalization reactions.[35] Limited catalyst turnover in C–H functionalization reactions with a C–H activation step can be another significant problem. While understanding of the mechanistic aspects of C–H functionalization has deepened in recent years,[36,37] activation of the kinetically inert C–H bond remains inherently difficult. Electrochemistry can enable reaction pathways which break the C– H bond selectively under mild conditions by generating radicals, cations, anions and other reactive species which can be exploited in subsequent reactions.[18] 1.2.1 Electrochemical C–H Functionalization Numerous examples over the past two decades demonstrate the versatility of electrochemical strategies towards C–H functionalization, as detailed in a review by Kärkäs.[33] Notable contributions to the field include Shono-type oxidations,[38] Yoshida’s “cation pool” methodology,[17] and Waldvogel’s selective biaryl cross- coupling (Scheme 3).[39] Scheme 3. Important milestones in electrochemical C–H functionalization. 22 Shono and coworkers developed an electrochemical oxidation of carbamates to N-carbamoyl iminium ions as early as 1975.[40] First, a nitrogen-centered radical is formed which is further oxidized to an iminium ion, which in turn can be reacted with a nucleophile (e.g. alcohol solvent molecule or cyanide). This gives rise to C–H functionalization of nitrogen-containing heterocycles in the alpha position. Of note is that only nucleophiles with oxidation potentials higher than those of the starting material (mostly amides and carbamates) can be applied. An elegant strategy enabling use of a wider variety of nucleophiles (also with lower oxidation potentials than the starting material) is the ‘‘cation pool’’ method, where electrolysis and addition of the nucleophile are performed in two separate steps.[17] First, cations are generated and accumulated through electrolysis at low temperatures (such as N-acyl iminium ions). The nucleophile is then added to the reaction mixture. Nucleophiles which have been successfully employed include allyl silanes, enol silyl ethers, enol acetates, allyl stannanes, benzyl silanes, Grignard reagents and organo- aluminum compounds, as well as electron-rich arenes and C–H acidic compounds. In the Waldvogel group, anodic C–H functionalization and coupling reactions of aromatic compounds have been under investigation since 2006.[39] Initially, the group was focused on the synthesis of 2,2′-biphenols as precursors for catalysts in the hydroformylation process.[41] After successfully developing procedures for the electrochemical synthesis of biphenols,[42] selective phenol-arene cross-coupling,[43] the coupling of anilides,[44] meta- and para-terphenyls,[45] and cross-coupling of different heterocycles with phenols was investigated.[46–48] Selectivity was achieved by using boron-doped diamond (BDD) electrodes and fluorinated alcohols as a solvent. So far, this methodology has been limited to electron-rich arenes. Therefore, establishing a procedure to successfully couple phenols carrying electron-withdrawing groups is highly desired. 1.2.1.1 Benzylic C–H Functionalization There are several established electrochemical methods towards benzylic C–H functionalization in which a benzylic methyl group is oxidized to the corresponding alcohol[49] or ketone.[50] An industrial example is the first step in the synthesis of 3-(4- tert-butylphenyl)-2-methylpropanal (Lilial®, Lysmeral®); a twofold anodic oxidation of 4- 23 Introduction 4-tert-butyl toluene on >10,000 ton per year scale towards an acetal.[18] Another electrochemical activation of toluene derivatives via initial oxidation of the aromatic core was demonstrated in work by the Wang group.[51] The aryl radical cation generated can subsequently undergo deprotonation, followed by further oxidation to give a benzylic cation. This cation can then be trapped by a range of oxygen-based nucleophiles, in this case water, which directly undergoes further oxidation from the benzylic alcohol to furnish the corresponding ketone (Scheme 4). Scheme 4. Selective electrochemical benzylic oxidation towards ketones by Wang et al. Consequently, over-oxidation plays a major role in these kinds of reactions. An elegant strategy to avoid this problem is the “stabilized cation pool” method developed by Yoshida and coworkers.[52] As in the regular “cation pool” method, the oxidation and coupling events are divided, which leads to bond formation in a selective manner (Scheme 5). However, in this method, accumulation of the electrochemically oxidized species is achieved by trapping the intermediate benzylic cations with an additional reagent. After elimination of the stabilizing reagent, coupling with aromatic nucleophiles was then carried out. Scheme 5. „Stabilized cation pool“ method by Yoshida et al. Despite the large scope of this method, it exhibits some drawbacks. The stabilizing reagent S,S-diphenyl-N-(4-methylphenylsulfonyl)sulfimine is not commercially available and needs to be applied in 5- to 10-fold excess. The procedure suffers from long reaction times (up to 35 hours to reach completion) and has only been demonstrated on a small scale (0.1 mmol). Free phenols could not be used in the anodic step. In addition, a complex electrolysis setup has been used (a divided cell 24 equipped with a very specific carbon fiber anode), limiting the procedure’s scalability. In addition, this method suffers from the use of expensive supporting electrolytes and a poor atom efficiency. Consequently, a simple, sustainable, and scalable approach for the synthesis of diarylmethanes remains highly desired. 1.2.1.2 Aromatic C–H Functionalization The direct introduction of alcohols into aromatic systems is challenging, due to the electron-donating nature of alkoxy groups, making the corresponding aryl ethers prone to over-oxidation.[19] Although monoalkoxylated arenes can be obtained after elimination, the anodic C–H bond alkoxylation is limited to only few examples in low yields (Scheme 6).[53,54] Scheme 6. Anodic methoxylation towards 2,3,4-trimetoxyacetophenone. Furthermore, the yield of electrochemical C–H acetoxylation of arenes is limited by either over-oxidation or the formation of various regioisomers. Therefore, almost exclusively symmetrical substrates have been explored.[19] A formal anodic hydroxylation has been achieved in a one-pot sequence, with electrochemical synthesis of aryl acetates followed by hydrolysis (Scheme 7).[55–57] Benzylic positions are preferentially attacked over arylic positions by acetic acid as a nucleophile to give benzyl acetate, due to the high stability of benzylic cations. Palladium on carbon reacts with hydrogen generated at the cathode to selectively cleave the benzyl acetates, which leads to accumulation of aryl acetates.[58] Scheme 7. Selective anodic core acetoxylation of alkylated benzene derivatives. 25 Introduction Another approach to C(sp2)–H alkoxylations and acetoxylations is transition metal- catalyzed transformation. Anodic oxidation is used as a clean, cheap and safe substitute for oxidizing agents in transition metal-catalyzed C–H functionalization. Ackermann et al. developed an electrochemical cobalt-catalyzed ortho-C–H alkoxylation of N-(pyridine-N-oxide)-benzamides utilizing pyridinium-N-oxide as a directing group in yields up to 78%.[59] In contrast to purely non-mediated electrochemical transformations, transition metal-catalysis requires a directing group which allows the pre-coordination of the substrate to the metal (Scheme 8). A variety of directing groups such as oxime ethers, pyridines, pyrazoles, and quinolones are suitable for palladium acetate catalyzed electrochemical C–H acetylation and afford aryl acetates in moderate to good yields.[60,61] An intrinsic drawback of transition metal- catalyzed C–H activation is the requirement of a directing group and the use of additional metals, which limits the general applicability and the scope. Scheme 8. Catalytic cycle of the Pd-catalyzed C–H activation and acetoxylation of oxime ethers. 1.2.2 Aryl-Aryl C-C Bond Formation The Suzuki−Miyaura reaction is a well-known general strategy towards the biaryl structural motif. This transition-metal-catalyzed coupling reaction of aryl(pseudo)halides and nucleophilic organometallic species makes use of organoboron reagents (Scheme 9).[62–64] Although this transformation is highly selective and high-yielding, it is associated with some environmental and economic 26 disadvantages. Pre-functionalized substrates and expensive transition metal catalysts producing toxic reagent waste are required. Oxidative, reagent-mediated coupling reactions represent an alternative strategy to access the biaryl motif.[65–67] Oxidative R1–H/R2–H cross-coupling is a leaving-group- free, step-economic approach which requires no pre-functionalization. However, the C–C bond formation step with loss of H2 is typically thermodynamically unfavorable and usually requires a suitable sacrificial oxidant as an external driving force. Conveniently obtained oxidizers such as iron(III) chloride, vanadyl chloride and molybdenum(V) reagents can be used to give selective coupling.[68] Organo-based reagents like (bis(trifluoroactoxy)iodo)benzene (PIFA) or 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ) can also be used but require additional reagents such as Lewis acids.[69,70] This approach is hindered by limited regioselectivity and over-oxidation to form oligomers and polymers. Additionally, competing reactions to form the homo- coupled products a significant problem. Scheme 9. Comparison between different aryl-aryl cross-coupling methodologies. Electrochemistry poses an environmentally friendly, inherently safe, robust and selective alternative for the formation of carbon-carbon bonds.[19] Oxidative R1–H/R2– H cross-coupling with hydrogen gas evolution has recently been achieved via anodic oxidation and concomitant cathodic proton reduction. Further developments and 27 Introduction opportunities for electrochemical C–C bond formation are outlined in a recently published account by Waldvogel et al.[39] 1.3 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP)/ Base System as a Unique Electrolyte Highly fluorinated alcohols such as 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) demonstrate high electrochemical stability and the ability to stabilize intermediary radical cations.[71–75] Therefore, fluorinated alcohols have emerged as excellent choices for a broad range of applications in organic chemistry, due to their high hydrogen-bonding donor ability,[76,77] high polarity,[77,78] outstanding (electro-)chemical stability,[71,79] and micro-heterogeneity[80,81]. This is illustrated by their use as solvents, co-solvents or promoters in organic syntheses.[71,77,82,83] Several examples have showcased the utility of HFIP in transition metal-catalyzed,[83,84] and metal-free reactions[85,86]. In combination with bases, HFIP promotes unusual transformations like the generation of aza-oxyallyl cationic intermediates from α-haloamides[87–89] or HFIP- promoted nucleophilic substitutions.[82,90] These unique features of HFIP make it particularly well-suited as a solvent for electrochemical reactions, especially its ability to stabilize radical intermediates. HFIP has demonstrated superiority to other solvents when it comes to improving selectivity and yield of various electrochemical transformations.[8,18,39,91] 28 2 Objective A common drawback in electrochemistry is the need for supporting electrolytes, which are often salts which can be harmful to the environment.[92] For example, perchlorates can lead to explosive events and symmetric tetraalkylammonium salts strongly affect the wastewater treatment.[93,94] These salts have to be removed upon workup in multiple steps, making recovery and purification difficult. The aim of this work was to find novel electrolytic systems that circumvent these problems and enable new transformations in electrochemical C−H functionalization. When applying a combination of base with acidic HFIP (pKa = 9.3) to electro-organic synthesis, a supporting electrolyte is formed in situ, eliminating the need for additional supporting electrolyte. Avoiding the use of salts simplifies the work-up procedure, facilitating easy removal of the electrolyte by distillation, simplifying downstream processing and recycling of the electrolyte. Additionally, the lack of salts allows for coupling with mass spectrometry for real-time reaction monitoring in, for example, automated synthesis. Furthermore, the enhanced nucleophilicity of deprotonated HFIP allows trapping of reactive intermediates, which can be applied to different coupling reactions to open new pathways in organic synthesis. 29 3 Results and Discussion 3.1 Benzyl-Aryl Cross-Coupling via Anodic C–H Functionalization with HFIP Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Metal- and Reagent-Free Dehydrogenative Benzyl-Aryl Formal Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol, Angew. Chem. Int. Ed. 2018, 57, 12136–12140; (VIP manuscript) (Inside back cover) Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Metall- und reagensfreie dehydrierende formale Benzyl-Aryl-Kreuzkupplung durch anodische Aktivierung in 1,1,1,3,3,3-Hexafluorpropan-2-ol, Angew. Chem. 2018, 130, 12312–12317. During the work on dehydrogenative N,N-coupling, HFIP aryl ethers were discovered as a by-product (Scheme 11).[95] Of particular interest for subsequent functionalization were the benzylic HFIP ethers, due to their unique reactivity.[96] Scheme 11. Discovery of HFIP ethers during the work on anodic N,N-bond formation. After initial screenings, we found that by adding a base to HFIP as solvent, the anodic oxidation of phenols, anisols and anilids delivers HFIP ethers in very high yields, making additional supporting electrolyte superfluous. Moreover, it was discovered that after treatment of HFIP ethers with acid (acetic acid, trifluoroacetic acid), benzyl cations are formed and HFIP is released again. These benzyl cations are very stable in HFIP[71] and can easily be trapped with arenes as nucleophiles (Scheme 12). This gives rise to 31 Results and Discussion the cross-coupled products in exceptionally high yields (up to 93% over 2 steps) with a very broad substrate spectrum (Scheme 12).[96] Scheme 12. Benzyl-aryl cross-coupling of phenols with various nucleophiles after anodic activation with HFIP. Even late-stage functionalization of a variety of natural products and pharmaceuticals was possible in yields up to 44% by slightly changing the protocol and using Lewis acids instead of 2,2,2-trifluoroacetic acid for HFIP ether cleavage (Scheme 13). 32 Scheme 13. Lewis acid directed late-stage functionalization of natural products and pharmaceuticals. Mechanistic investigations revealed that the respective phenol, anisole or even anilide is oxidized twofold at the anode, which after twofold deprotonation results in the formation of a quinone methide derivative (Scheme 14). This intermediate is activated in acidic solution and nucleophilic attack of a HFIP anion in the benzylic position can take place. HFIP anions are present from the beginning of the reaction, due to addition of base. The concentration is maintained by the cathodic formation of hydrogen. Scheme 14. Proposed mechanism towards benzylic HFIP ethers. 33 Results and Discussion Treatment with acid leads to benzylic cations; these are in equilibrium with quinone methide derivatives which can react with nucleophiles, such as electron-rich arenes, to give valuable diarylmethanes (Scheme 15). Scheme 15. Mechanistic proposal of HFIP-ether cleavage and benzyl-aryl cross-coupling. Contribution statement: Tile Gieshoff (Waldvogel lab) discovered the reaction during other work towards pyrazolidinones via electrochemical N,N-bond formation. Anton Wiebe (Waldvogel lab) and Yasushi Imada (Chiba lab) discovered the application of this reaction towards benzyl-aryl cross-coupling. I developed the procedure for the late-stage functionalization, finished the manuscript describing the benzyl-aryl cross-coupling and contributed to further mechanistic investigations. This work was carried out under supervision of Prof. Dr. S. R. Waldvogel at the Johannes Gutenberg University in Mainz. 34 3.2 Benzylic Anodic C–H Functionalization with HFIP and Subsequent Cyanation to Generate 2-Phenylacetonitriles J. L. Röckl, Y. Imada, K. Chiba, R. Franke, S. R. Waldvogel, Dehydrogenative Anodic Cyanation Reaction of Phenols in Benzylic Positions, ChemElectroChem 2019, 6, 4184–4187. It was found that liberation of the benzylic cation is not necessary to achieve selective bond formation when stronger nucleophiles are used.[97] With cyanides, a direct substitution reaction is observed to yield 2-phenylacetonitriles, which represent important building blocks in organic synthesis. The structural feature is a precursor to many biologically active molecules such as 2-phenylethylamines[98] or pharmaceuticals such as the calcium ion channel blocker verapamil or the fungicide mandipropamid (Scheme 16).[99,100] Scheme 16. Representative examples for biologically active molecules incorporating the 2-phenylaceotnitrile and/or phenylethyl amine motif. The reaction only works with p-methylphenols, which is noteworthy as phenols typically need to be protected for conversion into 2-phenylacetonitriles using conventional routes. The commonly used route involves a radical bromination and subsequent substitution with cyanide, with additional protection and deprotection steps (Scheme 17). Scheme 17. Common synthetic route to 2-phenylacetonitriles. 35 Results and Discussion The new procedure allows for a simple, sustainable, easily scalable, reagent- and metal-free electrochemical cyanation reaction. It consists of a two-step sequence and the HFIP ether generated in-situ can be used without further purification. The reaction is selective, with yields up to 90% over 2 steps and multiple alkyl groups, halogens, and methoxy groups being tolerated (Scheme 18). Phenols can be converted in a protective-group-free manner, shortening the usual synthetic route by one to two steps. Additionally, only a small excess of cyanide source is used and therefore less toxic reagent waste is generated. The solvent can be redistilled, allowing for a greener procedure. Scheme 18. Scope of the benzylic anodic activation with HFIP and subsequent cyanation. The mechanism of the anodic HFIP ether formation is the same as in the benzyl-aryl cross-coupling explained in the previous section. As this method only proceeds well with phenols, the following mechanism is proposed: deprotonation of the phenolic hydroxy group, followed by the loss of the HFIP anion to form a quinone methide intermediate, which can be attacked in a 1,6-addition by cyanide to form the desired 2- phenylacetonitrile (Scheme 19). 36 Scheme 19. Mechanism of the cyanation of benzylic HFIP ethers. Contribution statement: The formation of HFIP ethers was developed during previous work. The concept and the optimization of the second reaction were my work. I was responsible for the development of the scope and preparation of the manuscript. Yasushi Imada is listed as a co-author, due to his contribution to the optimization and development of the HFIP ether formation. This work was carried out under supervision of Prof. Dr. S. R. Waldvogel at the Johannes Gutenberg University in Mainz. 37 Results and Discussion 3.3 Anodic C–H Functionalization Towards Fluorinated Orthoesters from 1,3-Benzodioxoles J. L. Röckl, A. V. Hauck, D. Schollmeyer, S. R. Waldvogel, Electrochemical Synthesis of Fluorinated Orthoesters from 1,3-Benzodioxoles, ChemistryOpen. 2019, 8, 1167–1171. (Front cover) During the substrate screening in previous work, 1,3-benzodioxoles were found to exhibit unexpected reactivity at complete conversion.[101] Functionalization occurred at position 2, even in the presence of benzylic methyl groups, contrary to previous work where the benzylic position was functionalized (Scheme 20). Scheme 20. Selectivity of the anodic C–H functionalization of 1,3-benzodioxoles with HFIP. These orthoesters exhibit interesting properties. They are surprisingly stable to acids and bases and do not undergo substitution reactions, even when transition metals are present in the reaction mixture. Therefore, it was possible to perform a bromination, followed by a palladium-catalyzed Suzuki coupling, in the presence of the HFIP orthoester (Scheme 21). Scheme 21. Synthetic transformations at acidic and transition-metal containing conditions at elevated temperatures in the presence of fluorinated orthoesters, demonstrating their outstanding chemical stability. It was also possible to install various fluorous groups, allowing for modulation of the properties of the pharmaceutically relevant 1,3-benzodioxole moiety (Scheme 22).[102] Higher yields and improved selectivity were observed with increasingly larger π- 38 systems. This can be explained by stabilization of the respective cations after twofold oxidation and deprotonation. Scheme 22. Scope of electrochemically accessible fluorinated orthoesters. The logP–values of 1,3-benzodioxoles and the corresponding orthoesters were calculated and compared to determine the lipophilicity of the orthoesters in comparison to the respective 1,3-benzodioxoles (see SI of ref.[101]). It is remarkable that these values increased by a factor of 1.5 to 2 when fluorinated side chains were installed. This transformation could boost the potency of bioactive compounds and impact target selectivity tremendously by influencing pKa, modulating conformation, and hydrophobic interactions of the 1,3-benzodioxole moiety.[103] 39 Results and Discussion The mechanism was studied by cyclic voltammetry (Figure 4). Upon initial oxidation, a radical cation is generated which is highly acidic and therefore undergoes deprotonation. After a further oxidation step, a 6π aromatic 1,3-benzodioxolium species is formed, which can react with a HFIP anion. These intermediates are stabilized by larger π-systems to circumvent side reactions (Scheme 22). Scheme 22. Proposed mechanism for the formation of fluorinated orthoesters. The anticipated 6π aromatic intermediates were isolated as tetrafluoroborate salts and spectroscopically investigated by NMR by Dimroth et al.[104] Studying the CVs, we found that addition of base plays an important role. First, 5-methyl-1,3-benzodioxole in HFIP without base and MTBS as supporting electrolyte was measured. The electron transfer process to the radical cation is reversible, even at a low scan rate of 5 mV/s, indicative of a highly stable radical cation (Figure 4). Upon adding base to this solution, it was found that the process became irreversible. This is due to the subsequent deprotonation reaction. Again, two irreversible oxidation steps (Eox1= 1.17 V vs. FcH/FcH+, Eox2= 1.52 V vs. FcH/FcH+) were observed (Figure 4). This confirms an initial oxidation step to the radical cation, followed by the loss of a proton. Figure 4. Cyclic voltammograms of a 5 mM solution of 5-methyl-1,3-benzodioxole in HFIP at 50 mV/s; left: HFIP/MTBS; right: HFIP/MTBS + DIPEA. 40 Contribution statement: I discovered the reaction during screening for a previous project. During his B.Sc. thesis, Adrian Hauck optimized the reaction conditions and finished the scope under my supervision. I studied the mechanism by cyclic voltammetry and prepared the manuscript. This work was carried out under supervision of Prof. Dr. Waldvogel at the Johannes Gutenberg University in Mainz. 41 Results and Discussion 3.4 Anodic C–H Functionalization of Purine Derivates and Subsequent Cross-Coupling M. Dörr, J. L. Röckl, J. Rein, S. R. Waldvogel, Electrochemical C-H Functionalization of (Hetero)Arenes – Optimized by DoE, Chem. Eur. J., 2020, accepted. After developing the benzylic activation reactions and isolating arylic HFIP ethers as side components, it was considered to use the HFIP moiety attached to aryls as a leaving group in metal-catalyzed cross-couplings. A selective, scalable, and sustainable electrochemical synthesis of HFIP aryl ethers was thus developed. Of particular interest is the electrochemical modification of bioactive purine derivatives, such as caffeine and theophylline derivatives (Scheme 23). Scheme 23. Linear and DoE optimized reaction conditions of the anodic oxidation of purines and other arenes to 8-(1,1,1,3,3,3- hexafluoro-2-propoxy)-arenes in the presence of a base. OVAT optimized a) 7.2 mA/cm2, 2.0 F, 300 rpm (stirrer velocity), 0.25 M (concentration caffeine), 0.1 M concentration NEt3), yield 8-(1,1,1,3,3,3- hexafluoro-2-propoxy)caffeine: 33%; DoE optimized a) 22.1 mA/cm2, 2.61 F, 700 rpm (stirrer velocity), 0.2 M (concentration caffeine), 0.2 M concentration NEt3), yield 8-(1,1,1,3,3,3- hexafluoro-2-propoxy)caffeine: 42%. The optimization to increase the yield for the electrosynthesis of the HFIP caffeyl ether was conducted via a Design of Experiment approach. Optimal reaction conditions were 42 successfully applied to a variety of aryl substrates to extend the scope to non-purine derivatives. Further, the HFIP caffeyl ether was successfully used as the electrophile in transition metal-catalyzed and transition metal-free reactions with excellent yields up to 94% (Scheme 24). Scheme 24. Derivatization of HFIP caffeyl ether with various nucleophiles. [a] NiCl2(PPh3) 2 (10 mol%) , PPh3 (20 mol%) , KCN (4 eq.) , Zn (1 eq.) in DMF 115 °C, 4 h; [b] Pd(OAc) 2 (5 mol%) , XantPhos (10 mol%) , KCN (1.5 eq) , DMF, 85 °C, 14 h; [c] Pd(OAc) 2 (5 mol%) , XantPhos (10 mol%) , amine (2.0–3.0 eq) , DMA, 100 °C, 3 – 14 h; [d] amine (3.0 eq) , DMA, 100 °C, 14 h; [e] Cs2CO3 (3.0 eq.) , phenol/thiophenol (2.0 eq.) , DMF, r.t. [f] NaOH (15 eq.) in propan-1-ol/water 1/3, 60 °C, 2 h; [g] K2CO3 (3.0 eq.) , propan-1-thiol (2.0 eq.) , in DMF, 65 °C, 2 h; The cyclic voltammogram (CV) of caffeine in HFIP/NEt3 with a scan rate of 100 mV/s shows only one peak at 1.80 V (vs. Ag/AgCl in saturated LiCl in EtOH, orange). This indicates that the reaction follows an ECEC pathway, where the oxidation potential of the second oxidation is lower than that of the first oxidation. The oxidations are coupled with an irreversible fast chemical reaction, as indicated by the lack of a cathodic peak at scan rates up to 500 mV/s. The cyclic voltammogram of caffeine in HFIP/MTBS at 100 mV/s shows two distinct anodic peaks at anodic peak potentials of 1.88 V (vs. Ag/AgCl in saturated LiCl in EtOH) for the first oxidation and 2.41 V (vs. Ag/AgCl in saturated LiCl in EtOH) for a second oxidation step. The oxidations are also coupled with an irreversible fast chemical reaction. The second peak in the cyclic voltammogram of caffeine in HFIP/MTBS is evidence for an oxidation pathway that differs from the ECEC mechanism of caffeine in HFIP/NEt3. The high anodic peak potential (2.41 V vs. Ag/AgCl in saturated LiCl in EtOH) suggests that the second oxidation results in a high energy intermediate. The potential shift of the first anodic peak potential in the anodic direction (+0.08 V) suggests that the follow-up reaction is slower or hindered in HIFP/MTBS.[105] 43 Results and Discussion Figure 5. Left: Cyclic voltammogram of a 5 mM solution of caffeine in a 0.1 M solution of NEt3 in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s (orange) and 500 mV/s (blue). Right: Cyclic voltammogram of a 5 mM solution of caffeine in a 0.1 M solution of tributylmethylammonium sulfate (MTBS) in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s (green) and 500 mV/s (purple). NEt3 deprotonates HFIP and generates HFIP anions, which either deprotonate or undergo nucleophilic attack of cationic intermediates with second-order rate laws. Therefore, a study of the potential shift which is dependent on the concentration of HFIP anions is not applicable to discern the mechanism of the follow-up reaction, as HFIP anions are involved in both possible ECEC mechanisms. Scheme 25. Proposed ECEC mechanism of the electrolysis of caffeine in HFIP/TEA. 44 Contribution statement: I determined that the application with purines and further derivatizations was viable. Jonas Rein performed a linear optimization approach and looked into Ni-catalyzed cross-couplings using arylic HFIP ethers as leaving groups and investigated the mechanism as part of his B.Sc. thesis under my supervision. Maurice Dörr undertook the DoE approach and found a more robust and reliable method. This work was carried out under supervision of Prof. Dr. S. R. Waldvogel at the Johannes Gutenberg University in Mainz. 45 Results and Discussion 3.5 Dehydrogenative Anodic C–C Coupling of Phenols Bearing Electron-withdrawing Groups J. L. Röckl, D. Schollmeyer, R. Franke, S. R. Waldvogel, Dehydrogenative C,C – coupling of Phenols bearing Electronwithdrawing Groups, Angew. Chem. Int. Ed. 2020, 59, 315–319 (Hot Paper); J. L. Röckl, D. Schollmeyer, R. Franke, S. R. Waldvogel, Dehydrierende anodische C,C – Kupplung von Phenolen mit elektronenziehenden Substituenten, Angew. Chem. 2020, 132, 323–327. During the work on the C–H functionalization with alcohols, it was found that specific substrates undergo a different reaction pathway. Interestingly, phenols carrying electron-withdrawing groups (EWGs) in position 2 undergo dehydrodimerization. This posed the first selective electrochemical coupling of phenols bearing EWGs.[106] After optimization, the reaction was selective and yielded 2,2’-biphenols in up to 64% yield (Scheme 26). Scheme 26. First selective homo-coupling of phenols bearing electron-withdrawing groups. These types of structures are used for the synthesis of several binuclear boron[107] and aluminum complexes,[108] for application in optoelectronic devices and as catalysts in polymerization reactions[109,110] and are often produced via sophisticated multi-step syntheses.[111] Cross-coupling reactions were also investigated. Co-electrolysis with naphthalene unexpectedly yielded polycyclic structures, which were analyzed by X-ray analysis, NMR spectroscopy and ESI/MS. The aromatic system was broken by the nucleophilic attack of the phenolic oxygen, which is quite unusual. It was also found that the equilibrium is influenced by the pH value, which poses a new type of tautomerism. Further oxidation with DDQ yielded dibenzofurans. Therefore, it was possible to choose between the simple cross-coupled or polycyclic product (Scheme 27). Scheme 27. Cross-coupling of phenols bearing electron-withdrawing groups with naphthalene – discovery of a new form of tautomerism. 46 To further investigate the mechanism of the reaction, cyclic voltammetry studies were conducted. It was found that the oxidation potential was significantly lower when DIPEA was added. All major side products were isolated, including the O,C- and the C,C-coupled product. These were crystallized and their structures were determined by X-ray analysis (Scheme 28). The corresponding HFIP ether was also observed by GC- MS and NMR spectroscopy as in previous work.[96] It is therefore proposed that initial anodic oxidation and subsequent loss of a proton gives the oxygen-centered radical, which can also be written as a carbon-centered radical. This radical can either be attacked by the nucleophilic oxygen or carbon of another molecule of phenol, leading to, after another oxidation step and subsequent re-aromatization, the undesired O,C- coupled side product or to the desired C,C-coupled product. At high current densities, further oxidation of the radical gives more likely a quinone methide intermediate, which is then trapped by HFIP in a 1,6-addition, giving a HFIP ether. This also explains why at lower current density, as well as a higher concentration of phenol, no HFIP ether can be detected and higher yields of desired 2,2’-biphenol are achieved. At high concentration, the radical is more likely to be trapped immediately by another molecule of starting material or another radical instead of being further oxidized at the anode or undergoing other side reactions. Scheme 28. Proposed mechanism for the formation of 2,2-biphenols carrying EWGs. 47 Results and Discussion Contribution statement: I discovered the reactivity and carried out all the work related to this publication. The crystal structure analysis was conducted by Dr. Dieter Schollmeyer. This work was carried out under supervision of Prof. Dr. S. R. Waldvogel at the Johannes Gutenberg University in Mainz. 48 3.6 Electrochemistry-Enabled Isodesmic Shuttle Reaction J. L. Röckl, X. Dong, S. R. Waldvogel, B. Morandi, Electrochemistry enabled isodesmic shuttle reaction, Nature, 2020, in preparation. During my PhD studies, I had the opportunity to undertake a research stay in Bill Morandi’s group at ETH Zurich. The group focuses mainly on isodesmic shuttle reactions, in which the aim is to transfer functional groups from one molecule to another (Scheme 29). Unusually, these reactions are inherently reversible processes, which is the key to their synthetic utility. The shuttled group (also known as the payload) is transferred from a donor molecule to an acceptor molecule.[112,113] Scheme 29. Shuttle concept.[113] While the total number and type of bonds remain unchanged throughout the reaction, the number of bonds in each reaction partner does change. This can be understood by looking at a prime example of shuttle catalysis, transfer hydrogenation (Scheme 30).[114] Here, hydrogen is transferred between an alcohol donor and a ketone acceptor. Scheme 30. Transfer hydrogenation as a simple example for a shuttle reaction. A more sophisticated application of shuttle catalysis is the use of aliphatic nitriles as HCN donors, which are significantly less toxic alternatives to other cyanide sources (Scheme 31). In the work of the Morandi group, isovaleronitrile was employed as an efficient donor, using a Ni catalyst with an Al Lewis acid. It was possible to perform hydrocyanation on a broad range of alkenes using this approach.[115] The formation of volatile isobutene as a by-product acts as a driving force for the transformation. These examples can be considered as mono-functionalization, because there is always hydrogen involved. We were curious to know if di-functionalization is also possible in e.g. chlorine, bromine or halogen-X transfer reactions, to avoid the use of molecular halogens and use inexpensive, less corrosive liquid donor molecules. 49 Results and Discussion Scheme 31. Catalytic HCN-shuttle by Morandi et al. After more than 3000 experiments towards a metal-catalyzed approach were carried out by Xichang Dong (postdoctoral researcher in the Morandi group), it was considered that electrochemistry could be a promising alternative (Scheme 32). Scheme 32. Electrochemistry enabled halogen shuttle reaction. Electrochemistry represents a perfect match for these types of reactions, because the reaction is redox neutral and can therefore be performed as a paired electrolysis. At the cathode, a reduction of the dihalo-donor is performed, two halides and the respective alkene are extruded. Scheme 33. Proposed mechanism for the Br2-shuttle reaction. The halides can then be oxidized at the anode to give Br+-ions or Cl-radicals, which can then react with another alkene to refurnish the two C–X bonds (Scheme 33). In the case of Br2-shuttle reactions, simple 1,2-dibromoethane could be used as a donor to extrude ethylene as a driving force, which was shown by headspace GC/MS. 50 It was possible to apply these conditions to a broad variety of substrates and in late- stage functionalization (Scheme 34). Scheme 34. Scope of the Br2-shuttle reaction using 1,2-dibromoethane as a donor. Additionally, unusual reactions were enabled, including a formal intramolecular shuttle and intramolecular ring-closing domino reactions (Scheme 35). The mechanistic proposal was also supported by radical clock experiments, which reveal an ionic mechanism or only short-lived radical intermediates. It is proposed that extrusion of the bromide takes place in a stepwise manner, rather than concerted, because the threo-isomer reacts preferentially to give the E-alkene. We were also able to trap the bromonium ion using a sterically hindered alkene. 51 Results and Discussion Scheme 35. Unusual reactions enabled by shuttle chemistry. Another interesting application of the shuttle reaction is its use in a protect/deprotect strategy (Scheme 36). Due to the low concentration of reactive agent in the electrochemical reaction, it possible to achieve regioselective bromination of 4-vinylcyclohex-1-ene. Subsequent epoxidation or dihydroxylation and reverse reaction with an excess of 1,4-cyclohexadiene as acceptor deliver the desired epoxide or dihydroxy compound in the desired position only. Scheme 36. Protective group strategy enabled through reversibility of the Br2-shuttle. This approach was also applied to the shuttle of Cl2, which is Mn-catalyzed and works well with a large variety of substrates when 1,1,1,2-tetrachloroethane is used as a donor. Activated systems, as well as acid sensitive substrates, are converted into the respective vicinal dihalides (Scheme 37). The mechanism of this reaction is thought to proceed via a MnII/MnIII redox couple of the chloride-bound complex, as described in work of Lin et al.[116] 52 Scheme 37. Scope of the Cl2-shuttle reactions using 1,1,1,2-tetrachloroethane as a donor. We also looked into a variety of other di-functionalization reactions, such as SPhBr- and SPhCl-shuttle reactions (Schemes 38 and 39). On applying similar conditions to those of the halogen shuttle, similar reactivity was observed. The reactions proceed particularly well if intramolecular follow-up reactions, such as cyclization, are possible (up to 71% yield). Scheme 38. Scope of the SPhBr-shuttle reaction. 53 Results and Discussion A crucial aspect of these reactions is the regioselectivity: for SPhBr-shuttle reactions the secondary halide is formed primarily, whereas in the SPhCl-case the primary halide is observed. This is probably due to the reversibility and the reaction rate of the sulfonium ion formation. For SPhBr this is a highly reversible process, which leads to the formation of the thermodynamically more stable product, the secondary bromide. In the second case, when chloride is involved, the sulfonium ion formation is disfavored and this leads to the formation of the kinetic product as the major product, which is the primary chloride. Scheme 39. Scope of the SPhCl-shuttle reaction. A further fascinating feature of this methodology is the use of polychlorinated waste as a Cl2 – donor. We were able to selectively degrade lindane, a persistant organic pollutant, to benzene and use the 3 equivalents of Cl2 to selectively chlorinate alkenes (Scheme 40). The generation of the by-product benzene was quantified by GC using an internal standard. Scheme 40. Degradation of lindane to benzene Contribution statement: Xichang Dong (postdoctoral researcher, Morandi group), worked on a transition-metal based solution for the existing concept behind this transformation. Both Xichang and I contributed equally to the ideation and optimization of the methodology. 54 4 Conclusion This thesis covers studies towards various C–H functionalization reactions of different types of C–H bonds. Benzylic C–H functionalization of methyl groups with HFIP and subsequent cross-coupling was successfully demonstrated (Scheme 41). Valuable insights relating to the leaving group abilities and the stability of HFIP ethers were gained by treating these with a range of nucleophiles, such as cyanides. Scheme 41. Selective anodic benzylic C-H functionalization and utility of HFIP ethers. The unique properties of 1,3-benzodioxoles have been used to synthesize orthoesters electrochemically (Scheme 42). A closer look at the properties of these structures revealed their extraordinary stability towards acids and bases and their high lipophilicity. Scheme 42. Selective anodic C-H functionalization of 1,3-benzodioxoles in position 2. It was attempted to apply the approach to sp2-hybridized atoms, such as purines and other aryls. Successful introduction of the HFIP moiety with further functionalization of purines was achieved (Scheme 43). In this context, we encountered a major challenge in the electrochemical synthesis of oxygen substituted arenes, namely over-oxidation. This is due to the mesomeric electron-releasing effect of oxygen substituents that leads 55 Conclusion to a lowered oxidation potential compared to the starting material. However, applying a DoE approach we were able to achieve higher yields up to 59%. Scheme 43. Selective anodic C-H functionalization of arenes and subsequent use in coupling reactions. During this work, it was discovered that certain substrates undergo different, interesting reaction pathways, such as phenols bearing EWGs (Scheme 44). These react in dehydrogenative homo-coupling reactions, in the first successful electrochemical synthesis of such electron-deficient phenols to the best of our knowledge. Studies towards cross-coupling of such phenols with naphthalene revealed a novel type of tautomerism, where the aromaticity of the naphthalene moiety is broken to form a polycyclic dihydrodibenzofuran system. This was exploited to synthesize heterocycles by further oxidation towards dibenzofurans. Scheme 44. Selective anodic homo- and cross-coupling of phenols bearing EWG. During my work on electrochemically enabled shuttle reactions, the isodesmic difunctionalization of alkenes was investigated (Scheme 45). This was achieved by using a dihalo donor, such as 1,2-dichloroethane or 1,2-dibromoethane, which was reduced at the cathode and the resulting halogenides oxidized to react with the alkene. This formed a new vicinal dihalide with release of ethylene, indicating that novel intramolecular bromine or chlorine shuttle reactions can be achieved. This concept was 56 expanded to Br(Cl)SPh shuttle reactions, which were thus far unprecedented. The reversibility was utilized in various synthetic applications, such as intramolecular bromine shuttle reactions or the protection and deprotection of double bonds and the degradation of persitant organic pollutants like lindane. 50 examples, yields up to 8 9% Scheme 45. Electrochemically enabled halogen shuttle. 57 58 5 Outlook A promising extension of the chemistry shown would be the stereoselective formation of HFIP ethers. In this case, three different approaches would be possible: synthesis in chiral solvents, at chiral electrodes or using a chiral supporting electrolyte. The synthesis using a chiral supporting electrolyte seems very promising, especially because induced formation of helices in HFIP could be possible e.g. by a chiral base. However, electro-organic transformations using chiral supporting electrolytes are under-explored and to date only one report on asymmetric electrochemical reactions in a chiral solvent has been published, by Seebach and Oei in the 1970s.[117] The first example using a chiral supporting electrolyte by Horner in 1968 was an electroreduction of acetophenone using ephedrine hydrochloride in 4.6% ee.[118] A similar approach has also been attempted for the formation of HFIP ethers. (-)- Sparteine, which acts as a supporting electrolyte in combination with HFIP, showed an enantiomeric excess of 15% in the reaction with 2-methoxy-4-propylphenol (Scheme 45). However, several other chiral bases and additives have failed to induce chirality. Also, racemization after aqueous work up and purification was observed. Mechanistic studies into the inducement are very challenging and still ongoing. Insights from these studies could help to further improve the enantiomeric excess. Additionally, subsequent stereospecific reactions could help to trap chirality into a more stable molecule. Scheme 45. Asymmetric synthesis of HFIP ethers using sparteine as a chiral additive. A major problem of our time is the pollution of the oceans, especially by poorly or non- degradable plastics. One approach to this issue could be to develop strategies to facilitate upcycling or recycling of commodity polymers. One such strategy is to recycle chemically-bound chlorine from polyvinyl chloride (PVC) and transfer it to other molecules to create valuable fine chemicals via our developed shuttle catalysis approach. The most significant potential barrier to success of this approach is the poor solubility of PVC. In initial trials, only DMF and THF, which might have been viable solvents in the e-shuttle reaction, showed dwelling of the polymer. However, these 59 solvents shut down the reaction even with small molecules as donors, which are similar to the subunit of PVC (e.g. 2-chlorobutane). Only acetonitrile shows sufficient reactivity using these donors. There are many reports of thermal dehydrochlorination of PVC;[119] if this would be used as a pretreatment to set chloride free, subsequent electrochemical chlorination could be achieved. 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Morandi, Merging shuttle reactions and paired electrolysis: e-shuttle enables the reversible interconversion of alkenes and vicinal dihalides, 2020, in preparation. M. Dörr*, J. L. Röckl*, J. Rein, S. R. Waldvogel, Electrochemical C-H Functionalization of (Hetero)Arenes – Optimized by DoE, Chem. Eur. J., 2020, accepted, (DOI: 10.1002/chem.202001171). J. Dickhaut, A. Molt, J. L. Röckl, CYCLOCLAVINE: A NATURAL PRODUCT WITH INSECTICIDAL POTENTIAL, book chapter, Elsevier 2020, ASAP. J. L. Röckl, D. Pollok, R. Franke, S. R. Waldvogel, A Decade of Electrochemical Dehydrogenative C,C – Coupling of Aryls, Acc. Chem. Res 2020, 53, 45–61. (Front Cover) J. L. Röckl, D. Schollmeyer, R. Franke, S. R. Waldvogel, Dehydrogenative C,C – coupling of Phenols bearing Electronwithdrawing Groups, Angew. Chem. Int. Ed. 2020, 59, 315–319; (Hot Paper) J. L. Röckl, D. Schollmeyer, R. Franke, S. R. Waldvogel, Dehydrierende anodische C,C – Kupplung von Phenolen mit elektronenziehenden Substituenten, Angew. Chem. 2020, 132, 323–327. J. L. Röckl, A. V. Hauck, D. Schollmeyer, S. R. Waldvogel, Electrochemical Synthesis of Fluorinated Orthoesters from 1,3-Benzodioxoles, ChemistryOpen 2019, 8, 1167–1171. (Front cover) J. L. Röckl, Y. Imada, K. Chiba, R. Franke, S. R. Waldvogel, Dehydrogenative Anodic Cyanation Reaction of Phenols in Benzylic Positions, ChemElectroChem 2019, 6, 4184– 4187. Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Metal- and Reagent-Free Dehydrogenative Benzyl-Aryl Formal Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol, Angew. Chem. Int. Ed. 2018, 57, 12136–12140; (VIP manuscript) (Inside back cover) Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Metall- und reagensfreie dehydrierende formale Benzyl-Aryl-Kreuzkupplung durch anodische Aktivierung in 1,1,1,3,3,3-Hexafluorpropan-2-ol, Angew. Chem. 2018, 130, 12312–12317. M. J. McLaughlin, K. Koerber, B. Gockel, P. Bindschaedler, S. Soergel, D. Vyas, J. Roeckl, Oxy-cope rearrangement for the manufacture of insecticidal cyclopentene compounds, PCT Int. Appl. 2018, WO 2018007175A1. * Authors contributed equally 67 Appendix 7.2 Supervised work 2018 Adrian Hauck, B.Sc.–Thesis Title: Elektrochemische Darstellung von Orthoestern 2019 Jonas Rein, B.Sc.–Thesis Title: Electrochemical Functionalization of Purine Derivatives 7.3 Curriculum vitae Johannes Röckl Johannes Ludwig Röckl Department of Organic Chemistry Nationality: German Johannes Gutenberg University Date of Birth: 20.01.1991 Room 1.125, Duesbergweg 10-14, 55128 Mainz E-mail: joroeckl@uni-mainz.de Phone: +49 15129109412 Education 2017 – now: PhD. Candidate Electro-organic Chemistry with Prof. S. R. Waldvogel at Johannes Gutenberg University Mainz Fast-Track Ph.D. program: awarded to above-average students. 2013 – 2016: B.Sc. Applied Organic Chemistry at Johannes Gutenberg University Mainz Bachelor-Thesis: “Cycloclavine as a Potential Insecticide” Total synthesis of Natural Product derivatives under supervision of Prof. Dr. S. R. Waldvogel and Dr. J. Dickhaut. 2010 – 2013: BBS Naturwissenschaften, Ludwigshafen am Rhein Laboratory Technology – Training during apprenticeship. 2001 – 2010: Benedikt-Stattler-Gymnasium, Bad Kötzting Graduation courses: chemistry, sports; Graduation project: Chemistry in Dental Medicine. Relevant Experience 2018 – now: PhD student at Johannes Gutenberg University, Mainz Supervision of Master and Bachelor students; Work on direct electrochemical C,H – functionalization reactions. 2019: Visiting Researcher at ETH Zurich with Prof. Dr. Bill Morandi, Zurich Work on novel amination reactions and electrochemistry enabled halogen transfer reactions. 2016 – 2018: Scientific Lab Expert at BASF SE, Crop Protection Division, Ludwigshafen Scientist in agricultural research Responsible for early stage projects in insecticide science: - Evaluation of biological data - Planning of the synthesis of new target molecules - Coordinating parallel synthesis of new derivatives - Scale up of reactions into technical scale - Route scouting - Purchase of new compounds for testing. 69 2017: Lab Associate at BASF India Ltd., Crop Protection Division, Navi Mumbai Work on early stage projects in Insecticide science. 2013 – 2016: Lab Technician at BASF SE, Crop Protection Division, Ludwigshafen Synthesis of lead structures for novel insecticides. 2010 – 2013: Apprenticeship as a Laboratory Technician at BASF SE, Ludwigshafen 2012–2013: Combinatorial chemistry for crop protection and LC/MS routine analytics. 2011–2012: Polymers for fiber-bonding - Application technology. 2011–2012: Synthesis of zeolites in catalysis, surface-analytics for zeolites and metal-organic frameworks. 2010–2011: Synthesis of lead structures for fungicides. 2012: Internship at Jotun Group, Sandefjord, Norway (Leonardo da Vinci program) Lab assistant at Jotun research and development center. Studied the application of fungicides in paint. Awards & Achievements 2019: MPGC – Max-Planck-Graduate Center Accepted as a member of the virtual department across two Max Planck Institutes and four facilities of the Johannes Gutenberg University 2018: Prize for best graduate in the degree program Applied Organic Chemistry Awarded for high grades during studies at Johannes Gutenberg University, Mainz 2018: MAINZ - Materials Science in Mainz Graduate School Scholarship and Graduate School (Uni Mainz/MPI/P /TU Kaiserslautern) 2017: Gutenberg Lehrkolleg Thesis Prize – GLK Johannes Gutenberg University, Mainz Awarded for outstanding Bachelor thesis in the department of Chemistry 2014 – 2016: Scholarship: Weiterbildungsstipendium Bundesministerium für Bildung und Forschung Scholarship for gifted students, IHK Pfalz 2013: Prize for Best Apprenticeship Graduate Industrie- und Handelskammer Pfalz Awarded for high grades during apprenticeship Languages & Other Relevant Skills Native: German Other: English (advanced), French (basic), Swedish (basic) Experience with Microsoft Office, electronic laboratory notebook systems, and scientific databases such as SciFinder and Reaxys. Experience using specialist software such as Origin for data presentation & analysis. 70 7.4 Attached Publications 71 Communications AngewandteChemie International Edition: DOI: 10.1002/anie.201804997 Electrochemistry Very Important Paper German Edition: DOI: 10.1002/ange.201804997 Metal- and Reagent-Free Dehydrogenative Formal Benzyl–Aryl Cross- Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol Yasushi Imada, Johannes L. Rçckl, Anton Wiebe, Tile Gieshoff, Dieter Schollmeyer, Kazuhiro Chiba, Robert Franke, and Siegfried R. Waldvogel* Abstract: A selective dehydrogenative electrochemical func- share several major disadvantages: The synthesis of the tionalization of benzylic positions that employs 1,1,1,3,3,3- desired diarylmethanes involves a multistep sequence, is cost- hexafluoropropan-2-ol (HFIP) has been developed. The intensive and time-consuming, and lacks atom efficiency. electrogenerated products are versatile intermediates for sub- Prefunctionalized starting materials have to be prepared sequent functionalizations as they act as masked benzylic under difficult reaction conditions. Catalysts, mostly palla- cations that can be easily activated. Herein, we report dium-based, are also required for the final coupling reaction. a sustainable, scalable, and reagent- and metal-free dehydro- Furthermore, reagent waste is generated in each individual genative formal benzyl–aryl cross-coupling. Liberation of the step. The activation of CˇH bonds in such reactions has only benzylic cation was accomplished through the use of acid. been achieved in a few examples, with a limited substrate Valuable diarylmethanes are accessible in the presence of scope.[5] Friedel–Crafts-type conversions are the second aromatic nucleophiles. The direct application of electricity available option. Hydroxy, halogen, or acetoxy substituents enables a safe and environmentally benign chemical trans- in benzylic positions are cleaved by metal catalysts to formation as oxidizers are replaced by electrons. A broad generate cationic intermediates, which can then undergo variety of different substrates and nucleophiles can be coupling reactions with nucleophilic arenes. The activation by employed. metal catalysts is indispensable in most cases, and a variety of catalysts have been employed (RhCl ,[6] IrCl ,[6] [6]D 3 3 H2PdCl4,iarylmethanes are important motifs in biologically active H [6] [7] [8] [9]2PtCl6, HAuCl4, FeCl3, and Bi(OTf)3). compounds,[1] medicinal chemistry,[2] and materials science.[3] In addition to the complex reaction conditions required In general, there are two different synthetic approaches to (elevated temperature, dry solvents, and/or inert atmos- symmetric and non-symmetric diarylmethanes. Common phere), low regioselectivities and the generation of large procedures exploit transition-metal-catalyzed coupling reac- amounts of salts as reagent waste are further disadvantages.[6] tions of benzyl halides with prefunctionalized aromatic Avoiding the use of stoichiometric reagents and the nucleophiles, or aryl halides with benzylic nucleophiles.[4] generation of reagent waste is an important factor in However, conventional cross-coupling reactions (e.g., developing an environmentally benign, “greener” route to Suzuki–Miyaura or Kumada–Corriu coupling reactions) diarylmethanes.[10] For this purpose, methods for dehydrogen- ative coupling reactions are of great interest. Electrochemis- [*] Y. Imada, J. L. Rçckl, Dr. A. Wiebe, Dr. T. Gieshoff, Dr. D. Schollmeyer, try, in particular anodic conversion, is a valuable tool for the Prof. Dr. S. R. Waldvogel development of such metal- and reagent-free sustainable Institute of Organic Chemistry transformations.[11] This has been recently demonstrated by Johannes Gutenberg University Mainz the development of an electrochemical benzyl–aryl coupling Duesbergweg 10–14, 55128 Mainz (Germany) E-mail: waldvogel@uni-mainz.de for the synthesis of diarylmethanes by Yoshida and co- [12] Homepage: http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/ workers. For accumulation of the electrochemically oxi- Y. Imada, Prof. Dr. K. Chiba dized species in this procedure, the intermediary generated Department of Applied Biological Science benzylic cations had to be trapped with an additional reagent Tokyo University of Agriculture and Technology (Japan) owing to their high reactivity. Subsequent elimination of the Y. Imada, Dr. T. Gieshoff, Prof. Dr. S. R. Waldvogel stabilizing reagent and coupling with aromatic nucleophiles Graduate School Materials Science in Mainz was then carried out. Owing to the separation of the oxidation Johannes Gutenberg University Mainz (Germany) and coupling events, bond formation occurred in a selective Dr. A. Wiebe, Prof. Dr. S. R. Waldvogel manner. However, this method exhibits some drawbacks. The Max Planck Graduate Center stabilizing reagent is not commercially available and has to be Johannes Gutenberg University Mainz (Germany) used in large excess. The coupling reaction can take up to Prof. Dr. R. Franke 35 hours to reach completion, and all reactions were only Evonik Performance Materials GmbH demonstrated on small scale (0.1 mmol). The application of Marl (Germany) free phenols for the anodic step was not reported. In addition, Prof. Dr. R. Franke Lehrstuhl f¸r Theoretische Chemie owing to the complex electrolysis setup (a divided cell Ruhr-Universit‰t Bochum (Germany) equipped with a very specific carbon fiber anode), the Supporting information and the ORCID identification number(s) for procedure is not easily scalable. Consequently, a simple, the author(s) of this article can be found under: sustainable, and scalable approach for the synthesis of https://doi.org/10.1002/anie.201804997. diarylmethanes is still highly desired. In a recent contribution, 12136 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2018, 57, 12136 –12140 Communications AngewandteChemie Stahl and co-workers reported an electrochemical iodination that delivers substates for benzyl–aryl couplings.[13] Following our interest in electrochemical reactions, our group has developed efficient electrochemical CˇC and NˇN coupling reactions involving phenols,[14] anilides,[15] and dianilides as substrates.[16] Key to these conversions was the application of 1,1,1,3,3,3- hexafluoropropan-2-ol (HFIP) as the solvent. HFIP has unique properties. It stabilizes reactive intermedi- ates,[17] has a unique solvent microstructure,[18] as well as interesting solvation properties, and as such, it can enable selective transformations.[14e, 19] HFIP was also used as a solvent by Paquin and co-workers in a non- electrochemical approach for the activation of benzyl fluorides in benzyl–aryl coupling reactions.[20] Owing to its low nucleophilicity, reactions involving nucleophilic attack of HFIP are rarely reported.[21] Recently, our group described an anodic functionalization of anilides with HFIP at the benzylic and aromatic position.[16b] Herein, we report the selective electrochemical functionalization of benzylic positions with HFIP. Such direct electrochemical CˇH functionalizations often require catalyst systems.[22] The generated ether acts as a molecular mask for the benzylic cation, and stabilizes this reactive intermediate by solvent trapping in a less reactive state. The activation of such masked cations to facilitate an efficient and selective benzyl–aryl cou- pling reaction is reported for the first time. We present a simple, sustainable, easily scalable, and reagent- and Scheme 1. Strategies for benzyl–aryl couplings in comparison to our new metal-free electrochemical benzyl–aryl cross-coupling method. reaction that proceeds in a two-step, one-pot sequence (Scheme 1). Initially, the electrochemical HFIP ether formation was optimized (Table 1). Phenol 1 was selected as the test substrate. The electrochemical parameters developed for Table 1: Optimization of the anodic functionalization of 4-methylguaia- col with HFIP.[a]the anodic phenol–thiophene cross-coupling were used as the initial conditions.[14c] Additive screening resulted in efficient HFIP ether formation with 0.57 equiv of diisopropylethyl- amine (DIPEA; Table 1, entry 1). We attributed this to the base character of the additive. A similar effect, but with lower yield and selectivity, was observed using triethylamine Entry Deviation from the standard conditions Yield[b] [%] (TEA), K2CO3, or Cs2CO3 as the base (Table 1, entry 2; see also the Supporting information). The optimal electrolysis 1 – 72 parameters were 2.2 F and 7.2 mA cmˇ2 (Table 1, entries 3–7). 2 TEA instead of DIPEA 42 Notably, oxidation at graphite anodes, which are less 3 1.9 F 64 4 2.2 F 78 expensive than boron-doped diamond (BDD) anodes, pro- 5 2.4 F 56 vided the desired HFIP ether in similar yields (Table 1, 6 2.2 F, 5 mAcmˇ2 67 entry 8). This is particularly interesting for technical large- 7 2.2 F, 10 mAcmˇ2 63 scale applications. However, it should be noted that we 8 graphite electrodes, 2.2 F 76 proceeded here with BDD anodes in the subsequent elec- 9 graphite electrodes, without supporting 72 trolysis because of the slightly better yield according to our electrolyte, 2.2 F 10 without supporting electrolyte, 2.2 F 78 optimization studies. A significant step towards a greener 11 without supporting electrolyte, 2.2 F, 69 procedure was made by noting that DIPEA forms in situ 1.14 equiv DIPEA a supporting electrolyte so that additional salt is not required 12 without DIPEA 0 for this transformation (entries 9 and 10). This can be [a] All reactions were carried out with 1.0 mmol of phenol 1 in 5 mL of rationalized by salt formation between the solvent HFIP HFIP in an undivided cell. [b] Yields determined by 1H NMR spectros- (pK = 9.3)[21]a and DIPEAH + (pKa = 11.4), [23] which leads to copy with benzaldehyde as the internal standard. MTBS = methyltribu- sufficient electrical conductivity. Doubling the amount of tylammonium methyl sulfate. Angew. Chem. Int. Ed. 2018, 57, 12136 –12140 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 12137 Communications AngewandteChemie DIPEA did not improve the yield (entry 11). In a control and anisole derivatives could be coupled in high yields (8–10). experiment (entry 12), the significance of DIPEA as an Product 10 is particularly interesting as the nitrile moiety additive was confirmed. Without additive, phenol homocou- allows for further facile functionalization. When dehydrodi- pling and oligomerization dominated. merization or oligomerization became noticeable during While the selective formation of benzylic HFIP ethers electrolysis (8 and 9), the concentration of the starting using HFIP as a nucleophile is an unprecedented trans- material was reduced, leading to high yields (83% and formation, we were particularly interested in exploring 88%) of the desired coupling products. As a logical step, we applications of this motif in further synthesis. The ether can investigated couplings with different nucleophiles. For this be seen as a molecular mask for the benzylic cation in this approach, the electrolysis was carried out under the optimized case. However, compared to an approach presented in 2013 reaction conditions with 4-methylguaiacol as the test system, demonstrating the trapping of cations in the a-position of and the subsequent coupling step was investigated amides in Shono oxidation products of lactams,[24] the (Scheme 3). The reaction was found to be successful with stabilization and subsequent activation of benzylic cations is a broad variety of different nucleophiles. Arenes with strongly a significantly more challenging task. We found that treat- electron-releasing groups (3 and 11), as well as methylated ment with 2,2,2-trifluoroacetic acid (TFA) led to subsequent arenes (12 and 13), were successfully cross-coupled with formation of an active benzylic cation. When this activation is 4-methylguaiacol. The reaction with a free phenol proceeded carried out in the presence of one to three equivalents of an in good yield (23). Naphthalene derivatives, including aromatic nucleophile, selective benzyl–aryl cross-coupling 1-methoxynaphthalene and unprotected 2-naphthol, were can be achieved. We optimized this coupling reaction with coupled in high yields of up to 81% (14 and 15). Coupling of 1,2,4-trimethoxybenzene as a test substrate. With optimized 4-methylguaiacol with heterocycles such as benzofuran, conditions for the first and second step in hand, we explored the scope of potential substrates for HFIP ether formation. For the subsequent benzylic cross-coupling reaction, 1,2,4- trimethoxybenzene served as the test nucleophile (Scheme 2). Electrochemical functionalization with HFIP at the benzylic position and subsequent benzyl–aryl cross-coupling was achieved with a variety of substrates in yields up to 93% (5). Unprotected phenols can be coupled at primary (3, 5, 6) and secondary benzylic positions (4). Additionally, a biphenol was functionalized (7). Our method proved to be comple- mentary to the “stabilized cation pool” approach as anisole Scheme 2. Scope of the anodic functionalization with HFIP and the subsequent coupling to 1,2,4-trimethoxybenzene. Electrolysis was carried out in 5 mL HFIP with 1 mmol of substrate in an undivided cell. [a] Yield of the benzylic HFIP ether after electrolysis, determined by 19F NMR analysis. [b] With 0.5 mmol of substrate and 3.0 F for Scheme 3. Variation of the nucleophile in the coupling reaction with optimum electrochemical conversion. [c] Electrolysis with 1.8 F; activa- 4-methylguaiacol. Electrolysis carried out in 5 mL HFIP with 1 mmol of tion with p-TsOH instead of TFA, 3 h. phenol 1 in an undivided cell. 12138 www.angewandte.org ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2018, 57, 12136 –12140 Communications AngewandteChemie benzothiophene, N-methylindole, N-methylpyrrole, and thio- phene derivatives is possible in moderate to high yields (16– 22b). The transformation tolerates a variety of substituents (methoxy, methyl, hydroxy, chlorine, and bromine). In most cases, the coupling reaction proceeded smoothly and selec- tively. Only in the case of 3-methylthiophene, the formation of regioisomers (22 a and 22 b) was observed. Importantly, the benzyl–aryl cross-coupling reaction can be conducted in a much shorter period of time compared to Yoshidas process.[12] It should be noted that HFIP was used as both the solvent and nucleophile in this procedure, and that it can be fully recovered and reused.[21] This leads to an overall reaction balance with hydrogen as the only byproduct for the CˇC cross-coupling reaction. To explore the full potential of this method, its application to natural product derivatization was of high interest. Our initial approaches to this end using 2,2,2-trifluoroacetic acid led to the generation of complex mixtures. Further attempts using Lewis acids in dichloromethane proved promising. The use of b-estradiol as a nucleophile and aluminum chloride led to a 32% yield of the coupled product. Further optimization of this system using BF3OEt2 (2.2 equiv) increased the yield of the coupled product to 44%. Based on these initial results, we were able to carry out late-stage functionalizations of a range of natural products and biologically active compounds in moderate yields (Scheme 4). Five different classes of natural products (steroid 27, umbelliferone 26, psolarene 25, phenyl- ethylamine 29, and flavone 28) were successfully derivatized. Scheme 4. Benzylation of natural products and bioactive compounds Couplings were achieved at a range of positions, illustrating using BF3OEt2 (2.2 equiv), 0.1m in CH2Cl2, room temperature, 2–12 h. the generality of this method for exclusive carbon function- alization even in the presence of nucleophilic oxygen (26, 27, and 28) or nitrogen moieties (29). Additionally, crystal structures of the psolarene and umbelliferone derivatives were obtained (see the Supporting Information). These novel derivatives may be of interest as potentially biologically active compounds. Their biological activities are currently being tested. To demonstrate the scalability of our method, we chose the synthesis of compound 17 as a model reaction. The structural moiety of 17 is of significant interest for pharma- ceutically active compounds.[25] Therefore, a simple and scalable method for the synthesis of these diarylmethanes would provide a new versatile strategy. The electrolysis was scaled up by a factor of 40, and was conducted with 40 mmol of phenol 1 in a 200 mL beaker-type cell (Figure 1). No erosion of selectivity was observed for the anodic function- alization with HFIP. This mixture was directly subjected to the coupling reaction with benzothiophene to give 6.91 g of the Figure 1. For the scale-up studies, 5 mL and 200 mL beaker-type cells desired product 17 in a single batch (64% yield). The yield is were employed. For size comparison, a 2E coin (diameter: 25.75 mm, slightly lower compared to that obtained on 5 mL scale ca. 1.01 inches) was placed between the two cells. See the Supporting (76 %). This can be rationalized by the not yet optimized Information for details. addition of TFA on larger scale. Nevertheless, the reaction time could even be decreased from 2 h to 1 h within this ing electrolyte. The scope was exemplified with phenols and upscaling approach. anisoles as well as through the late-stage functionalization of In conclusion, we have established a very efficient natural products. The benzylic HFIP ethers can be activated procedure for the electrochemical functionalization of ben- with acid to undergo dehydrogenative benzyl–aryl cross- zylic groups that is based on the use of HFIP. Small amounts coupling reactions with a variety of different nucleophiles in of DIPEA can be used as an additive to selectively enable this high yields. This method provides a scalable, metal-free, and reaction pathway and to fully replace any additional support- reagent-saving route to diarylmethanes, which has the poten- Angew. Chem. Int. Ed. 2018, 57, 12136 –12140 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 12139 Communications AngewandteChemie tial to shorten a variety of synthetic routes. Activation of [11] a) A. Wiebe, T. Gieshoff, S. Mçhle, E. Rodrigo, M. Zirbes, S. R. electrogenerated HFIP ethers for applications in various Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594 – 5616; Angew. reactions with nucleophiles can be imagined. In addition, this Chem. 2018, 130, 5694 – 5721; b) S. Mçhle, M. Zirbes, E. method could be extended and optimized for anilides, as Rodrigo, T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew.Chem. Int. Ed. 2018, 57, 6018 – 6041; Angew. Chem. 2018, 130, already shown by our group for the first step. Therefore, this 6124 – 6149. approach provides a general route for numerous chemical [12] R. Hayashi, A. Shimizu, J.-I. Yoshida, J. Am. Chem. Soc. 2016, transformations. 138, 8400 – 8403. [13] M. Rafiee, F. Wang, D. P. Hruszkewycz, S. S. Stahl, J. Am. Chem. Soc. 2018, 140, 22 – 25. Acknowledgements [14] a) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 11801 – 11805; Angew. Chem. 2016, 128, 11979 – 11983; b) A. Wiebe, B. Riehl, S. We thank the DFG (GSC 266, Wa 1276/17-1, Wa 1276/14-1) Lips, R. Franke, S. R. Waldvogel, Sci. Adv. 2017, 3, eaao3920; for financial support. Support of the Advanced Lab of c) A. Wiebe, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Electrochemistry and Electrosynthesis—ELYSION (Carl Angew. Chem. Int. Ed. 2017, 56, 14727 – 14731; Angew. Chem. Zeiss Stiftung) is gratefully acknowledged. Y.I. gratefully 2017, 129, 14920 – 14925; d) S. Lips, A. Wiebe, B. Elsler, D. acknowledges support from the Program for Leading Grad- Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. uate School of TUAT, granted by the Ministry of Education, Chem. Int. Ed. 2016, 55, 10872 – 10876; Angew. Chem. 2016, 128, 11031 – 11035; e) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Culture, Science and Technology (MEXT), Japan. Y.I. and Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, T.G. thank the Material Science in Mainz (MAINZ) graduate 12321 – 12325. school for financial support. A.W. thanks the Max Planck [15] L. Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, Graduate Center for financial support. R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 4877 – 4881; Angew. Chem. 2017, 129, 4955 – 4959. [16] a) T. Gieshoff, D. Schollmeyer, S. R. Waldvogel, Angew. Chem. Conflict of interest Int. Ed. 2016, 55, 9437 – 9440; Angew. Chem. 2016, 128, 9587 –9590; b) T. Gieshoff, A. Kehl, D. Schollmeyer, K. D. Moeller, S. R. Waldvogel, J. Am. Chem. Soc. 2017, 139, 12317 – 12324. The authors declare no conflict of interest. [17] L. Eberson, O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. Engl. 1995, 34, 2268 – 2269; Angew. Chem. 1995, 107, 2417 – 2418. Keywords: benzylic coupling · electrochemistry · [18] O. 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Ed. 2018, 57, 12136 –12140 Zuschriften AngewandteChemie Deutsche Ausgabe: DOI: 10.1002/ange.201804997 Elektroorganische Chemie Very Important Paper Internationale Ausgabe: DOI: 10.1002/anie.201804997 Metall- und reagensfreie dehydrierende formale Benzyl-Aryl-Kreuz- kupplung durch anodische Aktivierung in 1,1,1,3,3,3-Hexafluorpropan- 2-ol Yasushi Imada, Johannes L. Rçckl, Anton Wiebe, Tile Gieshoff, Dieter Schollmeyer, Kazuhiro Chiba, Robert Franke und Siegfried R. Waldvogel* Abstract: Eine selektive dehydrierende elektrochemische aromatischen Nukleophilen oder Arylhalogeniden mit ben- Funktionalisierung benzylischer Positionen durch 1,1,1,3,3,3- zylischen Nukleophilen.[4] Herkçmmliche Kreuzkupplungen Hexafluorpropan-2-ol (HFIP) wurde entwickelt. Die elektro- (z. B. Suzuki-Miyaura- oder Kumada-Corriu-Kupplungen) lytisch generierten Produkte sind vielseitige Zwischenprodukte haben jedoch mehrere große Nachteile gemein: Die Synthese f¸r nachfolgende Funktionalisierungen, da sie als maskierte, der gew¸nschten Diarylmethane ist mehrstufig, kosten- sowie leicht aktivierbare Benzylkationen reagieren. Hier wird eine zeitaufw‰ndig und l‰uft mit niedriger Atomçkonomie ab. nachhaltige, skalierbare, reagens- und metallfreie, dehydrie- Vorfunktionalisierte Ausgangsverbindungen m¸ssen unter rende, formale Benzyl-Aryl-Kreuzkupplung vorgestellt. Die schwierigen Reaktionsbedingungen hergestellt werden. Es Freisetzung des benzylischen Kations erfolgt durch S‰ure. werden Katalysatoren, meist auf Palladiumbasis, f¸r die finale Wertvolle Diarylmethane sind in Gegenwart von aromatischen Kupplungsreaktion bençtigt. Dar¸ber hinaus fallen in jedem Nukleophilen zug‰nglich. Die direkte Nutzung von Strom er- einzelnen Schritt Reagensabf‰lle an. Die Aktivierung von C- mçglicht eine sichere und umweltvertr‰gliche chemische Um- H-Bindungen in derartigen Reaktionen wurde nur in wenigen wandlung, da Oxidationsmittel durch Elektronen ersetzt Beispielen mit begrenztem Substratumfang erreicht.[5] Als werden. Es kann eine große Vielfalt an Substraten und Nu- zweite Mçglichkeit kann die Friedel-Crafts-Reaktion ange- kleophilen eingesetzt werden. sehen werden. Hydroxy-, Halogen- oder Acetoxysubstituen- D ten in benzylischen Positionen werden durch Metallkataly-iarylmethane sind eine wichtige Strukturform f¸r biolo- satoren zu kationischen Zwischenstufen gespalten. Diese gisch aktive Verbindungen,[1] in der medizinischen Chemie[2] kçnnen Kupplungen mit nukleophilen Arenen eingehen. Die und in den Materialwissenschaften.[3] Generell stehen zwei Aktivierung durch Metallkatalysatoren ist in den meisten Ans‰tze f¸r die Synthese symmetrischer und nicht-symme- F‰llen unerl‰sslich, und es wurden verschiedene Katalysato- trischer Diarylmethane zur Verf¸gung. G‰ngige Vorgehens- ren eingesetzt (RhCl ,[6]3 IrCl ,[6] H PdCl ,[6]3 2 4 H2PtCl [6]6, weisen nutzen ‹bergangsmetall-katalysierte Kupplungsre- HAuCl ,[7] FeCl [8]4 3 und Bi(OTf) ).[9]3 aktionen von Benzylhalogeniden mit vorfunktionalisierten Weitere Nachteile sind außer den anspruchsvollen Re- aktionsbedingungen (erhçhte Temperatur, wasserfreie Lç- [*] Y. Imada, J. L. Rçckl, Dr. A. Wiebe, Dr. T. Gieshoff, Dr. D. Schollmeyer, sungsmittel und/oder inerte Atmosph‰re) auch die geringe Prof. Dr. S. R. Waldvogel Regioselektivit‰t und große Mengen an Salzabf‰llen.[6] Institut f¸r Organische Chemie Die Vermeidung von stçchiometrischen Reagentien und Johannes Gutenberg-Universit‰t Mainz Reagensabf‰llen ist ein wichtiger Faktor bei der Entwicklung Duesbergweg 10–14, 55128 Mainz (Deutschland) E-Mail: waldvogel@uni-mainz.de eines umweltvertr‰glicheren, „gr¸neren“ Weges zu Diaryl- [10] Homepage: http://www.chemie.uni-mainz.de/OC/AK-Waldvogel/ methanen. Zu diesem Zweck sind Methoden f¸r dehy- Y. Imada, Prof. Dr. K. Chiba drierende Kupplungsreaktionen von großem Interesse. Die Department of Applied Biological Science Elektrochemie, besonders die anodische Umwandlung, ist ein Tokyo University of Agriculture and Technology (Japan) wertvolles Hilfsmittel f¸r die Entwicklung von solchen Y. Imada, Dr. T. Gieshoff, Prof. Dr. S. R. Waldvogel metall- und reagensfreien, nachhaltigen Transformationen.[11] Graduate School Materials Science in Mainz Dies wurde 2016 mit einer von Yoshida et al. entwickelten, Johannes Gutenberg-Universit‰t Mainz (Deutschland) elektrochemischen Benzyl-Aryl-Kupplung f¸r die Synthese Dr. A. Wiebe, Prof. Dr. S. R. Waldvogel von Diarylmethanen gezeigt.[12] F¸r die Anreicherung der Max Planck Graduate Center elektrochemisch oxidierten Spezies in diesem Verfahren Johannes Gutenberg-Universit‰t Mainz (Deutschland) m¸ssen die gebildeten Benzylkationen wegen ihrer hohen Prof. Dr. R. Franke Reaktivit‰t mit einem zus‰tzlichen Reagens abgefangen Evonik Performance Materials GmbH werden. Anschließend erfolgen die Eliminierung des Stabili- Marl (Deutschland) sierungsreagens und die Kupplung mit aromatischen Nu- Prof. Dr. R. Franke Lehrstuhl f¸r Theoretische Chemie kleophilen. Durch die Trennung von Oxidations- und Kupp- Ruhr-Universit‰t Bochum (Deutschland) lungsreaktion erfolgt die Bindungsbildung selektiv. Diese Hintergrundinformationen und die Identifikationsnummer (ORCID) Methode weist jedoch einige Nachteile auf: Das Stabilisie- eines Autors sind unter: rungsreagens ist nicht im Handel erh‰ltlich und muss in https://doi.org/10.1002/ange.201804997 zu finden. großem ‹berschuss verwendet werden. Die Kupplungsreak- 12312 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2018, 130, 12312 –12317 Zuschriften AngewandteChemie tion kann bis zu 35 h dauern, und alle Umsetzungen wurden nur im kleinen Maßstab (0.1 mmol) demon- striert. ‹ber die Anwendung von freien Phenolen f¸r die anodische Umsetzung wurde nicht berichtet. Zudem ist das Verfahren infolge des komplexen Elektrolyseaufbaus (eine geteilte Zelle mit sehr spe- zifischer Kohlefaser-Anode) nicht einfach skalierbar. Daher ist ein einfacher, nachhaltiger und skalierbarer Ansatz f¸r die Synthese von Diarylmethanen immer noch von großem Interesse. In einem aktuellen Beitrag von Stahl und Mitarbeitern liefert eine elektroche- misch vermittelte Iodierung Substrate f¸r die Benzyl- Aryl-Kupplung.[13] Als Folge unseres Interesses an elektrochemischen Umsetzungen hat unsere Gruppe effiziente elektro- chemische C-C- und N-N-Kupplungen mit Pheno- len,[14] Aniliden[15] und Dianiliden als Substrate entwi- ckelt.[16] Der Schl¸ssel zu diesen Umwandlungen war die Verwendung von 1,1,1,3,3,3-Hexafluorpropan-2-ol (HFIP) als Lçsungsmittel. HFIP hat einzigartige Ei- genschaften. Es stabilisiert reaktive Zwischenproduk- te,[17] hat eine einzigartige Lçsungsmittelmikrostruk- tur[18] sowie interessante Solvatisierungseigenschaften und kann somit selektive Transformationen ermçgli- chen.[14e,19] HFIP wurde auch von Paquin et al. als Lç- sungsmittel in einem nicht-elektrochemischen Ansatz Schema 1. Strategien zur Benzyl-Aryl-Kupplung im Vergleich zu unserer neuen zur Aktivierung von Benzylfluoriden in Benzyl-Aryl- Methode. Kupplungen verwendet.[20] Wegen der geringen Nu- kleophilie gibt es kaum Berichte ¸ber Reaktionen mit Tabelle 1: Optimierung der anodischen Funktionalisierung von 4-Me- nukleophilem HFIP-Angriff.[21] K¸rzlich hat unsere Gruppe thylguajacol mit HFIP.[a] die anodische Funktionalisierung von Aniliden mit HFIP an benzylischen und aromatischen Positionen gezeigt.[16b] Hier berichten wir ¸ber die selektive elektrochemische Funktionalisierung von benzylischen Positionen durch HFIP. Diese direkten elektrochemischen C-H-Funktionalisierungen erfordern oft Katalysatorsysteme.[22] Der Ether fungiert als Nr. Abweichung von den Ausb.[b] molekulare Maske f¸r das Benzylkation und stabilisiert dieses Standardbedigungen [%] reaktive Zwischenprodukt durch Abfangen mit Lçsungsmit- 1 – 72 tel in einem weniger reaktiven Zustand. Eine derartige Ak- 2 TEA statt DIPEA 42 tivierung dieser maskierten Kationen zur Erleichterung einer 3 1.9 F 64 effizienten und selektiven Benzyl-Aryl-Kupplung wird hier 4 2.2 F 78 erstmals beschrieben. Wir pr‰sentieren eine einfache, nach- 5 2.4 F 56 ˇ2 haltige, leicht skalierbare, reagens- und metallfreie elektro- 6 2.2 F, 5 mAcm 67 7 2.2 F, 10 mAcmˇ2 63 chemische Benzyl-Aryl-Kreuzkupplung in einer zweistufigen 8 Graphitelektroden, 2.2 F 76 Eintopfreaktion (Schema 1). 9 Graphitelektroden, ohne Leitsalz, 2.2 F 72 Zun‰chst wurde die elektrochemische HFIP-Etherbil- 10 ohne Leitsalz, 2.2 F 78 dung optimiert (Tabelle 1). Als Testsubstrat wurde Phenol 11 ohne Leitsalz, 2.2 F, 1.14 æquiv. DIPEA 69 1 ausgew‰hlt. Die elektrochemischen Parameter f¸r die 12 ohne DIPEA 0 anodische Phenol-Thiophen-Kreuzkupplung wurden als [a] Alle Reaktionen wurden mit 1.0 mmol Phenol 1 in 5 mL HFIP in einer Ausgangsbedingungen verwendet.[14c] Ein Screening von Ad- ungeteilten Zelle durchgef¸hrt. MTBS =Methyltributylmethylsulfat. ditiven f¸hrte zu einer effizienten HFIP-Etherbildung mit [b] Die Ausbeuten wurden mittels 1H-NMR-Spektroskopie mit Benzal- 0.57 æquivalenten N-Ethyl-N,N-di(methylethyl)amin dehyd als Standard bestimmt. (DIPEA; Tabelle 1, Nr. 1). Wir haben dies dem Grundcha- rakter des Additivs zugeschrieben. Ein ‰hnlicher Effekt, Die Oxidation an Graphitanoden, die g¸nstiger sind als jedoch bei geringerer Ausbeute und Selektivit‰t, wurde mit bordotierte Diamantanoden (BDD-Anoden), liefert den ge- Triethylamin (TEA), K2CO3 oder Cs2CO3 als Basen erreicht w¸nschten HFIP-Ether in ‰hnlichen Ausbeuten (Tabelle 1, (Tabelle 1, Nr. 2 und Hintergrundinformationen (SI)). 2.2 F Nr. 8). Dies ist besonders interessant f¸r technische Anwen- und 7.2 mA cmˇ2 waren die optimalen elektrolytischen Be- dungen. Wir merken allerdings an, dass wir hier wegen der dingungen (Tabelle 1, Nr. 3–7). etwas besseren Ausbeuten auf BDD-Anoden zur¸ckgegriffen Angew. Chem. 2018, 130, 12312 –12317 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.de 12313 Zuschriften AngewandteChemie haben. Ein wichtiger Schritt zu einem gr¸neren Verfahren wurde mit der Feststellung gemacht, dass DIPEA mit HFIP eine ausreichende Leitf‰higkeit erzeugt und deshalb kein zus‰tzliches Leitsalz bei dieser Umwandlung erforderlich ist (Tabelle 1, Nr. 9 und 10). Dies kann durch Salzbildung zwi- schen dem Lçsungsmittel HFIP (pK = 9.3)[21]a und DIPEAH + (pKa = 11.4)[23] erkl‰rt werden. Eine Verdoppelung der DIPEA-Menge hat die Ausbeute nicht verbessert (Tabelle 1, Nr. 11). In einem Kontrollversuch (Tabelle 1, Nr. 12) wurde die Bedeutung von DIPEA als Additiv ermittelt. Ohne Ad- ditiv dominierten Phenol-Homokupplung sowie -Oligomeri- sierung. W‰hrend die selektive Bildung von benzylischen HFIP- Ethern unter Verwendung von HFIP als Nukleophil eine beispiellose Transformation darstellt, waren wir besonders daran interessiert, Anwendungen dieses Motivs in der wei- teren Synthese zu untersuchen. Gegen¸ber einem 2013 vor- gestellten Ansatz, der das Einfangen von Kationen in der a- Position von Amiden in Shono-Oxidationsprodukten von Lactamen demonstriert,[24] ist die Stabilisierung und an- schließende Aktivierung von Benzylkationen eine deutlich anspruchsvollere Aufgabe. Wir fanden heraus, dass die Um- Schema 2. Mçglichkeit der anodischen Funktionalisierung mit HFIP setzung mit 2,2,2-Trifluoressigs‰ure (TFA) zur Bildung eines und anschließende Kupplung an 1,2,4-Trimethoxybenzol. Die Elektroly- aktiven Benzylkations f¸hrte. Erfolgt diese Aktivierung in se wurde in 5 mL HFIP mit 1 mmol Substrat in einer ungeteilten Zelle Gegenwart einer ‰quimolaren bis hin zu einer dreifachen durchgef¸hrt. [a] Ausbeute des benzylischen HFIP-Ethers nach der 19 Menge eines aromatischen Nukleophils, kann eine selektive Elektrolyse, bestimmt durch F-NMR-Spektroskopie. [b] 0.5 mmol Sub- Benzyl-Aryl-Kreuzkupplung erreicht werden. Wir haben strat und 3.0 F wurden zur optimalen elektrochemischen Umsetzung verwendet. [c] Elektrolyse mit 1.8 F, Aktivierung f¸r die zweite Reaktion diese Kupplungsreaktion mit 1,2,4-Trimethoxybenzol als mit p-Toluolsulfons‰ure statt TFA, Reaktionszeit 3 h. Testsubstrat optimiert. Unter den optimierten Bedingungen f¸r den ersten und zweiten Schritt wurde die Bandbreite der mçglichen Substrate f¸r die HFIP-Etherbildung untersucht. 1-Methoxynaphthalin und ungesch¸tztes 2-Naphthol, wurden F¸r die anschließende benzylische Kreuzkupplung fungierte in hohen Ausbeuten von bis zu 81% (14 und 15) gekuppelt. 1,2,4-Trimethoxybenzol als Testnukleophil (Schema 2). Die Kupplung von 4-Methylguajacol mit Heterocyclen wie Die elektrochemische Funktionalisierung mit HFIP an Benzofuran, Benzothiophen, N-Methylindol, N-Methylpyrrol der benzylischen Position und anschließende Benzyl-Aryl- und Thiophenderivaten ist mçglich (16–22b). Die Umwand- Kreuzkupplung wurden mit einer Vielzahl von Substraten in lung ist vertr‰glich mit einer Vielzahl von Substituenten Ausbeuten von bis zu 93% (5) erreicht. Ungesch¸tzte Phe- (Methoxy, Methyl, Hydroxy, Chlor und Brom). In den meis- nole kçnnen an prim‰re (3, 5, 6) und sekund‰re benzylische ten F‰llen erfolgt die Kupplung mild und selektiv. Nur bei 3- Positionen (4) gekuppelt werden. Zus‰tzlich wurde die Methylthiophen wurde die Bildung von Regioisomeren (22 a Funktionalisierung von Biphenolen nachgewiesen (7). und 22b) beobachtet. Wichtig ist, dass diese Benzyl-Aryl- Unsere Methode erwies sich als komplement‰r zum „stabili- Kreuzkupplung in wesentlich k¸rzerer Zeit als die von Yo- sierten Kation-Pool“, da Anisol und Anisolderivate in hoher shida et al. durchgef¸hrt werden kann.[12] Außerdem ist zu Ausbeute gekuppelt werden konnten (8–10). Produkt 10 ist beachten, dass HFIP als Lçsungsmittel wie auch als Nukleo- besonders interessant, da die Nitrilgruppe eine weitere ein- phil in diesem Verfahren verwendet wurde und vollst‰ndig fache Funktionalisierung ermçglicht. Falls bei der Elektrolyse zur¸ckgewonnen sowie wiederverwendet werden kann.[21] (8 und 9) eine Dehydrodimerisierung oder Oligomerisierung Dies f¸hrt zu einer Gesamtreaktionsbilanz mit lediglich zu beobachten waren, wurde die Konzentration des Aus- Wasserstoff als Nebenprodukt f¸r die C-C-Kreuzkupplung. gangsmaterials verringert, was zu hohen Ausbeuten (83 und Um das volle Potenzial dieser Methode auszuschçpfen, 88%) der gew¸nschten Kupplungsprodukte f¸hrte. Als logi- war die Derivatisierung von Naturstoffen von großem Inter- schen Schritt f¸hrten wir Untersuchungen zur Kupplung mit esse. Erste Ans‰tze mit 2,2,2-Trifluoressigs‰ure f¸hrten zu verschiedenen Nukleophilen durch. F¸r diesen Ansatz wurde komplexen Mischungen. Weitere Versuche mit Lewis-S‰uren die Elektrolyse unter optimierten Reaktionsbedingungen mit in Dichlormethan waren vielversprechend. Die Verwendung 4-Methylguajacol als Testsystem durchgef¸hrt und der nach- von b-Estradiol als Nukleophil und Aluminiumchlorid f¸hrte folgende Kupplungsschritt untersucht (Schema 3). Die Re- zu einer Ausbeute von 32 % des gekuppelten Produkts. Die aktion gelang mit vielf‰ltigen Nukleophilen. Arene mit stark weitere Optimierung dieses Systems mit BF3·OEt2 elektronenschiebenden Gruppen (3 und 11) sowie methy- (2.2 æquivalente) steigerte die Ausbeute des gekuppelten lierte Arene (12 und 13) wurden mit 4-Methylguajacol Produktes auf 44 %. Auf Grundlage dieser ersten Ergebnisse kreuzgekuppelt. Die Reaktion mit einem freien Phenol ver- konnten wir eine Reihe von Naturstoffen und biologisch ak- lief in guter Ausbeute (23). Naphthalinderivate, einschließlich tiven Substanzen in moderaten Ausbeuten funktionalisieren 12314 www.angewandte.de ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2018, 130, 12312 –12317 Zuschriften AngewandteChemie Schema 4. Benzylierte Naturstoffe und bioaktive Verbindungen unter Verwendung von BF3·OEt2 (2.2 æquiv.), 0.1m in CH2Cl2, RT, 2–12 h. 40 mmol Phenol 1 in einer 200-mL-Becherglaszelle durchge- f¸hrt (Abbildung 1). F¸r die anodische Funktionalisierung mit HFIP wurde kein Abfallen der Selektivit‰t beobachtet. Diese Mischung wurde direkt der Kupplungsreaktion mit Benzothiophen unterzogen, um schließlich 6.91 g des ge- w¸nschten Produkts 17 in einem einzigen Ansatz (64% Ausbeute) zu erhalten. Die Ausbeute ist etwas geringer als im Schema 3. Variation des Nukleophils in der Kupplungsreaktion mit 4- 5-mL-Maßstab (76%). Dies kann durch eine noch nicht op- Methylguajacol. Die Elektrolyse wurde in 5 mL HFIP mit 1 mmol Phenol 1 in einer ungeteilten Zelle durchgef¸hrt. (Schema 4). F¸nf Klassen von Naturstoffen (Steroid 27, Umbelliferon 26, Psolaren 25, Phenylethylamin 29 und Flavon 28) wurden derivatisiert. Die Kupplung wurde an verschiedenen Stellen erreicht, was die Allgemeing¸ltigkeit dieser Methode zur exklusiven C-Funktionalisierung auch in Gegenwart von nukleophilen Sauerstoff- (26, 27 und 28) oder Stickstoffatomen (29) verdeutlicht. Zus‰tzlich wurden Mo- lek¸lstrukturen durch Rçntgenstukturanalyse der Psolaren- und Umbelliferonderivate gewonnen (siehe Hintergrundin- formationen). Diese neuen Derivate kçnnten als potenziell biologisch aktive Verbindungen von Interesse sein. Die Pr¸- fung der biologischen Aktivit‰t ist im Gange. Um die Skalierbarkeit unserer Methode zu demonstrie- ren, haben wir die Synthese von 17 als Modellreaktion ge- w‰hlt. Die Struktureinheit von 17 ist von großem Interesse f¸r pharmazeutische Wirkstoffe.[25] Eine einfache und skalierbare Abbildung 1. 5-mL- und 200-mL-Becherzellen f¸r die Hochskalierung. Methode zur Synthese dieser Diarylmethane bietet daher Zum Grçßenvergleich wurde eine 2E-M¸nze (Durchmesser 25.75 mm, eine neue, vielseitige Strategie. Wir haben die Elektrolyse um ca. 1.01 Zoll) zwischen die beiden Zellen gelegt. Weitere Details finden den Faktor 40 vergrçßert. Es wurde also eine Elektrolyse mit Sie in den Hintergrundinformationen. Angew. Chem. 2018, 130, 12312 –12317 ⌫ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.de 12315 Zuschriften AngewandteChemie timierte Zugabe von TFA in grçßerem Maßstab erkl‰rt [4] a) A. LÛpez-Pÿrez, J. Adrio, J. C. Carretero, Org. Lett. 2009, 11, werden. Dennoch konnte die Reaktionszeit innerhalb dieser 5514 – 5517; b) M. J. Burns, I. J. S. Fairlamb, A. R. Kapdi, P. Hochskalierung sogar von 2 auf 1 h verringert werden. Sehnal, R. J. K. Taylor, Org. Lett. 2007, 9, 5397 – 5400; c) B. P. Wir haben ein sehr effizientes Verfahren f¸r die elektro- Bandgar, S. V. Bettigeri, J. Phopase, Tetrahedron Lett. 2004, 45, 6959 – 6962; d) S. M. Nobre, A. L. Monteiro, Tetrahedron Lett. chemische Funktionalisierung von benzylischen Positionen 2004, 45, 8225 – 8228; e) J.-Y. Yu, R. Kuwano, Org. Lett. 2008, 10, durch HFIP entwickelt. Kleine Mengen DIPEA kçnnen als 973 – 976. Additiv verwendet werden, um selektiv zu diesem Reakti- [5] a) T. Mukai, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, onsweg zu f¸hren und einen zus‰tzlichen Hilfselektrolyten 1360 – 1363; b) D. Lapointe, K. Fagnou, Org. Lett. 2009, 11, vollst‰ndig zu ersetzen. Der Anwendungsbereich wurde mit 4160 – 4163; c) J. Zhang, A. Bellomo, A. D. Creamer, S. D. Phenolen, Anisolen und der Funktionalisierung von Natur- Dreher, P. J. Walsh, J. Am. Chem. Soc. 2012, 134, 13765 – 13772. stoffen demonstriert. Die benzylische HFIP-Funktionalisie- [6] K. Mertins, I. Iovel, J. Kischel, A. Zapf, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 238 – 242; Angew. Chem. 2005, 117, 242 – 246. rung kann mit S‰ure aktiviert werden, um eine dehydrierende [7] K. Mertins, I. Iovel, J. Kischel, A. Zapf, M. Beller, Adv. Synth. Benzyl-Aryl-Kreuzkupplung mit einer Vielzahl von ver- Catal. 2006, 348, 691 – 695. schiedenen Nukleophilen in hoher Ausbeute durchzuf¸hren. [8] I. Iovel, K. Mertins, J. Kischel, A. Zapf, M. Beller, Angew. Chem. Dieses Verfahren bietet einen skalierbaren, metallfreien und Int. Ed. 2005, 44, 3913 – 3917; Angew. Chem. 2005, 117, 3981 – reagentiensparenden Weg zu Diarylmethanen, der das Po- 3985. tenzial hat, verschiedene Synthesewege zu verk¸rzen. Es ist [9] M. Rueping, B. J. Nachtsheim, W. Ieawsuwan, Adv. Synth. Catal. gut vorstellbar, dass die Aktivierung von elektrogenerierten 2006, 348, 1033 – 1037. HFIP-Ethern in verschiedenen Reaktionen Anwendung [10] P. Anastas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301 – 312. [11] a) A. Wiebe, T. Gieshoff, S. Mçhle, E. Rodrigo, M. Zirbes, S. R. finden wird. Zus‰tzlich kçnnte diese Methode erweitert und Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594 – 5619; Angew. f¸r Anilide optimiert werden, wie bereits in ersten Schritten Chem. 2018, 130, 5694 – 5721; b) S. Mçhle, M. Zirbes, E. Rodri- von unserer Gruppe gezeigt. Diese Route ist damit allge- go, T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew. Chem. Int. meing¸ltig f¸r zahlreiche chemische Umwandlungen. Ed. 2018, 57, 6018 – 6041; Angew. Chem. 2018, 130, 6124 – 6149. [12] R. Hayashi, A. Shimizu, J.-I. Yoshida, J. Am. Chem. Soc. 2016, 138, 8400 – 8403. Danksagung [13] M. Rafiee, F. Wang, D. P. Hruszkewycz, S. S. Stahl, J. Am. Chem. Soc. 2018, 140, 22 – 25. [14] a) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Wir danken der DFG (GSC 266, Wa 1276/17-1, Wa 1276/14-1) Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 11801 – 11805; f¸r die finanzielle Unterst¸tzung. Die Unterst¸tzung durch Angew. Chem. 2016, 128, 11979 – 11983; b) A. Wiebe, B. Riehl, S. das Advanced Lab of Electrochemistry and Electrosynthesis Lips, R. Franke, S. R. Waldvogel, Sci. Adv. 2017, 3, eaao3920; – ELYSION (Carl Zeiss Stiftung) wird dankbar gew¸rdigt. c) A. Wiebe, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Y.I. dankt dem Ministerium f¸r Bildung, Kultur, Wissenschaft Angew. Chem. Int. Ed. 2017, 56, 14727 – 14731; Angew. Chem. und Technologie (MEXT), Japan, f¸r die Unterst¸tzung 2017, 129, 14920 – 14925; d) S. Lips, A. Wiebe, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. durch das Program for Leading Graduate School of TUAT. Chem. Int. Ed. 2016, 55, 10872 – 10876; Angew. Chem. 2016, 128, Y.I. und T.G. bedanken sich bei der Graduiertenschule Ma- 11031 – 11035; e) B. Elsler, A. Wiebe, D. Schollmeyer, K. M. terial Science in Mainz (MAINZ) f¸r die finanzielle Unter- Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, st¸tzung. A.W. dankt dem Max-Planck-Graduiertenzentrum 12321 – 12325. f¸r die finanzielle Unterst¸tzung. [15] L. Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 4877 – 4881; Angew. Chem. 2017, 129, 4955 – 4959. Interessenkonflikt [16] a) T. Gieshoff, D. Schollmeyer, S. R. Waldvogel, Angew. Chem.Int. Ed. 2016, 55, 9437 – 9440; Angew. Chem. 2016, 128, 9587 – 9590; b) T. Gieshoff, A. Kehl, D. Schollmeyer, K. D. Moeller, Die Autoren erkl‰ren, dass keine Interessenkonflikte vorlie- S. R. Waldvogel, J. Am. Chem. Soc. 2017, 139, 12317 – 12324. gen. [17] L. Eberson, O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. Engl. 1995, 34, 2268 – 2269; Angew. Chem. 1995, 107, 2417 – 2418. Stichwçrter: Benzylische Kupplungen · Elektrochemie · [18] O. HollÛczki, A. Berkessel, J. Mars, M. Mezger, A. Wiebe, S. R. Gr¸ne Chemie · HFIP · Naturstoffe Waldvogel, B. Kirchner, ACS Catal. 2017, 7, 1846 – 1852. [19] a) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2014, 53, 5210 – 5213; Angew. Zitierweise: Angew. Chem. Int. 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Waldvogel* anie_201804997_sm_miscellaneous_information.pdf Table of Contents General information ........................................................................................................ 3 General protocol for benzyl-aryl cross-coupling reaction (GP) ........................................ 4 Proposed mechanisms for anodic HFIP ether formation and benzyl-aryl cross-coupling reaction .......................................................................................................................... 6 Cyclic voltammetry studies ............................................................................................. 7 Synthesis of benzylic HFIP ether ...................................................................................10 Synthesis of benzyl-aryl cross-coupling product ............................................................11 Synthesis of benzylated natural products and bioactive compounds (late-stage functionalization) ...........................................................................................................34 40 mmol scale synthesis in a 200 mL beaker-type cell ..................................................41 NMR spectra .................................................................................................................42 References ....................................................................................................................73 S2 General information All reagents were used in analytical or sufficiently pure grades. Solvents were purified by standard methods.[1] N-Methyl-N,N,N-tributylammonium methylsulfate (kindly provided by BASF SE, Ludwigshafen, Germany) was used as supporting electrolyte. Electrochemical reactions were carried out at boron-doped diamond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 diamond layer) on silicon support. Column chromatography was performed on silica gel 60 M (0.040 0.063 mm, Macherey- Nagel GmbH & Co, Düren, Germany) with a maximum pressure of 1.6 bar. In addition, a preparative chromatography system (Büchi Labortechnik GmbH, Essen, Germany) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluents mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminum (F254, Merck, Darmstadt, Germany) were used for thin layer chromatography. Gas chromatography was performed on a Shimadzu GC-2010 (Shimadzu, Japan) using a ZB-5 column (Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: hydrogen/air). GC-MS measurements were carried out on a Shimadzu GC-2010 (Shimadzu, Japan) using a ZB-5 column (Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: helium). The chromatograph was coupled to a mass spectrometer: Shimadzu GCMS-QP2010. High Performance Liquid Chromatography (HPLC) was performed on a Azura preparative HPLC (KNAUER Wissenschaftliche Geräte GmbH, Germany) using a Eurospher II column (pore size: 100 Å, particle size: 5 µM, length: 250 mm, inner diameter: 30 mm), deuterium lamp as a detector and 2.1 L pomp. Melting points were determined with a Melting Point Apparatus B-545 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 2 °C/min. Spectroscopy and spectrometry 1H NMR, 13C and 19F NMR spectra were recorded at 25 °C, using a Bruker Avance III HD 400 (400 MHz) (5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces in the corresponding deuterated solvent. Mass spectra and high-resolution mass spectra were obtained by using a QTof Ultima 3 (Waters, Milford, Massachusetts) apparatus employing ESI+. Cyclic voltammetry a a M 663 VA S a a A ab type III potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Solvent: HFIP. v = 100 mV/s, T = 20 °C, c = 0.005 M, supporting electrolyte (if used): nBu3NMe O3SOMe (MTBS), c (MTBS) = 0.09 M. S3 General protocol for benzyl-aryl cross-coupling reaction (GP) GP I: Undivided PTFE cell (5 mL) The undivided 5 mL PTFE electrolysis cells were homemade by the mechanical shop of the university. Detailed information about used cells are already reported.[2,3] It is operated with boron-doped diamond electrodes (BDD, 0.3 x 1 x 7 , 15 diamond layer, support of silicon was used). A solution of phenol or anisol derivative (0.5 1.0 mmol) and N-Ethyl-N-(propan-2-yl)propan- 2-amine (DIPEA) (0.1 mL, 0.57 mmol) in 5 mL 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was electrolyzed with a boron-doped Diamond (BDD) anode and a BDD cathode. A constant current electrolysis with a current density of 7.2 mA/cm2 was performed at room temperature. After 1.8 3.0 F were applied, the reaction solution was diluted with HFIP to 10 mL total volume (to unify the concentration for each reaction). Then, 1.0 eq. - 3.0 eq. of the coupling partner and 10 eq. 2,2,2-trifluoroacetic acid were added to the solution. The mixture was stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation. Residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography yielded the product. Fig. S1: 5 mL PTFE cells in a stainless steel screening block (for temperature equilibration). S4 GP II: Beaker-type cell (200 mL) 40 mmol phenol, 200 mL HFIP, and 4.0 mL (0.57 eq.) DIPEA were transferred into an undivided beaker-type electrolysis cell equipped with a BDD anode and a BDD cathode. A constant current electrolysis with a current density of 7.2 mA/cm2 was performed at room temperature. After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 400 mL. Then, 3.0 eq. of the coupling partner and 10 eq. 2,2,2-trifluoroacetic acid were added to the solution. The mixture was stirred at 40 °C for 1 h. The conversion was monitored by GC. After completion of the reaction, HFIP was recovered by distillatio Residue was dissolved in 70 mL dichloromethane and washed with 150 mL water. The aqueous phase was afterwards washed with 70 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, excess amount of the nucleophile was recovered by bulb-to-bulb distillation (60 °C, 1·10-3 mbar). The pure product was obtained by column chromatography of the residue. The beaker-type cell (200 mL) consists of a simple glass beaker and a glass adapter, closed by a PTFE plug. This cap allows precise arrangement of the BDD electrodes. Total dimension of the BDD electrodes are 14 cm x 3.5 cm x 0.3 cm. Fig. S2: 200 mL beaker-type cell; left: assembled; right: individual parts. For size comparison 2 ( a 25.75 1.01 ) a glass cell. S5 GP III: Cyclic voltammetry protocol A 5 mM solution of the substrate in 5 mL HFIP (with 0.09 M MTBS and/or 0.1 mL DIPEA) was placed in a 10 mL beaker-type glass cell. After degassing of the solution with argon, cyclic voltammetry was performed with a 100 mV/s (or 10 mV/s) scan rate using a BDD working electrode, glassy carbon counter electrode and Ag/AgCl (in saturated LiCl in EtOH) reference electrode. The peak potentials were referenced versus the FcH/FcH+ couple. Proposed mechanisms for anodic HFIP ether formation and benzyl- aryl cross-coupling reaction Fig. S3: Proposed mechanism for the electrochemical HFIP ether formation at benzylic position. Mechanism is shown for 4-methylguaiacol and can vary for other substrates. Twofold oxidation of the phenol at the anode will result in the formation of a quinone methide derivative. This can be activated in the acidic solution to allow nucleophilic attack of the HFIP anion at the benzylic position. The resulting product is a benzylic HFIP ether. Due to addition of DIPEA, HFIP anions are present from the beginning of the reaction. This concentration will be maintained by the cathodic reaction. S6 Fig. S4: Proposed mechanism for the benzyl-aryl coupling by cleavage of the HFIP ether with TFA, followed by a nucleophilic attack at benzylic position. Mechanism is shown for 4- methylguaiacol and can vary for other substrates. The addition of acids like TFA or p-TsOH will lead to the cleavage of the benzylic HFIP ether. The resulting benzylic cation is in equilibrium with the quinone methide species. Both substances are capable and stable enough to be attacked by the coupling partner in a nucleophilic attack. After proton abstraction the desired product is formed. Cyclic voltammetry studies 2 0 -2,5 -2 -1,5 -1 -0,5 0 0,5 1 1,5 2 2,5 -2 -4 MTBS/HFIP -6 MTBS+DIPEA/HFIP -8 DIPEA/HFIP -10 -12 -14 -16 -18 Potential (V vs FcH/FcH+) Fig. S5: Cyclic voltammogram of different blank electrolytic solutions (100 mV/s scan rate). S7 current density (mA/cm²) According to GP III, cyclic voltammetry was performed using different electrolytes. As expected, the oxidation peak of DIPEA was not observed in HFIP (Fig. S5). This suggests that DIPEA is protonated by HFIP and does not act as a mediator in this electrolyte system in the applied potential range. 2,5 2 1,5 1 MTBS/HFIP 0,5 MTBS+DIPEA/HFIP DIPEA/HFIP 0 -1 -0,5 0 0,5 1 1,5 2 -0,5 -1 Potential (V vs FcH/FcH+) Fig. S6: Cyclic voltammogram of a 5 mM solution of 2-methoxy-4-methylphenol in different electrolytes (100 mV/s scan rate). According to GP III, different electrolytes with 5 mM 2-methoxy-4-methylphenol were conducted and the oxidation potential was measured (100 mV/s scan rate). A decrease of the oxidation peak-potential of the phenol can be measured in electrolytic media containing DIPEA (MTBS+DIPEA/HFIP: Eox = 1.12 V vs Fc/FcH+, DIPEA/HFIP: Eox = 1.21 V vs Fc/FcH+) compared to HFIP/MTBS solutions (MTBS/HFIP: Eox = 1.34 V vs Fc/FcH+) (Fig. S6). We tested faster scan rates for a separation of both oxidation steps to the quinone methide intermediate. Nevertheless, no difference of the cyclic voltammogram in any media was observed for scan rates up to 0.5 V/s. This indicates, that both oxidation steps are too fast to be clearly visible by CV measurements. In contrast, a shift to slow scan rates (10 mV/s) showed interesting differences for the cyclovoltammograms in different electrolytes (Fig. S7). According to GP III, different electrolytes with 5 mM 2-methoxy-4-methylphenol were prepared and the oxidation potential was measured (10 mV/s scan rate). In electrolytes containing DIPEA two shoulders close to the oxidation potential of the substrate have been observed (Fig. S7, orange and red curve). A shift for higher potentials decreases the oxidation current. This is comparable to the oxidation behavior when applying fast scan rates (Fig. S6). In contrast, in the electrolyte without any DIPEA (Fig. S7, blue curve), the S8 current density (mA/cm²) oxidation current first decreases after reaching the peak potential and then rises fast with increasing potential values. This can be rationalized with subsequent fast oligomerization reactions close and/or on the electrode surface, whereas in solutions with DIPEA formed intermediates seem to be relatively stable in the applied potential range. This clearly indicates a changed reaction pathway by addition of DIPEA to the electrolyte. 0,9 0,8 0,7 0,6 MTBS/HFIP 0,5 MTBS+DIPEA/HFIP 0,4 DIPEA/HFIP 0,3 0,2 0,1 0 -1 -0,5 0 0,5 1 1,5 2 -0,1 Potential (V vs FcH/FcH+) Fig. S7: Cyclic voltammogram of 5 mM 2-methoxy-4-methylphenol in different electrolytic solution (10 mV/s scan rate). S9 current density (mA/cm²) Synthesis of benzylic HFIP ether 4-((1-Trifluoromethyl-2,2,2-trifluoroethyl)oxymethyl)-2-methoxyphenol (2) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 54%, 164 mg, 0.54 mmol). To be mentioned, the HFIP ether is sensitive to silica gel and can decompose during column chromatography. Rf (cyclohexane:ethyl acetate = 10:3) = 0.52 1H NMR (400 MHz, Chloroform- ) = 6.94 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.0, 1.9 Hz, 1H), 5.77 (s, 1H), 4.81 (s, 2H), 4.13 (p, J = 6.0 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.86, 146.48, 126.21, 122.61, 114.26, 111.27, 75.72, 73.94, 73.62, 73.29, 72.97, 72.65, 55.91. 19F NMR (376 MHz, CDCl3) = -74.61, -74.62. HRMS for C H F O +11 10 6 3 (APCI+) [M+]+: calc.: 304.0529, found: 304.0532. S10 Synthesis of benzyl-aryl cross-coupling product 2-Methoxy-4-(2,4,5-trimethoxybenzyl)phenol (3) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4- trimethoxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 77%, 235 mg, 0.77 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.21 1H NMR (400 MHz, CDCl3) = 6.83 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.69 (dd, J = 8.0, 1.9 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 3.88 (s, 3H), 3.86 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3) = 151.44, 148.02, 146.41, 143.71, 142.99, 133.21, 121.49, 121.34, 114.57, 114.17, 111.42, 98.01, 56.69, 56.54, 56.24, 55.82, 34.92. HRMS for C17H20NaO5 (ESI+) [M+Na]+: calc.: 327.1203, found: 327.1203. S11 2-Methoxy-4-(1-(2,4,5-trimethoxyphenyl)propyl)phenol (4) According to the GPI for the electrochemical HFIP ether formation, 166.1 mg (1.0 mmol) 2- methoxy-4-propylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4- trimethoxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 75%, 249 mg, 0.75 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.13 1H NMR (400 MHz, CDCl3) = 6.83 (d, J = 8.0 Hz, 1H), 6.80 6.74 (m, 3H), 6.52 (s, 1H), 5.60 (s, 1H), 4.17 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.12 1.79 (m, 2H), 0.90 (t, J = 7.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) = 151.41, 147.72, 146.23, 143.57, 143.08, 125.72, 120.28, 114.01, 112.18, 110.94, 98.19, 56.88, 56.75, 56.11, 55.80, 55.80, 44.35, 28.26, 12.81. HRMS for C19H24O +5 (APPI+) [M+]+: calc.: 332.1618, found: 332.1616. S12 2,6-Dimethyl-4-(2,4,5-trimethoxybenzyl)phenol (5) According to the GPI for the electrochemical HFIP ether formation, 136.2 mg (1.0 mmol) 2,4,6-trimethylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4- trimethoxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as white solid (yield: 93%, 281 mg, 0.93 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.12 Melting point: 142.0 °C 142.8 °C 1H NMR (400 MHz, CDCl3) = 6.81 (s, 2H), 6.66 (s, 1H), 6.56 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.80 (s, 2H), 3.79 (s, 3H), 2.21 (s, 6H). 13C NMR (101 MHz, CDCl3) = 151.46, 150.29, 147.91, 142.97, 132.85, 128.78, 122.84, 121.75, 114.65, 98.08, 56.69, 56.65, 56.23, 34.32, 15.98. HRMS for C H + +18 21O4 (APCI+) [M+] : calc.: 301.1434, found: 301.1428. S13 2,6-Di-tert-butyl-4-(2,4,5-trimethoxybenzyl)phenol (6) According to the GPI for the electrochemical HFIP ether formation, 220.6 mg (1.0 mmol) 2,6- Di-tert-butyl-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4-trimethoxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 99:1 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 41%, 158 mg, 0.41 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.47 1H NMR (400 MHz, CDCl3) = 7.06 (s, 2H), 6.69 (s, 1H), 6.57 (s, 1H), 5.06 (s, 1H), 3.91 (s, 3H), 3.86 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 1.44 (s, 18H). 13C NMR (101 MHz, CDCl3) = 151.84, 151.41, 147.76, 142.83, 135.58, 131.58, 125.34, 121.85, 114.52, 97.76, 56.58, 56.43, 56.24, 35.11, 34.30, 30.35. HRMS for C H O +24 34 4 (APCI+) [M+]+: calc.: 385.2373, found: 385.2366. S14 3,3´,5-Trimethyl-5´-(2,4,5-trimethoxybenzyl)-[1,1´-biphenyl]-2,2´-diol (7) According to the GPI for the electrochemical HFIP ether formation, 242.3 mg (1.0 mmol) 3,3',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4-trimethoxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as brown oil (yield: 57%, 233 mg, 0.57 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.12 1H NMR (400 MHz, CDCl3) = 7.01 (d, J = 4.0 Hz, 2H), 6.91 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.69 (s, 1H), 6.54 (s, 1H), 5.17 (s, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 3.80 (s, 6H), 2.27 (s, 9H). 13C NMR (101 MHz, CDCl3) = 151.48, 149.50, 149.22, 148.06, 142.95, 133.72, 132.00, 131.56, 129.97, 128.47, 128.19, 125.27, 122.27, 122.10, 121.17, 114.60, 97.96, 56.71, 56.50, 56.21, 34.57, 20.47, 16.34, 16.22. HRMS for C25H + +28NaO5 (ESI+) [M+Na] : calc.: 431.1829, found: 431.1829. S15 1,2,4-Trimethoxy-5-(4-methoxybenzyl)benzene (8) According to the GPI for the electrochemical HFIP ether formation, 61.1 mg (0.5 mmol) 4- methylanisol, 5 mL HFIP, and 0.05 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 3.0 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 224 µL (1.5 mmol) 1,2,4- trimethoxybenzene and 383 µL (5.0 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as brown oil (yield: 83%, 120 mg, 0.42 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.25 1H NMR (400 MHz, CDCl3) = 7.12 (d, J = 4.0 Hz, 2H), 6.82 (d, J = 4.0 Hz, 2H), 6.65 (s, 1H), 6.55 (s, 1H), 3.89 (s, 3H), 3.87 (s, 2H), 3.79 (s, 3H), 3.78 (d, J = 1.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) = 157.74, 151.44, 147.96, 142.97, 133.45, 129.63, 121.56, 114.52, 113.71, 97.97, 56.63, 56.53, 56.23, 55.23, 34.44. HRMS for C17H20O +4 (APCI+) [M+]+: calc.: 288.1356, found: 288.135. S16 1,2,4-Trimethoxy-5-(4-methoxy-2-methylbenzyl)benzene (9) According to the GPI for the electrochemical HFIP ether formation, 69.9 mg (0.5 mmol) 3,4- Dimethylanisol, 5 mL HFIP, and 0.05 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 3.0 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 224 µL (1.5 mmol) 1,2,4- trimethoxybenzene and 383 µL (5.0 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as brown oil (yield: 88%, 133 mg, 0.44 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.25 1H NMR (400 MHz, CDCl3) = 6.93 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.67 (dd, J = 8.4, 2.8 Hz, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.70 (s, 3H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) = 157.84, 151.49, 147.81, 142.93, 137.87, 131.14, 130.31, 120.65, 115.80, 114.18, 110.81, 97.65, 56.61, 56.46, 56.23, 55.18, 31.76, 19.83. HRMS for C18H22NaO +4 (ESI+) [M+Na]+: calc.: 325.141, found: 325.1401. S17 2-(3,4-Dimethoxyphenyl)-2-(2,4,5-trimethoxyphenyl)acetonitrile (10) According to the GPI for the electrochemical HFIP ether formation, 177.2 mg (1.0 mmol) (3,4-Dimethoxyphenyl)acetnitrile, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 1.8 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 448 µL (3.0 mmol) 1,2,4-trimethoxybenzene and 1.90 g (10 mmol) p-Toluenesulfonic acid monohydrate were added to the solution and stirred at 40 °C for 3 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 52%, 178 mg, 0.52 mmol). Rf (cyclohexane:ethyl acetate = 1:1) = 0.38 1H NMR (400 MHz, CDCl3) = 6.89 (dd, J = 8.3, 2.9 Hz, 1H), 6.84 (d, J = 2.9 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.53 (s, 1H), 5.47 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) = 150.55, 149.84, 149.13, 148.61, 143.36, 128.16, 120.31, 119.76, 115.64, 112.36, 111.18, 110.66, 97.42, 56.70, 56.47, 56.16, 55.94, 55.92, 35.30. HRMS for C19H + +22NO5 (APCI+) [M+H] : calc.: 344.1492, found: 344.1488. S18 4-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-methoxyphenol (11) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 344 µL (3.0 mmol) 1,2- methylenedioxybenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 35%, 90 mg, 0.35 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.25 1H NMR (400 MHz, CDCl3) = 6.85 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.71 6.64 (m, 4H), 5.92 (s, 2H), 5.53 (s, 1H), 3.84 (s, 3H), 3.83 (s, 2H). 13C NMR (101 MHz, CDCl3) = 147.69, 146.51, 145.81, 143.97, 135.41, 133.14, 121.52, 114.26, 111.31, 109.27, 108.14, 100.83, 55.87, 41.27. HRMS for C15H13O +4 (APCI+) [M+]+: calc.: 257.0808, found: 257.0815. S19 2-Methoxy-4-(2,3,4,5,6-pentamethylbenzyl)phenol (12) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 484.9 mg (3.0 mmol) pentamethylbenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as white solid (yield: 47%, 133 mg, 0.47 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.60 Melting point: 140.0 °C 140.8 °C 1H NMR (400 MHz, CDCl3) = 6.80 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 6.47 (d, J = 8.1, 1H), 5.31 (s, 1H), 4.07 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H), 2.28 (s, 6H), 2.22 (s, 6H). 13C NMR (101 MHz, CDCl3) = 146.49, 143.57, 133.94, 133.08, 132.78, 132.49, 120.35, 114.18, 110.72, 55.94, 35.78, 16.99, 16.90, 16.87. HRMS for C19H23O +2 (APCI+) [M+]+: calc.: 283.1693, found: 283.1687. S20 2-Methoxy-4-(2,4,5-trimethylbenzyl)phenol (13) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 412 µL (3.0 mmol) 1,2,4- trimethylbenzene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as white solid (yield: 58%, 149 mg, 0.58 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.60 Melting point: 72.7 °C 73.5 °C 1H NMR (400 MHz, CDCl3) = 7.00 (s, 1H), 6.91 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 6.66 (dd, J = 8.1, 1.8 Hz, 1H), 3.91 (s, 2H), 3.87 (s, 3H), 2.27 (s, 3H), 2.25 (s, 6H). 13C NMR (101 MHz, CDCl3) = 146.50, 143.73, 136.51, 134.35, 133.87, 133.68, 132.73, 131.72, 131.12, 121.44, 114.25, 111.39, 55.91, 38.66, 19.30, 19.24, 19.10. HRMS for C17H20NaO +2 (ESI+) [M+Na]+: calc.: 279.1356, found: 279.1366. S21 2-Methoxy-4-((4-methoxynaphthalen-1-yl)methyl)phenol (14) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 432 µL (3.0 mmol) 1- methoxynaphtalene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 81%, 238 mg, 0.81 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.25 1H NMR (400 MHz, CDCl3) = 8.39 8.29 (m, 1H), 8.00 7.85 (m, 1H), 7.56 7.44 (m, 2H), 7.19 (d, J = 7.8 Hz, 1H), 6.86 (dd, J = 7.8, 1.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.74 6.68 (m, 2H), 5.30 (s, 1H), 4.32 (s, 2H), 4.01 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) = 154.50, 146.52, 143.81, 132.97, 132.91, 128.86, 126.94, 126.46, 126.02, 124.94, 124.10, 122.52, 121.43, 114.24, 111.26, 103.33, 55.84, 55.49, 38.29. HRMS for C19H18NaO +3 (ESI+) [M+Na]+: calc.: 317.1148, found: 317.1157. S22 1-(4-Hydroxy-3-methoxybenzyl)naphthalen-2-ol (15) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 432.5 mg (3.0 mmol) 2- naphthol and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as white solid (yield: 79%, 222 mg, 0.79 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.05 Melting point: 168.7 °C 169.5 °C 1H NMR (400 MHz, DMSO-d6) = 9.67 (s, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.38 (td, J = 8.6, 2.0 Hz, 1H), 7.28 7.20 (m, 2H), 6.90 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.50 (dd, J = 8.1, 2.0 Hz, 1H), 4.24 (s, 2H), 3.68 (s, 3H). 13C NMR (101 MHz, DMSO-d6) = 152.86, 147.71, 144.81, 133.79, 132.57, 128.69, 128.04, 126.46, 123.63, 122.64, 120.65, 118.88, 118.61, 115.62, 113.22, 109.98, 56.00, 29.89. HRMS for C H NaO +18 16 3 (ESI+) [M+Na]+: calc.: 303.0997, found: 303.0996. S23 2-((4-Hydroxy-3-methoxyphenyl)methyl)-benzofuran (16) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 107 µL (1.0 mmol) 2,3- benzofuran and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 78%, 199 mg, 0.78 mmol). Rf (cyclohexane:ethyl acetate = 20:3) = 0.25 1H NMR (400 MHz, CDCl3) = 7.52 (d, J = 7.0, 1H), 7.47 (d, J = 7.0, 1H), 7.30 7.20 (m, 2H), 6.94 (d, J = 8.6, 1H), 6.86 (d, J = 4.0, 2H), 6.41 (s, 1H), 5.64 (s, 1H), 4.08 (s, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) = 158.24, 154.97, 146.58, 144.48, 129.02, 128.83, 123.42, 122.55, 121.74, 120.44, 114.45, 111.44, 110.94, 103.20, 55.93, 34.71. HRMS for C16H14O +3 (APPI+) [M+]+: calc.: 254.0937, found: 254.0926. S24 3-((4-Hydroxy-3-methoxyphenyl)methyl)-benzo[b]thiophene (17) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 402.6 mg (3.0 mmol) benzo[b]thiophene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 76%, 205 mg, 0.76 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.54 1H NMR (400 MHz, CDCl3) = 7.91 7.84 (m, 1H), 7.76 7.71 (m, 1H), 7.40 7.35 (m, 2H), 7.01 (s, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.83 6.75 (m, 2H), 5.57 (s, 1H), 4.14 (s, 2H), 3.83 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.57, 144.12, 140.63, 138.82, 136.10, 131.17, 124.31, 123.97, 122.90, 121.97, 121.64, 114.35, 111.37, 55.90, 34.75. HRMS for C16H13O S-2 (ESI-) [M-H]-: calc.: 269.0642, found: 269.064. S25 1-Methyl-3-((4-hydroxy-3-methoxyphenyl)methyl)-indole (18) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 375 µL (3.0 mmol) 1- methylindole and 766 µL (10 mmol) trifluoroacetic acid were added to the solution. The flask was covered with aluminium foil to protect it from light and the solution was stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 44%, 117 mg, 0.44 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.36 1H NMR (400 MHz, CDCl3) = 7.54 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (td, J = 7.9, 1.1 Hz, 1H), 7.09 (td, J = 7.9, 1.1 Hz, 1H), 6.87 6.83 (m, 1H), 6.82 6.78 (m, 2H), 6.74 (t, J = 1.1 Hz, 1H), 5.48 (s, 1H), 4.04 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.39, 143.71, 137.17, 133.30, 127.77, 127.04, 121.57, 121.31, 119.18, 118.75, 114.72, 114.11, 111.31, 109.15, 55.88, 32.63, 31.24. HRMS for C + +17H18NO2 (ESI+) [M+H] : calc.: 268.1332, found: 268.1323. S26 1-Methyl-2-((4-Hydroxy-3-methoxyphenyl)methyl)-pyrrole (19) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 243 µL (3.0 mmol) 1- methylpyrrole and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 64%, 139 mg, 0.64 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.33 1H NMR (400 MHz, CDCl3) = 6.85 (d, J = 7.9 Hz, 1H), 6.72 - 6.67 (m, 2H), 6.59 (t, J = 2.7 Hz, 1H), 6.08 (t, J = 2.7 Hz, 1H), 5.92 5.86 (m, 1H), 5.53 (s, 1H), 3.88 (s, 2H), 3.84 (s, 3H), 3.45 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.56, 143.95, 131.79, 131.27, 121.77, 121.13, 114.20, 111.02, 107.71, 106.53, 55.89, 33.81, 32.55. HRMS for C13H16NO +2 (ESI+) [M+H]+: calc.: 218.1176, found: 218.1172. S27 2-((4-Hydroxy-3-methoxyphenyl)methyl)-3-bromothiophene (20) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 284 µL (3.0 mmol) 3- bromothiophene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 52%, 154 mg, 0.52 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.53 1H NMR (400 MHz, CDCl3) = 7.14 (d, J = 5.3 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.80 6.75 (m, 2H), 5.61 (s, 1H), 4.05 (s, 2H), 3.86 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.56, 144.41, 139.27, 131.09, 129.92, 123.96, 121.40, 114.42, 111.21, 108.87, 55.91, 34.87. HRMS for C +12H9BrNaO2S (ESI+) [M+Na]+: calc.: 318.9399, found: 318.9392. S28 2-((4-Hydroxy-3-methoxyphenyl)methyl)-5-chlorothiophene (21) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 277 µL (3.0 mmol) 2- chlorothiophene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 57%, 145 mg, 0.57 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.52 1H NMR (400 MHz, CDCl3) = 6.87 (d, J = 7.9 Hz, 1H), 6.76 6.68 (m, 3H), 6.56 (d, J = 3.7 Hz, 1H), 5.55 (s, 1H), 3.98 (s, 2H), 3.86 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.59, 144.45, 143.67, 131.39, 127.82, 125.71, 124.07, 121.35, 114.40, 111.07, 55.92, 36.17. HRMS for C +12H10ClO2S (APCI+) [M+]+: calc.: 253.0085, found: 253.0079. S29 2-((4-Hydroxy-3-methoxyphenyl)methyl)-3-methylthiophene (22a) and 2- ((4-Hydroxy-3-methoxyphenyl)methyl)-4-methylthiophene (22b) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 292 µL (3.0 mmol) 3- methylthiophene and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 54%, 126 mg, 0.54 mmol). The ration of regioisomers is 10 : 1 determined by 1H NMR. Rf (cyclohexane:ethyl acetate = 10:3) = 0.50 1H NMR (400 MHz, CDCl3) = 7.06 (d, J = 5.1 Hz, 1H), 6.88 6.82 (m, 2H), 6.74 6.69 (m, 2H), 5.55 (s, 1H), 4.01 (s, 2H), 3.86 (s, 3H), 2.20 (s, 3H). 13C NMR (101 MHz, CDCl3) = 146.59, 144.17, 137.33, 133.28, 132.35, 130.17, 121.94, 121.21, 114.36, 111.10, 55.97, 33.58, 13.90. HRMS for C H + +13 15O2S (ESI+) [M+H] : calc.: 235.0787, found: 235.0788. S30 4-(4-Hydroxy-3-methoxybenzyl)-2,6-diisopropylphenol (23) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 556 µL (3.0 mmol) 2,6- diisopropylphenol and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as yellow oil (yield: 57%, 179 mg, 0.57 mmol). Rf (cyclohexane:ethyl acetate = 10:3) = 0.42 1H NMR (400 MHz, CDCl3) = 6.94 (s, 2H), 6.92 (d, J = 8.5 Hz, 1H), 6.77 6.74 (m, 2H), 5.67 (s, 1H), 4.84 (s, 1H), 3.92 (s, 2H), 3.87 (s, 3H), 3.20 (hept, J = 6.9 Hz, 2H), 1.30 (d, J = 6.9 Hz, 12H). 13C NMR (101 MHz, CDCl3) = 148.26, 146.47, 143.74, 133.81, 133.74, 133.14, 123.92, 121.55, 114.30, 111.47, 55.90, 41.27, 27.28, 22.87. HRMS for C H + +20 26O3 (APPI+) [M+] : calc.: 314.1876, found: 314.1874. S31 4-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one (24a) and 2-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2- g]chromen-7-one (24b) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 10 mL to unify the concentration for each reaction. Then, 648.6 mg (3.0 mmol) xanthotoxin and 766 µL (10 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 2 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, excess amount of the nucleophile was recovered by bulb-to-bulb distillation (120 °C, 1·10-3 mbar). Preparative High performance liquid chromatography (prep. HPLC) (solvent: solution A: solution B* = from 30:70 for 10 min to 60:40 for 90 min; Initial flow-rate was 10 mL/min. After 10 seconds, the flow rate was raised to 20 mL/min; column 250 mm x 30 mm) yielded the product 24a as white solid (yield: 31%, 109 mg, 0.31 mmol) and product 24b as white solid (yield: 10%, 35 mg, 0.10 mmol) in total 41%. *A = Acetonitril, B = water with 5% Acetonitril and 0.1% Phosporic acid Rf (cyclohexane:ethyl acetate = 1:1) = 0.43 (both compounds) 4-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one (24a) Melting point: 173.1 °C 173.8 °C S32 1H NMR (400 MHz, CDCl3) = 7.94 (d, J = 9.9 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 5.57 (s, 1H), 4.31 (s, 2H), 4.27 (s, 3H), 3.76 (s, 3H). 13C NMR (101 MHz, CDCl3) = 160.31, 147.34, 146.78, 146.40, 144.30, 143.94, 141.06, 131.57, 131.30, 126.65, 123.80, 120.61, 114.76, 114.55, 114.33, 110.37, 105.75, 61.43, 55.89, 34.17. HRMS for C20H +17O6 (APCI+) [M+H]+: calc.: 353.102, found: 353.1016. 2-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one (24b) Melting point: 144.1 °C 144.9 °C 1H NMR (400 MHz, CDCl3) = 7.73 (d, J = 9.6 Hz, 1H), 7.19 (s, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.83 6.79 (m, 2H), 6.40 6.32 (m, 2H), 5.57 (s, 1H), 4.26 (s, 3H), 4.06 (s, 2H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) = 160.80, 160.75, 147.85, 146.75, 144.80, 144.57, 142.88, 132.45, 128.27, 127.63, 121.93, 116.32, 114.66, 114.61, 112.23, 111.56, 103.12, 77.16, 61.49, 56.07, 34.83. HRMS for C20H17O +6 (ESI+) [M+H]+: calc.: 353.102, found: 353.1019. S33 Synthesis of benzylated natural products and bioactive compounds (late-stage functionalization) 2-(4-Hydroxy-3,5-dimethylbenzyl)-4-methoxy-7H-furo[3,2-g]chromen-7- one (25) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered and the residue was taken up in CH2Cl2 (10 mL). Then, 216.2 mg (1.0 mmol) of Bergapten and 272 µL (2.2 mmol) BF3OEt2 were added to the solution and stirred at room temperature for 12 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (70 mL). The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried over Na2SO4 and filtered. After evaporation of the solvent, preparative high performance liquid chromatography (HPLC) (solvent: solution A:solution B* = from 30:70 for 10 min to 60:40 for 120 min; flow rate 20 mL/min; column 250 mm x 30 mm) yielded the product 25 as white solid (yield: 24%, 84 mg, 0.24 mmol) *A = Acetonitril, B = water with 5% Acetonitril and 0.1% Phosporic acid 1H NMR (400 MHz, CDCl3) 8.15 (dd, J = 9.8, 0.7 Hz, 1H), 7.28 (s, 1H), 7.07 (t, J = 0.7 Hz, 1H), 6.93 (s, 2H), 6.59 (q, J = 1.1 Hz, 1H), 6.27 (d, J = 9.8 Hz, 1H), 4.67 (s, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 2.26 (s, 6H). 13C NMR (101 MHz, CDCl3) 161.60, 158.79, 158.60, 152.28, 151.37, 148.83, 139.56, 129.12, 127.97, 123.50, 114.23, 112.40, 106.48, 101.13, 93.84, 60.21, 34.12, 16.09. HRMS for C + +21H19O5 (ESI+) [M+H] : calc.: 351.1227, found: 351.1223. S34 Crystal structure determination of 25 (CCDC 1840040): C21H18O5, Mr = 350.35 g/mol, yellow needle (0.034 x 0.041 x 0.642 mm³), P 21/c (monoklin), a = 4.8224 Å, b = 14.5298 Å, c = 23.4618 Å, V = 1640.5 3, Z = 4, F(000) = 736, = 1.419 / 3, = 0.101 1, Mo-K graphite monochromator, -80 °C, 9491 reflections, 4146 independent reflections, wR2 = 0.1436, R1 = 0.066, 0.26 e/Å3, 0.25 e/Å3, GoF = 1.145 Single crystals for structure determination were obtained by recrystallization from ethyl acetate/cyclohexane at room temperature. Intermolecular interaction via hydrogen bonds of the phenolic hydroxyl groups with the methoxy group and the lactone is observed (figure 2). Also hydrogen bonds via the furan can be observed (figure 2). Figure 1 crystal structure of 25 Figure 2 Packing of 25 in the solid state S35 6-Hydroxy-3-(4-hydroxy-3,5-dimethylbenzyl)-4-methyl-2H-chromen-2-one (26) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered and the residue was taken up in CH2Cl2 (10 mL). Then, 216.2 mg (1.0 mmol) of 4-Methylumbelliferone and 272 µL (2.2 mmol) BF3OEt2 were added to the solution and stirred at room temperature for 12 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (70 mL). The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried over Na2SO4 and filtered. After evaporation of the solvent, preparative high performance liquid chromatography (prep. HPLC) (solvent: solution A: solution B* = from 30:70 for 10 min to 50:50 for 120 min; flow rate 20 mL/min; column 250 mm x 30 mm) yielded the product 26 as white solid (yield: 37%, 115 mg, 0.37 mmol) *A = Acetonitril, B = water with 5% Acetonitril and 0.1% Phosporic acid 1H NMR (400 MHz, DMSO-d6) 10.41 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (s, 2H), 6.69 (d, J = 2.4 Hz, 1H), 3.73 (s, 2H), 2.36 (s, 3H), 2.09 (s, 6H). 13C NMR (101 MHz, DMSO-d6) 161.39, 160.32, 153.38, 151.36, 147.94, 129.66, 127.71, 126.64, 124.10, 120.78, 112.86, 112.53, 101.91, 31.25, 16.67, 15.08. HRMS for C + +19H18NaO4 (ESI+) [M+Na] : calc.: 333.1097, found: 333.1093. S36 Crystal structure determination of 26 (CCDC 1840041): C19H18O4, Mr = 310.3 g/mol, colorless needle (0.09 x 0.18 x 0.41 mm³), P -1 (triklin), a = 8.4245 Å, b = 13.3710 Å, c = 14.8922 Å, V = 1522.6 Å3, Z = 4, F(000) = 656, ρ = 1.354 g/cm3, μ = 0.09 mm 1, Mo-K graphite monochromator, -20 °C, 14360 reflections, 7522 independent reflections, wR2 = 0.1475, R1 = 0.0523, 0.22 e/Å3, 0.20 e/Å3, GoF = 1.015 Single crystals for structure determination were obtained by recrystallization from ethyl acetate/cyclohexane at room temperature. Intermolecular interaction via hydrogen bonds of the phenolic hydroxyl groups with the lactone is observed (figure 1). Also / stacking of the benzyl groups can be seen (figure 2). Figure 3 crystal structure of 26 showing two slightly different conformers Figure 4 Packing of 26 in the solid state - / stacking of the phenols S37 (8R,9S,13S,14S,17S)-2-(4-Hydroxy-3,5-dimethylbenzyl)-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene- 3,17-diol (27a) and (8R,9S,13S,14S,17S)-4-(4-Hydroxy-3,5- dimethylbenzyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthrene-3,17-diol (27b) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered and the residue was taken up in CH2Cl2 (10 mL). Then, 272 mg (1.0 mmol) of ß-estradiol and 272 µL (2.2 mmol) BF3OEt2 were added to the solution and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (70 mL). The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried over Na2SO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 15 mL/min) yielded the product 27a and 27b as a white foam and a mixture of regioisomers 5/1 27a/27b, determined by H1NMR (yield: 44%, 179 mg, 0.44 mmol). 1H NMR (400 MHz, DMSO-d6) 10.41 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.7, 2.4 Hz, 1H), 6.72 (s, 2H), 6.69 (d, J = 2.4 Hz, 1H), 3.73 (s, 2H), 2.36 (s, 3H), 2.09 (s, 6H). 13C NMR (101 MHz, CDCl3) 151.93, 150.90, 136.43, 132.68, 131.47, 128.74, 128.28, 127.95, 124.61, 123.47, 116.05, 82.10, 50.17, 44.09, 43.39, 39.00, 36.86, 36.19, 30.72, 29.40, 27.39, 26.51, 23.27, 16.09, 11.24. S38 HRMS for C27H34NaO +3 (ESI+) [M+Na]+: calc.: 429.2400 found: 429.2390 5,7-Dihydroxy-8-(4-hydroxy-3,5-dimethylbenzyl)-2-phenyl-4H- chromen-4-one (28a) and 5,7-Dihydroxy-6-(4-hydroxy-3,5- dimethylbenzyl)-2-phenyl-4H-chromen-4-one (28b) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered and the residue was taken up in CH2Cl2 (10 mL). Then, 254 mg (1.0 mmol) of Crysin and 272 µL (2.2 mmol) BF3OEt2 were added to the solution and stirred at room temperature for 12 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (70 mL). The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried over Na2SO4 and filtered. After evaporation of the solvent, preparative high performance liquid chromatography (prep. HPLC) (solvent: solution A : solution B* = from 50:50 for 10 min to 80:20 for 120 min; flow rate 20 mL/min; column 250 mm x 30 mm) yielded the product 28a (yield: 18.3%, 71 mg, 0.18 mmol) as yellow solid and 28b also as a yellow solid (yield: 12.3%, 46 mg, 0.12 mmol) *A = Acetonitril, B = water with 5% Acetonitril and 0.1% Phosporic acid Regioisomer 28a: 1H NMR (400 MHz, DMSO-d6) 12.77 (s, 1H), 11.19 (s, 1H), 8.01 7.83 (m, 2H), 7.71 7.45 (m, 3H), 6.91 (s, 1H), 6.79 (s, 2H), 6.51 (s, 1H), 3.92 (s, 2H), 2.03 (s, 6H). 13C NMR (101 MHz, DMSO) 182.14, 163.08, 162.33, 159.18, 154.82, 151.17, 131.96, 130.98, 130.94, 129.10, 127.80, 126.39, 123.98, 106.74, 105.03, 103.90, 98.75, 27.02, 16.71. S39 HRMS for C H O +24 21 5 (ESI+) [M+H]+: calc.: 389.1384, found: 389.1377 Regioisomer 28b: 1H NMR (400 MHz, DMSO-d6) 13.13 (s, 1H), 11.09 (s, 1H), 8.09 8.02 (m, 2H), 7.90 (s, 1H), 7.64 7.53 (m, 3H), 6.96 (s, 1H), 6.78 (s, 2H), 6.66 (s, 1H), 3.71 (s, 2H), 2.08 (s, 6H). 13C NMR (101 MH , DMSO) 213.85, 181.94, 162.98, 162.36, 158.55, 155.34, 151.02, 131.95, 130.97, 130.81, 129.16, 128.05, 126.39, 123.66, 111.71, 105.11, 103.74, 93.49, 26.59, 16.72. HRMS for C +24H21O5 (ESI+) [M+H]+: calc.: 389.1384, found: 389.1377 4-(4,5-Dimethoxy-2-(2-(methylamino)ethyl)benzyl)-2,6-dimethylphenol(29) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered and the residue was taken up in CH2Cl2 (10 mL). Then, 206 mg (1.0 mmol) of N-Methylhomoveratrylamine and 408 µL (3.3 mmol) BF3OEt2 were added to the solution and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (70 mL). The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried over Na2SO4 and filtered. After evaporation of the solvent, column chromatography on a preparative column chromatography apparatus (gradient: ethyl acetate/MeOH = from 100:0 to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 15 mL/min) yielded the product yielded the product 29 (yield: 31%, 101 mg, 0.31 mmol) as a colourless oil) 1H NMR (400 MHz, CDCl3) 6.69 (s, 1H), 6.66 (s, 2H), 6.64 (s, 1H), 3.84 (s, 3H), 3.80 (s, 2H), 3.79 (s, 3H), 2.75 (ddd, J = 8.3, 6.6, 1.9 Hz, 2H), 2.67 (ddd, J = 8.3, 6.6, 1.9 Hz, 1H), 2.37 (s, 2H), 2.17 (s, 6H). S40 13C NMR (101 MHz, CDCl3) 150.76, 147.51, 132.57, 131.51, 129.28, 128.60, 123.54, 114.19, 113.22, 56.08, 52.03, 37.75, 35.29, 31.97, 16.22. HRMS for C H NO +20 28 3 (ESI+) [M+H]+: calc.: 329.2000, found: 330.2063 40 mmol scale synthesis in a 200 mL beaker-type cell According to GP II for the electrochemical HFIP ether formation, 5.53 g (40 mmol) 2- methoxy-4-methylphenol, 200 mL HFIP, and 4.0 mL (0.57 equiv) DIPEA were transferred into an undivided beaker-type electrolysis cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, the reaction solution was diluted with HFIP to a total volume of 400 mL (to unify the concentration with the 5 mL scale reaction). Then, 16.1 g (3.0 equiv, 120 mmol) benzo[b]thiophene and 30.6 mL (10 equiv, 400 mmol) trifluoroacetic acid were added to the solution and stirred at 40 °C for 1 h. After completion of the reaction, HFIP was recovered by distillation on the rotary evaporator. The residue was dissolved in 30 mL dichloromethane and washed with 70 mL water. The aqueous phase was afterwards washed with 30 mL of dichloromethane. Combined organic phases were dried with MgSO4 and filtered. After evaporation of the solvent, excess amount of the nucleophile was recovered by bulb-to-bulb distillation (60 °C, 1·10-3 mbar). Then, column chromatography on a preparative column chromatography apparatus (gradient: cyclohexane:ethyl acetate = from 100:0 for 10 min to 98:2 for 60 min; column 40 mm x 150 mm; flow rate 50 mL/min) yielded the product as yellow oil (yield: 64 %, 6.91 g, 25.6 mmol). S41 NMR spectra 4-((1-Trifluoromethyl-2,2,2-trifluoroethyl)oxymethyl)-2-methoxyphenol (2) S42 S43 2-Methoxy-4-(2,4,5-trimethoxybenzyl)phenol (3) S44 2-Methoxy-4-(1-(2,4,5-trimethoxyphenyl)propyl)phenol (4) S45 2,6-Dimethyl-4-(2,4,5-trimethoxybenzyl)phenol (5) S46 2,6-Di-tert-butyl-4-(2,4,5-trimethoxybenzyl)phenol (6) S47 3,3´,5-Trimethyl-5´-(2,4,5-trimethoxybenzyl)-[1,1´-biphenyl]-2,2´-diol (7) S48 1,2,4-Trimethoxy-5-(4-methoxybenzyl)benzene (8) S49 1,2,4-Trimethoxy-5-(4-methoxy-2-methylbenzyl)benzene (9) S50 2-(3,4-Dimethoxyphenyl)-2-(2,4,5-trimethoxyphenyl)acetonitrile (10) S51 4-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-methoxyphenol (11) S52 2-Methoxy-4-(2,3,4,5,6-pentamethylbenzyl)phenol (12) S53 2-Methoxy-4-(2,4,5-trimethylbenzyl)phenol (13) S54 2-Methoxy-4-((4-methoxynaphthalen-1-yl)methyl)phenol (14) S55 1-(4-Hydroxy-3-methoxybenzyl)naphthalen-2-ol (15) S56 2-((4-Hydroxy-3-methoxyphenyl)methyl)-benzofuran (16) S57 3-((4-Hydroxy-3-methoxyphenyl)methyl)-benzo[b]thiophene (17) S58 1-Methyl-3-((4-hydroxy-3-methoxyphenyl)methyl)-indole (18) S59 1-Methyl-2-((4-hydroxy-3-methoxyphenyl)methyl)-pyrrole (19) S60 2-((4-Hydroxy-3-methoxyphenyl)methyl)-3-bromothiophene (20) S61 2-((4-Hydroxy-3-methoxyphenyl)methyl)-5-chlorothiophene (21) S62 2-((4-Hydroxy-3-methoxyphenyl)methyl)-4-methylthiophene (23) and 2-((4-Hydroxy-3- methoxyphenyl)methyl)-3-methylthiophene (22) S63 4-(4-Hydroxy-3-methoxybenzyl)-2,6-diisopropylphenol (24) S64 4-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one (24a) S65 2-(4-Hydroxy-3-methoxybenzyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one (24b) S66 2-(4-Hydroxy-3,5-dimethylbenzyl)-4-methoxy-7H-furo[3,2-g]chromen-7-one (25) S67 6-Hydroxy-3-(4-hydroxy-3,5-dimethylbenzyl)-4-methyl-2H-chromen-2-one (26) S68 (8R,9S,13S,14S,17S)-2-(4-Hydroxy-3,5-dimethylbenzyl)-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol (27a) and (8R,9S,13S,14S,17S)-4-(4-Hydroxy-3,5-dimethylbenzyl)-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol (27b) S69 5,7-Dihydroxy-8-(4-hydroxy-3,5-dimethylbenzyl)-2-phenyl-4H-chromen-4-one (28a) and 5,7-Dihydroxy-6-(4-hydroxy-3,5-dimethylbenzyl)-2-phenyl-4H-chromen-4-one (28b) S70 S71 4-(4,5-Dimethoxy-2-(2-(methylamino)ethyl)benzyl)-2,6-dimethylphenol (29) S72 References [1] W. L. F. Armarego, C. L. L. Chai, Purification of laboratory chemicals, Elsevier, Amsterdam, 2013. [2] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26 32. [3] A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983 987. (see SI thereof). S73 DOI: 10.1002/celc.201801727 Communications 1 2 3 Dehydrogenative Anodic Cyanation Reaction of Phenols in 4 Benzylic Positions 5 6 Johannes L. Röckl,[a, c] Yasushi Imada,[b, c] Kazuhiro Chiba,[b] Robert Franke,[d, e] and 7 8 Siegfried R. Waldvogel*[a, c] 9 10 11 The selective dehydrogenative electrochemical activation of 12 benzylic positions by 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) 13 and subsequent cyanation is presented for the first time. Herein, 14 we report a sustainable, scalable, and metal-free dehydrogen- 15 ative benzylic cyanation protocol. Valuable 2-phenylacetonitrile 16 derivatives are accessible in the presence of a cyanide source 17 and an electrolytically-derived HFIP ether. The direct application Scheme 1. Important biologically active molecules derived from or contain- 18 of electricity enables a safe and environmentally benign ing 2-phenylethyl acetonitrile moieties. 19 chemical transformation, since oxidizers are replaced by elec- 20 tricity. 21 tion of activated arenes and heteroarenes was published by 22 Gooßen et al.[12] Alternatively, cyano groups can also be 23 2-Phenylacetonitriles represent important building blocks in established by electro-conversion of a renewable feedstock, 24 organic synthesis and are precursors for biologically active such as glutamic acid, towards the bulk chemical adiponitrile,[13] 25 molecules, such as tetrazoles[1] or 2-phenylethylamines,[2] includ- or by a domino electrolysis of aldoximes.[14] This makes chemical 26 ing the fungicide mandipropamid,[3] and the calcium channel synthesis sustainable and environmentally friendly.[15] Addition- 27 blocker verapamil (Scheme 1).[4] ally an electrochemical method for the direct alpha-cyanation 28 2-Phenylacetonitriles are amenable to a wide range of of N-protected cyclic amines on graphite electrodes has been 29 synthetic transformations, such as monoalkylation,[5] reduction reported by Onomura and co-workers.[16] However, a benzylic 30 to 2-phenylethyl-amines,[6] oxidation to acids or amides,[7] electrochemical cyanation is presented here for the first time. 31 conversion with azides to tetrazoles,[8] or in Knoevenagel A common synthetic route to 2-phenylacetonitriles consists 32 reactions with aldehydes to form alkenes (Scheme 1, Support- of initial protection of the phenolic hydroxyl moiety, followed 33 ing Information).[9] by radical halogenation of the benzyl group (usually by NBS, 34 Electrochemical installation of cyano groups has been AIBN in a halogenated solvent). This is followed by substitution 35 reported for electron-rich arenes several decades ago.[10] In of the halo substituent by cyanide, employing sodium,[17] 36 addition a direct cyanation was feasible on side chains of highly potassium,[18] TMS-cyanide,[19] or tetraethylammonium cyanide 37 electron-rich pyrroles.[11] Recently, the dehydrogenative cyana- [20] with final liberation of the phenol. This strategy has several 38 major disadvantages: additional alkyl groups are not tolerated, 39 [a] J. L. Röckl, Prof. Dr. S. R. Waldvogel due to poor regioselectivity of the radical halogenation40 Institute of Organic Chemistry reaction.[21] Furthermore, this route leads to the generation of41 Duesbergweg 10–14, 55128 Mainz, Germany significant reagent waste and requires two additional protection 42 E-mail: waldvogel@uni-mainz.de Homepage: https://www.blogs.uni-mainz.de/fb09akwaldvogel/ and deblocking steps. Additionally, radical halogenation often43 44 [b] Y. Imada, Prof. Dr. K. Chiba leads to low yields, due to multiple halogenation processes and Department of Applied Biological Science elimination reactions.[21] 45 Tokyo University of Agriculture and Technology 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan An alternative route starts from benzylic alcohols or46 [c] J. L. Röckl, Y. Imada, Prof. Dr. S. R. Waldvogel aldehydes.[22] The alcohol is converted in a Mitsunobu-type47 Graduate School Materials Science in Mainz reaction using triphenylphosphine, 2,3-dichloro-5,6-dicyano-1,4- 48 Johannes Gutenberg Universität Mainz Staudinger Weg 9, 55128 Mainz, Germany benzoquinone and tetrabutylammonium cyanide in acetonitrile49 [d] Prof. Dr. R. Franke to give the desired 2-phenylacetonitriles. While this route can50 Evonik Performance Materials GmbH lead to high yields, with a broad substrate scope tolerating 51 Paul-Baumann-Str. 1, 45772 Marl, Germany [e] Prof. Dr. R. Franke aliphatic branched, linear, and substituted benzylic alcohols, it52 Lehrstuhl für Theoretische Chemie has significant drawbacks. These include generation of large53 Ruhr-Universität Bochum amounts of waste and low atom efficiency, due to the use of 54 Universitätstraße 150, 44801 Bochum, Germany two equivalents of PPh , DDQ, and NBu CN per equivalent of 55 Supporting information for this article is available on the WWW under 3 4 https://doi.org/10.1002/celc.201801727 alcohol. Another route to 2-phenylacetonitriles starts from56 An invited contribution to a Special Issue on Organic Electrosynthesis carbonyl compounds, which are reduced to the corresponding 57 ChemElectroChem 2019, 6, 4184–4187 4184 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley VCH Mittwoch, 14.08.2019 1916 / 127775 [S. 4184/4187] 1 Communications alcohols in the presence of a Ru(TMHD) 1 2 complex, and are then sequence with only one purification step is presented. The transformed in-situ into their corresponding nitriles.[23] One electrochemical activation is selective, with multiple alkyl 2 shortcoming of this route is, in the case of phenols, that an groups being tolerated. It is also protective group-free, short- 3 additional protective group is needed. Furthermore, the reac- ening the usual synthetic route by one to two steps. Addition- 4 tion must be carried out under 500 psi H2, and activation of ally, less toxic reagent waste is generated, allowing for a5 methyl groups needs to be carried out first, by oxidation to the greener procedure. 6 aldehyde. These disadvantages, coupled with the use of an The electrolytic conditions of the initial electrochemical step 7 expensive transition metal catalyst, make this route less were optimized in our previous work.[24] Non-protected phenols 8 attractive. The limits of the current synthetic routes to 2- can be converted into HFIP ethers and subsequently reacted 9 phenylacetonitriles discussed here highlight the need for a with sodium cyanide or potassium cyanide in yields up to 90% 10 facile and environmentally benign route to these valuable over both steps, with only a single purification within the 11 building blocks (Scheme 2). second step (Scheme 3). Secondary nitriles can be obtained in 12 Recently, we reported the selective electrochemical func- 37% yield (5). Phenols containing more than one alkyl group 13 tionalization of benzylic positions using HFIP,[24] which has can be transformed to the corresponding nitriles in high yields 14 extraordinary properties. It stabilizes reactive intermediates,[25] up to 89% (6). Substrates with halo substituents are tolerated, 15 and has a unique solvent microstructure.[26] Its interesting resulting in moderate yields up to 27% (7), and even the dimer 16 solvation properties can enable various transformations.[27] The (4) underwent the cyanation with 29% yield of the cyanation 17 generated ether acts as a molecular mask for the benzylic product. The cyanation reactions proceed rapidly and selec- 18 cation, and stabilizes this reactive intermediate by solvent tively within 5 to 60 min at room temperature, when NaCN in 19 trapping in a less reactive state. Notably, the oxidation also an ethanol/water mixture (9/1) is used, demonstrating the 20 works on graphite anodes, DIPEA acts together with HFIP as a suitability of HFIP as a leaving group. A suggested mechanism 21 supporting electrolyte, and HFIP can be reused completely,[28] can be found in the SI (Figure S3). In acetonitrile with KCN, the 22 which makes this protocol attractive for technical applications. conversions can take up to 6 h. Concentration was found to be 23 BDD electrodes are used here as they allowed for slightly higher crucial in the cyanation step: in some cases a subsequent 24 yields.[29] The HFIP ether can act as a leaving group in a reaction is faster than the initial cyanation itself, resulting in low 25 nucleophilic substitution reaction with cyanides. A simple, yields. Also 4-methylanisoles form the respective HFIP ethers, 26 sustainable, easily scalable, reagent- and metal-free electro- but do not undergo the cyanation reaction. 27 chemical cyanation reaction that proceeds in a two-step To demonstrate the scalability of our method, we chose the 28 synthesis of compound 1 as test reaction. The structural motif 29 of 1 is of significant interest as a precursor for pharmaceutically 30 relevant compounds.[2] We scaled-up the electrolysis by a factor 31 of 50. The electrolysis was conducted with 50 mmol of 1 in a 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Scheme 3. Scope of the reaction. a) 1 mmol, 3 F were applied. KCN (1.5 eq.) 55 in acetonitrile (10 mL); b) 0.5 mmol, polarity reversal of each 10 s, 3 F, KCN 56 (1.5 eq.) in acetonitrile (10 mL); c) 0.5 mmol, KCN (1.5 eq.) in acetonitrileScheme 2. Synthetic strategies to 2-phenylacetonitrile. (10 mL); 57 ChemElectroChem 2019, 6, 4184–4187 www.chemelectrochem.org 4185 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley VCH Mittwoch, 14.08.2019 1916 / 127775 [S. 4185/4187] 1 Communications Conflict of Interest 1 2 The authors declare no conflict of interest. 3 4 5 Keywords: cyanides · electrochemistry · green chemistry · 6 HFIP · oxidation 7 8 9 [1] V. A. Ostrovskii, R. E. Trifonov, E. A. Popova, Russ. Chem. Bull. 2012, 61, 10 768–780. 11 [2] M. Irsfeld, M. Spadafore, B. M. Prüß, WebmedCentral 2013, 4, 4409–4426. [3] C. Lamberth, A. Jeanguenat, F. Cederbaum, A. de Mesmaeker, M. Zeller, 12 H.-J. Kempf, R. Zeun, Bioorg. Med. Chem. 2008, 16, 1531–1545. 13 [4] R. N. Brogden, P. Benfield, Drugs 1996, 51, 792–819. 14 [5] I. Choi, H. Chung, J. W. Park, Y. K. Chung, Org. Lett. 2016, 18, 5508–5511. [6] K. Rice, A. Brossi, J. Org. Chem. 1980, 45, 592–601. 15 Figure 1. 500 mL round bottomed flask with Teflon plug and two BDD [7] N. Dittrich, L. I. Pilkington, E. Leung, D. Barker, Tetrahedron 2017, 73, 16 electrodes (14 cm×3.5 cm×0.3 cm) used in the scale up reaction. A 50 1881–1894. 17 Eurocent coin for comparison. (diameter: 24,25 mm) [8] J. W. Tilley, W. Danho, K. Lovey, R. Wagner, J. Swistok, R. Makofske, J. Michalewsky, J. Triscari, D. Nelson, S. Weatherford, J. Med. Chem. 1991, 18 34, 1125–1136. 19 [9] Y. Yue, H. Fang, M. Wang, Z. Wang, M. Yu, J. Chem. Res. 2009, 377–381. 20 [10] a) L. Eberson, B. Helgée Chem. Abstr. 1974, 80, 82473; b) L. Eberson, B. 500 mL round-bottomed flask (Figure 1). No erosion of selectiv- Helgée, Acta Chem. Scand. 1977, 31, 813–817; c) S. Andreas, E. W. 21 ity was observed for the anodic functionalization with HFIP. The Zahnow, J. Am. Chem. Soc. 1969, 91, 4181–4190; d) L. Eberson, B. 22 Helgée, Acta Chem. Scand. 1975, 29, 451–456; e) F. Fichter, W. Dietrich , resulting mixture was concentrated and reacted with sodium 23 Helv. Chim. Acta 1924, 7, 131–143. cyanide in the ethanol/water mixture yielding in 3.5 g of the [11] Y. Kunihiso, J. Am. Chem. Soc. 1979, 101, 2116 24 desired compound 1 in a single batch (41% yield). The yield is [12] D. Hayrapetyan, R. K. Rit, M. Kratz, K. Tschulik, L. J. Gooßen, Chem. Eur. J. 25 2018, 24, 11288–11291. significantly lower compared to that observed on the 5 mL 26 [13] J.-J. Dai, Y.-B. Huang, C. Fang, Q.-X. Guo, Y. Fu, ChemSusChem 2012, 5, scale (90%). This can be explained by the previously mentioned 617–620. 27 side-reactions, which take place at high concentrations of HFIP [14] a) M. F. Hartmer, S. R. Waldvogel, Chem. Commun. 2015, 51, 16346– 28 16348; b) C. Gütz, V. Grimaudo, M. Holtkamp, M. Hartmer, J. Werra, L. ether. However, the reaction was repeated, adding the HFIP 29 Frensemeier, A. Kehl, U. Karst, P. Broekmann, S. R. Waldvogel, ChemElec- ether to the sodium cyanide solution in ethanol/water dropwise troChem 2018, 5, 247–252. 30 and slowly. The yield of 1 was then increased to 78%. The [15] a) S. Möhle, M. Zirbes, E. Rodrigo, T. Gieshoff, A. Wiebe, S. R. Waldvogel, 31 Angew. Chem. Int. Ed. 2018, 57, 6018–6041; Angew. Chem. 2018, 130, slightly lower yield can be rationalized as a result of insufficient 32 6124–6149. b) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R. mixing and therefore localized high concentration of HFIP ether. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594–5619; Angew. Chem. 33 A mechanical stirrer can raise the yield to the original screening 2018, 130, 5694–5721. c) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev 34 2017, 117, 13230–13319. cell result. 35 [16] S. S. Libendi, Y. Demizu, O. Onomura, Org. Biomol. Chem. 2009, 7, 351– In conclusion, we have established a selective, protective- 356. 36 group-free and environmentally benign cyanation protocol, [17] a) Reynold C. Fuson, William C. Hammann, Paul R. Jones, J. Am. Chem. 37 Soc. 1957, 79, 928–931; b) V. Boekelheide, T. Miyasaka, J. Am. Chem. Soc. using electrochemically derived HFIP ethers. 2-Phenylacetoni- 38 1967, 89, 1709–1714. triles are valuable building blocks in organic synthesis, which [18] A. Saeed, P. A. Mahesar, Tetrahedron 2014, 70 1401–1407. 39 can be synthesized in two steps from 4-methylphenol deriva- [19] U. Schmidt, A. Lieberknecht, H. Griesser, J. Talbiersky, J. Org. Chem. 40 1982, 47, 3261–3264. tives in high yields. This route provides a scalable, metal-free, 41 [20] K. Hilpert, F. Hubler, M. Murphy, D. Renneberg; Benzamide derivatives and reagent-saving route to 2-phenylacetonitriles. This has the as p2x7 receptor agonists, Eur. Pat. Appl. 2678317 A1, 2014. 42 potential to shorten many synthetic routes towards biologically [21] F. A. Carey, Organic Chemistry, McGraw-Hill Higher Education, Boston, 43 2006. active structures and relevant intermediates for pharmaceuticals 44 [22] N. Iranpoor, H. Firouzabadi, B. Akhlaghinia, N. Nowrouzi, J. Org. Chem. and pesticides. 2004, 69, 2562–2564. 45 [23] M. D. Bhor, A. G. Panda, N. S. Nandurkar, B. M. Bhanage, Tetrahedron 46 Lett. 2008, 49, 6475–6479. 47 [24] Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R.Acknowledgements Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 12136–12140; 48 Angew. Chem. 2018, 130, 12312–12317. 49 [25] L. Eberson, O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. 1995, 34, The authors thank the DFG (GSC 266, Wa 1276/17-1, Wa 1276/14- 50 2268–2269; Angew. Chem. 1995, 107, 2417–2418. 1) for financial support. Support of the Advanced Lab of Electro- [26] O. Hollóczki, A. Berkessel, J. Mars, M. Mezger, A. Wiebe, S. R. Waldvogel, 51 chemistry and Electrosynthesis – ELYSION (Carl Zeiss Stiftung) is B. Kirchner , ACS Catal. 2017, 7, 1846–1852. 52 [27] a) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel , gratefully acknowledged. Y.I. gratefully acknowledges the support 53 Angew. Chem. Int. Ed. 2014, 53, 5210–5213; Angew. Chem. 2014, 126, from the Program for Leading Graduate School of TUAT granted 5311–5314; b) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. 54 by the Ministry of Education, Culture, Science and Technology Waldvogel , Angew. Chem. Int. Ed. 2010, 49, 971–975; Angew. Chem. 55 2010, 122, 983–987; c) A. Kirste, M. Nieger, I. M. Malkowsky, F. Stecker, (MEXT), Japan. 56 A. Fischer, S. R. Waldvogel, Chem. Eur. J. 2009, 15, 2273–2277; d) A. Wiebe, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Angew. Chem. 57 ChemElectroChem 2019, 6, 4184–4187 www.chemelectrochem.org 4186 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley VCH Mittwoch, 14.08.2019 1916 / 127775 [S. 4186/4187] 1 Communications Int. Ed. 2017, 56, 14727–14731; Angew. Chem. 2017, 129, 14920–14925; [29] A. Kirste, B. Elsler, G. Schnakenburg, S. R. Waldvogel , J. Am. Chem. Soc. 1 e) S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Angew. Chem. Int. 2012, 134, 3571–3576. 2 Ed. 2018, 57, 13325–1332; Angew. Chem. 2018, 130, 13509–13513; f) L. 3 Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 4877–4881; Angew. Chem. 4 2017, 129, 4955–4959; g) S. Lips, A. Wiebe, B. Elsler, D. Schollmeyer, 5 K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 6 10872–10876; Angew. Chem. 2016, 128, 11031–11035; h) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Manuscript received: November 30, 2018 7 Ed. 2016, 55, 11801–11805; Angew. Chem. 2016, 128, 11979–11983. Revised manuscript received: December 20, 2018 8 [28] I. Colomer, A. E. R. Chamberlain, M. B. Haughey, T. J. Donohoe, Nat. Rev. Accepted manuscript online: December 20, 2018 9 Chem. 2017, 1, 88, 1–12. Version of record online: January 22, 2019 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 ChemElectroChem 2019, 6, 4184–4187 www.chemelectrochem.org 4187 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Wiley VCH Mittwoch, 14.08.2019 1916 / 127775 [S. 4187/4187] 1 1 2 3 4 5 6 7 8 Supporting Information 9 10 ⌫ Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2019 11 12 13 Dehydrogenative Anodic Cyanation Reaction of Phenols in 14 Benzylic Positions 15 16 Johannes L. Röckl, Yasushi Imada, Kazuhiro Chiba, Robert Franke, and 17 18 Siegfried R. Waldvogel*An invited contribution to a Special Issue on Organic Electrosynthesis 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Wiley VCH Mittwoch, 14.08.2019 1916 / 127775 [S. 4188/4188] 1 S1 Table of Contents General information ........................................................................................................... 3 General protocol for electrolytic cyanation reaction (GP) ................................................. 4 Proposed mechanisms for anodic HFIP ether formation .................................................. 6 Synthesis of benzylic HFIP ether ...................................................................................... 8 Synthesis of 2-phenylacetonitriles ..................................................................................... 9 NMR spectra ................................................................................................................... 17 References ...................................................................................................................... 27 S2 General information All reagents were used in analytical or sufficiently pure grades. Solvents were purified by standard methods.[1] Electrochemical reactions were carried out at boron-doped diamond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 μm diamond layer) on silicon support. Column chromatography was performed on silica gel 60 M (0.040–0.063 mm, Macherey- Nagel GmbH & Co, Düren, Germany) with a maximum pressure of 1.6 bar. In addition, a preparative chromatography system (Büchi Labortechnik GmbH, Essen, Germany) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluents mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminum (F254, Merck, Darmstadt, Germany) were used for thin layer chromatography. Gas chromatography was performed on a Shimadzu GC-2010 (Shimadzu, Japan) using a ZB-5 column (Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: hydrogen/air). GC-MS measurements were carried out on a Shimadzu GC-2010 (Shimadzu, Japan) using a ZB-5 column (Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 µm, carrier gas: helium). The chromatograph was coupled to a mass spectrometer: Shimadzu GCMS-QP2010. High Performance Liquid Chromatography (HPLC) was performed on a Azura preparative HPLC (KNAUER Wissenschaftliche Geräte GmbH, Germany) using a Eurospher II column (pore size: 100 Å, particle size: 5 µM, length: 250 mm, inner diameter: 30 mm), deuterium lamp as a detector and 2.1 L pomp. Melting points were determined with a Melting Point Apparatus B-545 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 2 °C/min. Spectroscopy and spectrometry 1H NMR, 13C and 19F NMR spectra were recorded at 25 °C, using a Bruker Avance III HD 400 (400 MHz) (5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to traces in the corresponding deuterated solvent. Mass spectra and high-resolution mass spectra were obtained by using a QTof Ultima 3 (Waters, Milford, Massachusetts) apparatus employing ESI+. Cyclic voltammetry was performed with a Metrohm 663 VA Stand equipped with a μAutolab type III potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Solvent: HFIP. v = 100 mV/s, T = 20 °C, c = 0.005 M, supporting electrolyte (if used): nBu3NMe O3SOMe (MTBS), c (MTBS) = 0.09 M. S3 General protocol for electrolytic cyanation reaction (GP) GP I: Undivided PTFE cell (5 mL) The undivided 5 mL PTFE electrolysis cells can be homemade. Detailed information about used cells are already reported.[2,3] However, the complete setup with these cells are also commercially available as IKA Screening System, IKA-Werke GmbH & Co. KG, Staufen, Germany. It is operated with boron-doped diamond electrodes (BDD, 0.3 x 1 x 7 cm, 15 μm diamond layer, support of silicon was used). A solution of a phenol derivative (0.5–1.0 mmol) and N-ethyl-N-(prop-2-yl)propan-2-amine (DIPEA) (0.1 mL, 0.57 mmol) in 5 mL 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was electrolyzed at a boron-doped diamond (BDD) anode and a BDD cathode. A constant current electrolysis with a current density of 7.2 mA/cm2 was performed at room temperature. After 1.8–3.0 F were applied, HFIP was recovered by distillation. Then, the reaction was taken up in EtOH/water or MeCN (10 mL) and 1.2 eq. - 2.0 eq. sodium or potassium cyanide were added. The mixture was stirred at r.t. for 5 min to 12 h. After completion of the reaction, the solvent was removed under reduced pressure and the residue was dissolved in 50 mL ethyl acetate and washed with 70 mL water. The aqueous phase was afterwards extracted to 30 mL of ethyl acetate. Combined organic phases were washed with 50 mL brine and dried with Na2SO4. After evaporation of the solvent, column chromatography yielded the pure product. Fig. S1: Left: schematic 5 mL Teflon cells; Right: The commercially available IKA Screenings System, IKA-Werke GmbH & Co. KG, Staufen, Germany. S4 GP II: Round bottomed flask cell (500 mL) – Scale-up 50 mmol phenol, 250 mL HFIP, and 5.0 mL (0.57 eq.) DIPEA were transferred into a 500 mL round-bottomed flask equipped with a BDD anode and a BDD cathode. A constant current electrolysis with a current density of 7.2 mA/cm2 was performed at room temperature. After 2.2 F were applied, HFIP was recovered by distillation. Then, sodium cyanide (2 eq.) was dissolved in 1000 mL EtOH/water (9/1) and the reaction mixture was added slowly dropwise under vigorous stirring. The mixture was stirred at r.t. for 5 min. After completion of the reaction, the solvent was removed under reduced pressure and the residue was dissolved in 200 mL ethyl acetate and washed with 200 mL water (3x). The aqueous layer was afterwards extracted to 100 mL of ethyl acetate. Combined organic fractions were first washed with 100 mL brine and dried with Na2SO4. After evaporation of the solvent, column chromatography yielded the product. The flask (500 mL) is closed by a PTFE plug. This cap allows precise arrangement of the BDD electrodes. Total dimension of the BDD electrodes are 14 cm x 3.5 cm x 0.3 cm. Fig. S2: 500 mL flask cell; left: BDD electrode removed; right: assembled. For size comparison one 50 Eurocent coin is placed in front of the glass cell. S5 Proposed mechanisms for anodic HFIP ether formation Fig. S3: Proposed mechanism for the electrochemical HFIP ether formation at benzylic position. Mechanism is shown for 4-methylguaiacol and can vary for other substrates. Twofold oxidation of the phenol at the anode will result in the formation of a quinone methide derivative. This can be activated in the acidic solution to allow nucleophilic attack of the HFIP anion at the benzylic position. The resulting product is a benzylic HFIP ether. Due to addition of DIPEA, HFIP anions are present from the beginning of the reaction. This concentration will be maintained by the cathodic reaction. The HFIP ether moiety is then substituted in a SN- reaction to yield the desired 2-phenylacetonitriles. Previous CV measurements are inline to this mechanism assumption.[4] S6 Scheme 1: Significance of 2-phenylacetonitriles as important building blocks in organic synthesis. S7 Synthesis of benzylic HFIP ether 4-((1-Trifluoromethyl-2,2,2-trifluoroethyl)oxymethyl)-2-methoxyphenol According to the GPI for the electrochemical HFIP ether formation, 138 mg (1.0 mmol) 2- methoxy-4-methylphenol, 5 mL HFIP, and 0.1 mL DIPEA were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The residue was dissolved dichloromethane (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to dichloromethane (30 mL). Combined organic phases were dried over MgSO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 93:7 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as colorless oil (yield: 54%, 164 mg, 0.54 mmol). Noteworthy, the HFIP ether is sensitive to silica gel and can decompose during column chromatography. Rf (cyclohexane:ethyl acetate = 10:3) = 0.52 1H NMR (400 MHz, CDCl3) δ = 6.94 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.0, 1.9 Hz, 1H), 5.77 (s, 1H), 4.81 (s, 2H), 4.13 (s, J = 6.0 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 146.86, 146.48, 126.21, 122.61, 114.26, 111.27, 75.72, 73.44 (p, J = 32.3 Hz), 55.91. 19F NMR (376 MHz, CDCl3) δ = -74.61, -74.62. HRMS for C +11H10F6O3 (APCI+) [M]+: calc.: 304.0529, found: 304.0532. S8 Synthesis of 2-phenylacetonitriles 2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (1) According to the GPI for the electrochemical HFIP ether formation, 138.16 mg (1.0 mmol) 2- methoxy-4-methylphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in a mixture of ethanol (9 mL) and water (1 mL). Sodium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as colorless oil (yield: 90%, 147 mg, 0.90 mmol). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.0 Hz, 1H), 6.83 – 6.75 (m, 2H), 5.71 (s, 1H), 3.89 (s, 3H), 3.67 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 147.02, 145.52, 121.55, 121.04, 118.34, 114.92, 110.44, 56.11, 23.34. HRMS for C +10H11NaNO (ESI+) [M+Na]+: calc.: 186.0522, found: 186.0520. S9 2-(4-Hydroxy-3-methoxyphenyl)butanenitrile (2) According to the GPI for the electrochemical HFIP ether formation, 191 mg (1.0 mmol) 2- methoxy-4-propylphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in a mixture of ethanol (9 mL) and water (1 mL). Sodium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as colorless oil (yield: 44%, 84 mg, 0.44 mmol). 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 8.1 Hz, 1H), 6.84 – 6.73 (m, 2H), 5.77 (s, 1H), 3.88 (s, 3H), 3.65 (dd, J = 7.5, 6.6 Hz, 1H), 1.91 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.93, 145.48, 127.61, 120.41, 114.79, 109.70, 56.11, 38.67, 29.42, 11.59. HRMS for C +11H13NO2 (APCI+) [M]+: calc.: 191.0941, found: 191.0939. S10 2-(4-Hydroxy-3,5-dimethylphenyl)acetonitrile (3) According to the GPI for the electrochemical HFIP ether formation, 136 mg (1.0 mmol) 2,4,6- trimethylphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in a mixture of ethanol (9 mL) and water (1 mL). Sodium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as colorless oil (yield: 75%, 119 mg, 0.75 mmol). 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 2H), 4.99 (s, 1H), 3.63 (s, 2H), 2.26 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 152.09, 128.12, 124.09, 121.07, 118.63, 22.80, 16.01. HRMS for C +10H11NO (APCI+) [M]+: calc.: 161.0841, found: 161.0831. S11 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)acetonitrile (4) According to the GPI for the electrochemical HFIP ether formation, 220 mg (1.0 mmol) 2,6-di- tert-butyl-4-methylphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in a mixture of ethanol (9 mL) and water (1 mL). Sodium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as crystalline solid (yield: 30%, 72 mg, 0.30 mmol). 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H), 5.26 (s, 1H), 3.66 (s, 2H), 1.45 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 153.61, 136.85, 124.82, 120.58, 118.73, 34.51, 30.26, 23.56. HRMS for C +16H24NO (ESI+) [M+H]+: calc.: 246.1852, found: 246.1813. S12 5-Cyanomethyl-3,3’,5’-trimethyl-2,2’-biphenol (5) According to the GPI for the electrochemical HFIP ether formation, 242 mg (1 mmol) 3,3’,5,5’- tetramethyl-2,2’-biphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in acetonitrile (10 mL). Potassium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as crystalline solid (yield: 29%, 75 mg, 0.29 mmol). 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 2.3 Hz, 1H), 7.05 – 7.00 (m, 2H), 6.87 – 6.83 (m, 1H), 5.45 (d, J = 2.3 Hz, 1H), 4.98 (d, J = 2.3 Hz, 1H), 3.67 (s, 2H), 2.31 (s, 3H), 2.29 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 151.33, 148.90, 132.40, 130.65, 130.49, 128.77, 127.91, 126.60, 125.23, 123.65, 121.89, 121.59, 118.16, 22.82, 20.44, 16.28, 16.14. HRMS for C17H +17NNaO2 (ESI+) [M+Na]+: calc.: 290.1151, found: 290.1149. S13 2-(3-(tert-Butyl)-4-hydroxy-5-methylphenyl)acetonitrile (6) According to the GPI for the electrochemical HFIP ether formation, 178 mg (1.0 mmol) 2-(tert- butyl)-4,6-dimethylphenol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in a mixture of ethanol (9 mL) and water (1 mL). Sodium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 10 min. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 90:10 for 60 min; column 12 mm x 150 mm; flow rate 10 mL/min) yielded the product as crystalline solid (yield: 89%, 180 mg, 0.89 mmol). 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 2.4, 0.8 Hz, 1H), 5.01 (s, 1H), 3.64 (s, 2H), 2.25 (s, 3H), 1.42 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 152.54, 136.67, 128.04, 124.83, 124.12, 120.83, 118.68, 34.69, 29.66, 23.12, 16.10. HRMS for C +13H17O (APCI+) [M]+: calc.: 203.1310, found: 203.1261. S14 2-(3,5-Dibromo-4-hydroxyphenyl)acetonitrile (7) According to the GPI for the electrochemical HFIP ether formation, 133 mg (0.5 mmol) 2,6- dibromo-4-methylphenol (1 eq.), diol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in acetonitrile (10 mL). Potassium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 80:20 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as crystalline solid (yield: 27%, 39 mg, 0.135 mmol). 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.55 (s, 1H), 3.95 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 150.79, 132.47, 125.98, 119.39, 112.55, 21.17. HRMS for C H 79Br NO-8 4 2 (ESI-) [M-H]-: calc.: 287.8665, found: 287.8661 for C H 79 818 4 Br BrNO- (ESI-) [M-H]-: calc.: 289.8639, found: 289.8640 for C 81 -8H4 Br2NO (ESI-) [M-H]-: calc.: 291.8619, found: 291.8623 S15 2-(4-Hydroxy-3,5-dimethoxyphenyl)acetonitrile (8) According to the GPI for the electrochemical HFIP ether formation, 84 mg (0.5 mmol) 2,6- dimethoxy-4-methylphenoldiol (1 eq.), HFIP (5 mL), and DIPEA (0.1 mL) were transferred into an undivided 5 mL PTFE cell. Electrolysis was carried out at room temperature with a current density of 7.2 mA/cm². After 2.2 F were applied, HFIP was recovered in vacuo. The crude HFIP ether was dissolved in acetonitrile (10 mL). Potassium cyanide (1.2 eq.) was then added and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with water (70 mL). The aqueous layer was afterwards extracted to ethyl acetate (30 mL). The combined organic fractions were dried over Na2SO4. After evaporation of the solvent, column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 75:25 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielded the product as crystalline solid (yield: 37%, 36 mg, 0.18 mmol). 1H NMR (400 MHz, CDCl3) δ 6.51 (s, 2H), 5.56 (s, 1H), 3.88 (s, 6H), 3.67 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 147.39, 134.45, 120.75, 118.13, 104.74, 56.41, 23.63. HRMS for C10H +10NO3 (APCI+) [M]+: calc.: 192.0655, found: 192.0656 S16 NMR spectra 4-((1-Trifluoromethyl-2,2,2-trifluoroethyl)oxymethyl)-2-methoxyphenol S17 S18 2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (1) S19 2-(4-Hydroxy-3-methoxyphenyl)butanenitrile (2) S20 2,6-Dimethyl-4-(2,4,5-trimethoxybenzyl)phenol (3) S21 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)acetonitrile (4) S22 5-Cyanomethyl-3,3’,5’-trimethyl-2,2’-biphenol (5) S23 2-(3-(tert-Butyl)-4-hydroxy-5-methylphenyl)acetonitrile (6) S24 2-(3,5-Dibromo-4-hydroxyphenyl)acetonitrile (7) S25 2-(4-Hydroxy-3,5-dimethoxyphenyl)acetonitrile (8) S26 References [1] W. L. F. Armarego, C. L. L. Chai, Purification of laboratory chemicals, Elsevier, Amsterdam, 2013. [2] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26–32. [3] A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983–987. (see SI thereof). [4] Y. Imada, J. L. Röckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Angew.Chem. Int. Ed. 2018, 57,12136–1214 S27 DOI: 10.1002/open.201900127 1 2 3 Electrochemical Synthesis of Fluorinated Orthoesters from 4 1,3-Benzodioxoles 5 6 Johannes L. Röckl,[a, b] Adrian V. Hauck,[a] Dieter Schollmeyer,[a] and 7 8 Siegfried R. Waldvogel*[a, b] 9 10 11 A scalable, dehydrogenative, and electrochemical synthesis of also be applied to a broader variety of substrates compared to novel highly fluorinated orthoesters is reported. This protocol the Pinner approach. However, this reaction only proceeds with12 13 provides easy and direct access to a wide variety of derivatives, aliphatic moieties in the position b to the carboxylic acid (R2, 14 using a very simple electrolysis setup. These compounds are Scheme 1).[11] First reports on the direct anodic conversion of surprisingly robust towards base and acid with an unusual high 1,3-benzodioxoles was given by Thomas et al.[12] The installation15 16 lipophilicity, making them interesting motifs for potentially of the methoxy moiety at the heterocyclic skeleton could be 17 active compounds in medicinal chemistry or agro applications. achieved. However, the reaction is limited to a narrow scope. The use of electricity enables a safe and environmentally benign Only a few substrates with substituents on the aromatic system18 chemical transformation as only electrons serve as oxidants. are tolerated. Furthermore, the setup for the electrolytic19 conversion is not straightforward, since carbon dioxide has to 20 be applied and the reaction is carried out with cooling to 10 °C. 21 The use of expensive platinum electrodes incorporates an 22 The orthoester is an extremely versatile structural feature, used additional disadvantage (Scheme 1). 23 as a protective group for esters[1] in peptide synthesis[2] and for Here, a scalable electrosynthetic method towards novel 24 alcohols in nucleoside synthesis.[3] This functional group is vital highly fluorinated orthoesters is presented. These molecules are 25 for transformations such as the Claisen-Johnson a new class for potentially biologically active compounds with a 26 rearrangement,[4] the synthesis of a variety of nitrogen-based high lipophilicity (Scheme 1).[13] LogP values were found to 27 heterocycles[5] and various condensation reactions.[6] Orthoest- increase dramatically compared to those of the corresponding 28 ers were first prepared via conversion of chloroform with substrates, while the volatility remains almost the same like the 29 alcoholates by Williamson and Kay in 1854.[7] This route 30 generates a large amount of salt waste and results in low 31 yields.[8] A common alternative is the Pinner route to orthoesters 32 involving conversion of nitriles with alcohols in the presence of 33 strong acids.[9] Hydrogen cyanide is often used in these 34 reactions, which should be avoided. Additionally, a large 35 amount of waste is generated. This can be avoided using an 36 electrochemical approach, which was developed in 2000 by 37 Fischer et al. at BASF.[10] This process is particularly suitable for 38 the preparation of methyl orthoformate, from 1,1,2,2-tetrame- 39 thoxy-ethane via anodic oxidation. Additionally, orthoesters can 40 be synthesized using the Hofer-Moest reaction, a Kolbe-type 41 electrolysis. This reaction leads to high yields (95%) and can 42 43 44 [a] J. L. Röckl, A. V. Hauck, D. Schollmeyer, Prof. Dr. S. R. Waldvogel 45 Johannes Gutenberg University Mainz 46 Institute of Organic Chemistry 47 Duesbergweg 10–14, 55128 Mainz, GermanyE-mail: waldvogel@uni-mainz.de 48 Homepage: https://www.blogs.uni-mainz.de/fb09akwaldvogel/ 49 [b] J. L. Röckl, Prof. Dr. S. R. Waldvogel 50 Johannes Gutenberg Universität MainzGraduate School Materials Science in Mainz 51 Staudingerweg 9, 55128 Mainz, Germany 52 Supporting information for this article is available on the WWW under 53 https://doi.org/10.1002/open.201900127 ©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. 54 This is an open access article under the terms of the Creative Commons 55 Attribution Non-Commercial NoDerivs License, which permits use and dis- 56 tribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Scheme 1. Synthetic strategies to orthoesters. 57 ChemistryOpen 2019, 8, 1167–1171 1167 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Donnerstag, 29.08.2019 1909 / 136578 [S. 1167/1171] 1 starting materials (see SI). Furthermore, this reaction allows the 1 Table 1. Constant current electrolysis of 5-chloro-1,3-benzodioxole 1 lipophilicity to be modulated via the installation of various (0.5 mmol) was performed in HFIP/TFE (5 mL) and 1.0 equiv. of a base 2 highly fluorinated side-chains in the difficult-to-address position (DIPEA/DBU) in an undivided Teflon cell. Isolated yields. BDD: Boron-doped 3 diamond. 2 of 1,3-benzodioxoles. These products proved to be surpris- 4 ingly inert towards acids and bases, suggesting they are Entry Current Anode Charge [F] Yield 1 5 density [%] amenable to further functionalization or applicable in active 6 [mA/cm 2] ingredients. A broad substrate scope is tolerated (Scheme 2–4), 7 providing access to a wide variety of derivatives in moderate 1 1.0 BDD 3.0 0 8 2 15 BDD 3.0 24 yields. Graphite, glassy carbon, or boron-doped diamond (BDD) 3 90 BDD 3.0 23 9 can be used as electrode material and no additional supporting 4 7.2 BDD 2.2 19 10 electrolyte is needed. The constant current electrolysis is carried 5 7.2 BDD 2.8 26 11 6 7.2 BDD 4.0 13 out in a simple undivided electrolytic cell at room temperature 7 7.2 BDD 3.0 30 12 with the corresponding alcohols as solvent. This simple reaction 8 7.2 Graphite 3.0 23 13 9 7.2 Glassy carbon 3.0 27 14 10 7.2 Mo 3.0 0 15 16 setup makes this reaction easily scalable and therefore partic- 17 ularly attractive for technical applications. 18 Electrochemistry is an attractive concept in performing 19 organic synthesis, because it can potentially diminish the 20 amount of reagent waste, plus renewable energy can be used 21 to contribute to more sustainable conversions.[14] The use of 22 fluoroalcohols (in particular 1,1,1,3,3,3-hexafluoropropan-2-ol, 23 HFIP) in electrosynthesis has major advantages, as it modulates 24 the reactivity of intermediates,[15] and has an exceptional 25 solvent microhetero-geneity.[16] This has been recently demon- 26 strated by conversion of electrogenerated HFIP ethers with 27 nucleophiles towards diarylmethanes[17] and 2- 28 phenylacetonitriles.[18] We have also developed efficient electro- 29 chemical CN, SS, CC, and NN coupling reactions involving 30 phenols,[19] anilides,[20] and dianilides as substrates.[21] 31 By electrosynthetic screening, the ideal reaction conditions 32 such as concentration, electrode material, applied charge and 33 current density were identified (Table 1).[22] The screening 34 experiments were performed with 5-chloro-1,3-benzodioxole (1) 35 as test system. Optimal reaction conditions were achieved 36 when working with BDD electrodes at a concentration of 37 0.1 mol/L and an applied charge of 3.0 F. When more charge 38 was applied, the respective orthocarbonates were observed as 39 by-products, resulting in lower yields (Table 1, Entry 6). The 40 optimal current density identified was 7.2 mA/cm2. (Table 1, 41 Entry 7). It should be noted that the protocol is very robust, 42 since the yield remains almost unchanged up to a current 43 density of 90 mA/cm2 (Table 1, Entry 3). Inexpensive electrode 44 materials can also be used, such as glassy carbon or graphite 45 (Table 1, Entries 8 and 9). However, BDD is slightly superior. 46 Sufficient conductivity was achieved, when using 0.02 vol% of 47 N,N-diisopropylethylamine (DIPEA) consequently no additional 48 supporting electrolyte is needed.[17] In addition, the concen- 49 tration played an important role, as increased oligomerization 50 was observed on the electrodes at higher concentrations (see 51 SI). 52 Electrochemical functionalization with HFIP was achieved in 53 yields up to 60%. Various functional groups are tolerated. 54 Scheme 2. Scope of the reaction with HFIP. Electrolysis was carried out in 55 HFIP (5 mL) with 0.5 mmol substrate, 0.02 vol% of DIPEA, using BDD Substrates carrying an electron-withdrawing substituent such as electrodes and 3.0 F at 7.2 mA/cm2 in an undivided cell. Molecular structure halogen or nitrile (1, 2) can be converted in yields up to 33%.56 (based on X-ray crystallography) of 13 is displayed. Isolated yields are given. The yields were significantly lower for substrates involving 57 ChemistryOpen 2019, 8, 1167–1171 www.chemistryopen.org 1168 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Donnerstag, 29.08.2019 1909 / 136578 [S. 1168/1171] 1 phenyl-acetates (3), allylic groups (10), or methoxyacetates (9). irreversible oxidation steps (Eox1=1.17 V vs Fc/FcH+, E =1 ox2 The unsubstituted 1,3-benzodioxole undergoes the reaction in 1.52 V vs Fc/FcH+) (Figure 2). This confirms our assumption that 2 16% yield (4). Electron-releasing groups such as alkyl- (5–7) and initially an oxidation step to a radical cation and then a 3 methoxy groups (8) were also tolerated. Interestingly, benzylic deprotonation step occurs. 4 positions (5) were not oxidized to the corresponding HFIP The reaction could be applied to other fluorinated alcohols, 5 ethers.[17] Sterically demanding groups such as tert-butyl groups such as 2,2,2-trifluoroethanol (TFE) or, 2,2,3,3,4,4,5,5-octafluoro- 6 in 2- and 4-positions had no significant influence onto the pentan-1-ol. Therefore, stronger bases like 1,8-diazabicyclo- 7 yields (6, 7). Substrates carrying a second aromatic system also [5.4.0]undec-7-ene (DBU) and 1,8-bis(dimethylamino)naphtha- 8 formed the desired products (12). Substrates involving larger lene, are required in order to achieve sufficient conductivity. It 9 systems form the corresponding 2-alkoxy-1,3-benzodioxoles in was possible to convert the 1,3-benzodioxoles to TFE orthoest- 10 enhanced yields (13, 21) (Scheme 2). ers in slightly lower yields, compared to the HFIP orthoesters. 11 This can be rationalized upon analysis of the mechanism: However, the trends are similar. Larger systems also resulted 12 First, a radical cation is generated, which undergoes the loss of in enhanced yields (21, 37%) (Scheme 4). Recently, an electro- 13 a proton and a further oxidation step to a 1,3-benzodioxolium 14 species. This cation will be trapped by a HFIP anion. Larger 15 systems can stabilize these cations and avoid unwanted side 16 reactions (Scheme 3). 17 The proposed mechanism is supported by cyclic voltamme- 18 try (Figure S4 and Figure S5 in SI) and the anticipated 6 19 aromatic intermediates were isolated as BF 4 -salts and spectro-20 scopically investigated by NMR.[23] We also found that the 21 addition of base plays a crucial role. 22 Subsequently, we investigated the starting material in HFIP 23 without any base and MTBS as supporting electrolyte. We found 24 that this electron transfer process to the radical cation is 25 reversible (Figure 1). 26 Afterwards, we added base to this solution and found that 27 the process is now irreversible, due to the subsequent 28 deprotonation reaction and we can again observe the two 29 Scheme 3. Proposed mechanism for the formation of orthoesters. 30 31 32 33 34 35 36 37 38 39 40 41 42 Figure 1. Cyclic voltammogram of a 5 mM solution of 5-methyl-1,3-benzo- 43 dioxol in HFIP/MTBS at 50 mV/s. 44 45 46 47 48 49 50 51 52 53 Scheme 4. Scope of the reaction with TFE. Electrolysis was carried out in TFE 54 (5 mL) with 0.5 mmol substrate, 0.03 vol% of DBU and BDD electrodes using 55 BDD electrodes and 3.0 F at 7.2 mA/cm2 in an undivided cell. Isolated yields 56 Figure 2. cyclic voltammogram of a 5 mM solution of 5-methyl-1,3-benzo- are displayed.dioxol in HFIP/MTBS+DIPEA at 50 mV/s 57 ChemistryOpen 2019, 8, 1167–1171 www.chemistryopen.org 1169 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Donnerstag, 29.08.2019 1909 / 136578 [S. 1169/1171] 1 chemical installation of TFE has been reported by an iodine(III)- conversion could be observed, leading to complete recovery of 1 mediated cyclisation reaction for the synthesis of 4-(2,2,2- the orthoesters. Methoxy orthoesters usually undergo rapid 2 trifluoroethoxy)isochroman-1-ones.[24] reactions with Grignard reagents,[25] Lewis acids[26] and even 3 For longer fluorinated alkyl chains the yields decreased to water.[12,27] It was therefore possible to convert these molecules 4 15–17% (22, 23). This can be explained by the higher viscosity in presence of the orthoester moiety: 5 was selectively 5 of the solvent and therefore high local concentrations, and less brominated in 68% yield, using bromine in CH2Cl2 with pyridine6 conductivity (Scheme 5). as additive. The resulting product 24 was then subjected to a 7 Suzuki-Miyaura coupling in 64% yield (25) without affecting the 8 orthoester functionality (Scheme 6). This proves the usefulness 9 and robustness of these functionalities. The logP values of 1,3- 10 benzodioxoles and the corresponding orthoesters have been 11 calculated and compared (see SI). It was remarkable that these 12 values increase by a factor of 1.5 to 2 when fluorinated side 13 chains were installed. This transformation could boost the 14 potency and impact target selectivity tremendously by influenc- 15 ing pKa, modulating conformation, and hydrophobic16 interactions.[28] The unprecedented robustness and the high 17 lipophilicity further enhance the potential of bioactive com- 18 pounds involving 1,3-benzodioxoles. 19 In conclusion, we have established a scalable and simple 20 protocol towards novel highly fluorinated orthoesters. This 21 Scheme 5. Scope of the reaction with 2,2,3,3,4,4,5,5-octafluoropentan-1-ol. transformation allows the functionalization of 1,3-benzodiox- 22 Electrolysis was carried out in the corresponding alcohol (5 mL) with 0.5 mmol substrate, 1 equiv. of 1,8-bis(dimethylamino)naphthalene using oles in position 2 with different fluorinated alcohols. This makes23 24 BDD electrodes and 3.0 F at 7.2 mA/cm 2 in an undivided cell. Isolated yields it possible to adjust the physicochemical properties of a broad are given. variety of potentially bioactive substrates. The high robustness 25 towards acids and bases gives rise to subsequent conversions 26 without affecting the moiety. This makes these structural 27 motives particularly interesting for applications in medicinal 28 and agrochemistry. 29 30 31 Acknowledgements 32 33 J. L. Röckl is a recipient of a DFG fellowship through the Excellence 34 Initiative by the Graduate School Materials Science in Mainz (GSC 35 266). Support of the Advanced Lab of Electrochemistry and 36 Scheme 6. Further conversions of fluorinated orthoesters. i) Bromine Electrosynthesis – ELYSION (Carl-Zeiss-Stiftung) is gratefully37 (1.5 equiv.) was added to pyridine (2 equiv.) and 5 (1 equiv.) in dichloro- acknowledged. 38 methane (2 mL) at 0 °C. ii) Pd(dppf)Cl2 (0.05 equiv.), 4-methoxyphenylboronic 39 acid (1.2 equiv.), caesium carbonate (2 equ to 1,2-dimethoxyethane and heated to 75 °iv.) and 24 ( 1 equiv.) was added40 C for 8 h. Conflict of Interest 41 42 The authors declare no conflict of interest. 43 In addition, to demonstrate the scalability of our method, 44 the electrolysis was scaled-up by a factor of 50. For this, we 45 Keywords: oxygen heterocycles · electrochemistry · oxidation · used 25 mmol of 5-methyl-1,3-benzodioxole in a 500 mL round- 46 orthoesters · fluorine bottomed flask cell (Figure S2 in SI). No erosion of selectivity 47 was observed. HFIP was then recovered and the residue was 48 directly purified to give 2.75 g of the desired product 5 in a 49 [1] J. L. Giner, Org. 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Manuscript received: April 8, 2019 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 ChemistryOpen 2019, 8, 1167–1171 www.chemistryopen.org 1171 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Donnerstag, 29.08.2019 1909 / 136578 [S. 1171/1171] 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Supporting Information 16 17 ⌫ Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2019 18 19 20 Electrochemical Synthesis of Fluorinated Orthoesters from 21 1,3-Benzodioxoles 22 23 Johannes L. Röckl, Adrian V. Hauck, Dieter Schollmeyer, and Siegfried R. Waldvogel*©2019 24 25 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. 26 This is an open access article under the terms of the Creative Commons Attribution Non- 27 Commercial NoDerivs License, which permits use and distribution in any medium, provided 28 the original work is properly cited, the use is non-commercial and no modifications or 29 adaptations are made. 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Wiley VCH Donnerstag, 29.08.2019 1909 / 136578 [S. 1172/1172] 1 I Table of Contents 1. GENERAL INFORMATION .............................................................................. 2 2. GENERAL PROTOCOL FOR ELECTROLYTIC SYNTHESIS OF ORTHOESTERS (GP) ................................................................................................ 3 2.1. GPI: SYNTHESIS OF HFIP-ORTHOESTERS ........................................ 3 2.2. GPII: SYNTHESIS OF TFE-ORTHOESTERS ........................................ 3 2.3. GPIII: SYNTHESIS OFP-ORTHOESTERS ........................................... 4 2.4. GPIV: SCALEUP OF HFIP-ORTHOESTERS ........................................ 4 3. CYCLIC VOLTAMMETRY STUDIES ............................................................... 5 4. POSTULATED MECHANISM FOR THE ANODIC ORTHOESTER FORMATION ............................................................................................................... 7 5. EXPERIMENTAL SECTION ............................................................................. 8 5.1. SYNTHESIS OF 1,3-BENZODIOXOLES ............................................... 8 5.2. SYNTHESIS OF HFIP-ORTHOESTERS ............................................. 15 5.3. SYNTHESIS OF TFE-ORTHOESTERS............................................... 29 5.4. SYNTHESIS OF OFP-ORTHOESTERS .............................................. 37 5.5. ORTHOCARBONATES .................................................................... 39 5.6. FURTHER FUNCTIONALIZATIONS OF HFIP-ORTHOESTERS ................ 40 5.7. OPTIMIZATION OF REACTION PARAMETERS ..................................... 42 6. LIPOPHILICITY: LOGP – VALUES OF 1,3-BENZODIOXOLES AND THE CORRESPONDING ORTHOESTERS ...................................................................... 43 7. NMR SPECTRA ............................................................................................. 44 8. REFERENCES ............................................................................................... 89 2 1. General information All reagents were used in analytical or sufficiently pure grades. Solvents were purified by standard methods.[1] Electrochemical reactions were carried out at boron-doped di- amond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 Column chromatography was performed on basic aluminiumoxide (0.05-0.15 mm; pH 9.5±0.5). In addition, a preparative chromatography system (Büchi Labortechnik GmbH, Essen, Germany) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, Büchi fraction collector C-660 and two Pump Modules C- 605 for adjusting the solvent mixtures. As eluents mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminum (F254, Merck, Darmstadt, Ger- many) were used for thin layer chromatography. Spectroscopy and spectrometry 1H NMR, 13C and 19F NMR spectra were recorded at 25 °C, using a Bruker Avance III HD 400 (400 MHz) (5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts ( ) are reported in parts per million (ppm) rela- tive to TMS as internal standard or traces of CHCl3 or DMSO-d6 in the corresponding deuterated solvent. For the 19F spectra, ethyl fluoroacetate served as external standard ( Mass spectra and high-resolution mass spectra were obtained by using a QTof Ultima 3 (Waters, Milford, Massachusetts) apparatus employing ESI+ or APCI. Melting points were determined with a Melting Point Apparatus B-545 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 1 °C/min. Cyclic voltammetry was performed with a Metrohm 663 VA Stand equipped with a Autolab type III potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Sol- vent: HFIP. v = 100 mV/s, T = 20.0 °C, c = 0.00500 M, supporting electrolyte DIPEA: c = 0.100 M. 3 2. General protocol for electrolytic synthesis of orthoesters (GP) The undivided 5 mL PTFE electrolysis cells are homemade. Detailed information about used cells are already reported.[2,3] However, the complete setup with these cells are also commercially available as IKA Screening System, IKA-Werke GmbH & Co. KG, Staufen, Germany. It is operated with boron-doped diamond electrodes (BDD, 0.3 x 1 x 7 cm, 15 m diamond layer, the support material is silicon). 2.1. GPI: Synthesis of HFIP-orthoesters The 1,3-benzodioxole substrate (0.5 mmol) was dissolved in HFIP (5.0 mL, 47 mmol, 95 equiv.) in an undivided 5 mL PTFE electrolysis cell and mixed with DIPEA (0.1 mL, 0.6 mmol, 1 equiv.). The electrolysis was carried out with BDD electrodes at room temperature and a current density of 7.2 mA/cm2. After applying a charge of 3.0 F, HFIP was recovered by evaporation. The crude product was purified by column chro- matography on basic aluminiumoxide (0.05-0.15 mm; pH 9.5±0.5) to yield the desired product. 2.2. GPII: Synthesis of TFE-orthoesters The 1,3-benzodioxole substrate (0.50 mmol, 1.0 equiv.) was dissolved in HFIP (5.0 mL, 69 mmol, 138 equiv.) in an undivided 5 mL PTFE electrolysis cell and mixed with DBU (0.15 mL, 1.0 mmol, 2.0 equiv.). The electrolysis was carried out with BDD elec- trodes at room temperature and a current density of 7.2 mA/cm2. After applying a charge of 3.0 F, TFE was recovered by evaporation. The crude product was purified by column chromatography on basic aluminiumoxide (0.05-0.15 mm; pH 9.5±0.5) to yield the desired product. Fig. S1: Left: schematic 5 mL Teflon cells; Middle: The commercially available IKA Screenings System, IKA-Werke GmbH & Co. KG, Staufen, Germany; right: 5 mL Teflon cell with two parallel electrodes (size: 3 x 10 x 70 mm, 1 Euro coin for comparison, diameter: 23,25 mm). 4 2.3. GPIII: Synthesis OFP-orthoesters The 1,3-benzodioxole substrate (0.50 mmol, 1.0 equiv.) was dissolved in 2,2,3,3,4,4,5,5 -octafluoropentan-1-ol (OFP) (5.0 mL, 36 mmol, 72 equiv.) in an undi- vided 5 mL PTFE electrolysis cell and mixed with 1,8-bis(dimethylamino)naphthalene (0.107 g, 0.50 mmol, 1.0 equiv.). The electrolysis was carried out with BDD electrodes at room temperature and a current density of 7.2 mA/cm2. After applying a charge of 3.0 F, the solvent was recovered by evaporation. The crude product was purified by column chromatography on basic aluminiumoxide (0.05-0.15 mm; pH 9.5±0.5) to yield the desired product. 2.4. GPIV: Scaleup of HFIP-orthoesters The 1,3-benzodioxole substrate (25 mmol, 1.0 equiv.) was dissolved in HFIP (250 mL) in an undivided 500 mL glass electrolysis cell and mixed with DIPEA (5.0 mL, 10 mmol, 1.0 equiv.). The electrolysis was carried out with BDD electrodes at room temperature and a current density of 7.2 mA/cm2. After applying a charge of 3.0 F, HFIP was re- covered by evaporation. The crude product was purified by column chromatography on basic aluminiumoxide (0.05-0.15 mm; pH 9.5±0.5) to yield of the desired product. For 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl))-5-methyl-1,3-benzodioxole (5) 2.75 g were isolated as a colourless liquid (yield: 37%). The flask (500 mL) is closed by a PTFE plug. This cap allows precise arrangement of the BDD electrodes. Total dimension of the BDD electrodes are 6.0 cm x 2.0 cm x 0.3 cm. Fig. S2: 500 mL flask cell; left: BDD electrode removed; right: assembled. For size comparison one 50 Eurocent (diameter: 24,25 mm) coin is placed in front of the glass cell. 5 3. Cyclic voltammetry studies Fig. S4: left: cyclic voltammogram of a 5 mM solution of 5-methyl-1,3-benzodioxol in HFIP/DIPEA at 100 mV/s right: cyclic voltammogram of a 5 mM solution of 2-(1-trifluoromethyl-(2,2,2-trifluoroethyl))-5- methyl-1,3-benzodioxole in HFIP/DIPEA at 100 mV/s. In the cyclic voltammogram of the starting material (Fig. S4 left), two oxidation steps were observed (Eox1 = 1.17 V vs Fc/FcH+, Eox2 = 1.52 V vs Fc/FcH+). This suggests that first a radical cation is produced, which is then further converted by deprotonation and a further oxidation step to a benzodioxolium ion. This cation represents a 6 - ar- omatic system, wich is rather stable. This benzodioxolium ion can then be trapped with the corresponding alcoholate to form the orthoester. The oxidation potential of the product is found to be higher (Eox = 1.55 V vs Fc/FcH+) (Fig. S4 right). Fig. S5: left: cyclic voltammogram of a 5 mM solution of 5-Chloro-1,3-benzodioxol in HFIP/DIPEA at 100 mV/s right: cyclic voltammogram of a 5 mM solution of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl))- 5-chloro-1,3-benzodioxole in HFIP/DIPEA at 100 mV/s. The same trends were found for 5-chloro-1,3-benzodioxole, eventhough the oxidation potentials were higher (Eox1 = 1.30 V vs Fc/FcH+, Eox2 = 1.89 V vs Fc/FcH+) (Fig. S5 6 left). For the product Eox = 1.66 V vs Fc/FcH+ was found (Fig. S6 right). The lower ox- idation potential of the product in comparison to Eox2 of the starting material explains the lower yield for this substrate. Fig. S6: cyclic voltammogram of a 5 mM solution of 5-methyl-1,3-benzodioxol in HFIP/MTBS at 50 mV/s Subsequently, we investigated the starting material in HFIP without any base and with MTBS as supporting electrolyte. We found that this electron transfer process to the radical cation is reversible (Fig. S6). Fig. S7: cyclic voltammogram of a 5 mM solution of 5-methyl-1,3-benzodioxol in HFIP/MTBS + DIPEA at 50 mV/s Afterwards, we added base to this solution and found that the process is now irreversi- ble, due to the subsequent deprotonation reaction and we can again observe the two irreversible oxidation steps (Eox1 = 1.17 V vs Fc/FcH+, Eox2 = 1.52 V vs Fc/FcH+) (Fig. S7). This confirms our assumption that initially an oxidation step to a radical cation and then a deprotonation step occurs. It could be shown by cyclic voltammetry that the reaction proceeds via an ECEC-mech- anism. This was also suggested by Thomas et al.[4] This ionic mechanism is also in 7 accordance with works, in which benzodioxolium ions were isolated as tetrafluorobo- rates and caracterized by NMR spectroscopy.[5] This hypothesis is supported by our observation that reactions of substrates with larger systems result in higher yields. 4. Postulated mechanism for the anodic orthoester formation CF3 H2 2 O CF3 C A H3C O e– = 1.17 V CF T E 3ox1 –2 HO 2e H O O A CF3 D N H C EO 3 O D e– O CFE 3 = 1.52 V O Eox2 CF H+ 3O CH3 H3C O H O F O O F F F F F E = 1.55 VoxP Fig. S8: Postulated mechanism for the electrochemical orthoester formation of 1,3-benzodioxoles. First a radical cation is produced, which is then further converted by deprotonation and a further oxidation step to a benzodioxolium ion. This cation represents a 6 -aromatic system, wich is rather stable. This benzodioxolium ion can then be trapped with the corresponding alcoholate to form the orthoester. Due to addition of base, alcoholates are present from the beginning of the reaction. This concentration will be maintained by the cathodic reaction. 8 5. Experimental section 5.1. Synthesis of 1,3-Benzodioxoles 5-Methoxy-1,3-benzodioxole O O O In a 50 mL round-bottomed flask, 5-hydroxy-1,3-benzodioxole (3.0 g, 22 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (6.0 g, 43 mmol, 2 equiv.) was added to the solution. Iodomethane (13.5 mL, 168 mmol, 8 equiv.) was added slowly while stirring. After three hours, the solvent was distilled off in vacuum. The residue was mixed with water (350 mL) and extracted three times with ethyl acetate (50 mL). The combined extracts were dried over sodium sulfate and con- centrated. The residue was purified by column chromatography using silica gel 60 (0.040-0.063 mm). The product was obtained as a colourless oil (yield: 70%, 2.31 g, 15.18 mmol). 1H NMR (400 MHz, CDCl3) 6.71 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.32 (dd, J = 8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 3.75 (s, 3H). 13C NMR (101 MHz, CDCl3) 155.3, 148.4, 141.7, 108.0, 104.8, 101.2, 97.6, 56.1. HRMS of C8H8O3+ (APCI+) [M]+: calc.: 152.0468, found: 152.0464. The analytical data are consistent with the literature.[6] 9 5-(Methoxymethyl)-1,3-benzodioxole O O O 5-(Hydroxymethyl)-1,3-benzodioxole (3.0 g, 20 mmol, 1 equiv.) was dissolved in N,N- dimethylformamide (25 mL) in a 50 mL round-bottomed flask. Sodium hydride (2.4 g, 99 mmol, 5 equiv.) was added to the solution as a 60% mineral oil dispersion (3.95 g). Iodomethane (12.3 mL, 153 mmol, 8 equiv.) was added slowly while stirring. After three hours the solvent was distilled off in vacuum. The residue was mixed with water (350 mL) and extracted three times with ethyl acetate (50 mL). The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by column chro- matography using silica gel 60 (0.040-0.063 mm). The product was obtained as color- less oil (yield: 82%, 2.72 g, 16.37 mmol). 1H NMR (400 MHz, CDCl3) 6.85-6.76 (m, 3H), 5.95 (s, 2H), 4.35 (s, 2H), 3.35 (s, 3H). 13C NMR (101 MHz, CDCl3) 147.9, 147.2, 132.2, 121.5, 108.6, 108.2, 101.1, 74.7, 57.9. HRMS of C9H10O3+ (APCI+) [M]+: calc.: 166.0624, found: 166.0622. The analytical data are consistent with the literature.[7] 10 5-(Methoxycarbonylmethyl)-1,3-benzodioxole O O O O 5-(Carboxymethyl)-1,3-benzodioxole (1.00 g, 5.6 mmol, 1 equiv.) was dissolved in methanol in a 50 mL round-bottomed flask. Thionyl chloride (0.5 mL, 7 mmol, 1 equiv.) was added while stirring. After two hours the solvent was distilled off. The residue was purified by column chromatography using silica gel 60 (0.040-0.063 mm). The product was obtained as colourless oil (yield: 78%, 0.84 g, 4.34 mmol). GCMS (Methode „hart“) tR: 10.0 min; m/z: 194 [M]+ 1H NMR (400 MHz, CDCl3) 6.78 (d, J = 1.7 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.71 (dd, J = 7.9, 1.7 Hz, 1H), 5.94 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H). 13C NMR (101 MHz, CDCl3) 172.2, 147.9, 146.8, 127.6, 122.5, 109.8, 108.4, 101.2, 52.2, 40.9. HRMS of C10H10O4+ (APCI+) [M]+: calc.: 194.0574, found: 194.0573. The analytical data are consistent with the literature.[8] 11 5-(Methoxycarbonylmethoxy)-1,3-benzodioxole O O O O O 5-(Carboxymethoxy)-1,3-benzodioxole (0.53 g, 2.7 mmol, 1 equivalent) was dissolved in methanol in a 50 mL round-bottomed flask. p-Toluenesulfonic acid monohydrate (0.11 g, 0.64 mmol, 0.2 equiv.) was added with stirring. After one hour the solvent was distilled off. The residue was purified by acid chromatography using silica gel 60 (0.040-0.063 mm). The product precipitated as a colorless crystalline solid (yield: 83%, 0.47 g, 2.23 mmol). GCMS (Methode „hart“) tR: 11.0 min; m/z: 210 [M]+ 1H NMR (400 MHz, CDCl3) 6.96 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 6,31 (dd, J = 8.5, 2.6 Hz, 1H), 5.92 (s, 2H), 4.56 (s, 2H), 3.80 (s, 3H). 13C NMR (101 MHz, CDCl3) 169.6, 153.4, 148.5, 142.6, 108.0, 106.0, 101.5, 98.7, 66.5, 52.4. HRMS of C10H10O5+ (APCI+) [M]+: calc.: 210.0523, found: 210.0519 . The analytical data are consistent with the literature.[9] 12 5-(2,2-Dimethylethyl)-1,3-benzodioxole O O To a solution of 4-(2-methyl-2-propanyl)-1,2-benzenediol (2.06 g, 12,39 mmol, 1 equiv.) in DMSO (25 mL), an aqueous sodium hydroxide solution (2.04 g, 51 mmol, 4 equiv.) was slowly added at 90 °C. After heating for two hours at 90 °C, diiodomethane (2.5 mL, 31 mmol, 2.5 equiv.) was added. After a further two hours, the reaction mixture was extracted with ethyl acetate and then purified by column chromatography using silica gel 60 (0.040-0.063 mm). The product was obtained as colourless oil (yield: 39%, 0.87 mg, 4.86 mmol). 1H NMR (400 MHz, CDCl3) 6.97-6.96 (m, 1H), 6.82-6.77 (m, 2H), 5.95 (s, 2H), 1.23 (s, 9H). 13C NMR (101 MHz, CDCl3) 147.1, 144.8, 144.8, 117.6, 107.5, 106.2, 100.6, 34.3, 31.3. HRMS of C11H14O2+ (APCI+) [M]+: calc.:178.0988, found: 178.0985. The analytical data are consistent with the literature.[10] 13 5-Cyano-6-methyl-1,3-benzodioxole N O H O3C 6-Bromo-5-cyano-1,3-benzodioxole (0.5 g, 2.2 mmol, 1.0 eq), trimethylboroxine (304 mg, 2,4 mmol, 1.1 equiv.), Pd(dppf)Cl2 (82 mg, 5 mol%) was dissolved in 1,4-dioxane (9 mL) and water (1 mL). Cs2CO3 (1.1g, 3.4 mmol, 1.5 equiv) was added to the solution and the reaction was stirred for 16 h at 110 °C. The reaction mixture was filtered and concentrated in vacuo. Purification by column chromatography using silica gel 60 (0.040-0.063 mm) and a gradient (cyclohexan/ethyl acetate 97/3) at a flow of 12.5 mL/min yielded 280 mg of the desired product as a white solid (yield: 78%, 270 mg, 1.7 mmol). 1H NMR (400 MHz, CDCl3) 6.96 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) 151.6, 146.0, 138.6, 118.5, 111.2, 110.5, 104.6, 102.2, 20.6. HRMS of C9H8NO2+ (ESI+) [M]+: calc.:162.0550, found: 162.0550. 14 2-(1,1-Dimethylethyl)-1,3-benzodioxole O O To Catechol (5 g, 46 mmol, 1 eq.) in toluene (50 mL) was added pivaldehyde (4 g, 46 mmol, 1 eq.) and p-toluenesulfonic acid monohydrate (0.1 g, 0.5 mmol, 0.01 eq.) re- fluxed for 3 h using a Dean-Stark trap. After completion of the reaction, toluene was evaporated and the residue was purified by column chromatography using silica gel 60 (0.040-0.063 mm) and a gradient (cyclohexan/ethyl acetate 90/10) at a flow of 45.0 mL/min. This yielded 0.5 g of the desired product as a white solid (yield: 11%, 500 mg, 2.8 mmol). 1H NMR (400 MHz, CDCl3) 6.78 (s, 1H), 5.75 (s, 0H), 1.05 (s, 3H). 13C NMR (101 MHz, CDCl3) 148.4, 121.2, 117.1, 108.1, 35.8, 23.6. HRMS of C11H8NO2+ (ESI+) [M]+: calc.:179.1065, found: 179.1067. 15 5.2. Synthesis of HFIP-Orthoesters 5-Chloro-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (1) F F F F Cl O F O F O The compound was synthesized according to GPI. The product was obtained as a colourless oil (51 mg, 0.16 mmol, yield: 30%). 1H NMR (400 MHz, DMSO-d6) 7.44 (s, 1H), 7.36 (d, J = 2.1, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.22 (hept, J = 6.3 Hz, 1H) 13C NMR (101 MHz, DMSO-d6) 145.0, 143.3, 126.4, 122.6, 119.1, 110.3, 110.2, 69.7 (hept, J = 33.2 Hz). 19F NMR (376 MHz, DMSO-d6) = -74.28, -74.30. HRMS of C10H535ClF6O3+ (APCI+) [M]+: calc.: 321.9826, found: 321.9826. 16 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-cyano-6-methyl-1,3-benzodiox- ole (2) N O O F O F F F F F The compound was synthesized according to GPI. The product was obtained as col- ourless wax (54 mg, 0.17 mmol, 33%). 1H NMR (400 MHz, DMSO-d6) 7.64 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 6.26 (hept, J = 6.3 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 147.9, 142.6, 139.2, 119.3, 117.7, 112.3, 111.3, 105.0, 69.7 (hept, J = 33.2 Hz), 19.9. 19F NMR (376 MHz, DMSO-d6) -74.31, -74.32. HRMS of C12H7F6NO3+ (APCI+) [M+H]+: calc.: 327.0325, found: 327.0313. 17 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethyl)-1,3- benzodioxole (3) F F F F O O F O F O O The compound was synthesized according to GPI. The product was obtained as a colourless oil (36 mg, 0.10 mmol, yield: 19%). 1H NMR (400 MHz, DMSO-d6) 7.35 (s, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.90 (dd, J = 8.1 Hz, 1H), 6.19 (hept, J = 6.3 Hz, 1H), 3.66 (s, 2H), 3.61 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 171.6, 144.0, 143.0, 129.3, 123.8, 122.5, 119.6, 118.6, 110.5, 108.9, 69.7 (hept, J = 33.2 Hz) , 51.7, 40.2. 19F NMR (376 MHz, DMSO-d6) = -74.30, -74.32. HRMS of C13H10F6O5+ (APCI+) [M]+: calc.: 360.0432, found: 360.0425. 18 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-methoxy-1,3-benzodioxole (4) F F F F O F O F O The compound was synthesized according to GPI. The product was obtained as col- ourless oil (24 mg, 0.083 mmol, yield: 16%). 1H NMR (400 MHz, DMSO-d6) 7.35 (s, 1H), 7.18-7.13, (m, 2H), 7.03-6.99 (m, 2H), 6.19 (hept, J = 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) 144.0, 122.9, 118.2, 109.5, 109.4, 69.7 (hept, J = 33.2 Hz). 19F NMR (376 MHz, DMSO-d6) = -74.28, -74.30. HRMS of C10H6O6F3+ (APCI+) [M]+: calc.: 288.0221, found: 288.0212. 19 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole (5) F F F F O F O F O The compound was synthesized according to GPI. The product was obtained as col- ourless oil (64 mg, 0.21 mmol, yield: 39%). 1H NMR (400 MHz, DMSO-d6) 7.30 (s, 1H), 7.04-6.97 (m, 2H), 6.80 (m, 1H), 6.15 (hept, J = 6.3 Hz, 1H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 144.0, 141.9, 132.4, 122.8, 118.3, 110.0, 108.8, 69.7 (hept, J = 33.2 Hz), 20.7. 19F NMR (376 MHz, DMSO-d6) = -74.28, -74.30. HRMS of C11H8F6O3+ (APCI+) [M]+: calc.: 302.0372, found: 302.0379. Boiling point: 49 °C (1.2 mbar). Boiling point starting material: 49 °C (2.0 mbar). 20 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(1,1-dimethylethyl)-1,3-benzodi- oxole (6) F F F F O F O F O The compound was synthesized according to GPI. The product was obtained as a slightly greenish oil (48 mg, 0.14 mmol, yield: 28%). 1H-NMR (400 MHz, DMSO-d6) 7.31 (s, 1H,), 7.19 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.5 Hz, 1H), 6.17 (hept, J = 6.3 Hz 1H), 1.26, (s, 9H). 13C-NMR (101 MHz, DMSO-d6) 146.1, 144.1, 141.7, 119.0, 118.6, 108.3, 106.8, 69.8 (hept, J = 33.2 Hz), 34.6 , 31.3. 19F-NMR (376 MHz, DMSO-d6) = -74.27, -74.29. HRMS von C14H14F6O3+ (APCI+) [M]+: calc.: 344.0842, found: 344.0842. 21 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2-(1,1-dimethylethyl)-1,3-benzodi- oxole (7) O O O F F F F F F The compound was synthesized according to GPI. The product was obtained as col- ourless oil (53 mg, 0.15 mmol, yield: 30%). 1H NMR (400 MHz, DMSO-d6) 7.06 (dd, J = 5.8, 3.3 Hz, 1H), 6.93 (dd, J = 5.8, 3.3 Hz, 1H), 5.47 (hept, J = 6.0 Hz, 1H), 1.04 (s, 5H). 13C NMR (101 MHz, DMSO-d6) 147.7, 146.1, 130.2, 122.3, 121.2, 116.1, 108.4, 107.9, 68.0 (hept, J = 33.2 Hz), 40.6, 23.3. 19F NMR (376 MHz, DMSO-d6) -73.54, -73.56. HRMS von C14H14F6O3+ (APCI+) [M]+: berechnet: 344.0847, gefunden: 344.0845. 22 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methoxy-1,3-benzodioxole (8) F F F F O O F O F O The compound was synthesized according to GPI. The product was obtained as a colourless oil (45 mg, 0.14 mmol, yield: 28%). 1H NMR (400 MHz, DMSO-d6) 7.31 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.6, 2.5 Hz, 1H), 6.14 (hept, J = 6.3, 1H), 3.71 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 155.5, 144.8, 138.0, 122.5, 119.7, 118.8, 109.0, 106.6, 97.5, 69.7 (hept, J = 33.2 Hz), 55.9. 19F NMR (376 MHz, DMSO-d6) = -74.34, -74.36. HRMS of C11H8F6O4+ (APCI+) [M]+: calc.: 318.0321, found: 318.0319. 23 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethoxy)-1,3- benzodioxole (9) F F O F F O O O F O F O The compound was synthesized according to GPI. The product was obtained as a colourless oil (7 mg, 0.02 mmol, yield: 4%). 1H NMR (400 MHz, DMSO-d6) 7.32 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.89 (m, 1H), 6.53 (m, 1H), 6.16 (hept, J = 6.3 Hz, 1H), 4.76 (s, 2H), 3.69 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 169.2, 153.7, 144.8, 138.5, 118.9, 109.6, 109.0, 107.6, 98.3, 69.7 (hept, J = 33.2 Hz), 65.4, 51.8. 19F NMR (376 MHz, DMSO-d6) = -74.27, -74.29. HRMS of C13H10F6O6+ (APCI+) [M]+: calc.: 376.0382 , found: 376.0384. 24 5-Allyl-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (10) F F F F O F O F O The compound was synthesized according to GPI. The product was obtained as a colourless oil (24 mg, 0.073 mmol, yield: 11%). 1H NMR (400 MHz, DMSO-d6) 7.32 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.0, 1.6 Hz, 1H), 6.17 (hept, J = 6.3 Hz, 1H), 5.98-5.88 (m, 1H), 5.10-5.01 (m, 2H), 3.32 (d, 2H). 13C NMR (101 MHz, DMSO-d6) 144.2, 142.4, 137.7, 135.0, 122.5, 118.4, 115.9, 109.5, 109.0, 69.6 (hept, J = 33.2 Hz), 48.6. 19F NMR (376 MHz, DMSO-d6) = -74.29, -74.31. HRMS of C13H10F6O3+ (APCI+) [M]+: calc.: 328.0534, found: 328.0525. 25 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxymethyl)-1,3-benzodiox- ole (11) F F F F O O F O F O The compound was synthesized according to GPI. The product was obtained as a colourless oil (50 mg, 0.15 mmol, yield: 31%). 1H NMR (400 MHz, DMSO-d6) 7.36 (s, 1H, 7.12-7.09 (m, 2H), 6.98-6.95 (m, 1H), 6.19 (hept, J = 6.3 Hz, 1H), 4.35 (s, 2H), 3.26 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 144.1, 143.4, 133.5, 118.5, 108.8, 73.2, 69.6 (hept, J = 33.2 Hz), 57.3. 19F NMR (376 MHz, DMSO-d6) = -74.29, -74.31. HRMS of C12H10F6O4+ (APCI+) [M]+: calc.: 331.0400, found: 331.0399. 26 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-(3,4-dimethoxyphenyl)butyl)- 1,3-benzodioxole (12) O O F O F F F O F F O The compound was synthesized according to GPI. The product was obtained as col- ourless wax (53 mg, 0.19 mmol, 38%). 1H NMR (400 MHz, DMSO-d6) 7.30 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 1.4 Hz, 1H), 6.83 – 6.78 (m, 2H), 6.75 (d, J = 1.9 Hz, 1H), 6.66 (dd, J = 8.0, 1.9 Hz, 1H), 6.16 (hept, J = 6.3 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 2.56 (t, J = 6.8 Hz, 2H), 2.53 (s, 2H), 1.54 (t, J = 6.8 Hz, 4H). 19F NMR (376 MHz, DMSO-d6) -74.28, -74.30. 13C NMR (101 MHz, DMSO-d6) 148.6, 146.8, 144.1, 142.1, 137.5, 134.7, 122.3, 120.0, 118.4, 112.2, 111.8, 109.3, 108.8, 69.7 (hept, J = 33.2 Hz)., 55.5, 55.3, 39.5, 34.6, 34.5, 30.8, 30.7. HRMS of C22H22F6O5+ (APCI+) [M]+: calc.: 480.1366, found: 480.1354. 27 Ethyl 9-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2,3-dimethoxyphenan- thro[2,3-d][1,3]dioxole-5-carboxylate (13) O O F F F O O F O O F O F The compound was synthesized according to GPI. The product was obtained as col- ourless crystals (155 mg, 0.076 mmol, 60%). 1H NMR (600 MHz, DMSO-d6) 8.66 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.60 (s, 1H), 6.35 (hept, J = 6.3, 5.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, DMSO-d6 , 143.9, 129.6, 128.7, 125.7, 125.6, 123.4, 123.2, 120.1, 119.1, 107.6, 106.1, 104.3, 102.4, 69.8, 60.9, 56.0, 55.3, 14.3. 19F NMR (377 MHz, DMSO-d6) -74.11, -74.14, -74.15, -74.17, -74.18, -74.20, -74.22, -74.24. HRMS of C12H19F6O7+ (APCI+) [M+H]+: calc.: 521.1029, found: 521.1029. Melting point: 204 °C. Crystal structure determination of 13: C23H18F6O7, Mr = 520.37 g/mol, colourless plates (0.03 x 0.05 x 0.11 mm³), P -1 (triklin), a = 9.4787 Å, b = 10.5740 Å, c = 12.0956 Å, V = 1078.2 Å3, z = 2, F(000) = 532, = 1.603 g/cm3, µ = 0.151 mm-1, Mo- K graphite monochromator, -80 °C, 9976 reflections, 3786 reflections, wR2 = 0.2474, R1 = 0.0859, 0.3 eÅ-3, -0.27 eÅ-3, GoF = 1.012; Single crystals for structure determination were obtained by recrystallization from ac- etone at room temperature. Surprisingly no / - stacking was observed. The HFIP – moieties interlock into each other. 28 Fig. S9: left: crystal structure of 13; right: Packing of 13 in the solid state. 29 5.3. Synthesis of TFE-Orthoesters 5-Chlor-2-(2,2,2-trifluorethoxy)-1,3-benzodioxole (14) F Cl O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (33 mg, 0.13 mmol, yield: 25%). 1H NMR (400 MHz, DMSO-d6) 7.32 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4, 2.1 Hz 1H), 4.40 (q, J = 9.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) 145.7, 144.0, 125.8, 124.6, 122.7, 122.0, 119.0, 109.8, 109.7, 61.5 (q, J = 34.6 Hz). 19F NMR (376 MHz, DMSO-d6) = -74.05, -74.05, -74.10. HRMS of C9H6Cl35F3O3+ (APCI+) [M]+: calc.: 253.9958, found: 253,9938. 30 2-(2,2,2-Trifluorethoxy)-5-methyl-1,3-benzodioxole (15) F O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (39 mg, 0.17 mmol, yield: 33%). 1H NMR (400 MHz, DMSO-d6) 7.20 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.34 (q, J = 9.0 Hz, 2H), 2.25 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 144.7, 142.6, 122.2, 121.4, 118.0, 109.6, 108.3, 61.2 (q, J = 34.6 Hz), 20.7. 19F NMR (376 MHz, DMSO-d6) = -74.04, -74.06, -74.08. HRMS of C10H9F3O3+ (APCI+) [M]+: calc.: 234.0498, found: 234.0496. 31 2-(2,2,2-Trifluorethoxy)-5-(1,1-dimethylethyl)-1,3-benzodioxole (16) F O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (33 mg, 0.12 mmol, yield: 23%). 1H NMR (400 MHz, DMSO-d6) 7.20 (s, 1H), 7.12 (m, 1H), 6.95-6.93 (m, 2H), 4.36 (q, J = 9.0 Hz, 2H), 1.25 (s, 9H). 13C NMR (101 MHz, DMSO-d6) 145.6, 144.7, 142.2, 118.4, 118.2, 107.9, 106.4, 49.0 61.3 (q, J = 34.6 Hz), 34.5, 31.4. 19F NMR (376 MHz, DMSO-d6) = -74.02, -74.05, -74.07. HRMS of C13H15F3O3+ (APCI+) [M]+: calc.: 276.0968, found: 276.0971. 32 2-(2,2,2-Trifluoroethoxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (17) O O O F F F The compound was synthesized according to GPII. The product was obtained as col- ourless oil (53 mg, 0.15 mmol, 29%). 1H NMR (400 MHz, DMSO-d6) 7.04 (dd, J = 5.7, 3.3 Hz, 2H), 6.91 (dd, J = 5.8, 3.3 Hz, 2H), 4.01 (q, J = 8.9 Hz, 2H), 1.04 (s, 9H). 13C NMR (101 MHz, DMSO-d6) 146.2, 130.0, 122.0, 108.0, 60.0 (q, J = 34.6 Hz), 59.7, 59.3, 59.0, 40.0, 23.5. 19F NMR (376 MHz, DMSO-d6) -73.82, -73.84, -73.87. HRMS of C13H15F3O3+ (APCI+) [M]+: calc.: 276.0968, found: 276.0967. 33 2-(2,2,2-Trifluorethoxy)-5-methoxy-1,3-benzodioxole (18) F O O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (33 mg, 0.13 mmol, 26%). 1H NMR (400 MHz, DMSO-d6) 7.20 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.6, 2.5 Hz, 1H), 4.35 (q, J = 9.0 Hz, 2H), 3.70 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 155.6, 145.9, 139.1, 125.5, 122.8, 118.9, 106.4, 97.6, 61.7 (q, J = 34.6 Hz), 56.3. 19F NMR (376 MHz, DMSO-d6) = -74.03, -74.06, -74.08. HRMS of C10H9F3O4+ (APCI+) [M]+: calc.: 250.0447, found: 250.0441. 34 2-(2,2,2-Trifluorethoxy)-5-(methoxymethyl)-1,3-benzodioxole (19) F O O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (20 mg, 0.076 mmol, 15%). 1H NMR (400 MHz, DMSO-d6) 7.25 (s, 1H), 7.04-7.01 (m, 2H), 6.92-6.89 (m, 1H), 4.41-4.34 (q, J = 9.0 Hz, 2H), 4.33 (s, 2H), 3.25 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 145.2, 144.5, 133.3, 125.5, 122.7, 122.2, 118.7, 108.9, 73.7, 61.8 (q, J = 34.6 Hz), 57.7. 19F NMR (376 MHz, DMSO-d6) = -74.06, -74.08, -74.11. HRMS of C11H11F3O4+ (APCI+) [M]+: calc.: 264.0609, found: 264.0611. 35 2-(2,2,2-Trifluorethoxy)-1,3-benzodioxole (20) F O F O F O The compound was synthesized according to GPII. The product was obtained as col- ourless oil (29 mg, 0.13 mmol, yield: 26%). 1H NMR (400 MHz, DMSO-d6) 7.24 (s, 1H), 7.07 (m, 2H), 6.95 (m, 2H), 4.37 (q, J = 9.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) 144.6, 125.1, 122.4, 117.9, 108.9, 61.3 (q, J = 34.6 Hz). 19F NMR (376 MHz, DMSO-d6) = -74.05, -74.08, -74.10. HRMS of C9H7F3O3+ (APCI+) [M]+: calc.: 220.0366, found: 220.0344. 36 2-(2,2,2-Trifluoroethoxy)-2-(4-isopropylphenyl)-1,3-benzodioxole (21) O O O F F F The compound was synthesized according to GPII. The product was obtained as col- ourless oil (64 mg, 0.19 mmol, yield: 38%). 1H NMR (400 MHz, DMSO-d6) 7.53 – 7.46 (m, 2H), 7.38 – 7.31 (m, 2H), 7.11 (dd, J = 5.8, 3.3 Hz, 2H), 6.98 (dd, J = 5.8, 3.3 Hz, 2H), 4.26 (q, J = 8.9 Hz, 2H), 2.90 (h, J = 6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) 151.4, 145.7, 133.2, 127.1, 125.7, 125.6, 122.9, 109.2, 61.2 (q, J = 34.6 Hz)., 60.9, 60.5, 60.2, 33.7, 24.1. 19F NMR (376 MHz, DMSO-d6) -73.63, -73.66, -73.68. HRMS of C18H18F3O3+ (ESI+) [M+H]+: calc.: 339.1203, found: 339.1199. 37 5.4. Synthesis of OFP-orthoesters 5-Methyl-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole (22) F F FO F H O O F F F F The compound was synthesized according to GPIII. The product was obtained as yel- lowish oil (31 mg, 0.09 mmol, yield: 17%). 1H NMR (400 MHz, DMSO-d6) 7.22 (s, 1H), 7.05 (tt, J = 50.1 Hz, 5.6 Hz, 1H), 6.74 (ddd, J = 8.0, 1.6, 0.9 Hz, 1H), 4.40 (tt, J = 14.7, 1.6 Hz, 2H), 2.25 (s, 3H). 13 110.9, 110.6, 110.0, 108.8, 108.4, 61.1 (t, J = 26.9 Hz), 21.2. 19F NMR (376 MHz, DMSO-d6) -120.41 – -120.69 (m), -125.80 (t, J = 8.6 Hz), -130.91 (tq, J = 11.8, 5.55 Hz), -139.67 (dp, J = 50.3, 7.3 Hz). HRMS of C13H10F8O3+ (APCI+) [M+]: calc.: 366.0497, found: 366.501. 38 5-Chloro-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole (23) F Cl O F F F H O O F F F F The compound was synthesized according to GPIII. The product was obtained as yel- lowish oil (29 mg, 0.08 mmol, yield: 15%). 1H NMR (400 MHz, DMSO-d6) 7.33 (s, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.06 (tt, J = 50.3, 5.6 Hz, 1H), 7.01 (dd, J = 8.4, 2.1 Hz, 1H), 4.47 (t, J = 14.5 Hz, 2H). 13C NMR (101 MHz, DMSO) 146.1, 144.4, 126.3, 122.5, 119.5, 110.2, 110.2, 86.5, 61.5 (t, J = 26.9 Hz). 19F NMR (376 MHz, DMSO-d6) -120.56 (p, J = 13.4, 12.5 Hz), -125.74 (t, J = 8.8 Hz), -130.88 (dq, J = 11.2, 5.7 Hz), -139.64 (dq, J = 51.9, 8.4, 6.9 Hz). HRMS of C12H7ClF8O3+ (APCI+) [M+]: calc.: 385,9956, found: 385,9955. 39 5.5. Orthocarbonates 2,2-Bis(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole F F F F F F O O O O F F F F F F This compound was isolated as a side component in the reaction to 5 using 4 F applied charge. (2 mg were isolated and characterized). 1H NMR (400 MHz, DMSO-d6) 7.14 – 7.08 (m, 1H), 6.91 (ddd, J = 8.1, 1.7, 0.8 Hz, 1H), 6.29 (hept, J = 5.9 Hz, 1H). HRMS of C14H8F14O4+ (APCI+) [M+]: calc.: 468,0231, found: 468,0230. 40 5.6. Further functionalizations of HFIP-orthoesters 5-Bromo-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-6-methyl-1,3-benzodiox- ole (24) F F F F O F O F Br O Bromine (60 mg, 0.38 mmol, 1.5 equiv.) was added dropwise to a solution of 2-(1-Tri- fluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole (76 mg, 0.25 mmol, 1.0 equiv.) and pyridine (79 mg, 0.5 mmol, 2.0 equiv.) in CH2Cl2 (2 mL) at 0 °C. It was then allowed to warm up to r.t. and stirred for 48 h at r.t.. The reaction was quenched with saturated NaHCO3-solution. The phases were separated and the or- ganic phase dried over anhydrous sodium sulfate. The crude mixture was concen- trated under reduced pressure and purified by column chromatography on basic alu- miniumoxide (0.05-0.15 mm; pH 9.5±0.5) to yield the product as a colourless oil (65 mg, 0.17 mmol, 68% yield). 1H NMR (400 MHz, DMSO-d6) 7.45 (s, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 6.19 (hept, J = 6.3 Hz, 1H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO-d6 143.6, 132.1, 122.9, 119.3, 115.9, 113.3, 111.9, 70.3, 70.0, 69.7, 22.8. 19F NMR (376 MHz, DMSO-d6) -74.25, -74.27. HRMS of C11H779BrF6O3+ (APCI+) [M+]: calc.: 379.9483, found: 379.9487. C11H781BrF6O3+ (APCI+) [M+]: calc.: 381.9462, found: 379.9461. 41 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-methoxyphenyl)-6-methyl- 1,3-benzodioxole (25) F F F F O F F O O O A mixture of 5-bromo-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-6-methyl-1,3-ben- zodioxole (90 mg, 0.24 mmol, 1.0 equiv.), 4-methoxyphenylboronic acid (53.8 mg, 0.35 mmol, 1.50 equiv.), Pd(dppf)Cl2 (8.6 mg, 0.012 mmol, 0.050 equiv.) and Cs2CO3 (153.8 mg, 0.47 mmol, 2.0 equiv.) in 1,2-dimethoxyethane was heated to 75 °C for 6 h under an argon atmosphere. After cooling to r.t., the mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with NaOH solu- tion (1 M) three times (10 mL) and was then dried over sodium sulfate. After removal of the solvent in vacuo, the residue was purified by column chromatography using sil- ica gel (eluent: cyclohexane/EtOAc: 99/1) to afford the desired product as a colour- less wax (65 mg, 0.15 mmol, 64% yield). 1H NMR (400 MHz, CDCl3) 7.22 – 7.17 (m, 2H), 6.97 (s, 1H), 6.96 – 6.92 (m, 2H), 6.88 (s, 1H), 6.85 (s, 1H), 4.58 (hept, J = 5.8 Hz, 1H), 3.85 (s, 3H), 2.21 (s, 3H). 13C NMR (101 MHz, CDCl3) 158.6, 143.5, 142.7, 136.2, 133.6, 130.3, 117.4, 113.6, 110.64, 110.6, 110.0, 69.3 (p, J = 34.3 Hz), 55.3, 20.5. 19F NMR (376 MHz, CDCl3) -74.57, -74.58. HRMS of C18H14F6O4+ (APCI+) [M+]: calc.: 408.0801, found: 408.0796. 42 5.7. Optimization of reaction parameters Table S1: (left) and Fig. S10 (right): Yield (%) as a function of current density (mA/cm2). current density [mA/cm2] yield 1 0% 2.5 3% 5 11% 7.2 30% 10 21% 15 24% 20 22% 30 22% 50 22% 70 21% 90 23% Table S2: Optimized parameters: substrate concentration, applied charge and electrode material concentration yield applied [mol/L] charge [F] yield electrode yield 0.40 10% 2.2 19% BDD 30% 0.20 13% 2.4 25% Nickel 2% 0.11 19% 2.6 25% Graphite 23% 0.07 18% 2.8 26% Glassy carbon 27% 3.0 30% Molybdenum 0% 4.0 13% 43 6. Lipophilicity: LogP – Values of 1,3-benzodioxoles and the corresponding orthoesters SlogP values: Products: F FO F F O F F F N F O F F F O OO O F OCl O F O F F O F O F O F F F O F F 1 2 F F O 13 12O . 2.0687 F F 3.4313 O 5.7515 O 5 8337F F F F F F F F O O F O F Cl O F O F O F O F O F O FO O O O O 3 4 14 15 2.9667 3.2512 2.9737 2.6287F F F F F F F F F O O F O F O F O F O F O F O O O FO 6 O F 5 17 F 3.5596 4.5487 F F 16 F F 3.6178 3.7366O O O F F F O O F O O F O O FO F F O O F O F F F O O 7 F F 8 18 19 4.6675 F F 3.2598 F F 2.3289 2.7331 O F F F F F O F O O O F O F O O F O F O F O O O O O F 9 10 20 21 F F 2.8030 3.9797 2.303 5.2821 F F F F O O F F F H C FO F 3 O F Cl F F F O F O O O O F F 11 F F O F F F F 3.6640 22 23 4.5824 4.2374 Starting materials: N O Cl O O O O O O O O O O 1 2 9 10 2.0687 1.5954 0.9671 2.1438 O O OO O O O O OO O 3 4 11 12 1.1308 1.4153 1.8281 O 3.9978 O O O O O O O O 6 O O 5 O 1.7237 2.7128 O 13 21 O 3.9156 4.3755 O O O O O 7 8 2.8300 1.4239 Fig. S11: slogP-values, calculation according to S.A. Wildman, G.M. Crippen, Prediction of Physiochem- ical Parameters by Atomic Contributions, J. Chem. Inf. Comput. Sci. 1999, 39, 868–873. 44 7. NMR spectra CH3 O O O 6.8 6.7 6.6 6.5 6.4 6.3 6.2 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Methoxy-1,3-benzodioxole. CH3 O O O 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Methoxy-1,3-benzodioxol. 6.72 6.70 6.50 6.49 155.3 6.33 148.4 6.33 7.26 CDCl3 6.31 6.72 141.7 6.31 6.70 6.50 6.49 1.00 6.33 0.96 6.33 1.05 6.31 6.31 2.11 5.91 108.0 104.8 101.2 97.6 77.2 CDCl3 3.75 HDO 3.20 3.75 56.1 45 H3C O O O 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-(Methoxymethyl)-1,3-benzodioxole. H3C O O O 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-(Methoxymethyl)-1,3-benzodioxole. 7.26 CDCl3 6.85 6.84 3.01 147.9 6.84 147.2 6.84 6.80 6.78 6.78 132.2 2.03 6.78 6.76 5.95 121.5 108.6 108.2 101.1 2.02 4.35 77.2 CDCl3 74.7 2.99 3.35 57.9 46 CH3 O O O O ethyl acetate 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-(Methoxycarbonylmethyl)-1,3-benzodioxole. CH3 O O O O 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-(Methoxycarbonylmethyl)-1,3-benzodioxole. 172.2 7.26 CDCl3 1.00 6.78 6.78 147.9 1.05 1.05 6.77146.8 6.75 6.72 6.72 6.70 2.06 6.70 127.6 5.94 122.5 109.8 108.4 101.1 4.17 4.15 4.13 4.12 3.02 3.69 77.2 CDCl3 2.06 3.53 52.2 40.9 1.65 1.27 1.25 1.23 47 O H3C O O O O 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-(Methoxycarbonylmethoxy)-1,3-benzodioxole. O H3C O O O O 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-(Methoxycarbonylmethoxy)-1,3-benzodioxole. 169.6 7.26 CDCl3 6.70 6.68 6.53 153.4 6.53 148.5 0.97 6.32 142.6 0.92 6.32 1.00 6.30 6.29 1.96 5.92 108.0 106.0 101.5 2.06 4.56 98.7 3.03 3.80 77.2 CDCl3 66.5 52.4 48 CH3 H3C O H3C O 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 chemical shift (ppm) 1H NMR of 5-(2,2-Dimethylethyl)-1,3-benzodioxole. CH3 H3C O H3C O 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-(1,1-Dimethylethyl)-1,3-benzodioxole. 147.1 144.8 144.8 6.97 6.97 6.96 0.93 6.96 117.6 1.91 6.80 6.80 6.79 107.5 2.14 5.95 106.2 100.6 3.34 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 40.1 DMSO 9.35 1.23 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 34.3 31.3 49 N O H O3C 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Cyano-6-methyl-1,3-benzodioxole. N O H C O3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Cyano-6-methyl-1,3-benzodioxole. 151.62 146.03 7.26 CDCl3 138.55 1.00 6.96 6.73 1.03 2.15 6.02 118.48 111.18 110.53 104.58 102.22 3.25 2.46 20.59 50 O CH3 CH3 O CH3 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1,1-Dimethylethyl)-1,3-benzodioxole. O CH3 CH3 O CH3 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1,1-Dimethylethyl)-1,3-benzodioxole. 6.80 148.38 6.78 4.00 6.76 6.76 1.01 5.75 121.20 117.09 108.06 35.83 9.81 1.0523.59 51 Cl O O F O F F F F F 7.5 7.0 6.5 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Chlor-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (1). Cl O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Chlor-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (1). 7.44 7.36 7.36 7.19 7.17 7.08 7.08 7.06 7.44 7.06 7.36 7.36 0.97 7.19 0.91 7.17 1.01 7.08 1.02 7.08 7.06 7.06 145.0 6.27 6.27 143.3 6.26 6.26 6.24 1.06 6.246.22 6.22 6.21 6.21 6.19 6.19 126.4 6.18 6.18 122.6 119.1 110.3 110.2 3.35 HDO 69.7 2.51 DMSO 2.50 DMSO 2.50 DMSO 40.1 DMSO 2.50 DMSO 39.9 DMSO 2.49 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 52 Cl O O F O F F F F F -74.20 -74.25 -74.30 -74.35 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 5-Chlor-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (1). N O O F H3C O F F F F F 0.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-cyano-6-methyl-1,3-benzodioxole (2). -74.25 -74.27 -74.28 -74.30 0.99 7.64 1.09 7.51 1.04 7.31 6.29 6.27 6.26 1.15 -74.256.24 -74.27 6.23 -74.28 6.21 -74.30 3.34 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 3.18 2.50 DMSO-d6 2.50 DMSO 2.49 DMSO 2.44 53 N O O F H O F3C F F F F 00 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-cyano-6-methyl-1,3-benzodioxole (2). N O O F H C O F3 F F F F 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-cyano-6-methyl-1,3-benzodioxole (2). 147.91 142.64 139.16 -74.31 -74.32 119.32 117.73 112.33 111.32 105.03 70.43 70.10 69.77 69.44 69.11 19.90 54 CH3 O O O O F O F F F F F ethyl acetate 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethyl)-1,3-benzodioxole (3). CH3 O O O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethyl)-1,3-benzodioxole (3). 171.6 7.35 7.09 7.07 0.94 7.07 1.92 6.91 0.98 6.91 6.89 6.89 144.0 6.24 143.0 6.22 1.00 6.21 6.19 129.3 6.17 123.8 6.16 122.5 6.14 119.6 118.6 110.5 108.9 4.10 4.08 4.06 4.04 1.82 3.66 70.4 2.75 3.61 70.1 3.35 HDO 69.7 69.4 69.1 2.51 DMSO 2.50 DMSO 51.7 2.50 DMSO 40.2 2.50 DMSO 40.1 DMSO 2.49 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 1.39 39.1 DMSO 1.19 38.9 DMSO 1.18 1.16 55 CH3 O O O O F O F F F F F -74.24 -74.28 -74.32 -74.36 -74.40 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethyl)-1,3-benzodioxole (3). O O F O F F F F F 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (4). 7.35 7.35 7.18 7.18 7.17 7.17 7.16 7.16 -74.30 7.16 7.16 7.15 7.15 -74.32 7.14 7.14 7.13 7.13 7.13 7.13 7.03 7.03 7.03 7.03 7.02 7.02 1.00 7.01 7.01 1.98 7.01 7.01 1.99 7.00 7.00 6.99 6.99 6.99 6.99 6.22 6.23 6.20 6.22 1.04 6.19 6.20 -74.30 6.17 6.19 -74.32 6.15 6.17 6.14 6.15 6.14 3.35 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 56 O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (4). O O F O F F F F F -74.25 -74.30 -74.35 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (4). -74.28 -74.30 144.0 -74.28 -74.30 122.9 118.2 109.5 109.4 69.7 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 26.4 57 H3C O O F O F F F F F 7.0 6.5 6.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole (5). H3C O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole (5). 7.30 7.02 7.00 6.98 6.98 6.81 6.81 7.30 6.81 7.02 6.81 7.00 6.79 6.98 6.79 6.98 6.79 6.81 6.79 6.81 6.81 0.91 6.20 1.87 6.18 6.81 6.79 0.92 6.17 6.15 6.79 6.13 6.79 144.0 6.12 6.79 141.9 6.20 6.18 0.99 6.17 132.4 6.15 6.13 6.12 122.8 6.10 118.3 110.0 110.0 108.8 69.9 3.34 HDO 69.6 69.2 2.51 DMSO 2.50 DMSO 2.50 DMSO 40.1 DMSO 39.9 DMSO 2.89 2.50 DMSO 2.49 DMSO 39.7 DMSO 2.27 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 20.7 58 H3C O O F O F F F -74.25 -74.27 -74.29 -74.31 -74.33 F F chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole (5). CH3 H3C O H3C O F O F F F F F 7.0 6.5 6.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(1,1-dimethylethyl)-1,3-benzodioxole (6). -74.28 7.31 7.20 7.19 7.04 7.02 -74.30 7.00 7.00 7.31 6.98 7.20 6.98 7.19 1.00 7.04 1.00 7.02 1.04 7.00 1.03 7.00 6.98 6.98 6.22 6.22 6.21 6.21 6.19 6.19 -74.281.11 6.17 6.17 -74.30 6.16 6.16 6.14 6.14 6.13 6.13 3.33 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 9.20 1.26 59 CH3 H3C O H3C O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(1,1-dimethylethyl)-1,3-benzodioxole (6). CH3 H3C O H3C O F O F F F F F -74.20 -74.25 -74.30 -74.35 -74.40 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(1,1-dimethylethyl)-1,3-benzodioxole (6). 146.1 144.1 -74.27 141.7 -74.28 -74.29 119.0 118.6 108.3 106.8 -74.27 -74.28 -74.29 70.1 69.8 69.4 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 34.6 31.3 60 CH3 O CH3 CH3 O F O F F F F F 7.05 7.00 6.95 6.90 5.55 5.50 5.45 5.40 5.35 chemical shift (ppm) chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (7). CH3 O CH3 CH3 O F O F F F F F 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (7). 147.70 146.13 130.22 7.07 7.06 122.27 7.06 121.24 7.05 7.04 116.08 7.04 6.94 108.39 6.93 107.94 6.93 6.92 6.91 6.91 5.52 5.50 5.49 5.47 5.46 5.44 5.43 68.03 3.35 HDO 2.51 DMSO 2.50 DMSO 40.55 2.50 DMSO 2.50 DMSO 2.49 DMSO 23.25 1.04 61 H3C CH3 O CH3 O O F F 73.52 -73.53 -73.54 -73.55 -73.56 -73.57 -73.58 -73.59 chemical shift (ppm) F F F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (7). CH3 O O O F O F F F F F 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methoxy-1,3-benzodioxole (8). 7.31 -73.54 7.05 7.02 -73.56 6.85 6.84 6.54 6.53 7.31 6.52 7.05 6.51 7.02 1.00 6.19 6.85 1.02 6.18 6.84 0.98 6.16 6.54 6.14 6.53 1.04 6.13 6.52 6.11 6.51 6.10 6.19 -73.54 1.07 6.18 -73.56 6.16 6.14 6.13 6.11 6.10 2.96 3.71 3.35 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 62 CH3 O O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methoxy-1,3-benzodioxole (8). CH3 O O O F O F F F -74.30 -74.35 -74.40 F F chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methoxy-1,3-benzodioxole (8). -74.34 -74.36 155.5 144.8 -74.34 138.0 -74.36 122.5 119.7 118.8 109.0 106.6 97.5 70.3 70.0 69.7 69.3 69.0 55.9 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 63 CH3 O O O O O F O F F F F F 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 chemical shift (ppm) ethyl acetate 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethoxy)-1,3-benzodiox- ole (9). O H3C O O O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl))-5-(methoxycarbonylmethoxy)-1,3-benzodioxole (9). 7.32 7.05 7.03 6.89 6.89 6.88 6.55 7.32 6.54 7.05 6.54 7.03 6.53 169.2 6.896.52 6.89 6.52 6.88 1.07 6.55 1.16 6.20 6.54 153.7 0.99 6.18 6.54 6.16 6.53 6.15 144.8 6.526.13 6.52 6.12 138.5 6.21 1.26 6.20 6.18 6.16 6.15 6.13 118.9 6.12 109.6 109.0 107.6 4.762.30 4.74 98.3 4.18 4.16 4.15 4.13 2.79 3.69 70.0 3.35 HDO 69.7 69.4 65.4 2.51 DMSO 2.50 DMSO 51.8 2.50 DMSO 40.1 DMSO 2.50 DMSO 39.9 DMSO 2.49 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 1.39 38.9 DMSO 1.22 1.20 1.18 64 CH3 O O O O -74.20 -74.24 -74.28 -74.32 -74.36 -74.40 O F chemical shift (ppm) O F F F F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxycarbonylmethoxy)-1,3-benzodiox- ole (9). H2C O O F O F F F F F 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Allyl-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (10). 7.32 7.07 7.05 6.98 6.98 6.83 6.83 6.81 6.81 -74.27 6.21 -74.29 6.20 6.18 6.17 6.15 0.90 6.13 0.98 6.12 0.89 5.98 1.00 5.97 5.96 5.96 5.95 5.94 -74.27 0.99 5.92 -74.29 0.99 5.91 5.91 5.90 5.88 5.10 5.09 2.05 5.09 5.08 5.05 5.04 5.04 5.04 5.03 5.02 5.02 5.02 5.01 3.35 HDO 1.97 3.32 3.17 3.16 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 65 H2C O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Allyl-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (10). H2C O O F O F F F -74.22 -74.26 -74.30 -74.34 -74.38 -74.42 chemical shift (ppm) F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 5-Allyl-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-1,3-benzodioxole (10). -74.29 -74.31 144.2 142.4 -74.29 137.7 -74.31 135.0 122.5 118.4 115.9 109.5 109.0 70.0 69.6 69.3 48.6 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 66 H3C O O O F O F F F F F 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxymethyl)-1,3-benzodioxole (11). H3C O O O F O F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxymethyl)-1,3-benzodioxole (11). 7.36 7.12 7.10 7.10 7.09 6.98 6.97 6.96 6.95 7.36 7.12 7.10 7.10 1.00 7.09 2.06 6.98 1.04 6.97 6.23 6.96 6.22 6.95 144.1 6.20 6.23 143.4 6.19 6.22 1.09 6.17 6.20 133.5 6.16 6.19 6.14 6.17 122.5 6.16 122.2 6.14 119.7 118.5 108.8 2.04 4.35 73.2 70.3 70.0 3.34 HDO 69.6 3.05 3.26 69.3 69.0 2.51 DMSO 57.3 2.50 DMSO 2.50 DMSO 40.1 DMSO 2.50 DMSO 39.9 DMSO 2.49 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 67 H3C O O O F -74.22 -74.26 -74.30 -74.34 -74.38 O F chemical shift (ppm) F F F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(methoxymethyl)-1,3-benzodioxole (11). H3C O O H C O F F 3 O F O F F F 0.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H-NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-(3,4-dimethoxyphenyl)butyl)-1,3-benzo- dioxole (12). 7.30 7.03 7.01 6.99 6.99 6.83 6.81 -74.29 6.81 6.79 -74.31 6.79 6.76 1.00 6.75 1.01 6.68 0.97 6.67 2.09 1.07 6.66 1.05 6.65 6.21 -74.29 1.06 6.20 -74.31 6.18 6.16 6.15 6.13 6.12 2.97 3.71 3.07 3.69 3.35 2.58 2.56 2.14 2.55 2.00 2.53 2.50 DMSO-d6 1.56 1.55 4.18 1.54 1.53 1.52 68 H3C O O H3C O O F O F F F F F 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-(3,4-dimethoxyphenyl)butyl)-1,3-benzo- dioxole (12). H3C O -74.25 -74.27 -74.29 -74.31 -74.33 -74.35 O O F F chemical shift (ppm) H3C O F O F F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F-NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-(3,4-dimethoxyphenyl)butyl)-1,3-benzo- dioxole (12). -74.28 -74.30 148.58 146.84 144.07 142.05 -74.28 137.50 -74.30 134.68 122.26 119.97 118.42 112.16 111.82 109.32 108.79 70.33 70.00 69.68 69.35 69.02 55.50 55.34 39.52 DMSO-d6 34.62 34.50 30.81 30.69 69 CH 3 CH O 3 O O O CH 3 F F O 8.5 8.0 7.5 7.0 6.5 chemical shift (ppm) F O O F F F 0.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of Ethyl 9-(1-Trifluoromethyl-(2,2,2-trifluoroethyl))-2,3-dimethoxyphenanthro[2,3-d][1,3]diox- ole-5-carboxylate (13). CH3 CH3 O O O O CH3 F F O F O O 150 145 140 135 130 125 120 115 110 105 100 F chemical shift (ppm) F F 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 chemical shift (ppm) 13C NMR of Ethyl 9-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2,3-dimethoxyphenanthro[2,3-d][1,3]di- oxole-5-carboxylate (13). 8.66 8.43 8.36 8.66 1.00 8.15 0.99 8.43 1.11 8.36 1.00 7.86 8.15 0.97 7.86 0.97 7.60 7.60 167.17 6.38 149.30 6.37 6.38 146.65 6.36 6.37 149.30 143.92 6.35 6.36 146.65 129.62 6.34 1.04 6.35 143.92 128.65 6.33 6.34 125.68 6.32 6.33 125.63 6.32 123.42 123.17 129.62 120.14 128.65 119.10 125.68 107.55 125.63 106.07 4.46 123.42 104.29 4.45 123.17 102.40 2.04 4.44 120.14 4.43 119.10 3.03 4.04 2.94 3.91 107.55 106.07 69.84 104.29 60.92 102.40 55.97 55.26 1.44 3.15 1.43 14.32 1.42 70 CH3 CH3 O O O O -74.05 -74.15 -74.25 -74.35 chemical shift (ppm) CH3 F F O F O O F F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of Ethyl 9-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-2,3-dimethoxyphenanthro[2,3-d][1,3]di- oxole-5-carboxylate (13). Cl O O F O F F 7.4 7.3 7.2 7.1 7.0 6.9 4.50 4.45 4.40 4.35 4.30 4.25 chemical shift (ppm) chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Chlor-2-(2,2,2-trifluorethoxy)-1,3-benzodioxole (14). 7.32 7.25 7.25 7.11 -74.11 7.09 -74.14 7.02 -74.15 7.02 7.32 -74.17 7.00 7.25 -74.18 1.00 7.00 7.25 -74.20 0.91 7.11 -74.22 1.03 7.09 7.02 -74.241.00 7.02 -74.11 7.00 7.00 -74.14 -74.15 -74.17 -74.18 -74.20 -74.22 -74.24 4.44 4.42 4.39 4.37 4.44 4.42 2.23 4.39 4.37 3.33 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 1.39 71 Cl O O F O F F 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 chemical shift (ppm) 13C NMR of 5-Chlor-2-(2,2,2-trifluorethoxy)-1,3-benzodioxole (14). Cl O O F O F F -73.7 -73.8 -73.9 -74.0 -74.1 -74.2 -74.3 -74.4 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 5-Chlor-2-(2,2,2-trifluorethoxy)-1,3-benzodioxole (14). -74.05 -74.07 -74.10 148.3 146.5 145.7 -74.05 144.0 -74.07 125.8 -74.10 125.0 124.6 122.7 122.0 121.3 119.0 109.8 109.7 109.3 109.3 101.9 61.8 61.6 61.4 61.1 39.9 DMSO 39.8 DMSO 39.7 DMSO 39.5 DMSO 39.4 DMSO 39.2 DMSO 39.1 DMSO 26.4 72 H3C O O F 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 O F chemical shift (ppm) F 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluorethoxy)-5-methyl-1,3-benzodioxole (15). H3C O O F O F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-Trifluorethoxy)-5-methyl-1,3-benzodioxole (15). 7.20 7.20 6.94 6.92 6.90 6.90 6.79 6.77 6.94 6.76 6.92 6.75 6.90 6.75 6.90 6.75 6.79 6.74 6.77 6.73 6.75 6.73 6.73 6.73 1.00 6.73 6.63 1.07 6.63 6.63 1.03 6.63 6.63 1.24 6.61 6.63 144.7 6.61 6.61 142.6 6.61 6.61 6.61 131.8 5.94 122.2 121.4 118.0 109.6 108.3 4.38 4.35 2.30 4.33 4.31 3.33 HDO 61.7 61.4 61.0 2.51 DMSO 60.7 2.50 DMSO 2.50 DMSO 40.1 DMSO 2.50 DMSO 39.9 DMSO 3.14 2.49 DMSO 39.7 DMSO 2.25 39.5 DMSO 2.21 39.3 DMSO 39.1 DMSO 38.9 DMSO 20.7 73 H3C O O F -73.8 -73.9 -74.0 -74.1 -74.2 -74.3 O F chemical shift (ppm) F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluorethoxy)-5-methyl-1,3-benzodioxole (15). CH3 H3C O H3C O F O F F 1.00 1.04 2.02 2.36 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluorethoxy)-5-(2,2-dimethylethyl)-1,3-benzodioxole (16). 7.20 7.12 7.12 7.11 7.11 6.97 -74.04 6.96 -74.06 7.20 6.95 -74.08 7.12 6.94 7.12 6.94 7.11 6.94 7.11 1.00 6.92 6.97 1.04 6.92 6.96 2.02 6.95 6.94 6.94 6.94 6.92 -74.04 6.92 -74.06 -74.08 4.40 4.38 4.35 4.33 4.40 4.38 2.36 4.35 4.33 3.35 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 9.08 1.25 74 CH3 H3C O H3C O F O F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-Trifluorethoxy)-5-(2,2-dimethylethyl)-1,3-benzodioxole (16). CH3 H3C O H3C O F O F F -74.00 -74.02 -74.04 -74.06 -74.08 -74.10 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluorethoxy)-5-(2,2-dimethylethyl)-1,3-benzodioxole (16). -74.02 -74.05 -74.07 145.6 144.7 -74.02 142.4 -74.05 -74.07 118.4 118.2 107.9 106.4 61.9 61.5 61.2 60.8 49.0 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 34.5 31.4 75 CH3 O CH3 CH3 O O F F F 7.20 7.15 7.10 7.05 7.00 6.95 6.90 6.85 6.80 6.75 chemical shift (ppm) 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-trifluoroethoxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (17). CH3 O CH3 CH3 O O F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-trifluoroethoxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (17). 7.05 7.04 7.04 7.03 7.05 6.92 7.04 6.91 7.04 6.91 7.03 6.90 6.92 146.17 6.91 6.91 6.90 130.03 122.03 108.01 4.04 4.02 4.00 3.98 3.34 HDO 60.02 2.51 DMSO 59.68 2.50 DMSO 59.34 2.50 DMSO 58.99 2.50 DMSO 2.49 DMSO 39.99 23.53 1.04 76 H3C CH O 3 CH3 O O F -73.81 -73.82 -73.83 -73.84 -73.85 -73.86 -73.87 F chemical shift (ppm) F 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 chemical shift (ppm) 19F NMR of 2-(2,2,2-trifluoroethoxy)-2-(1,1-dimethylethyl)-1,3-benzodioxole (17). CH3 O O O F O F F 1.00 1.08 1.01 1.11 2.32 7.0 6.5 6.0 5.5 5.0 4.5 chemical shift (ppm) Cyclohexan 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluorethoxy)-5-methoxy-1,3-benzodioxole (18). 7.20 -73.82 6.97 6.94 6.76 6.76 6.49 6.48 -73.84 6.46 6.46 7.20 6.97 1.00 6.94 -73.87 1.08 6.76 1.01 6.76 1.11 6.49 6.48 6.46 6.46 -73.82 -73.84 -73.87 4.38 4.36 4.34 4.31 4.38 4.36 2.32 4.34 4.31 3.25 3.70 3.34 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 1.39 77 CH3 O O O F O F F cyclohexane 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-Trifluorethoxy)-5-methoxy-1,3-benzodioxole (18). CH3 O O O F O F -74.00 -74.05 -74.10 -74.15 chemical shift (ppm) F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluorethoxy)-5-methoxy-1,3-benzodioxole (18). -74.03 -74.06 -74.08 155.6 145.9 -74.03 139.1 -74.06 -74.08 125.5 122.8 118.9 108.9 106.4 97.6 62.2 61.9 61.5 61.2 56.3 40.6 DMSO 40.4 DMSO 40.2 DMSO 40.0 DMSO 39.8 DMSO 39.5 DMSO 39.3 DMSO 26.8 78 H3C O O O F O F F 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 chemical shift (ppm) cyclohexane 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluorethoxy)-5-(methoxymethyl)-1,3-benzodioxole (19). H3C O O O F O F F cyclohexane 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-Trifluorethoxy)-5-(methoxymethyl)-1,3-benzodioxole (19). 7.25 7.04 7.02 7.01 6.92 6.91 6.90 6.89 7.25 7.04 1.00 7.02 2.06 7.01 1.04 6.92 6.91 6.90 6.89 145.2 4.40 144.5 4.38 4.36 4.34 133.3 4.33 125.5 122.7 122.2 118.7 108.9 108.8 4.40 4.38 2.32 4.36 2.00 4.34 4.33 3.34 HDO 73.7 3.08 3.25 62.3 62.0 61.6 2.51 DMSO 61.3 2.50 DMSO 57.7 2.50 DMSO 40.6 DMSO 2.50 DMSO 40.4 DMSO 2.49 DMSO 40.2 DMSO 40.0 DMSO 39.8 DMSO 39.5 DMSO 39.3 DMSO 1.39 26.8 79 H3C O O -73.95 -74.00 -74.05 -74.10 -74.15 -74.20 -74.25 O F chemical shift (ppm) O F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluorethoxy)-5-(methoxymethyl)-1,3-benzodioxole (19). O O F O F F 1.00 2.05 2.11 2.31 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluorethoxy)-1,3-benzodioxole (20). 7.24 7.09 7.09 7.08 7.07 -74.06 7.07 -74.08 7.06 7.24 -74.11 7.05 7.09 7.05 7.09 6.98 7.08 6.97 7.07 6.96 7.07 6.96 7.06 1.00 6.95 7.05 2.05 6.94 7.05 2.11 6.93 6.98 6.93 6.97 6.96 6.96 6.95 -74.06 6.94 -74.08 6.93 -74.11 6.93 4.41 4.38 4.36 4.34 4.41 4.38 2.31 4.36 4.34 3.34 HDO 2.51 DMSO 2.50 DMSO 2.50 DMSO 2.50 DMSO 2.49 DMSO 1.39 80 O O F O F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(2,2,2-Trifluorethoxy)-1,3-benzodioxole (20). O O F O F F -74.05 -74.07 -74.09 -74.11 -74.13 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluorethoxy)-1,3-benzodioxole (20). -74.05 -74.08 -74.10 144.6 -74.05 -74.08 -74.10 125.1 122.4 117.9 108.9 61.9 61.5 61.2 60.8 40.1 DMSO 39.9 DMSO 39.7 DMSO 39.5 DMSO 39.3 DMSO 39.1 DMSO 38.9 DMSO 81 CH3 CH3 O O O 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 F chemical shift (ppm) F F 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(2,2,2-Trifluoroethoxy)-2-(4-isopropylphenyl)-1,3-benzodioxole (21). F F F O O O CH3 H3C 13C NMR of 2-(2,2,2-Trifluoroethoxy)-2-(4-isopropylphenyl)-1,3-benzodioxole (21). 7.51 7.52 7.51 7.51 7.50 7.51 7.49 7.50 7.49 7.49 7.37 7.49 7.36 7.37 7.35 7.36 7.34 7.35 7.34 7.34 1.91 7.12 7.34 2.01 7.11 7.13 1.85 1.90 7.11 7.12 7.10 7.11 151.42 6.99 7.11 145.65 6.98 7.10 6.97 7.09 133.21 6.97 7.00 127.11 6.99 125.69 6.98 125.57 6.97 122.93 6.97 6.96 109.24 4.30 4.28 1.92 4.25 4.23 3.34 HDO 61.21 2.96 60.86 2.941.00 60.51 2.93 60.17 2.91 2.89 2.88 2.86 2.51 DMSO 33.73 2.50 DMSO 2.50 DMSO 24.09 2.50 DMSO 5.97 2.49 DMSO 1.19 1.18 82 H3C CH3 O O O -73.61 -73.63 -73.65 -73.67 -73.69 -73.71 -73.73 F chemical shift (ppm) F F 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(2,2,2-Trifluoroethoxy)-2-(4-isopropylphenyl)-1,3-benzodioxole (21). H3C O F 7.3 7.2 7.1 7.0 6.9 6.8 6.7 O F F chemical shift (ppm)F O F F F F 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0. chemical shift (ppm) 1H NMR of 5-Methyl-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (22) 7.22 7.19 7.18 7.16 7.06 7.05 1.00 7.04 -73.63 0.29 0.56 6.95 2.25 6.94 1.06 6.93 -73.66 6.91 6.90 6.76 -73.68 6.75 6.75 6.75 6.74 6.73 6.73 6.73 -73.63 4.44 -73.66 4.44 -73.68 4.44 4.41 2.21 4.40 4.40 4.37 4.37 4.36 3.34 HDO 2.51 DMSO 2.51 DMSO 2.50 DMSO 2.50 DMSO 3.25 2.49 DMSO 2.25 83 H3C O O F F O F F F F F 150 140 130 120 110 100 F chemical shift (ppm) 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Methyl-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (22) H3C O F FO F F O F F F F -120 -122 -124 -126 -128 -130 -132 -134 -136 -138 -140 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 5-Methyl-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (22) 145.1 143.0 132.2 122.7 118.5 110.9 110.6 -120.49 110.0 -120.52 108.8 -120.55 145.1108.4 -120.56 143.0 -120.59 -120.63 132.2 -125.78 122.7 -125.80 118.5 -125.82 110.9 -130.84 110.6 -130.85 110.0 -130.87 108.8 -130.89 108.4 -130.90 -130.92 -130.93 1.00 0.97 -130.95 0.97 -130.96 -130.97 -139.55 0.96 -139.56 -139.58 61.4 -139.60 61.1 -139.62 60.9 -139.64 -139.65 -139.69 -139.70 -139.71 -139.73 -139.75 26.8 -139.77 21.2 -139.78 84 Cl O O F O F F F F F F 7.4 7.3 7.2 7.1 7.0 6.9 6.8 F chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Chloro-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (23) Cl O O F F O F F F F F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Chloro-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (23) 7.33 7.26 7.26 7.19 7.18 7.17 1.00 7.12 0.93 7.09 0.37 7.07 1.07 0.68 7.06 1.04 7.04 0.34 7.03 146.1 7.02 144.4 7.01 7.00 6.94 6.93 126.3 6.92 122.5 119.5 110.2 110.2 4.51 2.25 4.47 4.44 86.5 3.34 HDO 61.7 2.51 DMSO 61.5 2.50 DMSO 61.2 2.50 DMSO 2.50 DMSO 2.49 DMSO 85 Cl O O F -120 -124 -128 -132 -136 -140 O F chemical shift (ppm) F F F F F F -98 -102 -106 -110 -114 -118 -122 -126 -130 -134 -138 -142 -146 -150 -154 -158 -162 chemical shift (ppm) 19F NMR of 5-Chloro-2-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-1,3-benzodioxole. (23) F F F F F F H3C O O O O F F F F F F 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2,2-Bis(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-methyl-1,3-benzodioxole 7.13 7.11 7.09 -120.52 7.09 7.13 -120.557.09 7.11 -120.596.92 7.09 -125.726.92 7.09 -125.746.92 7.09 -125.776.92 6.92 -130.846.90 6.92 -130.856.90 6.92 -130.876.90 -130.88 6.90 6.92 -130.90 6.32 6.90 1.88 6.30 6.90 -130.91 1.00 6.90 -139.566.29 6.90 -139.586.27 -120.49 6.26 6.33 -139.60 -120.52 -139.70 2.06 6.32 1.00 -120.55 6.30 -139.72 -120.59 6.29 -139.73 -120.63 6.27 -125.72 6.26 -125.74 6.24 0.98 -125.77 -130.84 -130.85 -130.87 0.98 -130.88 -130.90 -130.91 -139.55 -139.56 -139.58 0.98 -139.60 -139.62 -139.68 -139.70 -139.72 -139.73 2.77 -139.74 86 H3C O O F Br O F F F F F 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 5-Bromo-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-6-methyl-1,3-benzodioxole (24) H3C O O F Br O F F F F F 145 140 135 130 125 120 115 110 105 chemical shift (ppm) 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 5-Bromo-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-6-methyl-1,3-benzodioxole (24) 144.30 143.63 7.45 132.09 7.39 7.22 122.89 119.30 1.00 7.45 115.95 1.07 7.39 113.27 1.05 7.22 111.85 6.24 6.22 144.30 6.24 6.21 143.63 6.22 6.21 6.19 1.19 6.19 6.18 132.09 6.18 6.18 6.17 122.89 6.18 119.30 6.17 6.16 6.15 115.95 6.16 113.27 6.15 111.85 70.33 70.01 3.34 HDO 69.68 2.50 DMSO 3.06 2.29 22.78 87 H3C O O F Br O F F F F F -74.20 -74.22 -74.24 -74.26 -74.28 -74.30 -74.32 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 5-Bromo-2-(1-trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-6-methyl-1,3-benzodioxole (24) H3C O O F O F F F H3C O F F 7.25 7.20 7.15 7.10 7.05 7.00 6.95 6.90 6.85 chemical shift (ppm) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) 1H NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-methoxyphenyl)-6-methyl-1,3-benzodiox- ole (25) 7.21 7.21 7.20 7.19 7.19 2.05 7.18 0.94 6.97 2.05 6.95 0.97 6.95 0.96 6.94 6.93 6.88 -74.25 6.85 -74.27 4.62 4.61 4.60 4.59 4.58 4.58 4.57 1.01 4.56 4.55 4.55 4.53 -74.25 3.08 3.85 -74.27 3.02 2.21 88 H3C O O F O F F F H3C O F F 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) 13C NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-methoxyphenyl)-6-methyl-1,3-benzodi- oxole (25) H3C O O F O F F F H3C O F F -74.48 -74.52 -74.56 -74.60 -74.64 -74.68 -74.72 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) 19F NMR of 2-(1-Trifluoromethyl-(2,2,2-trifluoroethyl)oxy)-5-(4-methoxyphenyl)-6-methyl-1,3-benzodiox- ole (25) 158.77 143.69 142.84 -74.57 136.36 -74.58 133.72 130.49 117.51 113.74 110.79 110.70 110.14 70.10 -74.57 69.75 -74.58 69.41 69.08 68.74 55.46 20.69 89 8. References [1] W. L. F. Armarego, C. L. L. Chai, Purification of laboratory chemicals, Elsevier, Amsterdam, 2013. [2] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26– 32. (see SI thereof). [3] A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983–987. (see SI thereof). [4] H.G. Thomas, A. Schmitz, Synthesis 1985, 31–33. [5] a) H. Volz, G. Zimmermann, Tet. Lett. 1970, 41, 1597-3800; b) K. Dimroth, P. Heinrich, K. Schromm, Angew. Chem. 1965, 77, 873. [6] De Hardo, T.; Nevado, C. J. Am. Chem. Soc., 2010, 132, 1512–1513. [7] Victor, S. R.; Crisóstomo, F. R.; Bueno, F. C.; Pagnocca, F. C.; Fernandes, J. B.; Correa, A. G.; Bueno, O. C.; Hebling, M. J.; Bacci, M.; Vieira, P. C.; da Silva, M. F. Pest Management Science, 2001, 57 [8] Li, Y.; Wang, Z.; Wu, X.-F. Green Chemistry, 2018, 20 (5), . [9] Del Carmen Cruz, M.; Tamariz, J. Tetrahedron 2005, 61 [10] Cai, X.; Qian, C.; Zhai, H. US2008/234314, 2008. Communications AngewandteChemie International Edition: DOI: 10.1002/anie.201910077 Electrochemistry Hot Paper German Edition: DOI: 10.1002/ange.201910077 Dehydrogenative Anodic C!C Coupling of Phenols Bearing Electron- Withdrawing Groups Johannes L. Rçckl, Dieter Schollmeyer, Robert Franke, and Siegfried R. Waldvogel* Abstract: We herein present a metal-free, electrosynthetic method that enables the direct dehydrogenative coupling reactions of phenols carrying electron-withdrawing groups for the first time. The reactions are easy to conduct and scalable, as they are carried out in undivided cells and obviate the necessity for additional supporting electrolyte. As such, this conversion is efficient, practical, and thereby environmentally friendly, as production of waste is minimized. The method features a broad substrate scope, and a variety of functional groups are tolerated, providing easy access to precursors for novel polydentate ligands and even heterocycles such as dibenzofurans. Scheme 1. Important ligands for transition metal catalysis involving the 2,2’-biphenol motif. 2,2’-Biphenols are an important structural feature of a variety of ligands in transition metal catalysis.[1] Phosphite ligands 1 are used on the industrial scale in the hydro- synthesis of 2,2’-biphenols exhibiting electron-withdrawing formylation process.[2] The biphenols carrying electron-with- moieties in 3,3’-positions have been rarely reported. A very drawing groups are excellent precursors for salen-type ligands efficient copper-catalyzed reaction providing symmetrical 2, which can be employed in various polymerization reactions, and unsymmetrical 2,2’-BINOL derivatives in > 90% ee in such as in the asymmetric copolymerization of CO2 with the presence of O2 was developed by Kozlowski et al.[5] The meso-epoxides to give optically active polycarbonates, and in protocol tolerates a variety of electron-withdrawing groups in neutral nickel and palladium complexes 3 used as precatalysts position 3 and proceeds in good yields and high selectivity. for norbornene polymerization (Scheme 1).[3] However, the synthesis of cross-coupled naphthols proceeded The dehydrogenative coupling plays an important role in with low selectivity. Furthermore, this method seems to be modern organic chemistry, since it is a very efficient way to limited to naphthols as substrates. To the best of our selectively form C!C bonds.[4] Therefore, numerous studies knowledge, only substrates carrying electron-releasing on the syntheses of biaryls have been reported, but the direct groups or halogens have been successfully converted by electrochemistry so far.[6] Halo-2,2’-biphenols have been successfully synthesized via anodic oxidation of o,o’-dihalo- [*] J. L. Rçckl, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel genated phenols by the Nishiyama group.[7] The reaction was Institute of Organic Chemistry conducted at a very low current density and using undesirable Johannes Gutenberg University Mainz LiClO4 as an additional supporting electrolyte provided the Duesbergweg 10–14, 55128 Mainz (Germany) coupled product in only 25 % yield (Scheme 2). E-mail: waldvogel@uni-mainz.de Homepage: https://www.aksw.uni-mainz.de In previous work, our group was also able to access 3,3’- J. L. Rçckl, Prof. Dr. S. R. Waldvogel dihalo-2,2’-biphenols. [8] When trifluoroacetic acid in combi- Graduate School Materials Science in Mainz (Germany) nation with methyltriethylammonium methylsulfate as the Prof. Dr. R. Franke supporting electrolyte is used, 2-halophenols can be con- Evonik Performance Materials GmbH verted in high current efficiency when a high current density is Paul-Baumann-Str. 1, 45772 Marl (Germany) applied. Noteworthy are the high yields of 76% for the 3,3’- Prof. Dr. R. Franke dibromo-2,2’-biphenol and 47% for the 3,3’-dichloro-2,2’- Lehrstuhl f!r Theoretische Chemie, Ruhr-Universit"t Bochum biphenol. However, this methodology is still limited to Universit"tstraße 150, 44801 Bochum (Germany) substrates equipped with electron-releasing substituents. As Supporting information and the ORCID identification number(s) for a complementary method, the anodic C!C coupling of the author(s) of this article can be found under https://doi.org/10. phenols with electron-withdrawing groups is presented here 1002/anie.201910077. for the first time. This electrolytic conversion represents an # 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. efficient, metal-free route to symmetric 2,2’-biphenols having KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which electron-withdrawing groups in good yields and high selec- permits use and distribution in any medium, provided the original tivity. Coupling these phenols with naphthalenes leads to work is properly cited, the use is non-commercial, and no polycyclic intermediates, which can be further oxidized to modifications or adaptations are made. dibenzofurans or cleaved to access the desired cross-coupled Angew. Chem. Int. Ed. 2020, 59, 315 –319 ! 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 315 Communications AngewandteChemie easily recovered and reused. Aside from stabilization, HFIP can decouple nucleophilicity from oxidation potential.[14] For the anodic coupling, it was found that HFIP performed best in combination with boron-doped diamond (BDD) as the electrode material, but here inexpensive graphite serves just as well. In order to achieve high selectivity in the homo-coupling reaction, the formation of HFIP benzylic ether had to be suppressed.[15] This was accomplished by using a low current density of 5 mAcm!2. The greatest impact on the yield of this reaction was the concentration of starting material. The highest yield of 4 was obtained at a starting material concentration of 0.5 m. However, the solubility limit of the starting material was also reached at this concentration, preventing higher concentrations from being obtained. The minimum amount of diisopropylethylamine (DIPEA) required in this reaction to ensure sufficient conductivity is as low as 0.12 equivalents relative to the phenolic substrate. When other bases such as pyridine are used, O!C coupling becomes dominant and the yield drops dramatically. The applied charge can be as low as 1.0–1.5 F (per mole of phenol), resulting in high current efficiency; when higher charge was applied, over-oxidation and oligomerization took place. The preferred electrode material is BDD, but in some cases, graphite is superior. The low cost of graphite is beneficial for latter technical applications.[16] Additionally, when halogens are present (4, 5, 12), BDD is preferred as electrode material, because graphite can promote formation of the O!C coupled product (Scheme 3). Other solvents, such Scheme 2. Synthetic strategies to 2,2’-biphenols incorporating electron- as acetonitrile, proved unsuccessful, as they lead to dehalo- withdrawing groups. EWG= electron-withdrawing group; TFA = tri- genation reactions and were not observed to facilitate any C! fluoroacetic acid; MTES=methyltriethylammonium methylsulfate; C or C!O coupling. For ketone (6) and ester (7) as functional BDD = boron-doped diamond; DIPEA =diisopropylamine; HFIP = 1,1,1,3,3,3-hexafluoroisopropanol. groups, graphite lead to significantly higher yields up to 64 %. Halogenated 2,2’-biphenols (4, 5, 12) can be synthesized yields up to 54%. Nitriles (8), oximes (9), and sulfones (10) products. The use of base as an additive in 1,1,1,3,3,3- are also tolerated, providing polydentate ligand precursors in hexafluoroisopropanol (HFIP) obviates additional support- a straightforward manner in yields up to 43 %. Even an ing electrolyte. The reactions are easy to conduct and scalable. aldehyde (11) was tolerated to give the product in low yields; Electro-organic synthesis has become an important part of the electrode material was not found to play a significant role the synthetic organic toolkit which offers a number of here. Notably, the very sterically hindered ketone (4) was advantages over conventional chemical processes. As well accessible in a yield of 50 %. The application of nitro groups as facilitating novel routes to obtain desired structures, yielded only a small amount of biphenol and phosphonates electro-organic synthesis is inherently safe and step-econom- were not tolerated at all. ical.[9] Reaction conditions are typically mild and importantly, The bromo moiety of 4 is amenable to further derivatiza- electrons can be used as a sustainable reagent. Consequently, tions and X-ray analysis revealed an angle about the aryl–aryl no reagent waste is produced. As a result, conventional axis of almost 908 (Scheme 5). Conjugation of the p-systems is chemical oxidizers and reducing agents can be replaced by no longer possible, which makes the product less prone to electric current as an inexpensive, renewable, and safe over-oxidation, as previously investigated by our group.[6c] alternative. Usually, electrochemistry is associated with Also, the product shows strong hydrogen bonds between the oxidative or reductive transformations, but this mild method keto moiety and the phenolic proton. to generate radicals from the substrates allows a much In addition, access to cross-coupling employing phenols broader and versatile scope of reactivity.[11] Moreover, such carrying electron-withdrawing groups was explored using our electrosyntheses may be performed discontinuously or on methodology. When 2-hydroxy-5-methylacetophenone and different power levels,[12] making it compatible with fluctuat- naphthalene were co-electrolyzed, a polycyclic structure 14 ing renewable energy sources. In our work, the control of was obtained as the main product, instead of the expected selectivity is achieved by HFIP. This solvent is capable of cross-coupled derivative 13 (Scheme 4). The highest yields stabilizing reactive intermediates generated at the anode were obtained at a concentration of 0.1m and with an excess of while being very electrochemically stable with a very broad naphthalene (3.0 equivalents). An applied charge of 2.0 F was potential window of 4.5 V.[13] Notably, this solvent can be sufficient and with BDD electrodes the best yields were 316 www.angewandte.org ! 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 315 –319 Communications AngewandteChemie Scheme 4. Reaction pathway of the cross-coupling with naphthalene. Isolated yield are shown. Molecular structure of 14 in cis-configuration (rac.) determined by X-ray analysis is displayed. carrying the carbonyl moiety showed not only the highest Scheme 3. Scope of the reaction. [a] Electrolysis was carried out in 5 mL HFIP with 2.5 mmol of substrate in an undivided cell and yield in the 5 mL beaker cells, but they also represent 0.12 equiv DIPEA. [b] Electrolysis was carried out in 5 mL HFIP with precursors for a variety of polydentate ligands, for example, 1.0 mmol of substrate in an undivided cell and 0.3 equiv DIPEA. salen-type ligands (2). In addition, these types of structures [c] Yield of isolated product obtained using BDD electrodes. [d] Yield are used for the synthesis of several binuclear boron[17] and of isolated product obtained using graphite electrodes. aluminum[18] complexes, for application in optoelectronic devices and as catalysts in polymerization reactions.[3,18] obtained. Product 14 could only be selectively oxidized to the Therefore, a simple and scalable method for the synthesis of corresponding dibenzofuran 15 using 2,3-dichloro-5,6- these structural motifs is of high interest. The synthesis routes dicyano-1,4-benzoquinone (DDQ) in 1,4-dioxane in 83% to this structural motif are mostly complicated, multistep, and yield. Further application of current did not yield the desired low-yielding: Compound 6 can be prepared starting from p- 15, contrary to our expectations. The same reaction pathway cresol in a five-step procedure in an overall yield of 1.1%, could be shown for 4-bromo-2-hydroxy-5-methylaceto- involving a iodination, p-tosyl protection, a reductive cou- phenone, and gave an even higher overall yield, but a lower pling using copper, and a Fries-type rearrangement.[19] The selectivity towards the polycyclic intermediate 17. This electrolysis was scaled up by a factor of 13.3 and was mixture was then subjected to further oxidation with DDQ conducted in a 500 mL flask-type cell (Figure S2 in the to furnish 18 in 76 % yield. When the cyclic product 14 is Supporting Information). The achieved yield of 59% corre- treated with 1m HCl, a ring opening leading to formation of sponds approximately to the yield in the 5 mL beaker-type phenol 16 occurred. After work-up of the mixture, the cell (64 %) and therefore clearly shows the scalability of this polycyclic product 17 could again be observed in NMR, method. which indicates that these two isomers are in equilibrium. This Both the O,C- 21 and the C,C-coupled product 12 could be represents an interesting, to our knowledge, previously crystallized and their structures were determined by X-ray unknown form of tautomerism. When treated with an analysis (Scheme 5). HFIP ether 20 could be observed during excess of 1m NaOH, this equilibrium is completely shifted the optimization (confirmed by GC-MS and NMR), which is to the phenolate (Scheme 4). When aldehydes instead of in accordance with observations in our previous work.[15] We ketones were employed, the yield dropped dramatically, due therefore propose that an oxidation step and a subsequent to over-oxidation (see the Supporting Information). deprotonation leads to 19. This intermediate can either be To demonstrate the scalability of our method, we synthe- attacked by the nucleophilic oxygen or carbon, leading, after sized compound 6 on a 66.6 mmol scale. The substrates a further oxidation and subsequent rearomatization, to 21 or Angew. Chem. Int. Ed. 2020, 59, 315 –319 ! 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 317 Communications AngewandteChemie Science in Mainz (GSC 266). Support of the Advanced Lab of Electrochemistry and Electrosynthesis – ELYSION (Carl- Zeiss-Stiftung) is gratefully acknowledged. Conflict of interest The authors declare no conflict of interest. Keywords: C!C coupling · cross-coupling · electrochemistry · oxidation · oxygen heterocycles How to cite: Angew. Chem. Int. Ed. 2020, 59, 315–319 Angew. Chem. 2020, 132, 323–327 [1] a) P. J. Walsh, A. E. Lurain, J. Balsells, Chem. Rev. 2003, 103, 3297 – 3344; b) A. Alexakis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660 – 5667. [2] R. Franke, D. Selent, A. Bçrner, Chem. Rev. 2012, 112, 5675 – 5732. [3] a) T. Hu, Y.-G. Li, Y.-S. Li, N.-H. Hu, J. Mol. Catal. Chem. 2006, 253, 155 – 164; b) Y. Liu, W.-M. Ren, J. Liu, X.-B. Lu, Angew. Chem. Int. Ed. 2013, 52, 11594 – 11598; Angew. Chem. 2013, 125, Scheme 5. Proposed mechanisms for the C!C and O!C coupling of 11808 – 11812; c) H.-C. Zhang, W.-S. Huang, L. Pu, J. Org. Chem. phenols carrying electron-withdrawing groups and the formation of 2001, 66, 481 – 487. HFIP ethers. Molecular structures of 21 and 12 determined by X-ray [4] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335 – 344; b) S. Tang, Y. Liu, analysis are displayed. A. Lei, Chem 2018, 4, 27 – 45; c) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. Lei, Chem. Rev. 2017, 117, 9016 – 9085; d) Z.- J. Wu, S.-R. Li, H. Long, H.-C. Xu, Chem. Commun. 2018, 54, 4601 – 4604; e) Z.-J. Wu, S. R. Li, H.-C. Xu, Angew. Chem. Int. to the desired product 12. Further oxidation of 19 provides Ed. 2018, 57, 14070 – 14074; Angew. Chem. 2018, 130, 14266 – a quinone methide intermediate which is likely to be attacked 14270; f) S. R. Waldvogel, S. Lips, M. Selt, B. Riehl, C. J. Kampf, by HFIP in a 1,6-addition, leading to 20. This explains why Chem. Rev. 2018, 118, 6706 – 6765; g) H. Shalit, A. Dyadyuk, D. a lower current density, as well as a higher concentration of Pappo, J. Org. Chem. 2019, 84, 1677 – 1686. phenol, leads to higher yields of desired 2,2’-biphenol. The [5] X. Li, B. Hewgley, C. A. Mulrooney, J. Yang, M. C. Kozlowski, J. radical can then be trapped immediately by phenol instead of Org. Chem. 2003, 68, 5500 – 5511. [6] a) B. Riehl, K. Dyballa, R. Franke, S. R. Waldvogel, Synthesis being further oxidized or undergoing other side reactions. 2016, 49, 252 – 259; b) B. Elsler, D. Schollmeyer, K. M. Dyballa, Also, the recombination of such two radicals seems to be R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2014, 53, a possible pathway to the desired product. 5210 – 5213; Angew. Chem. 2014, 126, 5311 – 5314; c) A. Wiebe, In conclusion, we have established a highly efficient and D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, scalable method for the electrochemical dehydrogenative Angew. Chem. Int. Ed. 2016, 55, 11801 – 11805; Angew. Chem. homo- and cross-coupling of a broad variety of phenols 2016, 128, 11979 – 11983; d) B. Dahms, P. J. Kohlpaintner, A. carrying electron-withdrawing groups in good yields. The Wiebe, R. Breinbauer, D. Schollmeyer, S. R. Waldvogel, Chem. Eur. J. 2019, 25, 2713 – 2716; e) S. Lips, A. Wiebe, B. Elsler, D. resulting products represent precursors for polydentate Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. ligands, which have great importance in transition metal Chem. Int. Ed. 2016, 55, 10872 – 10876; Angew. Chem. 2016, 128, catalysis. By electrosynthesis the route towards an important 11031 – 11035; f) B. Dahms, R. Franke, S. R. Waldvogel, Chem- example could be shortened by three steps (when started ElectroChem 2018, 5, 1249 – 1252; g) A. Wiebe, S. Lips, D. from p-cresol) and the overall yield enhanced by a factor of Schollmeyer, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 50. Cross-coupling reactions with naphthalenes deliver biaryls 2017, 56, 14727 – 14731; Angew. Chem. 2017, 129, 14920 – 14925; and precursors for dibenzofurans. The reactions are easy to h) S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 13325 – 13329; Angew. Chem. 2018, 130, conduct and no additional supporting electrolyte is needed, 13509 – 13513; i) S. Lips, B. A. Frontana-Uribe, M. Dçrr, D. since a very low amount of base ensures sufficient conduc- Schollmeyer, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2018, 24, tivity, resulting in a high atom efficiency. In addition, the 6057 – 6061. reaction proceeds with a high current efficiency. [7] M. Takahashi, H. Konishi, S. Iida, K. Nakamura, S. Yamamura, S. Nishiyama, Tetrahedron 1999, 55, 5295 – 5302. [8] A. Kirste, S. Hayashi, G. Schnakenburg, I. Malkowsky, F. Acknowledgements Stecker, A. Fischer, T. Fuchigami, S. R. Waldvogel, Chem. Eur.J. 2011, 17, 14164 – 14169. [9] a) E. J. Horn, B. R. Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2, J.L. Rçckl is a recipient of a DFG fellowship through the 302 – 308; b) E. J. Horn, B. R. Rosen, Y. Chen, J. Tang, K. Chen, Excellence Initiative by the Graduate School Materials M. D. Eastgate, P. S. Baran, Nature 2016, 533, 77 – 81. 318 www.angewandte.org ! 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 315 –319 Communications AngewandteChemie [10] a) S. R. Waldvogel, B. Janza, Angew. Chem. Int. Ed. 2014, 53, [14] B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, 7122 – 7123; Angew. Chem. 2014, 126, 7248 – 7249; b) S. R. S. R. Waldvogel, Chem. Eur. J. 2015, 21, 12321 – 12325. Waldvogel, S. Mçhle, Angew. Chem. Int. Ed. 2015, 54, 6398 – [15] a) Y. Imada, J. L. Rçckl, A. Wiebe, T. Gieshoff, D. Schollmeyer, 6399; Angew. Chem. 2015, 127, 6496 – 6497; c) S. R. Waldvogel, K. Chiba, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. M. Selt, Angew. Chem. Int. Ed. 2016, 55, 12578 – 12580; Angew. 2018, 57, 12136 – 12140; Angew. Chem. 2018, 130, 12312 – 12317; Chem. 2016, 128, 12766 – 12768. b) J. L. Rçckl, Y. Imada, K. Chiba, S. R. Waldvogel, ChemElec- [11] a) A. Wiebe, T. Gieshoff, S. Mçhle, E. Rodrigo, M. Zirbes, S. R. troChem 2019, 6, 4184 – 4187; c) J. L. Rçckl, A. V. Hauck, D. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594 – 5619; Angew. Schollmeyer, S. R. Waldvogel, ChemistryOpen 2019, 8, 1167 – Chem. 2018, 130, 5694 – 5721; b) S. Mçhle, M. Zirbes, E. 1171. Rodrigo, T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew. [16] J. Kotz, P. Treichel, G. Weaver, Chemistry and Chemical Chem. Int. Ed. 2018, 57, 6018 – 6041; Angew. Chem. 2018, 130, Reactivity, 6th ed., Enhanced Review Edition, Brooks/Cole 6124 – 6149. Thomson Learning, Belmont, CA, 2006. [12] A. Wiebe, B. Riehl, S. Lips, R. Franke, S. R. Waldvogel, Sci. Adv. [17] K. Dhanunjayarao, V. Mukundam, M. Ramesh, K. Venkatasub- 2017, 3, eaao3920. baiah, Eur. J. Inorg. Chem. 2014, 539 – 545. [13] a) R. Francke, D. Cericola, R. Kçtz, D. Weingarth, S. R. [18] H.-L. Han, Y. Liu, J.-Y. Liu, K. Nomura, Y. S. Li, Dalton Trans. Waldvogel, Electrochim. Acta 2012, 62, 372; b) L. Eberson, 2013, 42, 12346 – 12353. M. P. Hartshorn, O. Persson, J. Chem. Soc. Perkin Trans. 2 1995, [19] N. Tsu, K. Nagashima, Tetrahedron 1969, 25, 3017 – 3031. 1735 – 1744; c) M. Lucarini, V. Mugnaini, G. F. Pedulli, M. Guerra, J. Am. Chem. Soc. 2003, 125, 8318 – 8329; d) L. Eberson, Manuscript received: August 8, 2019 O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. Engl. 1995, Accepted manuscript online: September 9, 2019 34, 2268 – 2269; Angew. Chem. 1995, 107, 2417 – 2418. Version of record online: November 19, 2019 Angew. Chem. Int. Ed. 2020, 59, 315 –319 ! 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 319 Zuschriften AngewandteChemie Deutsche Ausgabe: DOI: 10.1002/ange.201910077 Elektrochemie Hot Paper Internationale Ausgabe: DOI: 10.1002/anie.201910077 Dehydrierende anodische C-C-Kupplung von Phenolen mit elektro- nenziehenden Substituenten Johannes L. Rçckl, Dieter Schollmeyer, Robert Franke und Siegfried R. Waldvogel* Abstract: Wir stellen hier eine metallfreie, elektrosynthetische Methode vor, die erstmals eine direkte dehydrierende Kupp- lungsreaktionen von Phenolen mit elektronenziehenden Gruppen ermçglicht. Die Reaktionen sind einfach durchzu- f!hren und skalierbar, da sie in ungeteilten Zellen durchgef!hrt werden und kein zus"tzliches Leitsalz bençtigt wird. Hier- durch ist diese Umsetzung effizient, praktisch und dadurch besonders umweltfreundlich, da Reagenzabfall minimiert wird. Das Verfahren zeichnet sich durch ein breites Spektrum an mçglichen Substraten aus und es werden eine Vielzahl von funktionellen Gruppen toleriert. Das ermçglicht einen einfa- chen Zugang zu Vorl"ufern f!r neuartige mehrz"hnige Li- Schema 1. Wichtige Liganden in der !bergangsmetallkatalyse, welche ganden und sogar zu Heterocyclen wie Dibenzofuranen. die 2,2’-Biphenol Struktureinheit beinhalten. Die 2,2’-Biphenole stellen eine wichtige Struktureinheit Die dehydrierende Kupplung spielt in der modernen or- einer Vielzahl von Liganden in der !bergangsmetallkatalyse ganischen Chemie eine wichtige Rolle, da sie eine sehr effi- dar.[1] Phosphitliganden 1 werden im industriellen Maßstab ziente Mçglichkeit darstellt, selektiv C-C-Bindungen zu im Hydroformylierungsprozess eingesetzt. Biphenole mit bilden.[4] Es gibt daher zahlreiche Studien zur Synthese von elektronenziehenden Gruppen sind ausgezeichnete Vorl"ufer Biarylverbindungen, aber der direkte Zugang zu 2,2’-Biphe- f#r mehrkernige Salenliganden 2, die in verschiedenen Poly- nolen mit elektronenziehenden Einheiten in 3,3’-Positionen merisationsreaktionen eingesetzt werden kçnnen, z. B. in wurde selten berichtet. Eine sehr effiziente kupferkatalysierte einer asymmetrischen Co-Polymerisation von CO2 mit meso- Reaktion zu symmetrischen und unsymmetrischen 2,2’- Epoxiden zu optisch aktiven Polycarbonaten (2) oder f#r BINOL-Derivaten in Gegenwart von Sauerstoff wurde von neutrale Nickel- und Palladiumkomplexe, die als Vorl"ufer Kozlowski et al. entwickelt.[5] Das Verfahren toleriert eine f#r Katalysatoren f#r die Norbornenpolymerisation verwen- Vielzahl von elektronenziehenden Gruppen in 3-Position in det werden (3, Schema 1).[3] guter Ausbeute und hoher Selektivit"t. Die Synthese von kreuzgekuppelten Naphtholen verlief jedoch mit geringer Selektivit"t. Dar#ber hinaus scheint sich diese Methode auf [*] J. L. Rçckl, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel Naphthole als Substrate beschr"nkt zu sein. Bisher konnten, Institut f"r Organische Chemie nach unserem Wissen, nur Substrate mit elektronenschie- Johannes Gutenberg Universit#t Mainz benden Gruppen oder Halogenen elektrochemisch erfolg- Duesbergweg 10–14, 55128 Mainz (Deutschland) reich umgesetzt werden.[6] Halo-2,2’-biphenole wurden durch E-Mail: waldvogel@uni-mainz.de anodische Oxidation von o,o’-dihalogenierten Phenolen von Homepage: https://www.aksw.uni-mainz.de Nishiyama und Mitarbeiter erfolgreich synthetisiert.[7] Die J. L. Rçckl, Prof. Dr. S. R. Waldvogel Graduate School Materials Science in Mainz (Deutschland) Reaktion lieferte das gekuppelte Produkt bei einer sehr ge- Prof. Dr. R. Franke ringen Stromdichte und mit unerw#nschtem LiClO4 als zu- Evonik Performance Materials GmbH s"tzlichem Leitsalz in lediglich 25 % Ausbeute (Schema 2). Paul-Baumann-Straße 1, 45772 Marl (Deutschland) In fr#heren Arbeiten konnte unsere Gruppe die Synthese Prof. Dr. R. Franke von 3,3’-Dihalogen-2,2’-biphenole zeigen. [8] Bei Verwendung Lehrstuhl f"r Theoretische Chemie, Ruhr-Universit#t Bochum von Trifluoressigs"ure in Kombination mit Methyltriethyl- Universit#tstraße 150, 44801 Bochum (Deutschland) ammoniummethylsulfat als Leitsalz kçnnen 2-Halogenphe- Hintergrundinformationen und die Identifikationsnummer (ORCID) nole bei hohen Stromdichten erfolgreich in hoher Stromaus- eines Autors sind unter https://doi.org/10.1002/ange.201910077 zu beute erhalten werden. Bemerkenswert sind die hohen Aus- finden. beuten von 76 % f#r 3,3’-Dibrom-2,2’-biphenol und 47% f#r $ 2019 Die Autoren. Verçffentlicht von Wiley-VCH Verlag GmbH & 3,3’-Dichlor-2,2’-biphenol. Diese Methode ist jedoch immer Co. KGaA. Dieser Open Access Beitrag steht unter den Bedingungen noch auf Substrate beschr"nkt, die mit elektronenschieben- der Creative Commons Attribution Non-Commercial NoDerivs Li- cense, die eine Nutzung und Verbreitung in allen Medien gestattet, den Substituenten oder Halogengruppen ausgestattet sind. sofern der urspr"ngliche Beitrag ordnungsgem#ß zitiert und nicht Als erg"nzendes Verfahren wird hier erstmals die anodische f"r kommerzielle Zwecke genutzt wird und keine %nderungen und C-C-Kupplung von Phenolen mit elektronenziehenden Anpassungen vorgenommen werden. Gruppen vorgestellt. Diese elektrolytische Umwandlung Angew. Chem. 2020, 132, 323 –327 ! 2019 Die Autoren. Verçffentlicht von Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 323 Zuschriften AngewandteChemie von Radikalen aus den Substraten erçffnet einen viel brei- teren und vielseitigeren chemischen Raum.[11] Dar#ber hinaus kçnnen Elektrosynthesen diskontinuierlich oder auf unter- schiedlichen Leistungsstufen betrieben werden,[12] was die Kompatibilit"t mit schwankenden erneuerbaren Energien ermçglicht. In unserer Arbeit wird die Kontrolle der Selek- tivit"t durch HFIP erreicht. Dieses Lçsungsmittel ist in der Lage, reaktive Zwischenprodukte, die an der Anode erzeugt werden, zu stabilisieren und gleichzeitig elektrochemisch stabil, mit einem sehr breiten Potentialfenster von 4,5 V, zu sein.[13] Des Weiteren kann das Lçsungsmittel leicht durch einfache Destillation zur#ckgewonnen und wiederverwendet werden. Neben der Stabilisierung kann HFIP die Nukleo- philie vom Oxidationspotential entkoppeln.[14] F#r die ano- dische Kupplung wurde gefunden, dass HFIP am besten in Kombination mit bordotiertem Diamanten (BDD) als Elek- trodenmaterial funktioniert, aber hier kann auch kosten- g#nstiger Graphit erfolgreich eingesetzt werden. Um eine hohe Selektivit"t in der Homokupplung der Phenole zu erreichen, musste die benzylische HFIP-Ether- bildung unterdr#ckt werden.[15] Dies wurde durch die Ver- wendung einer geringen Stromdichte von 5 mAcm!2 erreicht. Den grçßten Einfluss auf die Ausbeute dieser Reaktion hat die Konzentration des Ausgangsmaterials. Die hçchste Aus- beute von 4 wurde bei einer Ausgangsstoffkonzentration von 0.5m erzielt. Das Lçslichkeitslimit des Ausgangsmaterials in HFIP wurde jedoch bereits bei dieser Konzentration erreicht. Die Mindestmenge an Diisopropylethylamin (DIPEA), die in dieser Reaktion bençtigt wird, um eine ausreichende Leitf"- Schema 2. Synthetische Strategien zu 2,2’-Biphenolen mit elektronen- higkeit zu gew"hrleisten, betr"gt nur 0.12 $quivalente (be- ziehenden Gruppen. EWG= elektronenziehende Gruppe; TFA =Triflu- zogen auf das Phenolsubstrat). Wenn andere Basen wie Py- oressigs#ure; MTES= Methyltriethylammonium-methylsulfat; ridin verwendet werden, tritt die unerw#nschte O-C-Kupp- BDD = bordotierter Diamant; DIPEA =Diisopropylamin; lung vermehrt auf und die Ausbeute sinkt drastisch. Die be- HFIP = 1,1,1,3,3,3,3-Hexafluorisopropanol. nçtigte applizierte Strommenge betr"gt 1.0–1.5 F (pro Mol Phenol), was zu einer hohen Stromausbeute f#hrt. Das be- stellt einen effizienten, metallfreien Weg zu symmetrischen vorzugte Elektrodenmaterial ist BDD, aber in einigen F"llen 2,2’-Biphenolen dar, die in guter Ausbeute und mit hoher ist Graphit #berlegen. Dar#ber hinaus wird bei Anwesenheit Selektivit"t abl"uft. Die Kupplung dieser Phenole mit von Halogenen (4, 5, 12) BDD als Elektrodenmaterial be- Naphthalinen f#hrt zu polycyclischen Zwischenprodukten, vorzugt, da Graphit die Bildung des O-C-gekuppelten Pro- die zu Dibenzofuranen oxidiert oder gespalten werden dukts fçrdern kann (Schema 3). Andere Lçsungsmittel, wie kçnnen, um das gew#nschte kreuzgekuppelte Produkt zu er- beispielsweise Acetonitril, erwiesen sich als ungeeignet, da sie halten. Die Verwendung von Base als Additiv in zu Dehalogenierungsreaktionen beg#nstigen. F#r Ketone (6) 1,1,1,1,3,3,3,3-Hexafluorisopropanol (HFIP) vermeidet die und Ester (7) als funktionelle Gruppen f#hrt Graphit zu Verwendung von zus"tzlichem Leitsalz. Außerdem sind die deutlich hçheren Ausbeuten von bis zu 64 %. Halogenierte Reaktionen einfach durchzuf#hren und skalierbar. 2,2’-Biphenole (4,5,12) kçnnen in einer Ausbeute von bis zu Die elektroorganische Synthese ist zu einem wichtigen 54% synthetisiert werden. Nitrile (8), Oxime (9) und Sulfone Bestandteil des synthetischen organischen Handwerkszeugs (10) werden ebenfalls toleriert und ergeben auf einfache geworden, da sie eine Reihe von Vorteilen gegen#ber her- Weise Vorl"ufer von mehrz"hnigen Liganden mit Ausbeuten kçmmlichen chemischen Verfahren bietet. Neben Zugang zu von bis zu 43 %. Sogar Aldehyde (11) wurde toleriert, um das neuartigen Strukturen ist elektroorganische Synthese von Produkt in niedrigen Ausbeuten zu erhalten; das Elektro- Grund auf sicher und stufençkonomisch.[9] Die Reaktions- denmaterial spielte dabei keine wesentliche Rolle. Insbe- bedingungen sind typischerweise mild und Elektronen sondere das sehr sterisch gehinderte Keton (4) war in einer kçnnen als nachhaltiges Reagenz betrachtet werden. Da- Ausbeute von 50 % zug"nglich. Die Verwendung von Nitro- durch entsteht kein Reagenzabfall. Als Folge davon werden gruppen ergab nur einen geringen Anteil an Biphenol und herkçmmliche chemische Oxidationsmittel oder Redukti- Phosphonate wurden #berhaupt nicht toleriert. onsmittel durch elektrischen Strom als kosteng#nstige, er- Der Brom-Substituent bei 4 macht weitere Derivatisie- neuerbare und sichere Alternative ersetzt. Normalerweise ist rungen in dieser Position mçglich und die Rçntgenstruktur- die Elektrochemie mit oxidativen oder reduktiven Transfor- analyse von geeigneten Einkristallen ergab einen Aryl-Aryl- mationen verbunden, aber die milde Methode zur Erzeugung Achsenwinkel von fast 908 (Schema 5). Die Konjugation der 324 www.angewandte.de ! 2019 Die Autoren. Verçffentlicht von Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2020, 132, 323 –327 Zuschriften AngewandteChemie Schema 4. Reaktionsweg der Kreuzkupplung mit Naphthalin. Es werden isolierte Ausbeuten angegeben. Die durch die Rçntgenstruktur- analyse bestimmte Molek"lstruktur von 14 in cis-Konfiguration (rac.) ist abgebildet. Schema 3. Substratumfang der Reaktion. [a] Die Elektrolyse wurde in 5 mL HFIP mit 2.5 mmol Substrat in einer ungeteilten Zelle und droxy-5-methyl-acetophenon gezeigt werden, was zu noch 0.12 %quivalenten durchgef"hrt. DIPEA. [b] Die Elektrolyse wurde in hçheren Gesamtausbeuten, aber einer geringeren Selektivit"t 5 mL HFIP mit 1.0 mmol Substrat in einer ungeteilten Zelle und gegen#ber dem polycyclischen Zwischenprodukt 17 f#hrt. 0,3 %quivalenten durchgef"hrt. DIPEA. [c] Isolierte Ausbeute mit BDD- Diese Mischung wurde dann einer weiteren Oxidation mit Elektroden. [d] Isolierte Ausbeute mit Graphitelektroden. DDQ unterzogen, um 18 in 76 % Ausbeute zu erhalten. Wenn das cyclische Produkt 14 mit 1m HCl behandelt wird, trat eine Ringçffnung auf, die zur Bildung des Phenols 16 f#hrt. Nach p-Systeme ist daher nicht mehr mçglich, was dieses Produkt der Aufarbeitung des Reaktionsgemisches konnte das poly- weniger anf"llig f#r !beroxidation macht, wie bereits von cyclische Produkt 17 erneut via NMR beobachtet werden, was unserer Gruppe untersucht wurde.[6c] Außerdem zeigt das darauf hindeutet, dass sich diese beiden Isomere im Gleich- Produkt starke Wasserstoffbr#ckenbindungen zwischen der gewicht befinden. Dies stellt eine nach unserem Kenntnis- Ketogruppe und dem phenolischen Proton. stand interessante, unbekannte Form der Tautomerie dar. Bei Dar#ber hinaus wurde der Zugang zur Kreuzkupplung Behandlung mit einem !berschuss von 1m NaOH wird dieses mit Phenolen, die elektronenziehende Gruppen tragen, mit Gleichgewicht vollst"ndig auf die Seite des Phenolats ver- unserer Methodik untersucht. Wenn 2-Hydroxy-5-methyla- schoben (Schema 4). Wenn Aldehyde anstelle von Ketonen cetophenon und Naphthalin gemeinsam elektrolysiert verwendet wurden, sank die Ausbeute dramatisch (siehe wurden, wurde anstelle des erwarteten kreuzgekuppelten Hintergrundinformationen). Derivats 13 (Schema 4) eine polycyclische Struktur 14 als Um die Skalierbarkeit unserer Methode zu demonstrie- Hauptprodukt erhalten. Die hçchsten Ausbeuten wurden bei ren, haben wir die Verbindung 6 im 66.6 mmol-Maßstab Konzentrationen von 0.1m und einem !berschuss an Naph- synthetisiert. Die Substrate die eine Carbonyl-Einheit tragen, thalin (3.0 $quivalente) erzielt. Eine Ladungsmenge von zeigten nicht nur die hçchste Ausbeute in den 5 mL Becher- 2.0 F war ausreichend und mit BDD-Elektroden wurden die zellen, sondern sind auch Vorl"ufer f#r eine Vielzahl von besten Ausbeuten erzielt. 14 konnte selektiv zu dem ent- mehrz"hnigen Liganden, z. B. Salenliganden (2). Dar#ber sprechenden Dibenzofuran 15 mit 2,3-Dichlor-5,6-dicyano- hinaus werden diese Arten von Strukturen f#r die Synthese 1,4-benzochinon (DDQ) in 1,4-Dioxan in 83 % Ausbeute mehrerer binuklearer Bor-[17] und Aluminiumkomplexe,[18] oxidiert werden. Eine hçhere Ladungsmenge hat entgegen f#r den Einsatz in optoelektronischen Vorrichtungen oder als unseren Erwartungen nicht das gew#nschte Produkt 15 er- Katalysatoren in Polymerisationsreaktionen verwendet.[3,18] geben. Der gleiche Reaktionsweg konnte f#r 4-Brom-2-hy- Daher ist eine einfache und skalierbare Methode zur Syn- Angew. Chem. 2020, 132, 323 –327 ! 2019 Die Autoren. Verçffentlicht von Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.de 325 Zuschriften AngewandteChemie these dieser strukturellen Motive von großem Interesse. Die warum eine geringere Stromdichte sowie eine hçhere Kon- Synthesewege zu diesem strukturellen Motiv sind meist zentration an Phenol zu einer hçheren Ausbeute an ge- kompliziert, mehrstufig und verlaufen mit geringen Ausbeu- w#nschtem 2,2’-Biphenol f#hrt. Das Radikal kann dann ten: 6 wird in einem 5-stufigen Verfahren aus p-Kresol in sofort durch Phenol abgefangen werden, anstatt weiter oxi- einer Gesamtausbeute von 1,1% synthetisiert, wobei eine diert zu werden oder andere Nebenreaktionen einzugehen. Jodierung, ein p-Tosyl-Sch#tzung, eine reduktive Kupplung Auch die Rekombination dieser beiden Radikale scheint ein mit Kupfer und eine Fries-Umlagerung durchgef#hrt werden mçglicher Weg zum gew#nschten Produkt zu sein. m#ssen.[19] Die Elektrolyse wurde um den Faktor 13.3 Zusammenfassend l"sst sich sagen, dass wir eine hochef- hochskaliert und in einem 500-mL-Kolben durchgef#hrt fiziente und skalierbare Methode f#r die elektrochemische (Hintergrundinformationen, Abbildung S2). Die erzielte dehydrierende Homo- und Kreuzkupplung einer breiten Pa- Ausbeute von 59% entspricht in etwa der Ausbeute in der lette von Phenolen mit elektronenziehenden Gruppen in 5 mL Becherzelle (64%) und zeigt damit deutlich die Skali- guten Ausbeuten etabliert haben. Die daraus resultierenden erbarkeit dieses Verfahrens. Produkte sind Vorl"ufer f#r mehrz"hnige Liganden, die f#r Sowohl das O-C- 21 als auch das C-C-gekuppelte Produkt die !bergangsmetallkatalyse von großer Bedeutung sind. 12 konnten kristallisiert werden und ihre Strukturen wurden Durch Elektrosynthese konnte die Syntheseroute zu einem durch Rçntgenstrukturanalyse bestimmt (Schema 5). Der wichtigen Beispiel um drei Schritte verk#rzt werden (wenn man von p-Kresol ausgeht) und die Gesamtausbeute um den Faktor 50 erhçht werden. Kreuzkupplungsreaktionen mit Naphthalinen liefern Biaryle und Vorl"ufer f#r Dibenzof- urane. Die Reaktionen sind einfach durchzuf#hren und es wird kein zus"tzliches Leitsalz bençtigt, da eine sehr geringe Basenmenge eine ausreichende Leitf"higkeit gew"hrleistet, was zu einem hohen Atomwirkungsgrad f#hrt. Dar#ber hinaus verl"uft die Reaktion mit hoher Stromausbeute. Danksagung J.L. Rçckl erh"lt ein DFG-Stipendium im Rahmen der Ex- zellenzinitiative der Graduate School Materials Science in Mainz (GSC 266). Die Unterst#tzung des Advanced Lab of Electrochemistry and Electrosynthesis – ELYSION (Carl- Zeiss-Stiftung) wird dankbar angenommen. Interessenkonflikt Die Autoren erkl"ren, dass keine Interessenkonflikte vorlie- gen. Stichwçrter: C-C-Kupplungen · Elektrochemie · Schema 5. Vorgeschlagener Mechanismus f"r die C-C- und O-C-Kupp- Kreuzkupplungen · Oxidation · Sauerstoffheterocyclen lung von Phenolen mit elektronenziehenden Gruppen, sowie die Bil- dung von HFIP-Ethern. Es werden die durch die Rçntgenstrukturanaly- Zitierweise: Angew. Chem. Int. 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Waldvogel* anie_201910077_sm_miscellaneous_information.pdf Table of Contents General information ........................................................................................................ 3 General protocol for electrolytic coupling of phenols carrying EWG (GP) ....................... 4 CV studies ...................................................................................................................... 7 Synthesis of starting materials .......................................................................................12 Homo-coupling of phenols carrying EWG ......................................................................15 Cross-coupling of phenols carrying EWG ......................................................................25 NMR spectra .................................................................................................................33 References ....................................................................................................................52 S2 General information All reagents were used in analytical or sufficiently pure grades. Solvents were purified by standard methods.[1] Electrochemical reactions were carried out at boron-doped diamond (BDD) electrodes. BDD electrodes were obtained as DIACHEMTM quality from CONDIAS GmbH, Itzehoe, Germany. BDD (15 μm diamond layer) on silicon support and with isostatic graphite electrodes (SIGRAFINE®V2100, SGL Carbon, Bonn-Bad Godesberg, Germany). Column chromatography was performed on silica gel 60 M (0.040–0.063 mm, Macherey- Nagel GmbH & Co, Düren, Germany) with a maximum pressure of 1.6 bar. In addition, a preparative chromatography system (Büchi Labortechnik GmbH, Essen, Germany) was used with a Büchi Control Unit C-620, an UV detector Büchi UV photometer C-635, Büchi fraction collector C-660 and two Pump Modules C-605 for adjusting the solvent mixtures. As eluents mixtures of cyclohexane and ethyl acetate were used. Silica gel 60 sheets on aluminum (F254, Merck, Darmstadt, Germany) were used for thin layer chromatography. Spectroscopy and spectrometry 1H NMR, 13C and 19F NMR spectra were recorded at 25 °C, using a Bruker Avance III HD 400 (400 MHz) (5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). Chemical shifts (δ) are reported in parts per million (ppm) relative to TMS as internal standard or traces of CHCl3 or DMSO-d6 in the corresponding deuterated solvent. For the 19F spectra, ethyl fluoroacetate served as external standard (δ = −231.1ppm). Mass spectra and high- resolution mass spectra were obtained by using a QTof Ultima 3 (Waters, Milford, Massachusetts) apparatus employing ESI+ or APCI. Melting points were determined with a Melting Point Apparatus B-545 (Büchi, Flawil, Switzerland) and are uncorrected. Heating rate: 1 °C/min. Cyclic voltammetry was performed with a Metrohm 663 VA Stand equipped with a μAutolab type III potentiostat (Metrohm AG, Herisau, Switzerland). WE: BDD electrode tip, 2 mm diameter; CE: glassy carbon rod; RE: Ag/AgCl in saturated LiCl/EtOH. Sol-vent: HFIP. v = 100 mV/s, T = 20.0 °C, c = 0.00500 M, supporting electrolyte DIPEA: c = 0.100 M, MTBS: c = 0.200 M. X-ray analysis: All data were collected on a STOE IPDS2T diffractometer (Oxford Cryostream 700er series, Oxford Cryosystems) using graphite monochromated Mo Kα radiation (λ= 0.71073 Å). Intensities were measured using fine-slicing ω and φ-scans and corrected for background, polarization and Lorentz effects. The structures were solved by direct methods and refined anisotropically by the least-squares procedure implemented in the SHELX program system. S3 The supplementary crystallographic data for this paper can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Deposition numbers and further details are given with the individual characterization data. General protocol for electrolytic coupling of phenols carrying EWG (GP) The undivided 5 mL PTFE electrolysis cells are homemade. Detailed information about used cells are already reported.[2,3] However, the complete setup with these cells are also commercially available as IKA Screening System, IKA-Werke GmbH & Co. KG, Staufen, Germany. It is operated with boron-doped diamond electrodes (BDD, 0.3 x 1 x 7 cm, 15 μm diamond layer, the support material is silicon) or graphite electrodes (0.3 x 1 x 7 cm SIGRAFINE®V2100, SGL Carbon, Bonn-Bad Godesberg, Germany). GP I: Homocoupling of phenols undivided PTFE cell (1 mmol / 5 mL) A solution of a phenol derivative (1.0 – 2.5 mmol, 1.0 equiv.) and N-ethyl-N-(prop-2-yl)propan- 2-amine (DIPEA) (0.05 mL, 0.29 mmol, 0.12 equiv. – 0.3 equiv.) in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) (5 mL) was electrolyzed at a boron-doped diamond (BDD) or graphite anode and a BDD or graphite cathode. A constant current electrolysis with a current density of 5.0 mA/cm2 was performed at room temperature. After 1.0 - 1.5 F (per mole) were applied, HFIP was recovered by distillation. The residue was purified by column chromatography. Fig. S1: Left: schematic 5 mL Teflon cells; Middle: The commercially available IKA Screenings System, IKA-Werke GmbH & Co. KG, Staufen, Germany; right: 5 mL Teflon cell with two parallel electrodes (size: 3 x 10 x 70 mm, 1 Euro coin for comparison, diameter: 23,25 mm). S4 GP II: Flask-type cell (66 mmol / 500 mL) – Scale-up Phenol derivative (66.6 mmol, 1.0 equiv.) HFIP (134 mL), and 5.0 mL (1.5 mmol, 0.12 equiv.) DIPEA were transferred into an undivided 500 mL electrolysis cell equipped with a graphite anode and a graphite cathode. A constant current electrolysis with a current density of 5.0 mA/cm2 was performed at room temperature. After 1.0 F - 1.5 F (per mole) were applied, HFIP was recovered by distillation. Purification by column chromatography yielded the clean product as a yellow solid. For 3,3'-Diacetyl-5,5'-dimethyl-2,2'-biphenol (6): yellow solid (5.9 g, 19.6 mmol, 59%). The flask (500 mL) is closed by a PTFE plug. This cap allows precise arrangement of the electrodes. Total dimension of the graphite electrodes are 6.0 cm x 2.0 cm x 0.3 cm. Fig. S2: 500 mL flask cell; left: Electrode removed; right: assembled. For size comparison one 50 Eurocent (diameter: 24,25 mm) coin is placed in front of the glass cell. GP III: Cross-coupling of phenols with naphtalenes undivided PTFE cell (5 mL) A solution of a phenol derivative (0.5 mmol, 1.0 equiv.) naphthalene (1.5 mmol, 3.0 equiv.) and N-ethyl-N-(prop-2-yl)propan-2-amine (DIPEA) (0.1 mL, 0.57 mmol 1.15 equiv.) in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) (5 mL) was electrolyzed at a boron-doped diamond (BDD) anode and a BDD cathode. A constant current electrolysis with a current density of 5.0 mA/cm2 was performed at room temperature. After 2.0 F were applied, HFIP was recovered by distillation. The residue was purified by column chromatography. S5 Procedure with ElectraSyn ElectraSyn 2.0 (IKA, cat. no. 0020008980) Graphite electrode assembly (IKA, cat. no. 0040002858) Charge the ElectraSyn vial (10 mL volume) with a Teflon-coated magnetic stir bar, 2-hydroxy-5-methylacetophenone (375 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.). Adapt the graphite (W) and platinum or graphite (C) electrodes to the ElectraSyn vial cap. Screw the vial cap onto the vial. Premix the reaction mixture until a clear solution is obtained. Adapt the electrochemical cell to the ElectraSyn 2.0 vial holder. Select ‘New experiments’ and then ‘Constant current’. Set ‘5 mA’ for ’desired current’. Select ‘No’ for ‘Are you using a reference electrode?’ Choose ‘Total charge’. Adjust ‘mmols substrate’ to ‘2.5 mmol’ and ‘1.5’ for ‘equiv. of electrons’. Select ‘No’ for ‘Would you like to alternate the polarity’. After electrolysis for ca. 18 h, disconnect the reaction vial from the ElectraSyn 2.0, gently remove the cap with electrodes from the vial, and transfer the reaction mixture to a flask (recover HFIP, if wished), then rinse both electrodes with ethyl acetate (10 mL) to transfer any residual product. Remove the solvent using a rotary evaporator. The residue was purified by column chromatography to yield the desired biphenol (155 mg, 0.52 mmol of 6, 42%). S6 CV studies A general trend that has been observed in all CV measurements is the decrease of oxidation potentials with the addition of base (ca. 0.1 – 0.2 V). In orange the CVs with addition of base and in blue the CVs measured with MTBS as supporting electrolyte are shown. One rational would be, that upon deprotonation of the phenol the aromatic system becomes more electron- rich and therefore can be more easily oxidized. 4-bromo-2-hydroxy-5-methylacetophenone 2,50E-04 2,00E-04 1,50E-04 1,00E-04 5,00E-05 0,00E+00 -1 -0,5 0 0,5 1 1,5 2 2,5 3 -5,00E-05 E (V vs. Fc/FcH+) Blue: cyclic voltammogram of a 5 mM solution of 4-bromo-2-hydroxy-5-methylacetophenone in HFIP/MTBS at 100 mV/s Eox1 = 1.85 V vs Fc/FcH+ Orange: cyclic voltammogram of a 5 mM solution of 4-bromo-2-hydroxy-5-methylacetophenone in HFIP/DIPEA at 100 mV/s Eox2 = 1.78 V vs Fc/FcH+ S7 current density j mA/cm2 2-hydroxy-5-methylacetophenone 3,00E-04 2,50E-04 2,00E-04 1,50E-04 1,00E-04 5,00E-05 0,00E+00 -1 -0,5 0 0,5 1 1,5 2 2,5 3 -5,00E-05 E (V vs. Fc/FcH+) Blue: cyclic voltammogram of a 5 mM solution of 2-hydroxy-5-methylacetophenone in HFIP/MTBS at 100 mV/s Eox1 = 1.90 V vs Fc/FcH+ Orange: cyclic voltammogram of a 5 mM solution of 2-hydroxy-5-methylacetophenone in HFIP/DIPEA at 100 mV/s Eox2 = 1.72 V vs Fc/FcH+ S8 current density j mA/cm2 5-(tert-butyl)-2-hydroxybenzaldehyde 4,00E-04 3,50E-04 3,00E-04 2,50E-04 2,00E-04 1,50E-04 1,00E-04 5,00E-05 0,00E+00 -1 -0,5 0 0,5 1 1,5 2 2,5 3 -5,00E-05 E (V vs. Fc/FcH+) Blue: cyclic voltammogram of a 5 mM solution of 5-(tert-butyl)-2-hydroxybenzaldehyde in HFIP/MTBS at 100 mV/s Eox1 = 2.50 V vs Fc/FcH+ Orange: cyclic voltammogram of a 5 mM solution of 5-(tert-butyl)-2-hydroxybenzaldehyde in HFIP/DIPEA at 100 mV/s Eox2 = 1.79 V vs Fc/FcH+ S9 current density j mA/cm2 2-chloro-4-(tert-butyl)phenol 5,00E-04 4,00E-04 3,00E-04 2,00E-04 1,00E-04 0,00E+00 -1 -0,5 0 0,5 1 1,5 2 2,5 3 -1,00E-04 E (V vs. Fc/FcH+) Blue: cyclic voltammogram of a 5 mM solution of 2-chloro-4-(tert-butyl)phenol in HFIP/MTBS at 100 mV/s Eox1 = 1.78 V vs Fc/FcH+ Orange: cyclic voltammogram of a 5 mM solution of 2-chloro-4-(tert-butyl)phenol in HFIP/DIPEA at 100 mV/s Eox2 = 1.56 V vs Fc/FcH+ S10 current density j mA/cm2 4-methyl-2-(methylsulfonyl)phenol 3,00E-04 2,50E-04 2,00E-04 1,50E-04 1,00E-04 5,00E-05 0,00E+00 -1 -0,5 0 0,5 1 1,5 2 2,5 3 -5,00E-05 E (V vs. Fc/FcH+) Blue: cyclic voltammogram of a 5 mM solution of 4-methyl-2-(methylsulfonyl)phenol in HFIP/MTBS at 100 mV/s Eox1 = 2.05 V vs Fc/FcH+ Orange: cyclic voltammogram of a 5 mM solution of 4-methyl-2-(methylsulfonyl)phenol in HFIP/DIPEA at 100 mV/s Eox1 = 1.80 V vs Fc/FcH+ S11 current density j mA/cm2 Synthesis of starting materials 5-(tert-Butyl)-2-hydroxybenzaldehyde oxime 5-(tert-Butyl)-2-hydroxybenzaldehyde (0.89 g, 5.0 mmol, 1.0 equiv.) was dissolved in EtOH (35 mL), pyridine (0.79 g, 10 mmol, 2.0 equiv.), hydroxylammonium hydrochloride (1.7 g, 25 mmol, 5.0 equiv.) were added and the resulting mixture was stirred for 3h at 60 °C. It was then partioned between EtOAc (100 mL) and water (100 mL). The organic faction was then dried over sodium sulfate and evaporated under vacuum to yield 1.0 g (6.2 mmol, quantitative yield) of a colorless crystalline solid. This crude product was directly used in the next reaction. 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.32 (dd, J = 8.6, 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 1.30 (s, 10H). 13C NMR (101 MHz, CDCl3) δ 154.9, 153.3, 142.4, 128.5, 127.3, 116.2, 115.7, 34.0, 31.4. HRMS for C11H16NO +2 (ESI+) [M+H]+: calc. 194.1176, found: 194.1176. S12 5-(tert-Butyl)-2-hydroxybenzonitrile To a solution of the salicylaldoxime (386 mg, 2.0 mmol, 1 equiv.) and triphenylphosphine (PPh3) (1.3 g, 5.0 mmol, 2.5 equiv.) in anhydrous CH2Cl2 (28 mL) was added diisopropyl azodicarboxylate (DIAD) (1.0 g, 5.0 mmol, 2.5 equiv.) dropwise at room temperature. The reaction was stirred at the same temperature under an inert atmosphere until completion (TLC). The reaction mixture was partitioned between further CH2Cl2 (100 mL) and 0.1 M NaOH (50 mL). The aqueous layer was washed with CH2Cl2 (3×50 mL), and then acidified with 1 M HCl (10 mL). The acidic aqueous layer was then extracted by CH2Cl2 (2×50 mL). These organic fractions were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 50:50 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a colorless solid (yield: 53%, 185 mg, 1.06 mmol). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.44 (m, 2H), 6.93 (dd, J = 8.6, 0.6 Hz, 1H), 1.29 (s, 8H). 13C NMR (101 MHz, CDCl3) δ 156.2, 144.4, 132.4, 129.3, 116.9, 116.4, 98.9, 77.2, 34.4, 31.3. HRMS for C11H14NO+ (ESI+) [M+H]+: calc. 176.1070, found: 176.1068. S13 4-Methyl-2-(methylsulfonyl)phenol 4-Methyl-2-(methylthio)phenol (2.0 g, 13 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (25 mL). Then meta-chloroperoxybenzoic acid (5.6 g, 32.5 mmol, 2.5 equiv.) was added portionwise and the reaction was stirred overnight at room temperature. The reaction was then quenched with sat. sodium thiosulfate solution and extracted to CH2Cl2 (20 mL). The combined organic fractions were dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography to yield the desired product as a colorless solid (33%, 0.8 g, 4.3 mmol). 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.47 (dd, J = 2.3, 0.8 Hz, 1H), 7.33 (ddd, J = 8.5, 2.3, 0.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.11 (s, 3H), 2.32 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 153.8, 137.6, 130.6, 128.3, 122.4, 119.1, 77.2, 45.1, 20.4. HRMS for C8H9O3S+ (ESI+) [M+H]+: calc. 185.0272, found: 185.0280. S14 Homo-coupling of phenols carrying EWG 3,3'-Diacetyl-6,6'-dibromo-5,5'-dimethyl-2,2'-biphenol (4) According to the GPI for the electrochemical homocoupling of phenols, 4-bromo-2-hydroxy-5- methylacetophenone (573 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using BDD electrodes. After 1.5 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 95:5 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as an off white solid (yield: 50%, 285 mg, 0.63 mmol). 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 2H), 8.03 (s, 2H), 2.70 (s, 6H), 2.41 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 205.4, 157.3, 134.7, 132.4, 128.1, 127.6, 118.5, 27.2, 22.4. HRMS for C 79 +18H17 Br2O4 (ESI+) [M+H]+: calc.: 454.9488, found: 454.9493 for C 79 81 + +18H17 Br BrO4 (ESI+) [M+H] : calc.: 456.9473, found: 456.9471 for C H 81 + 18 17 Br2O4 (ESI+) [M+H]+: calc.: 458.9540, found: 458.9456 Melting point: >240 °C (decomposition). Crystal structure determination of 4: C18H16Br2O4, Mr = 456.1 g/mol, colourless needles (0.06 x 0.12 x 0.34 mm³), I 2/C (monoklin), a = 13.1111(11) Å, b = 9.5924(7) Å, c = 14.1624(12) Å, V = 1770.5(2) Å3, z = 4, F(000) = 904, ρ= 1.711 g/cm3, µ = 4.60 mm-1, Mo-Kα graphite monochromator, -80 °C, 5553 reflections, 2189 reflections, wR2 = 0.1710, R1 = 0.0859, 1.06 eÅ-3, -0.71 eÅ-3, GoF = 1.051. Single crystals for structure determination were obtained by recrystallization from acetone at room temperature. Deposition Number 1920410 A strong twist of the C-C – axis is observed (circa 90° angle). The molecules interact amongst each other via - – stacking of the respective aromatic systems. S15 Fig. S3: left: molecular structure of 4; right: Packing of 4 in the solid state. 1-(3-(2-Acetyl-5-bromo-4-methylphenoxy)-3-acetyl-5-bromo-4-methylphenol (21) was found as a minor side component in the reaction via GC/MS and could be identified by X-ray analysis. Crystal structure determination of 21 (O-C – coupled product): C18H16Br2O4, Mr = 456.13 g/mol, colourless block (0.06 x 0.7 x 0.13 mm³), C 2/C (monoklin), a = 18.8729 (11) Å, b = 8.7562 (4) Å, c = 21.8974 (10) Å, V = 3445.7 (3) Å3, z = 8, F(000) = 1808, ρ= 1.759 g/cm3, µ = 4.724 mm-1, Mo-Kα graphite monochromator, -80 °C, 4250 reflections, 2618 reflections, wR -3 -32 = 0.1234, R1 = 0.0554, 0.42 eÅ , -0.45 eÅ , GoF = 1.102. Single crystals for structure determination were obtained by recrystallization from acetone at room temperature. Deposition Number 1920411 The molecules are strongly twisted and interact amongst each other via - – stacking of the respective aromatic systems. Fig. S4: left: molecular structure of 21; right: Packing of 21 in the solid state. S16 3,3'-Dichloro-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (5) According to the GPI for the electrochemical homocoupling of phenols, 2-chloro-4-(tert- butyl)phenol (462 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using BDD electrodes. After 1.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 10:90 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a yellow wax, which crystallized upon standing (yield: 30%, 137 mg, 0.37 mmol). 1H NMR (400 MHz, CDCl3δ 7.40 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 5.81 (s, 1H), 1.33 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 146.4, 144.8, 127.5, 126.4, 125.4, 120.9, 34.6, 31.5. HRMS for C + +20H24Cl2O2 (APCI+) [M] : calc.: 366.1148, found: 366.1149. Melting point: 160 °C. S17 3,3'-Diacetyl-5,5'-dimethyl-2,2'-biphenol (6) According to the GPI for the electrochemical homocoupling of phenols, 2-hydroxy-5- methylacetophenone (375 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 1.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 95:5 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a yellow solid (yield: 64%, 238 mg, 0.8 mmol). 1H NMR (400 MHz, CDCl3) δ 12.53 (s, 2H), 7.56 (s, 2H), 7.35 (s, 2H), 2.66 (s, 6H), 2.35 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 204.8, 158.0, 139.3, 130.5, 127.6, 126.5, 119.6, 27.0, 20.7. HRMS for C18H18NaO +4 (ESI+) [M]+: calc.: 321.1098, found: 321.1098. Melting point: 180.5 °C. S18 3,3'-Di(ethyloxycarbonyl)-5,5'-dimethyl-2,2'-biphenol (7) According to the GPI for the electrochemical homocoupling of phenols, ethyl 2-hydroxy-5- methylbenzoate (450 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 1.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 50:50 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a white solid (yield: 41%, 184 mg, 0.51 mmol). 1H NMR (400 MHz, CDCl3) δ 11.08 (s, 2H), 7.71 (dd, J = 2.3, 0.9 Hz, 2H), 7.32 (d, J = 2.3 Hz, 2H), 4.42 (q, J = 7.1 Hz, 4H), 2.34 (s, 6H), 1.43 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 170.6, 157.2, 138.3, 129.6, 127.8, 126.1, 112.4, 61.5, 20.5, 14.6. HRMS for C20H23O +6 (ESI+) [M+H]+: calc.: 359.1489, found: 359.1491. Melting point: 161.5 °C. S19 3,3'-Dicyano-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (8) According to the GPI for the electrochemical homocoupling of phenols, 5-(tert-butyl)-2- hydroxybenzonitrile (175 mg, 1.0 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 1.2 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 50:50 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as an off white solid (yield: 32%, 55 mg, 0.16 mmol). 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 2.6 Hz, 2H), 7.32 (d, J = 2.6 Hz, 2H), 1.24 (s, 18H). 13C NMR (101 MHz, DMSO-d6) δ 132.5, 128.7, 128.0, 119.0, 118.2, 100.6, 59.8, 33.8, 31.1. HRMS for C + +22H25N2O2 (ESI+) [M+H] : calc.: 349.1911, found: 349.1899. S20 3,3'-Dicarboxime-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (9) According to the GPI for the electrochemical homocoupling of phenols, 5-(tert-butyl)- 2-hydroxybenzaldehyde oxime (193 mg, 1.0 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.30 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 1.25 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 0:100 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a yellow wax, which crystallized upon standing (yield: 18%, 35 mg, 0.51 mmol). 1H NMR (400 MHz, Chloroform-d) δ 10.25 (s, 2H), 8.26 (s, 2H), 7.35 (d, J = 2.4 Hz, 2H), 7.20 (d, J = 2.4 Hz, 2H), 1.33 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 153.1, 152.3, 142.4, 130.7, 127.2, 125.9, 116.3, 77.2, 34.2, 31.6. HRMS for C +22H19N2O4 (ESI+) [M+H]+: calc.: 385.2122, found: 385.2121. S21 5,5'-Dimethyl-3,3'-di(methylsulfonyl)-2,2'-biphenol (10) According to the GPI for the electrochemical homocoupling of phenols, 4-methyl- 2-(methylsulfonyl)phenol (450 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using BDD electrodes. After 1.5 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 0:100 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a yellow wax which crystallized upon standing (yield: 43%, 198 mg, 0.51 mmol). 1H NMR (400 MHz, DMSO-d6) δ 7.40 (dd, J = 2.4, 0.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 3.24 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.5, 136.1, 131.2, 127.8, 126.5, 122.4, 42.0, 39.5, 20.1. HRMS for C + +16H18NaO6S2 (ESI+) [M+H] : calc.: 393.0437, found: 393.0434. Melting point: 173.5 °C. S22 3,3'-Diformyl-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (11) According to the GPI for the electrochemical homocoupling of phenols, 5-(tert-butyl)-2- hydroxybenzaldehyde (445.5 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 1.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 10:90 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a colourless wax, which solified upon standing (yield: 14%, 63 mg, 0.18 mmol). 1H NMR (400 MHz, CDCl3) δ 11.25 (s, 2H), 9.95 (s, 2H), 7.72 (dd, J = 2.5, 0.6 Hz, 2H), 7.58 (d, J = 2.5 Hz, 2H), 1.37 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 197.0, 157.1, 142.4, 137.1, 130.1, 125.0, 120.5, 77.2, 34.4, 31.4. HRMS for C +22H17O4 (ESI+) [M+H]+: calc.: 355.1904, found: 355.1914. Melting point: 213.5 °C. S23 3,3'-Dibromo-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (12) According to the GPI for the electrochemical homocoupling of phenols, 2-bromo-4-(tert- butyl)phenol (573 mg, 2.5 mmol, 1.0 equiv.), HFIP (5 mL), and DIPEA (0.05 mL, 0.29 mmol, 0.12 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using BDD electrodes. After 1.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 10:90 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a yellow wax, which solified upon standing (yield: 54%, 250 mg, 0.55 mmol). 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 2H), 7.35 (d, J = 2.5 Hz, 2H), 7.20 (d, J = 2.5 Hz, 2H), 1.33 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 153.1, 152.3, 130.7, 127.2, 125.9, 116.3, 77.2, 34.2, 31.6. HRMS for C 79 +20H24 Br2O2 (ESI+) [M+H]+: calc.: 454.0143, found: 454.0148. for C H 81 +20 24 Br2O2 (ESI+) [M+H]+: calc.: 458.0102, found: 458.0105. for C H 7920 24 Br 81BrO +2 (ESI+) [M+H]+: calc.: 457.0156, found: 457.0157. Melting point: 180 – 182 °C. S24 Cross-coupling of phenols carrying EWG 2-Acetyl-4-methyl-6-(naphthyl)phenol (13) 1H NMR (400 MHz, Chloroform-d) δ 12.41 (s, 1H), 7.89 (ddt, J = 8.2, 4.6, 1.0 Hz, 2H), 7.65 (dd, J = 2.2, 1.0 Hz, 1H), 7.63 – 7.58 (m, 1H), 7.54 (dd, J = 8.2, 7.0 Hz, 1H), 7.48 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.36 (d, J = 2.2 Hz, 1H), 2.72 (s, 3H), 2.39 (s, 3H). HRMS for C +19H17O2 (ESI+) [M+H]+: calc.: 277.1223, found: 277.1225. In a mixture with 14. Sodium 2-acetyl-4-methyl-6-(naphthyl)phenolate (phenolate of 13) cis-8-Acetyl-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan was taken up in CH2Cl2 (0.5 mL) and treated with 1 M NaOH solution (5 mL). The reaction mixture was sirred vigorously over night at room temperature. CH2Cl2 and water were removed under vacuum. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (dd, J = 8.1, 1.4 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.41 (tdd, J = 8.1, 6.9, 2.2 Hz, 2H), 7.35 – 7.27 (m, 2H), 7.23 (dd, J = 7.0, 1.4 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 2.44 (s, 2H), 2.07 (s, 3H). 13C NMR (101 MHz, DMSO) δ 198.0, 159.9, 136.3, 135.3, 133.1, 132.5, 130.2, 127.9, 127.5, 127.5, 126.8, 125.5, 125.4, 124.9, 124.6, 80.6, 48.6, 39.5, 30.9, 20.4. S25 cis-8-Acetyl-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (14) According to the GPIII for the electrochemical cross-coupling of phenols with napthalenes, 2- hydroxy-5-methylacetophenone (75 mg, 0.5 mmol, 1.0 equiv.), naphthalene (192 mg, 1.5 mmol, 3.0 equiv.), HFIP (5 mL), and DIPEA (0.1 mL, 0.57 mmol 1.15 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 2.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 97:3 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as colourless crystals (yield: 35%, 48 mg, 0.17 mmol). 1H NMR (400 MHz, CDCl3) δ 7.50 (dt, J = 2.0, 0.9 Hz, 1H), 7.40 (ddd, J = 7.4, 1.5, 0.9 Hz, 1H), 7.32 (td, J = 7.4, 1.5 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 7.00 (ddd, J = 2.0, 1.5, 0.9 Hz, 1H), 6.52 (dd, J = 10.0, 1.5 Hz, 1H), 5.96 (ddd, J = 10.0, 3.0, 1.5 Hz, 1H), 5.87 (dd, J = 10.0, 3.0 Hz, 1H), 4.68 (d, J = 10.0 Hz, 1H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.2, 156.7, 132.5, 132.3, 130.6, 130.3, 130.2, 129.9, 128.8, 128.6, 128.4, 128.1, 127.9, 124.6, 120.8, 82.5, 43.3, 31.2, 20.8. HRMS for C19H17O +2 (ESI+) [M+H]+: calc.: 277.1223, found: 277.1225. Melting point: 133.5 °C. Crystal structure determination of 14: C19H16O4, Mr = 276.32 g/mol, colourless needle (0.09 x 0.1 x 0.77 mm³), P na21 (orthorombisch), a = 18.9656(16) Å, b = 4.7241(3) Å, c = 15.4178(10) Å, V = 1381.36(17) Å3, z = 4, F(000) = 584, ρ = 1.329 g/cm3, µ = 0.085 mm-1, Mo-Kα graphite monochromator, 120 K, 5378 reflections, 2753 reflections, wR2 = 0.0949, R1 = 0.0371, 0.15 eÅ-3, -0.16 eÅ-3, GoF = 1.005; S26 Single crystals for structure determination were obtained by slowly evaporating acetone at room temperature. Deposition Number 1920412 The structure analysis revealed that the aromatic system is suspended and a dihydrobenzofurane system in Z-conformation is formed. Fig. S5: left: molecular structure of 14; right: Packing of 14 in the solid state. Due to the equilibrium of 13 and 14 only mixtures could be obtained. 14 could be crystallized easily, whereas 13 could not be crystallized in a clean fashion. The phenolate of 13 could be analyzed. (see page 19 in SI). S27 8-Acetyl-10-methylnaphtho[2,1-b]benzo[d]furan (15) cis-8-Acetyl-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (50 mg, 0.18 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (1 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (50 mg, 0.22 mmol, 1.2 equiv.) were added. The mixture was stirred at reflux for 12 h. The resulting red mixture was diluted with ethyl acetate (10 mL) and washed with sat. NaHCO3 solution (10 mL) twice. The organic layer was dried over sodium sulfate and evaporated under vacuum. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 97:3 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a white solid (yield: 83%, 40 mg, 0.15 mmol). 1H NMR (300 MHz, CDCl3) δ 8.62 – 8.51 (m, 1H), 8.34 (dd, J = 1.9, 0.9 Hz, 1H), 8.07 – 7.99 (m, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 1.9, 0.9 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.73 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.57 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 2.97 (s, 3H), 2.62 (d, J = 0.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 196.6, 154.8, 153.1, 132.9, 130.8, 129.5, 129.3, 128.9, 127.6, 127.3, 127.2, 126.8, 124.8, 123.4, 122.2, 116.5, 112.8, 77.2, 31.3, 21.6. HRMS for C H +19 15O2 (ESI+) [M+H]+: calc.: 274.0994, found: 275.1071. S28 2-Acetyl-5-bromo-4-methyl-6-naphthylphenol (16) According to the GPIII for the electrochemical cross-coupling of phenols with napthalenes, 1- 4-bromo-2-hydroxy-5-methyl-acetophenone (115 mg, 0.5 mmol, 1.0 equiv.), naphthalene (192 mg, 1.5 mmol, 3.0 equiv.), HFIP (5 mL), and DIPEA (0.1 mL, 0.57 mmol 1.15 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 2.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 97:3 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a colorless solid (yield: 42%, 75 mg, 0.21 mmol). 1H NMR (400 MHz, CDCl3) δ 12.43 (s, 1H), 7.93 (tt, J = 7.0, 1.0 Hz, 2H), 7.73 (d, J = 1.0 Hz, 1H), 7.59 (dd, J = 8.3, 7.0 Hz, 1H), 7.48 (dq, J = 8.9, 4.9, 4.5 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.34 (dd, J = 7.0, 1.0 Hz, 1H), 2.70 (s, 3H), 2.50 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 204.2, 159.0, 136.4, 135.2, 133.8, 131.6, 131.4, 130.8, 128.9, 128.7, 128.6, 127.6, 126.4, 126.1, 125.6, 125.1, 118.5, 77.2, 27.1, 23.6. HRMS for C H 79BrO (ESI+) [M+H]+19 15 2 : calc.: 355.0289, found: 355.0333. for C 81 +19H15 BrO2 (ESI+) [M+H] : calc.: 357.0269, found: 357.0315. Melting point: 148.5 °C. Due to the equilibrium of 16 and 17 only mixtures could be obtained. 16 could be crystallized easily, whereas 17 could not be crystallized in a clean fashion. S29 cis-8-Acetyl-11-bromo-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (17) 1H NMR (400 MHz, CDCl3) δ 7.67 (ddt, J = 5.6, 1.9, 1.0 Hz, 1H), 7.26 – 7.22 (m, 2H), 7.20 (dt, J = 6.1, 3.1 Hz, 1H), 6.88 (dd, J = 9.6, 0.7 Hz, 1H), 6.23 (dd, J = 9.6, 5.6 Hz, 1H), 5.26 (dd, J = 7.7, 5.6 Hz, 1H), 4.60 – 4.54 (m, 1H), 2.56 (s, 3H), 2.44 (s, 3H). HRMS for C19H 79 +15 BrO2 (ESI+) [M+H] : calc.: 355.0289, found: 355.0333. for C H 81BrO (ESI+) [M+H]+19 15 2 : calc.: 357.0269, found: 357.0315. Due to the equilibrium of 16 and 17 only mixtures of 17 with 16 could be obtained. 16 could be crystallized easily, whereas 17 could not be crystallized in a clean fashion. 13C NMR spectra of the mixture is shown on page 42. S30 8-Acetyl-11-bromo-10-methylnaphtho[2,1-b]benzo[d]furan (18) cis-8-Acetyl-11-bromo-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (20 mg, 0.056 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (2 mL) and 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (50 mg, 0.22 mmol, 3.9 equiv.) were added. The mixture was stirred at reflux for 36 h. The resulting red mixture was diluted with ethyl acetate (10 mL) and washed with sat. NaHCO3 solution (10 mL) twice. The organic layer was dried over sodium sulfate and evaporated under vacuum. The residue was purified by reversed phase column chromatography (gradient: water:acetonitrile = from 50:50 for 3 min to 30:70 for 60 min;) yielding the product as an off white solid (yield: 76%, 15 mg, 0.042 mmol). 1H NMR (400 MHz, CDCl3) δ 9.77 (d, J = 8.8 Hz, 1H), 8.06 – 8.00 (m, 2H), 7.96 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.70 (ddd, J = 8.0, 6.9, 1.5 Hz, 1H), 7.58 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 2.98 (s, 2H), 2.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 196.1, 155.3, 153.7, 134.4, 131.7, 131.4, 129.5, 128.6, 128.5, 128.4, 128.3, 126.4, 124.8, 121.3, 116.7, 112.5, 110.1, 77.2, 31.6, 24.7. HRMS for C19H 7913 BrO2 (APCI+) [M+H]+: calc.: 353.0177, found: 353.0165. for C 8119H13 BrO2 (APCI+) [M+H]+: calc.: 355.0157, found: 355.0147. S31 cis-8-Formyl-6a,11b-dihydro-10-(2,2-dimethylethyl)naphtho[2,1-b]benzo[d]furan and 2- hydroxy-5-(2,2-dimethylethyl)-3-(naphthyl)benzaldehyde (mixture with a ratio of 1:3.3) According to the GPIII for the electrochemical cross-coupling of phenols with napthalenes, 5-(tert-butyl)-2-hydroxybenzaldehyde (89 mg, 0.5 mmol, 1.0 equiv.), naphthalene (192 mg, 1.5 mmol, 3 equiv.), HFIP (5 mL), and DIPEA (0.1 mL, 0.48 mmol, 0.96 equiv.) were transferred into an undivided PTFE cell. Electrolysis was carried out at room temperature with a current density of 5.0 mA/cm² using graphite electrodes. After 2.0 F was applied, HFIP was recovered in vacuo. The residue was purified by column chromatography (gradient: cyclohexane:ethyl acetate = from 100:0 for 3 min to 97:3 for 60 min; column 12 mm x 150 mm; flow rate 12.5 mL/min) yielding the product as a white solid (yield: 3.3%, 5 mg). Data phenolic structure: 1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), 9.89 (d, J = 0.6 Hz, 1H), 7.62 (dd, J = 2.2, 0.9 Hz, 3H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 2.2, 1.4 Hz, 3H), 6.94 (d, J = 8.8 Hz, 1H), 1.33 (s, 9H). Data cyclized structure: 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 7.42 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 7.37 (dd, J = 2.2, 1.4 Hz, 1H), 7.33 (td, J = 7.5, 1.5 Hz, 1H), 7.26 (s, 1H), 7.11 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 – 6.53 (m, 1H), 6.00 – 5.92 (m, 2H), 4.71 (d, J = 9.9 Hz, 1H), 1.33 (s, 3H), 1.26 (s, 9H). Mixture: 13C NMR (101 MHz, CDCl3) δ 197.0, 189.2, 159.6, 158.7, 144.4, 142.9, 134.9, 132.4, 130.5, 130.1, 129.9, 128.5, 128.4, 128.2, 127.9, 124.1, 123.8, 120.1, 119.2, 117.4, 83.1, 77.2, 42.9, 34.6, 31.6, 27.1. S32 NMR spectra Starting materials: 1H NMR of 5-(tert-Butyl)-2-hydroxybenzaldehyde oxime. 13C NMR of 5-(tert-Butyl)-2-hydroxybenzaldehyde oxime. S33 1H NMR of 5-(tert-Butyl)-2-hydroxybenzonitrile. 13C NMR of 5-(tert-Butyl)-2-hydroxybenzonitrile. S34 1H NMR of 4-Methyl-2-(methylsulfonyl)phenol. 13C NMR of 4-Methyl-2-(methylsulfonyl)phenol. S35 1H NMR of 3,3'-Diacetyl-6,6'-dibromo-5,5'-dimethyl-2,2'-biphenol (4). 13C NMR of 3,3'-Diacetyl-6,6'-dibromo-5,5'-dimethyl-2,2'-biphenol (4). S36 1H NMR of 3,3'-Dichloro-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (5). 13C NMR of 3,3'-Dichloro-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (5). S37 1H NMR of 3,3'-Diacetyl-5,5'-dimethyl-2,2'-biphenol. (6) 13C NMR of 3,3'-Diacetyl-5,5'-dimethyl-2,2'-biphenol. (6). S38 1H NMR of 3,3'-Di(ethyloxycarbonyl)-5,5'-dimethyl-2,2'-biphenol (7). 13C NMR of 3,3'-Di(ethyloxycarbonyl)-5,5'-dimethyl-2,2'-biphenol (7). S39 1H NMR of 3,3'-Dicyano-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (8). 13C NMR of 3,3'-Dicyano-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (8). S40 1H NMR of 3,3'-Dicarboxime-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (9). 13C NMR of 3,3'-Dicarboxime-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (9). S41 1H NMR of 5,5'-Dimethyl-3,3'-di(methylsulfonyl)-2,2'-biphenol (10). 13C NMR of 5,5'-Dimethyl-3,3'-di(methylsulfonyl)-2,2'-biphenol (10). S42 1H NMR of 3,3'-Diformyl-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (11). 13C NMR of 3,3'-Diformyl-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (11). S43 1H NMR of 3,3'-Dibromo-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (12). 13C NMR of 3,3'-Dibromo-5,5'-di(2,2-dimethylethyl)-2,2'-biphenol (12). S44 1H NMR of cis-8-Acetyl-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (14). 13C NMR of cis-8-Acetyl-6a,11b-dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (14). S45 1H NMR of 8-Acetyl-10-methylbenzo[2,1-b]dibenzo[d]furan (15). 13C NMR of 8-Acetyl-10-methylbenzo[2,1-b]dibenzo[d]furan (15). S46 1H NMR of 2-Acetyl-5-bromo-4-methyl-6-(naphthalen-1-yl)phenol (16). 13C NMR of 2-Acetyl-5-bromo-4-methyl-6-(naphthalen-1-yl)phenol (16). S47 1H NMR of 2-Acetyl-5-bromo-4-methyl-6-(naphthalen-1-yl)phenol (16) and cis-8-Acetyl-11-bromo-6a,11b-dihydro- 10-methylnaphtho[2,1-b]benzo[d]furan (17) (mixture; ratio 1:3). 13C NMR of 2-Acetyl-5-bromo-4-methyl-6-(naphthalen-1-yl)phenol (16) and cis-8-Acetyl-11-bromo-6a,11b- dihydro-10-methylnaphtho[2,1-b]benzo[d]furan (17) (mixture; ratio 1:3). S48 1H NMR of 8-Acetyl-11-bromo-10-methylnaphtho[2,1-b]dibenzo[d]furan (18). 13C NMR of 8-Acetyl-11-bromo-10-methylnaphtho[2,1-b]dibenzo[d]furan (18). S49 1H NMR 8-Formyl-10-methyl-6a,11b-dihydrobenzo[2,1-b]dibenzofuran and 5-(tert-butyl)-2-hydroxy-3-(naphthalen- 1-yl)benzaldehyde mixture (ratio 1:3.3). 13C NMR cis-8-Formyl-6a,11b-dihydro-10-(2,2-dimethylethyl)naphtho[2,1-b]benzo[d]furan and 5-(tert-butyl)-2- hydroxy-3-(naphthalen-1-yl)benzaldehyde mixture (ratio 1:3.3). S50 1H NMR of Sodium 2-acetyl-4-methyl-6-(naphthalen-1-yl)phenolate 13C NMR of Sodium 2-acetyl-4-methyl-6-(naphthalen-1-yl)phenolate. S51 1H NMR Equlibrium of 13 and 14 after treatment with 1 M HCl. References [1] W. L. F. Armarego, C. L. L. Chai, Purification of laboratory chemicals, Elsevier, Amsterdam, 2013. [2] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26–32. [3] A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49, 971-975; Angew. Chem. 2010, 122, 983–987. (see SI thereof). S52 Article Cite This: Acc. Chem. Res. 2020, 53, 45−61 pubs.acs.org/accounts A Decade of Electrochemical Dehydrogenative C,C-Coupling of Aryls Published as part of the Accounts of Chemical Research special issue “Electrifying Synthesis”. Johannes L. Röckl,‡,⊥ Dennis Pollok,†,⊥ Robert Franke,§,∥ and Siegfried R. Waldvogel*,†,‡ †Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany ‡Graduate School Materials Science in Mainz, Staudingerweg 9, 55128 Mainz, Germany §Evonik Performance Materials GmbH, Paul-Baumann-Str. 1, 45772 Marl, Germany ∥Lehrstuhl für Theoretische Chemie, Ruhr-Universitaẗ Bochum, Universitaẗstraße 150, 44801 Bochum, Germany CONSPECTUS: The importance of sustainable and green synthetic protocols for the synthesis of fine chemicals has rapidly increased during the last decades in an effort to reduce the use of fossil fuels and other finite resources. The replacement of common reagents by electricity provides a cost- and atom-efficient, environmentally friendly, and inherently safe access to novel synthetic routes. The selective formation of carbon− carbon bonds between two distinct substrates is a crucial tool in organic chemistry. This fundamental transformation enables access to a broad variety of complex molecular architectures. In particular, the aryl−aryl bond formation has high significance for the preparation of organic materials, drugs, and natural products. Besides well-known and well-established reductive- and oxidative-reagent-mediated or transition-metal-catalyzed coupling reactions, novel synthetic protocols have arisen, which require fewer steps than conventional synthetic approaches. Electroorganic conversions can be categorized according to the nature of the electron transfer processes occurring. Direct transformations at inert electrode materials are environmentally benign and cost-effective, whereas catalytic processes at active electrodes and mediated electrosynthesis using an additional soluble reagent can have beneficial properties in terms of selectivity and reactivity. In general, these conversions require challenging optimization of the reaction parameters and the appropriate cell design. Galvanostatic reactions enable fast conversions with a rather simple setup, whereas potentiostatic electrolysis may enhance selectivity. This Account discusses the development of seminal carbon−carbon bond formations over the past two decades, focusing on phenols leading to precursors for ligands in, e.g., hydroformylation reaction. A key element in the success of these electrochemical transformations is the application of electrochemically inert, non-nucleophilic, highly fluorinated alcohols such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which exhibit a large potential window for transformations and enable selective cross-coupling reactions. This selectivity is based on the capability of HFIP to stabilize organic radicals. Inert, carbon-based and metal-free electrode materials like graphite or boron-doped diamond (BDD) open up novel electroorganic pathways. Furthermore, novel active electrode materials have been developed to enable intra- and intermolecular dehydrogenative coupling reactions of electron-rich aryls. The application of 2,2′-biphenol derivatives as ligand components for catalysts requires reactions to be carried out on larger scale. In order to achieve this, continuous flow transformations have been established to overcome the drawbacks of heat transfer, overconversion, and conductivity. Modular cell designs enable the transfer of a broad variety of electroorganic conversions into continuous processes. Recent results demonstrate the application of organic electrochemistry to natural product synthesis of the pharmaceutically relevant opiate alkaloids (−)-thebaine or (−)-oxycodone. ■ INTRODUCTION thesis has emerged as an innovative approach which is experiencing a renaissance after being overlooked by the organic Electroorganic Synthesis synthetic community for several decades.5−9 Electric current can Over the past decades, the tremendous increase of global energy be used to induce reduction and oxidation reactions, which are consumption has become a major topic in political and social superior to conventional chemical oxidizing or reducing agents discussions.1 The limited supply of fossil resources will also have from an economic and environmental perspective. The significant influence on the organic synthesis of chemicals. opportunity to use inexpensive and readily accessible electrical Current research is focused not only on efficient reactions and current from renewable resources as an inherently safe reagent processes, but also on sustainable synthetic approaches with a enhances the sustainability aspect of electrooganic synthesis and minor ecological footprint. A strict cutback in carbon dioxide emissions and waste generation can be achieved with sustainable Received: September 29, 2019 synthetic approaches.2−4 In this context, electroorganic syn- Published: December 18, 2019 © 2019 American Chemical Society 45 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Downloaded via UNIV MAINZ on March 27, 2020 at 09:39:51 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Accounts of Chemical Research Article Figure 1. Natural products synthesized using electrochemical key steps. Scheme 1. Electrolysis Parameters and Mode of Operations for Electrodes in Electroorganic Synthesis economic transformations with a minimum of reagent waste produced if durable and nonsacrificial electrode materials are used.10 Research has demonstrated the robustness of electro- chemical reactions, which demonstrate outstanding perform- ance across a broad range of current densities. These high current densities enable short reaction times without signifi- cantly reducing the yield compared to other synthetic routes.11 Relevant progress has been achieved in the field of electro- organic synthesis in the past decades with the synthesis of complex organic molecules including natural products,12 as well as the development of organocatalysis and flow electro- chemistry.13,14Figure 2. Choice of cell design for electroorganic synthesis: Undivided Examples include the synthesis of dixiamycin B15 (a) and divided (b) beaker-type cell. Reproduced with permission from (1) via N,N′-dehydrodimerization, (−)-alliacol A (2) via 16 ref 9. Copyright 2018 American Chemical Society. anodic cyclization, and (−)-thebaine (3) via anodic coupling (Figure 1).17 A comprehensive review on developments in enables otherwise challenging reactions with few steps electroorganic synthesis since the year 2000 has been recently compared to traditional approaches. This leads to atom- provided by Baran et al.6 46 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article prior to establishing a new synthetic method. These parameters differ in their impact on different intermediates. Besides parameters which are in direct correlation with the electrode surface, further diffusion of the intermediates into the electrolyte system depends on parameters such as the ionic strength or solvation (Scheme 1). General parameters include the current density, applied charge, temperature, and addition of supporting electrolytes.8 The electrodes differ in their ability to work as inert or active electrodes according to in their material characteristics (Scheme 1).18 The simplest way is the use of inert electrodes, which are only involved in the electron transfer and the selectivity is proportional to the electrode potential. Common inert electrodes are platinum or carbon-based materials like graphite, glassy carbon, or boron-doped diamond (BDD). Of particular interest is boron-doped diamond which has strong σ- bonds between sp3-hybridized atoms, resulting in the highest (electro)chemical robustness. Additionally, BDD is self- cleaning, enables very clean electron transfers, and can even be considered as sustainable, because it can be produced from methane.19−23 These properties make BDD particularly applicable to electroorganic synthesis as a metal-free electrode Figure 3. (a) ElectraSyn. Reproduced with permission from ref 29. material.24−26Copyright 2019 IKA-Werke GmbH & CO. KG. (b) Setup for This is highly favorable in the synthesis of electrochemical screening experiments. Reproduced with permission pharmaceutically active compounds as it allows the prevention from ref 30. Copyright 2016 American Chemical Society. (c) Setup for of heavy metal contamination. A second approach uses an active continuous flow electrolysis with (d) enlarged view drawing developed electrode material which generates a nonsoluble electrocatalytic in the Waldvogel lab and commercialized by IKA. Reproduced with active species.27 This layer represents an immobilized redox permission from ref 14. Copyright 2017 American Chemical Society. mediator which is formed and regenerated in situ. This electrocatalyst enables electroorganic conversions, being less The general concept of electrosynthesis is based on single dependent on the applied potential since it serves as redox filter. electron transfers at the interface between a solid electrode Further approaches use a soluble active mediator which converts material and a substrate (cathodic reduction) dissolved in the the substrate and is electrochemically regenerated. This can be ion conductive reaction mixture (electrolyte), or from a thought of as the electrochemical regeneration of common substrate to the electrode (anodic oxidation). In comparison chemical reagents. An adaption of the conventional one-pot to conventional organic synthesis, the reaction setup offers a electrolysis for sensitive substrates, whereby all components are large variety of reaction parameters which need optimization present at the time of electrolysis (in-cell) is demonstrated in the Figure 4. Biaryl structures in catalysts, natural products, pharmaceutically active compounds, and materials science. 47 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 2. Different Approaches for Aryl−Aryl Cross-Coupling toward Biaryls Scheme 3. Challenges in Oxidative Cross-Coupling Reactions of Aryls 48 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 4. Research on Anodic Dehydrogenative C,C-Coupling in the Waldvogel lab over More than the Past Decade stepwise reaction. A reagent is converted into an active species components (sp2-hybridized carbon atoms) to give biaryl electrochemically and after complete electrolysis the substrate is structures is therefore of utmost importance (Figure 4).32 added to the active reagent which has already been synthesized There are many examples of biologically active compounds (ex-cell).28 Despite the unique reactivity and avoidance of large which exhibit the biaryl structural motif, such as Knipholone overpotentials, the necessity of additional reagents is disadvanta- (4), extracted from Kniphof ia foliosa, which demonstrates geous for scale-up in terms of economic and ecological aspects. antiplasmodial and antitumoral e ects.36ff In addition, these In general, oxidized or reduced intermediates generated in situ at compounds find application in material sciences, e.g., in the electrode are highly reactive and prone to further reactions.18 molecular electronics like organic light-emitting diodes.37 The Besides the choice of the electrode material, electrochemical broadest and most important field of application is the use of approaches differ in the setup. The advantageous galvanostatic biphenols as ligand precursors for a large variety of transition- protocol works at constant current which enables rapid metal-catalyzed reactions. Phosphite ligands, for example, are transformations at low cost due to a minimum number of very used on industrial scale in the hydroformylation process.38 simple electronic devices and is therefore amenable to scale-up. Biphenols carrying electron-withdrawing groups (EWGs) are This simple setup requires two electrodes in the electrolyte in an excellent precursors for salen-type ligands. These ligands can, for undivided cell connected to a constant current source (Figure example, be used in an asymmetric copolymerization of CO2 2a). Such simple DC power sources can be obtained easily from with meso-epoxides to give optically active polycarbonates.39 hardware stores. The reaction solution consists of an electrolyte 1,1′-Binaphthyl-2,2′-diamine (BINAM) is a promising ligand based on a solvent and, if necessary, additional supporting system which can be used in asymmetric Michael-type electrolyte to facilitate the conductivity. The supporting additions40 as well as hydrogenations of ketones and olefins.41 electrolyte can be a salt, base, or a strong acid. A divided cell A general strategy providing access to this biaryl structural setup has an additional semipermeable or porous membrane motif is the Suzuki−Miyaura reaction, based on the transition between the catholyte and anolyte, which is used for reversible metal-catalyzed coupling reaction of aryl(pseudo)halogenides redox reactions or to prevent instability toward the counter and nucleophilic organometallic species (Scheme 2). The electrode (Figure 2b).6 Potentiostatic electrolysis requires an Suzuki−Miyaura coupling reaction uses oragnoboron re- 42−44 additional reference electrode to control the potential which agents, whereas other commonly employed organometallic 45 46 47,48 enhances the selectivity but prolongs the reaction time and reagent classes are based on Mg, Zn, and Sn. Despite tremendously affords higher investment into the setup excellent selectivity and high yields, this transformation suffers (reference electrode and electrical appliances).9 from environmental and economic drawbacks. These synthetic In this context, various setups are known besides reactions in protocols need prefunctionalized substrates as well as expensive commercially available round-bottom flasks, including the transition-metal based catalysts, which result in (toxic) reagent ElectraSyn designed by Baran et al., screening setups (Figure waste. Additionally, sophisticated reaction conditions are 3a) and beaker-type cells, as well as electroorganic continuous required. flow setups (Figure 3c) developed in the Waldvogel lab. A Modern and more sophisticated alternatives to access biaryl parallel setup of the electrodes is desired to perform trans- structural motifs are oxidative, reagent-mediated coupling formations in a homogeneous electric field without local reactions with direct C−H activation (Scheme 2).49 An potential peaks which would lead to uncontrolled and undesired overview on oxidative coupling reactions with C−H activation side reactions, lowering the selectivity and efficiency of the in comparison with electrochemical reactions has been recently reactions.9 provided by Lei and co-workers. 50,51 The use of convenient − oxidizers such as iron(III) chloride, vanadyl chloride, andCarbon Carbon Bond Formation molybdenum(V) reagents removes the need for prefunctional- In the context of sustainable chemistry, a deeper insight into the ization for selective coupling reactions.52 Organo-based reagents major challenge of organic synthesis, the selective carbon− like (bis(trifluoroactoxy)iodo)benzene (PIFA) or 2,3-dichloro- carbon bond formation, is crucial. Transformations enabling the 5,6-dicyano-1,4-benzoquinone (DDQ) can also simplify intra- and intermolecular formation of these bonds enable access synthetic routes, but they always require additional agents, to a broad variety of complex organic structural motifs. These such as Lewis acids.49,53,54 However, these reactions suffer from motifs have potential for further modification toward natural limited regioselectivity as well as overoxidation, forming products, pharmaceutically active compounds, and ligands for oligomers and polymers (Scheme 3). The desired cross- catalytic transformations.31−35 In this context, a versatile coupling reactions compete with the formation of homocoupled synthetic approach toward the connection of two aromatic products and demonstrate the challenge of oxidative coupling 49 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 5. Mechanistic Rationale of Anodic Transformation of Phenols with Arenes reactions. These undesired byproducts, as well as the use of over- Scheme 6. Source of Selectivity in Anodic Transformations of stoichiometric amounts of the oxidizer, lead to a large amount of Phenols with Arenesa reagent waste. From this point of view, theWaldvogel lab has been interested in the development of a sustainable approach to the synthesis of biaryls to overcome the challenges of oxidative coupling reactions. Novel developments in electrochemical transforma- tions have opened up the possibility of aryl−aryl bond formation using only electric current as the reagent. This leads to an economic and ecologically friendly, inherently safe, robust, and selective synthesis of biaryls.5 Electrical current is considered the future primary energy.55 Due to the fluctuation in the electric grid, supplies of electricity can be extremely inexpensive and will be attractive as a reagent for synthesis. For producers, low costs in the range of 0.005−0.02 US$/kWh are anticipated.56 The use of renewable sources of electricity, such as wind power, photovoltaics, or hydro power, are increasing.57 ■ ANODIC DEHYDROGENATIVE C,C-COUPLING REACTIONS OF ARYLS Waldvogel et al. have been investigating anodic C−H functionalization and coupling reactions of aromatic com- pounds since 2006 (Scheme 4).58 In the early days, the group was devoted to the synthesis of 2,2′-biphenols as precursors for catalysts. After successful development of procedures for the electrochemical synthesis of biphenols, access toward arene- phenols,59 bianilides,60 meta- and para-terphenyls,61 as well as aSolvation shell is indicated in green. cross-coupled products of various heterocycles with phenols was achieved.62−64 Besides the inter- and intramolecular synthesis of 67−69 electron-rich arenes on active molybdenum anodes,65 phenols oxidizers. In this mechanism, an initial oxidation of a carrying electron-withdrawing groups were successfully synthe- phenol I occurs, having the lowest oxidation potential at the sized by adjusting the established procedure and switching to a anode. Subsequently, the deprotonation occurs almost imme- 1,1,1,3,3,3-hexa uoro-2-propanol (HFIP)/base electrolyte sys- diately, since the radical cation is extremely acidic. Thisfl tem.66 phenoxyl radical II still represents an electrophile and can beattacked by an arene III or a phenol that exhibits a higher Postulated Mechanism and Source of Selectivity oxidation potential than the initial phenol component. Rear- While working on the phenol-arene cross-coupling reactions, a omatization of intermediates IV and V followed by a second mechanistic rationale for this conversion (Scheme 5) was anodic oxidation gives rise to the desired biaryl VI.26,59,70,71 postulated by Waldvogel et al. which explains why electro- Highly fluorinated alcohols like HFIP have been revealed as a chemical cross-coupling reactions overcome the mentioned unique solvent class, showing a high electrochemical stability challenges (Scheme 3).59 It is noteworthy that this mechanism and ability to stabilize intermediary radical(-cations).72−77 This also applies when using this HFIP system with conventional protic and polar solvent has a larger solvate effect on phenols 50 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 7. First Attempts on Anodic Transformation of 2,4-Dimethylphenol towardC,C-Homocoupled Product Yield Polycycles Scheme 8. First Efficient C,C-Homocoupling of 2,4- Scheme 9. HFIP/BDD System Enables Efficient Dimethylphenol under Solvent-Free Conditions Homocoupling Reactions of Phenols and Comparison of a Linear Terphenyl with a Protein α-Helix than on arenes, due to its ability of hydrogen bonding. An electron-rich substrate is more prone to oxidation and further follow-up reactions like homocoupling in a nucleophilic attack. These follow-up reactions are likely to occur after diffusion of the intermediates from the electrode surface into the bulk electrolyte.71 The inherent challenge in engineering selectivity for the cross-coupling reaction derives from the direct linkage of oxidation potential and nucleophilicity. The more electron-rich species, the phenol, is (i) more nucleophilic than the arene and therefore (ii) oxidized more easily to create the electrophilic coupling partner in the reaction. Thus, the natural selectivity favors the formation of the homocoupled product. However, it was found that the nucleophilicity of the phenol can be selectively reduced by the use of HFIP as solvent, which facilitates the creation of a solvent shield via hydrogen bonding interactions. Furthermore, water and methanol are slightly basic in HFIP and are used as additives to lower the oxidation potential of the phenol by weakening the solvate shell and favor the deprotonation. These combined effects favor the formation of the desired cross-coupled product through a shift in the oxidation potential (Scheme 6).26,70,71 By theoretical studies employing ab initio molecular dynamics, it could be confirmed that HFIP in combination with additives interacts with the substrates, influencing the electronic structure of a phenoxyl radical intermediate in a cooperative manner to achieve maximum efficiency and selectivity. This is due to the microheterogeneous structure of HFIP, a segregation of polar, apolar, and fluorous phases, resulting in chemically active domains.78 Another rationale for the efficient coupling reaction is that an enrichment of the substrates at the electrode surface (shown for BDD) takes place. 51 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 10. Additives Such as Methanol or Water Allow The first direct selective anodic homocoupling of simple Cross-Coupling of Activated Arenes with Phenols in Good phenols was shown by our group in 2006.58 Anodic coupling Yields reaction of 2,4-dimethylphenol using BDD as anode material selectively provides the homocoupled biphenol 7 (Scheme 8). The electrolysis was performed under solvent-free conditions with small amounts of water and supporting electrolyte being required to enhance conductivity. The commonly used supporting electrolytes in the authors’ work, triethylmethylam- monium methylsulfate and tributylmethylammonium methyl- sulfate, are both technically common and nonsymmetric which enhances biodegradability. Methylsulfate is an inert and inexpensive anion, and the different chain length enables adjustment of the polarity. When tetraphenoxy borates of the corresponding phenol 6 serve as substrates and supporting electrolyte at the same time, this reaction provides the desired 2,2′-biphenol 7 in 85% yield after hydrolytic workup and enables an electroorganic synthesis of pure product from the simple template precursor86 on a multi-kilogram scale using either platinum59 or graphite electrodes.86,87 In 2009 an efficient general method for coupling of phenols The adsorption of the substrates at the electrode is favored by was established for the first time. It was clearly shown that HFIP the attractive lipophilic−lipophilic interactions between the as solvent and BDD as anode material is a very suitable lipophilic electrode and the substrate as well as by the decrease combination for carrying out these reactions selectively toward in the repelling lipophilic-fluorous areas.79 2,2′-biphenol derivatives (Scheme 9).76 The obtained yields Phenol−Phenol Homocoupling were high for the benzodioxole derivative (12), and rather good The selective homocoupling of phenols has faced a significant for 2-naphthol (11), but dropped when applied to different challenge, before the special features of HFIP were known, phenols. Ten years later, the very efficient synthesis of 4,4′- because, upon direct electrolysis in most solvents, overoxidation biphenols could be demonstrated by applying this method, in up and therefore formation of polycyclic structures occurs (Scheme to 60% yield, when the ortho-positions are blocked (13). 88 This 7).58 The Pummerer’s ketone (9) is usually formed as the main electrochemical approach allows not only the synthesis of product, which occurs as skeleton in many natural products, e.g., biarylic structures, but also the access to terarylic structures. (−)-galanthamine or lunarin.80 When Ba(OH)2 is used as Linear teraryls are potential α-helix mimetics, because the supporting electrolyte, the pentacyclic dehydrotetramer 10 is substituents of these teraryls are in sufficient accordance in angle formed in a yield up to 52% in a diastereoselective manner. and distance to amino acid side chains (i, i + 3, i + 7) as stated by Depending on the condition of the following up conditions, this Hamilton et al.89 Furthermore, these linear teraryls are more unusual scaffold 10 can undergo various transformations to stable regarding conformational and proteolytic stability than access a great variety of interesting polycyclic natural product peptide-based drugs for inhibiting protein−protein interac- like structures.81−85 tions.90 Scheme 11. Installation of a TIPS-Protecting Group Enhances the Yield of the Phenol−Phenol Cross-Coupling Reaction Tremendouslya aTIPS = triisopropylsilyl. 52 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Figure 5. Twist of biaryl axis of a TIPS-protected 2,2′-biphenol with HFIP solvation. Scheme 12. Synthesis of Terphenyls as OCO-Pincer Ligands or α-Helix Mimetics Phenol−Arene Cross-Coupling dramatic loss of yield. It was then possible to broaden the scope In 2010, the rst cross-coupling reactions were successfully of these reactions to 30 different phenol-arene combinations.fi performed using phenols and activated arenes.59 Although initial The reaction proceeds selectively in position 2 of the phenol and attempts showed only low yields (up to 39%), an initial proof of works with naphthalenes as arene components (15). concept was achieved. An optimized protocol used water or Phenol−Phenol Cross-Coupling methanol as additives, increasing the yields up to 69% (14, Afterward, Waldvogel et al. focused upon cross-coupling Scheme 10).26 The key parameter to this selectivity is based on reactions between different phenols, enabling the synthesis of the electrolyte (see Scheme 1) used, due to the possibility of nonsymmetric 2,2′-biphenols. Direct cross-coupling of non- using other electrodes like graphite or glassy carbon without modified phenols was achieved in yields up to 86%.91 A 53 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 13. First Efficient Anilide−Anilide C,C-Cross-Couplingsa aPG = protective group. significant increase of the yield up to 92% was achieved by is applied, the yield can be as high as 84% (21), whereas halo employing a triisopropylsilyl (TIPS) protective group on substituents on phenols lead to yields up to 21% (22). component B (17, 92%, Scheme 11), and the reaction was Cross-Coupling Reactions Involving Anilines found to proceed with a broader range of substrates, such as 92 The C,C-coupling of anilines poses a particular challenge. Thebenzodioxoles (18). The protective group can easily be oxidation of aniline with various oxidizers such as potassium cleaved after the dehydrogenative coupling reaction or could chlorate leads to aniline black, which is a complex mixture of serve already a suitably protected building block to install condensed aniline molecules and is used as a black pigment.95 different phosphorus moieties. The anilines must therefore be protected to suppress The extraordinary high yields can be rationalized by oligomerization. Since anilines are poor hydrogen bonding complementary effects due to the bulky TIPS protective acceptors, hydrogen-bonding-based control of selectivity is group. First, the TIPS-group causes a strong twist of the biaryl limited. When a protecting group is installed this situation alters. axis of least 53°, which prevents conjugation of the π-systems The developed synthetic strategy allows the synthesis of (Figure 5).92 Therefore, the products obtained are less prone to different coupling products between phenols and anilides or protected naphthylamines (Scheme 13).96overoxidation. Additionally, increased lipophilicity combined It was also shown with an unchanged electron-rich nature leads to solvation by that this methodology rises easy access to nonsymmetrical HFIP and therefore diminishes the nucleophilicity. This axially chiral N,O-biarylic structures, derived from enantioen- prevents subsequent coupling reactions. riched naphthylamines and phenols. 97 Derivative 25 was synthesized in 74% yield, using acetyl- and benzoyl-protective meta-Terphenyl-2,2′-diols and 2-Hydroxy-para-terphenyls groups. Also halogenated dianilides (26) and naphthylamides So far, the stepwise synthesis of symmetric and nonsymmetric (27) could be successfully converted as well as formanilides.60,98 meta-terphenyl-2,2″-diols and nonsymmetric 2-hydroxy-para- Phenol-Heterocycle Cross-Coupling terphenyls has been investigated (Scheme 12).61,93 First a Furthermore, the use of heterocycles within these electro- phenol-arene system was synthesized, which is later protected. chemical conversions is viable as well. The initial investigations This allows an adjustment of oxidation potentials. Subsequently, were conducted with thiophenes, allowing highly selective a second coupling reaction with a phenol was conducted. This coupling to bi- and teraryl structures in yields up to 60% (28) method provides access toward OCO-pincer ligands in depending on the electrochemical parameters applied (Scheme moderate to high yields, which have manifold applications in 14).64 When using benzo[b]thiophenes, both substitution catalysis, synthesis and material science.94 When an acetyl group patterns, in either position 2 or 3 of the benzothiophene, can 54 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 14. Cross-Coupling of Phenols with Thiophenes and Benzo[b]thiophenes be addressed selectively by the phenol, by simply blocking the inert electrode materials. Changing the electrode material to an other position. Moreover, coupling of phenols in position 2 or 4 active anode, like molybdenum, in HFIP enabled access to is possible, leading to large scope of accessible scaffolds in yields 63 anodic dehydrogenative coupling reactions of electron-richup to 88% (31). arenes analogous to molybdenum(V) reagent-mediated reac- Using benzofurans within the anodic C,C-coupling reaction, a simple C,C bond formation was not observed, but rather a furan tions. 65 It was shown that only traces of molybdenum were metathesis leading to an exchange of the substituents of phenol found in the electrolyte after electrolysis, which does not result and benzofuran occurred (Scheme 15).62 The reaction tolerates from dissolved active species but rather active Mo(HFIP)x halogens such as fluoride (37) and chloride (36) and reaches species, likely Mo(IV) and Mo(V), at the surface. The yields up to 61% (35). It takes place via a protonated established protocol enabled intermolecular access to biaryl dihydrobenzofuro[2,3-b]benzofuran similar to the isolated structures, starting from anisole derivatives in yields up to 67% intermediate (38). Ring opening of these intermediates (39, and starting from veratrole derivatives in yields up to 87% 42) to phenols (40, 43), subsequent β-phenonium shift for 3- substituted derivatives, and deprotonation lead to the respective (Scheme 16). This reaction is valuable for postfunctionalization product (41). After workup, unexpectedly, the more nucleo- reactions due to the tolerance of iodo functionalities (45). philic oxygen of the electron-rich phenol was found within the Furthermore, the application of this protocol on intramolecular benzofuran. coupling reactions gave access to five- to eight-membered rings Active Molybdenum Anode for Dehydrogenative Coupling as well as heterocycles in yields up to 80%, and substrates which Reactions of Activated Arenes notoriously tend to be chlorinated by the stoichiometric reagent To date, the anodic coupling reactions have been applied to (46) or equipped with carboxylic acids could also be phenols or anilides in cross-coupling reactions with arenes at transformed for the first time (47). 55 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 15. Metathesis of Benzo[b]furans with Phenolsa aScope of the reaction and isolated yields are shown. Molecular structure of the isolated tetracyclic intermediate, determined by X-ray analysis including the postulated mechanism for product formation is shown. Coupling of Phenols Carrying EWGs such as halogens (48), acetoxyls (49), sulfonyls (51), and So far, only phenols carrying electron-donating groups could be carbonyls (50) in yields up to 64% (Scheme 17). converted into the desired biphenols. By changing the protocol Application in the Synthesis of Natural Products and and switching to base as additive, without any further supporting Pharmaceutically Active Compounds electrolyte, it is possible to achieve the selective homo- and The isolation of natural products and pharmaceutically active cross-coupling of phenols carrying EWGs. The base lowers the compounds from naturally abundant sources or total synthesis is oxidation potential of the respective starting materials, challenging, cost- and time-demanding. Thus, the idea of facilitating the oxidation, as shown by cyclic voltammetry applying electroorganic transformations on these compounds is studies. This gives easy access to novel polydentate ligands and of high interest to enable an environmentally friendly and cost- precursors for binuclear salen complexes.39,99,100 The cross- effective synthesis. Electroorganic key reactions have been coupling with naphthalene yields cyclic dihydrodibenzofuranes applied to the regio- and stereoselective synthesis of the (52), which can be easily oxidized to dibenzofurans (54). naturally occurring opium alkaloids (−)-thebaine (3) and Interestingly cross-coupled phenol (53) is in equilibrium with (−)-oxycodone (56) (Scheme 18) by our group in a recent (54), which represents an unreported tautomerism. The collaboration with Opatz et al.13,17 The absence of metal-based reaction works with a variety of electron-withdrawing groups, reagents in the electrochemical key step is of high interest for 56 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 16. Intra- and Intermolecular Dehydrogenative Coupling Reaction of Activated Arenes on Active Molybdenum Anodes Scheme 17. Access to 2,2′-Biphenols Carrying Electron-Withdrawing Groups in HFIP/DIPEA Systems and Access to Tetracyclic Compounds 57 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article Scheme 18. Syntheis of (−)-Thebaine and (−)-Oxycodone Using an Anodic Cyclization as a Key Step further medical applications. The key to this electrochemical Author Contributions transformation is the use of a nonsymmetric set of protective ⊥J.L.R. and D.P. contributed equally to this work. groups at the benzylic moiety. This allows cyclization with excellent selectivity and enables suitable downstream processing Funding to the morphine series. It turned out that BDD electrodes J.L.R. is a recipient of a DFG fellowship through the Excellence provide even higher yields for the intermediate and enables Initiative by the Graduate School Materials Science in Mainz synthesis in flow electrolysis as well. (GSC 266). D.P. thanks the Verband der Chemischen Industrie (VCI) for a Kekule ́ Fellowship. ■ SUMMARY AND OUTLOOK Notes In a decade of research, electroorganic transformations have The authors declare no competing financial interest. emerged as a powerful and atom-efficient tool for arene−arene C,C-homo- and cross-coupling reactions. Starting from readily Biographies available compounds, a broad variety of different biaryl Johannes L. Röckl finished his apprenticeship as a laboratory structures have been obtained. The focus has been drawn technician in 2013 at BASF SE, Ludwigshafen and received his B.Sc. toward phenols which find applications in different areas, like from Johannes Gutenberg University in a collaboration with BASF SE catalysis for chemical synthesis as well as potential pharmaceut- working on the total synthesis of natural product derivatives under icals. The total synthesis of natural products can be further supervision of Prof. Dr. Siegfried R. Waldvogel and Dr. Joachim simplified and shortened by leveraging electrochemistry, using Dickhaut in 2016. Afterwards, he was appointed as a scientist in metal-free key steps. insecticide science working on early stage projects, thereof spending 2 We anticipate that future research will focus on optimizing months at the Innovation Campus of BASF India Ltd. as a delegate in electrochemical processes, utilizing effective screening techni- Navi Mumbai, India. After acceptance as a fast-track Ph.D. candidate, ques to maximize efficiency. Design of Experiments (DoE) is he started working on electroorganic synthesis in the Waldvogel lab. one such technique which is commonly used in industry and can Currently, he is a visiting researcher at the ETH, Zurich working on also be applied effectively to academic research. The synthesis of transition metal catalysis under the supervision of Prof. Dr. Bill different substrate classes to offer a broad variety of methods Morandi. including the selective synthesis of carbon−heteroatom bonds will be a challenge in aryl−aryl coupling reactions.Moreover, the Dennis Pollok received his B.Sc. degree from Johannes Gutenberg practical elements of the methods presented here have to be University Mainz in collaboration with the Max Planck Institute for improved to enable large-scale reactions, which do not require Polymer Research in Mainz working on polyphosphate based flame chromatographic purification but rather distillation or crystal- retardants under supervision of Dr. habil. Frederik R. Wurm. During an lization. Therefore, a continuous ow electroorganic setup internship at the University of Toronto he was working in the group offl would enable a transformation which is not interrupted by Prof. Dr. Dwight S. Seferos on polyselenophenes. He received his M.Sc. puri cation processes and which could rather be performed in from Johannes Gutenberg University Mainz working under supervisionfi an external setup. This would allow for the transfer of the of Prof. Dr. Siegfried R. Waldvogel where he is currently conducting methods to technical applications for pioneering sustainable research as a graduate student on electroorganic synthesis. chemical synthesis on an industrial scale. Robert Franke studied chemistry with focus on industrial chemistry and theoretical chemistry at the University of Bochum in Germany. He ■ AUTHOR INFORMATION earned his doctorate degree in 1994 in the field of relativistic quantumchemistry under Prof. Dr. Werner Kutzelnigg. After working for a Corresponding Author period as a research assistant, in 1998 he joined the process engineering *Email: waldvogel@uni-mainz.de. department of the former Hüls AG, a predecessor company of Evonik ORCID Industries AG. He is now Director Innovation Management Hydro- formylation. He was awarded his professorial research degree Siegfried R. Waldvogel: 0000-0002-7949-9638 (Habilitation) in 2002, and since then he has taught at the University 58 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 Accounts of Chemical Research Article of Bochum. In 2011, he was promoted to an adjunct professor. His (15) Rosen, B. R.; Werner, E. W.; O’Brien, A. G.; Baran, P. S. Total research focuses on homogeneous catalysis, process intensification, and Synthesis of Dixiamycin B by Electrochemical Oxidation. J. Am. Chem. computational chemistry. Soc. 2014, 136, 5571−5574. (16) Mihelcic, J.; Moeller, K. D. Oxidative Cyclizations: The Siegfried R.Waldvogel studied chemistry in Konstanz and received his Asymmetric Synthesis of (−)-Alliacol A. J. Am. Chem. Soc. 2004, 126, Ph.D. in 1996 from the University of Bochum/Max Planck Institute for 9106−9111. Coal Research with Prof. Dr. M. T. Reetz as supervisor. After (17) Lipp, A.; Ferenc, D.; Gütz, C.; Geffe, M.; Vierengel, N.; Postdoctoral research at the Scripps Research Institute in La Jolla, CA Schollmeyer, D.; Schaf̈er, H. J.; Waldvogel, S. R.; Opatz, T. A Regio- (Prof. Dr. J. Rebek, jr.), he started his own research career in 1998with a and Diastereoselective Anodic Aryl-Aryl Coupling in the Biomimetic habilitation at the University of Münster. In 2004, he moved to the Total Synthesis of (−)-Thebaine. Angew. Chem., Int. Ed. 2018, 57, University of Bonn as professor for organic chemistry. In 2010, he 11055−11059. became full professor at the Johannes Gutenberg University Mainz. His (18) Möhle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.; main research interests are electroorganic synthesis ranging from Waldvogel, S. R. Modern Electrochemical Aspects for the Synthesis of screening to scale-up, novel electroconversions and transformations of Value-AddedOrganic Products.Angew. Chem., Int. Ed. 2018, 57, 6018− renewables as well as supramolecular sensing. In 2018, he cofounded a 6041. start-up which provides custom electrosynthesis (ESy-laboratories (19) Martínez-Huitle, C. A.; Brillas, E. Synthetic Diamond Films: GmbH). Preparation, Electrochemistry, Characterization, and Applications; The Wiley Series on Electrocatalysis and Electrochemistry; Wiley: Hoboken, N.J, 2011. ■ ACKNOWLEDGMENTS (20) Macpherson, J. V. A Practical Guide to Using Boron Doped Support of the Advanced Lab of Electrochemistry and Diamond in Electrochemical Research. Phys. Chem. Chem. 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(94) Morales-Morales, D. Pincer Compounds: Chemistry and Applications, 1st ed.; Elsevier: Amsterdam, 2018. (95) Kittel, H. Pigmente, Füllstoffe und Farbmetrik. In Lehrbuch der Lacke und Beschichtungen, 2nd ed.; Spille, J., Ed.; Lehrbuch der Lacke und Beschichtungen 5 Bd.; S. Hirzel: Stuttgart, Leipzig, 2003. 61 DOI: 10.1021/acs.accounts.9b00511 Acc. Chem. Res. 2020, 53, 45−61 AAcccceepptteedd AArrttiiccllee 01/2020 Chemistry - A European Journal 10.1002/chem.202001171 COMMUNICATION Electrochemical C-H Functionalization of (Hetero)Arenes – Optimized by DoE Maurice Dörr,[a]+ Johannes L. Röckl,[a,b]+ Jonas Rein,[a] Dieter Schollmeyer, [a] Siegfried R. Waldvogel*[a,b] [a] M. Dörr, J. L. Röckl, J. Rein, Prof. Dr. S. R. Waldvogel Department of Chemistry Johannes Gutenberg University Mainz Duesbergweg 10–14, 55128 Mainz (Germany) E-mail: waldvogel@uni-mainz.de Homepage: https://www.aksw.uni-mainz.de [b] J. L. Röckl, Prof. Dr. S. R. Waldvogel Graduate School Materials Science in Mainz Staudingerweg 9, 55128 Mainz (Germany) [+] These authors contributed equally to this work. Supporting information for this article is given via a link at the end of the document. Abstract: A novel approach towards the activation of different arenes functionalization of different aromatic compounds for a and purines including caffeine and theophylline is presented. The subsequent metal-free or Ni- or Pd-catalyzed cross-coupling simple, safe and scalable electrochemical synthesis of reaction. The electroorganic reactions conducted in simple 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) aryl ethers was conducted beaker type cells left many parameters to optimize. Using a using an easy electrolysis setup with boron-doped diamond (BDD) simple but not very efficient one-variable-at-a-time approach electrodes. Good yields up to 59% were achieved. Triethylamine was (OVAT) does not always lead to satisfying results. Design of used as a base as it forms a highly conductive media with HFIP, Experiment techniques provide high quality information from a making additional supporting electrolytes superfluous. The synthesis comparably low number of experiments.[15],[16],[17] In order to make was optimized using Design of Experiment techniques giving a this efficient, an appropriate screening tool is required, providing detailed insight to the significance of the reaction parameters. The good quality results with sufficient accuracy.[18] In our previous mechanism was investigated by cyclic voltammetry (CV). Subsequent work, benzylic C-H functionalization using HFIP as both solvent transition metal-catalyzed as well as metal-free functionalization led and reagent was reported.[19]–[22] In addition, our group has a long- to interesting motifs in excellent yields up to 94%. standing interest in using HFIP based electrolytes in electro- organic synthesis, since unique reactivity can be attributed to solvent effects and stabilization of intermediates.[5],[23] In the work Cross-coupling reactions represent a very important synthetic described here, the scope of the reaction has been successfully tool used for the formation of aryl-carbon or aryl-heteroatom expanded to further aromatic compounds using a DoE approach, bonds. Substantial efforts have been taken to develop simple and demonstrating the broad applicability of this method. sustainable reactions of this kind, using methods like electrochemistry[1]–[8] or photoredox catalysis.[9] However, The functionalization of xanthine derivatives like caffeine or transition metal catalysis remains dominant in the field of cross- theophylline is of great interest for the development of coupling reactions,[10] despite that often it requires synthesis of pharmaceuticals.[24] The examples shown in Scheme 1 are precursors to introduce e.g. halides or pseudohalides. approved drugs used for the treatment of type II diabetes Furthermore, the costs rise for Rh, Pd or Pt constantly and (Linagliptin)[25] and Parkinson’s disease (Istradefylline)[26],[27] or to strongly, which further increases the desire to avoid transition prevent postoperative vomiting and symptoms of motion sickness metals in organic synthesis.[11] The high selectivity and efficiency (Dimenhydrinate)[28],[29]. Lei et al. recently demonstrated the of the cross-coupling reaction itself might be diminished by the electrochemical oxidative functionalization of caffeine.[30] lack of selectivity and the use of partly hazardous reagents such as bromine, chlorinating agents, trifluoromethanesulfonic anhydride or tosyl chloride during the pre-functionalization.[12] Besides the risks associated with handling such compounds, they generate stoichiometric amounts of reagent waste. In the case of direct oxidative cross-coupling reactions, pre-functionalization is not necessary but stoichiometric amounts of an oxidizer must be used, again resulting in stoichiometric amounts of reagent waste.[13] Electro-organic synthesis, on the other hand, fulfils many of the green chemistry postulates and uses only electrons as an inherently clean reactant, hence minimizing reagent waste to a certain degree.[1]–[8],[14] Furthermore, it offers safe-to-conduct protocols and simple cell setups. Combining the benefits of both Scheme 1. Xanthine derived pharmaceuticals functionalized in position 8 of the worlds we designed an electrochemical protocol for the pre- purine scaffold.[25]–[29] 1 This article is protected by copyright. All rights reserved. Accepted Manuscript Chemistry - A European Journal 10.1002/chem.202001171 COMMUNICATION We present the activation of position 8 of the purine scaffold low current density, high stirring rate and high concentration. The in caffeine and theophylline, as well as derivatization of yield at the center point did not indicate any curvature, so we did naphthalene and aromatic acetamides by installation of the not expect to be close to the maximum yet. With the obtained data 1,1,1,3,3,3-hexafluoroisopropoxide moiety (HFIP). Furthermore, a second plan was designed with these three significant factors the resulting HFIP ethers were amenable to subsequent and, considering that the reaction is electrochemically driven, the derivatization by metal-catalyzed as well as metal-free amount of charge was taken into consideration. A 24-1-plan was nucleophilic substitution reactions. The first electrochemical step conducted and analysed. This time the center point did not match is easy to conduct, free from metals, does not require inert the linear model and hence indicated curvature in the yield in this conditions and the substrates used are readily available, making area of the experimental space. Star points were added to convert this method cost-efficient, simple and quick (Scheme 2). The this plan into a central composite design (CCD).[15],[17] From the screening was conducted in undivided cells made of PTFE results it could be seen that a maximum was reached regarding equipped with two BDD electrodes. This allows for the parallel the amount of charge 𝑄 and the current density 𝑗. The optimal operation of 8. The limited number of electrolysis cells is rewarded conditions in this area were found using the Response Optimizer by highly accurate electrosynthetic data.[18] in Minitab. Scheme 2. Constant current electrolysis of caffeine. The oxidative peak potentials are 1.80 V for 1 and 1.60 V for 2 vs. Ag/AgCl, respectively (see Supporting Information). Figure 1. Minitabs Response Optimizer was used to maximize the yield from The electrochemical installation of alcohols to arenes involves the model obtained through a CCD plan. The predicted yield was 42%. The a major challenge, due to the electron-releasing properties of the labelling was rearranged for better readability. ether moiety. Cyclic voltammetry studies have revealed the mechanism to be of the ECEC type (see Supporting Information) and the products were found to have a lower redox potential than The result shown in Figure 1 indicates that an increase in the starting materials. Therefore, over-oxidation is a significant stirring rate and a decrease in concentration would improve the problem, hence careful optimization of the reaction conditions is yield even further. Due to the high stirring rates we experienced a needed. The caffeyl HFIP ether synthesis was first optimized in lot of failures, so we used the conditions from this step initial screening reactions using an OVAT approach. The isolated (conditions b) for all further reactions. This is discussed in more yield of 2 was 33% by these conditions. With the aim of increasing detail in the supporting information. To verify the model, we the yield and to obtain detailed information about the importance isolated 2 using these conditions and obtained exactly 42% yield. of the parameters investigated, we turned to a DoE approach and Table 2. Comparison between the results of the optimization processes. started with a 25-1-plan with a center point added.[15],[17] The yields during the optimization were determined by qNMR using conditions a) conditions b) 1,3,5-trimethoxybenzene as an internal standard. The factors OVAT optimized DoE optimized examined and their settings are shown in Table 1. mA 𝑗 / 7.2 22.1 Table 1. Factors used in the initial 25-1-plan. cm 𝑄 / F 2 2.61 factor - 0 + (lower level) (center point) (upper level) 𝑣 / rpm 300 700 mol 𝑣 / rpm 200 300 400 𝑐 / 0.25 0.2 L mol mol 𝑐 / 0.1 0.2 𝑐 / 0.15 0.25 0.20 L L mol electrolysis time 5 h 10 min 1 h 45 min 𝑐 / 0.10 0.20 0.15 L product 0.41 mmol 0.42 mmol 𝑄 / F 2.50 2.0 2.25 Isolated yield 33% 42% mA 𝑗 / 30 45 60 cm 𝑣 is the stirring rate, 𝑐 and 𝑐 are the concentrations of caffeine Comparing conditions a) and b), significant improvements and NEt3, 𝑄 is the amount of charge and 𝑗 is the current density. introduced by the optimization via DoE are apparent. The time It was observed that the current density, the stirring rate and needed for the electrolysis dropped to about one third and at the the concentration of caffeine were significant for the yield in this same time, the isolated yield increased by 9%. The significant area of the experimental space. With the best settings being the influence of the stirring rate on the reaction suggests that convection was crucial. Therefore, the setup was changed to 2 This article is protected by copyright. All rights reserved. Accepted Manuscript Chemistry - A European Journal 10.1002/chem.202001171 COMMUNICATION investigate temperature, electrode distance and stirring rate more In conclusion, we expanded the scope of the electroorganic effectively. With these parameters, a 23-plan and a subsequent synthesis of aryl HFIP ethers from our previous work to 22-plan excluding electrode distance (see Supporting Information) heterocycles. Key for these conversions is the amine-HFIP was explored. This way we were able to isolate 2 in 45% yield in electrolyte.[19]–[21] In addition, the value of these intermediates was a 10 mmol scale. The larger cell setup for these plans demonstrated in the activation within subsequent reactions. A demonstrated the scalability of the electrolysis and considering a sustainable alternative to common pre-functionalization using few parameters during the scale-up, the yield could even be hazardous compounds was presented. A DoE approach led to improved further. Besides using a different batch setup, we tried efficient optimization with mild reaction conditions, and shorter to bypass the problem of over-oxidation using a flow setup but the electrolysis times across a range of substrates. The subsequent yields obtained could not meet those of the batch electrolyses.[31] reactions of the caffeyl HFIP ether gave access to various functionalized caffeine derivatives. The scope was extended conducting reactions on a 1.00 to 1.25 mmol scale and both conditions a) and b) (see Table 2) were investigated. Improved results with yields up to 59% could be achieved (Scheme 3). Scheme 4. Scope of the reaction of the caffeyl HFIP ether and yields of the isolated products. [a] NiCl2(PPh3)2 (10 mol%), PPh3 (20 mol%), KCN (4 eq.), Zn (1 eq.) in DMF 115 °C, 4 h; [b] Pd(OAc)2 (5 mol%), XantPhos (10 mol%), KCN (1.5 eq), DMF, 85 °C, 14 h; [c] Pd(OAc)2 (5 mol%), XantPhos (10 mol%), amine (2.0 - 3.0 eq), DMA, 100 °C, 3-14 h; [d] amine (3.0 eq), DMA, 100 °C, 14 h; [e] Cs2CO3 (3.0 eq), phenol/thiophenol (2.0 eq.), DMF, r.t. [f] NaOH (15 eq.) in propan-1-ol/water 1/3, 60 °C, 2 h; [g] K2CO3 (3.0 eq.), propan-1-thiol (2.0 eq.), in DMF, 65 °C, 2h; Experimental Section Detailed information on general procedures, electrolytic conversions and product characterization can be found in the Supporting Information. Scheme 3. Scope of the reaction and yields of the isolated products. The conditions working better are displayed. Acknowledgements As shown in previous work, the HFIP moiety can be used as J. L. Röckl is a recipient of a DFG fellowship through the a leaving group.[20],[21] We wanted to show that this strategy can Excellence Initiative by the Graduate School Materials Science in also be applied to arenes and therefore various functionalization Mainz (GSC 266). J. Rein is a recipient of an undergraduate reactions were conducted. Cyanides could be installed by Scholarship by the Heinrich Böll Foundation. Support of the transition metal-catalysis using nickel or palladium in 38% and Advanced Lab of Electrochemistry and Electrosynthesis – 60% yield, respectively. Metal-free cyanation was not possible in ELYSION (Carl-Zeiss-Stiftung) is gratefully acknowledged. this case. Also, higher yields were achieved in amination reactions with morpholine (11), when Pd was used (94% vs. 75%). Allylic amine (13) and benzylic amine (12) provided yields up to Keywords: electrolysis • CH functionalization • anode • boron- 76%. 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Accepted Manuscript Contents 1 GENERAL METHODS ..................................................................................................................... 1 2 KINETIC AND MECHANISTIC CONSIDERATIONS ............................................................................. 6 3 OPTIMIZATION BY DESIGN OF EXPERIMENT ............................................................................... 12 4 GENERAL PROTOCOLS ................................................................................................................ 27 5 SYNTHESIS ................................................................................................................................. 28 6 REFERENCES .............................................................................................................................. 47 7 1H, 13C AND 19F NMR SPECTRA .................................................................................................... 48 1 Gene al Me hod 1.1 Gas Chromatography (GC/GC-MS) Crude reaction mixtures and purified products were analyzed by gas chromatography (GC) with a GC-2010 (Shimadzu, Ky to, Japan). A quartz capillary column ZB-5 (length: 30 cm, inner diameter: 0.25 mm, layer thickness of stationary phase: 0.25 µm, carrier gas: hydrogen, stationary phase: (5%-phenyl)-methylpolysiloxane (Phenomenex, Torrance, USA) was used. The carrier gas rate was 45.5 cm s-1 and the injection temperature 250 °C. A flame ionization detector (FID) with an inlet temperature of 310 °C was used. Further analysis by gas chromatography mass spectra (GC-MS) using a GC-2010 with a similar column, combined with a GC–MS-QP2010 (Shimadzu, Ky to, Japan) detector with an injection temperature of 250 °C and detection inlet temperature of 310 °C was conducted. All chromatographic data was recorded using the method “hart , which starts at 50 °C with a heating rate of 15 °C min-1 to 290 °C which is held for 8 min. 1.2 Liquid Chromatography Thin layer chromatography (TLC) was performed with “DC Kieselgel 60 F254 (Merck KGaA, Darmstadt, Germany) on aluminum plates and an UV lamp ( = 254 nm, NU-4 KL, Benda, Wiesloch, Germany). No stain was utilized as all starting materials and products absorbed in the UV light at = 254 nm. An automatic silica flash column chromatography system with a control unit C-620, a fraction collector C-666 and a UV photometer C–635 (Büchi, Flawil, Switzerland) was used for all isolations. Silica gel 60 M (0.040 – 0.063 mm, Macherey-Nagel GmbH & Co., Düren, Germany) was used as the stationary phase. Cyclohexane and ethyl acetate or dichloromethane and methanol were used as eluents. S1 The system connected to a computer and controlled with the software BÜCHI Sepacore Control 1.2 Standard Edition. 1.3 High Resolution Mass Spectrometry High resolution electrospray ionization mass spectrometry (HR-ESI) and high resolution atmospheric pressure chemical ionization (HR-APCI) was performed using an Agilent 6545 QTOF-MS (Agilent, Santa Clara, USA). The data given displays the mass-charge- ratio (m/z) of the corresponding compounds. 1.4 NMR Spectroscopy Nuclear magnetic resonance spectroscopy (NMR) was measured using a multi nuclear magnetic resonance spectrometer Bruker Avance III HD 400 (400 MHz) (5 mm BBFO- SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). The chemical shifts (δ) are reported in parts per million (ppm) relative to the residue signal of the deuterated solvent (CDCl3 or DMSO-d6) used for the measurements by the solvent data chart from Cambridge Isotopes Laboratories, USA. For the 19F spectra, ethyl fluoroacetate served as external standard ( = 231.1ppm). The evaluations of 1H and 13C were executed using the software MestReNova 10.0.1- 14719 (Mestrelab Research S.L., Spain) with the assistance of H,H–COSY, C,H–HSQC and C,H–HMBC experiments. The multiplicity of the signals were abbreviated in the following manner: s (singlet), d (doublet), t (triplet), hept (heptet) pseudo-quart (pseudo- quartet), pseudo-quint (pseudo-quintet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets). The coupling constants J have been given in Hertz (Hz). S2 1.5 Melting Point The melting ranges of purified products were measured using M-565 (Büchi, Flawil, Switzerland) with a heating rate of 2 °C min-1. The given melting ranges are not further corrected. 1.6 Cyclic voltammetry Cyclic voltammetry (CV) was performed with a Metrohm 663 VA Stand equipped with a Autolab type III potentiostat (Metrohm AG, Herisau, Switzerland). Working electrode: BDD electrode tip, 2 mm diameter; counter electrode: glassy carbon rod; reference electrode: Ag/AgCl in saturated LiCl/EtOH. Solvent: HFIP, scan rate (unless stated otherwise) v = 100 mV/s, T = 20 °C, c = 5 mM, supporting electrolyte (if used): n-Bu3NMe O3SOMe (MTBS), c(MTBS) = 90 mM. 1.7 X-ray Analysis All data were collected on a STOE IPDS2T diffractometer (Oxford Cryostream 700er series, Oxford Cryosystems, Oxford, United Kingdom) using graphite monochromated Mo K radiation ( = 0.71073 Å). Intensities were measured using fine-slicing and φ- scans and corrected for background, polarization and Lorentz effects. The structures were solved by direct methods and refined anisotropically by the least-squares procedure implemented in the SHELX program system. The supplementary crystallographic data for this paper can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Deposition numbers and further details are given with the individual characterization data. S3 1.8 Data Processing This work was created using the text processing program Word 2016 (Microsoft, Redmond, USA) and ChemDraw Ultra 12.0 (PerkinElmer Inc., Waltham, USA) for the design of the chemical structures and schemes. Figures and graphs have been designed using Excel 2016 (Microsoft, Redmond, USA) and Origin 7.5 (OriginLab Corperation, Northhampton, USA). The planning and evaluation of the experiments during the optimization by design of experiments was done in Minitab 19.2 (Minitab, LLC, State College, USA). 1.9 Electrochemistry Setup An undivided electrolysis cell made of polytetrafluoroethylene (PTFE) are used as the screening cells. The electrolysis cell has a maximum volume of 6 mL and can be capped with a cover made of PTFE. Detailed information about used cells are already reported.[1] Further, the complete setup with these cells is commercially available as the IKA Screening System, IKA-Werke GmbH & Co. KG, Staufen, Germany. The electrodes (boron-doped diamond electrodes, 0.3 cm x 1 cm x 7 cm, 15 m diamond layer, the support material is silicon) are attached to the cover. Since they dip about 1.8 cm into the reaction solution if 5.1 mL are used, they have an effective area of 1.8 cm2. Eight PTFE cells can be positioned in an arrangement of steel (Figure 5), which can be heated and cooled by connecting the steel block to a thermostat. The electrodes of the electrolysis cells are connected to an eight-channel galvanostat, made by the technical workshop at the University Bonn. The latter has an integrated charge counter so that it automatically stops the current supply and thus the electrolysis when a specified charge quantity is applied. The galvanostat allows electrolysis up to a voltage of 30 V and a current of 50 mA to be operated. Alternatively, the corresponding IKA System can be used. S4 Figure 1: Screening setup with eight undivided screening cells operated with an eight channel galvanostat (left) and a cross section of a metal screening arrangement equipped with undivided screening cells (right).[1] S5 2 Kine ic and Mechani ic Con ide a ion The major challenge in the electrochemical synthesis of oxygen substituted arenes is over-oxidation. This is due to the mesomeric electron-releasing effect of oxygen substituents that leads to a lowered oxidation potential compared to the starting material. In the case of the anodic oxidation of naphthalene in an acetone-water mixture 1-naphthol is only observed in traces as an intermediate.[2] In contrast the HFIP naphthyl ether was isolated as the major product of the electrolysis of naphthalene in HFIP, which is also a result of the strong negative inductive effect of the trifluoromethyl substituents increasing the oxidation potential, compared to non- fluorinated naphthyl ethers. As stated in subsection 3.1.3 and section 3.2, over-oxidation still limits yields of the electrolysis, as the reaction must be stopped prior to full conversion to achieve the maximal yield. Mechanistic insight can provide valuable information on how to limit over- oxidation. S6 2.1 Mechanism of the Formation of HFIP Caffeyl Ether Figure 2: (left) Cyclic voltammogram of a 5 mM solution of caffeine in a 0.1 M solution of NEt3 in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s (orange) and 500 mV/s (blue). (right) Cyclic voltammogram of a 5 mM solution of caffeine in a 0.1 M solution of tributylmethylammonium sulfate (MTBS) in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s (green) and 500 mV/s (purple). The oxidative formation of HFIP ethers requires at least four elementary steps: twofold oxidation of the aryl (E), deprotonation (C), and nucleophilic attack by HFIP (C), the order of the steps differs between different substrates. For instance, the formation of the HFIP benzyl ether from 4-methylguaiacol follows a ECECC mechanism, where the first and second homogeneous follow-up reactions (C) steps are deprotonations and the last step is the conjugated 1,6-addition of a HFIP. The cyclic voltammogram (CV) of caffeine in HFIP/ NEt3 with a scan rate of 100 mV/s has only one peak at 1.80 V (vs. Ag/AgCl in saturated LiCl in EtOH) (orange). This indicates that the reaction follows an ECEC pathway, where the oxidation potential of the second oxidation is lower than that of the first oxidation. The oxidations are coupled with an irreversible fast chemical reaction, as indicated by the lack of a cathodic peaks at scan rates up to 500 mV/s. S7 The cyclic voltammogram of caffeine in HFIP/MTBS at 100 mV/s shows two distinct anodic peaks at anodic peak potentials of 1.88 V (vs. Ag/AgCl in saturated LiCl in EtOH) for the first oxidation and 2.41 V (vs. Ag/AgCl in saturated LiCl in EtOH) for a second oxidation step. The oxidations are also coupled with an irreversible fast chemical reaction. The second peak in the cyclic voltammogram of caffeine in HFIP/MTBS is evidence for an oxidation pathway that differs from the ECEC mechanism of caffeine in HFIP/ NEt3. The high anodic peak potential (2.41 V) suggests that the second oxidation results in high energy intermediate. The potential shift of the first anodic peak potential in anodic direction (+0.08 V) suggest that the follow-up reaction is slower or hindered in HFIP/MTBS.[3] NEt3 deprotonates HFIP and generates HFIP anions, which either deprotonate or nucleophilicity attack cationic intermediates with second-order rate laws. Therefore, a study of the potential shift depending on the concentration of HFIP anions, cannot be used to determine the follow- up reaction, as HFIP anions are involved in both possible ECEC mechanisms. Computational calculations performed at the B3LYP/6-31G* level found that the electron density of caffeine s HOMO is mostly located in C-8, N-7 and in the double bond between C-4 and C-5.[4] The LUMO is mostly located at C-8, N-9 and in the double bond between C-4 and C-5. According to Koopmans theorem for open shell intermediates the SOMO and LUMO have a similar electronic structure after a SET oxidation.[5] Thus, a big C-8 LUMO coefficient is in line with a high regioselectivity of a nucleophilic attack of HFIP anions to that position, in caffeine and other xanthines. Figure 3 shows two mechanism for the electrolysis of caffeine in HFIP/ NEt3, for simplicity all oxidation steps are assumed to occur at the anode without involvement of homogeneous electron-transfer, as the data is insufficient to make such predictions. S8 Figure 3: Different ECEC mechanisms of the electrolysis of caffeine in HFIP/NEt3 (red and green). a) E vs. Ag/AgCl in saturated LiCl in EtOH. The first elementary reaction of the electrosynthesis of HFIP caffeyl ether (2) is a SET oxidation of caffeine (1) to the caffeine radical cation (I). The spin density is delocalized across C-8, N-7, C-4 and C-5. In HFIP/NEt3 solution an ECEC mechanism takes place. The open-shell intermediate IIa is formed after a second-order nucleophilic attack, of HFIP anions, to the LUMO orbital of the I (green). The spin density is delocalized as a -radical. IIa is anodically oxidized S9 to the delocalized iminium cation IIIa. The SOMO orbital of IIa is antibonding, as visualized by the valence bond structure displayed above, which has a high unpaired spin density in the antibonding *-orbital of the C8–N7 double bond. Hence, the oxidation leads to a delocalized iminium cation with an increased bond order, as no antibonding orbitals are occupied. This is in line with the CV data, that the oxidation potential of the second SET is lower than that of the first oxidation. Deprotonation IIIa with HFIP anions or NEt3 leads to the formation of the desired HFIP caffeyl ether (2). In the alternative ECEC mechanism (red) the caffeine radical cation (I) is deprotonated by HFIP/NEt3. This step has a high activation barrier, compared with the deprotonation of anilide or phenol radical cation, as the C8–H bond is orthogonal to the SOMO orbital. A resonance stabilized radical cation (I) reacting to a radical occupying a sp2-orbitals (IIc) is hence unlikely. The SET oxidation of this radical would lead to a sp2-cation (IIIb), which is highly unstable because sp2-orbitals are low in energy orthogonal to the -system of the imidazole subunit. Thus, the oxidation would require more energy than the initial oxidation of caffeine, which contrary to the cyclic voltammogram. Therefore, this reaction mechanism (red) can be excluded. The oxidation of caffeine in HFIP/MTBS follows a different pathway. This can be attributed to the lower nucleophilicity of HFIP, which stabilizes cationic intermediates such as the radical cation I, compared to HFIP anions.[6] Thus, the chemical follow-up reaction, which furnishes IIa, is a lot slower and enables other reaction pathways as evident by the second anodic peak at 2.41 V (vs. Ag/AgCl in saturated LiCl in EtOH). 2.2 Oxidation Potential of HFIP Ether Cyclic voltammograms of HFIP caffeyl ether, Naphthalene, and HFIP naphthyl ether in HFIP/NEt3 were recorded to examine the oxidation potential of the HFIP ethers compare to the starting materials (Figure 4). At a scan rate of 100 mV/s HFIP caffeyl ether is irreversible oxidized with an anodic peak potential of 1.60 V (vs. Ag/AgCl in saturated LiCl in EtOH), which is lower the anodic peak potential of caffeine 1.80 V (vs. Ag/AgCl in saturated LiCl in EtOH). S10 Figure 4: Left: Cyclic voltammogram of a 5 mM solution of HFIP caffeyl ether in a 0.1 M solution of NEt3 in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s (black) and 500 mV/s (red). Right: Cyclic voltammograms of 5 mM solutions of naphthalene (yellow) and HFIP naphthyl ether (blue) in a 0.1 M solution of NEt3 in HFIP. With a BDD anode and a glassy carbon cathode at scan rates of 100 mV/s. The anodic peak potential of HFIP naphthyl ether (1.39 V vs. Ag/AgCl in saturated LiCl in EtOH) is slightly lower than that naphthalene (1.41 V vs. Ag/AgCl in saturated LiCl in EtOH). This indicates that the mesomeric electron-donating effect is not fully suppressed by the negative inductive effect of the trifluoromethyl-groups, and results in an activation of the product. The similar or lower oxidation potential of the products lead to competing reaction. Thus, the maximal yields are achieved before full conversion of the starting material. S11 3 Op imi a ion b De ign of E pe imen The following experimental designs were planned and evaluated with Minitab 19.2. The given NMR Yields were obtained using 1,3,5-trimethoxybenzene as an internal standard. It was added after removing the solvent in vacuo. The experiments were conducted according to GP1 with the given changes to the experimental factors (Table 1, Table 2, Table 3 and Table 4). Caffeine was used to optimize the reaction conditions. Figure 5: Reaction optimized by DoE. 3.1 Initial experimental design (25-1-Plan) in 0.75–2.0 mmol scale The first design was a 25-1-plan, consisting of 34 experiments (2 x 16 corners, + 2 x 1 central point) and had a resolution of V. The factors investigated on, were the speed of the magnetic stirrer, the concentrations of caffeine and the base, the amount of charge applied to the system and the current density. The run order was randomized regarding their factor settings except for the stirrer speed. By having the experiments sorted by stirrer speed we could make use of the screening setup and perform 8 reactions simultaneously. S12 Table 1: Parameters of the first experimental design. Static parameters: 5 mL HFIP + NEt3, BDD- electrodes, 40 °C. Standard Run Stirrer Concentration Concentration Amount of Current NMR Order Order speed [mol/L] NEt3 [mol/L] charge [F] density Yield [min-1] [mA/cm²] [%] 25 1 200 0,15 0,10 2,50 30 19,2% 15 2 200 0,25 0,20 2,50 30 22,5% 5 3 200 0,15 0,20 2,00 30 21,7% 27 4 200 0,25 0,10 2,50 60 20,2% 13 5 200 0,15 0,20 2,50 60 16,2% 21 6 200 0,15 0,20 2,00 30 21,1% 31 7 200 0,25 0,20 2,50 30 23,0% 11 8 200 0,25 0,10 2,50 60 23,6% 9 9 200 0,15 0,10 2,50 30 24,2% 7 10 200 0,25 0,20 2,00 60 16,0% 1 11 200 0,15 0,10 2,00 60 15,0% 19 12 200 0,25 0,10 2,00 30 20,9% 29 13 200 0,15 0,20 2,50 60 13,3% 17 14 200 0,15 0,10 2,00 60 17,3% 3 15 200 0,25 0,10 2,00 30 21,9% 23 16 200 0,25 0,20 2,00 60 16,6% 33 17 300 0,20 0,15 2,25 45 22,5% 14 18 400 0,15 0,20 2,50 30 28,1% 32 19 400 0,25 0,20 2,50 60 23,4% 8 20 400 0,25 0,20 2,00 30 27,2% 24 21 400 0,25 0,20 2,00 30 27,9% 12 22 400 0,25 0,10 2,50 30 26,8% 6 23 400 0,15 0,20 2,00 60 19,9% 28 24 400 0,25 0,10 2,50 30 31,2% 16 25 400 0,25 0,20 2,50 60 24,7% 20 26 400 0,25 0,10 2,00 60 24,7% 18 27 400 0,15 0,10 2,00 30 26,1% 30 28 400 0,15 0,20 2,50 30 24,0% 26 29 400 0,15 0,10 2,50 60 20,9% 10 30 400 0,15 0,10 2,50 60 19,3% 4 31 400 0,25 0,10 2,00 60 20,1% 22 32 400 0,15 0,20 2,00 60 20,8% 2 33 400 0,15 0,10 2,00 30 21,3% 34 34 300 0,20 0,15 2,25 45 20,7% The models summary as well as a Pareto Chart, Residual Plots and the Main Effects Plot of the fit for the NMR yield are given below: S13 Model Summary S R-sq R-sq(adj) R-sq(pred) 0,0203403 86,78% 74,33% 47,11% S14 There are three significant factors to the system as can be seen from the Pareto Chart above. Those are the current density, the stirrer speed and the concentration of caffeine. The Main Effects Plot shows, that high stirrer speeds, high concentrations and low current densities seem to be beneficial in this area of the experimental space. Therefore, the next experiments were designed to follow this trend. 3.2 Second experimental design (24-1-Plan + CCD) in 5 mL-cells The experimental settings are shown in the upper part of Table 2. The concentration of the base was considered not significant and was not further investigated on in this design. The higher concentration was used to promote a good conductivity. With a confidence level of 95% the amount of charge showed no significant effect in the last design but was considered relevant anyway, since the reaction is driven electrochemically and therefore the amount of charge should be relevant even if the effect might be small between the chosen levels. With the four factors left we used a 24-1-Plan with a resolution of IV consisting of 18 experiments (2 x 8 corners + 2 x 1 central point). The central point did not fit the linear model as can be seen in the Main Effects Plot shown below. S15 Therefore the plan was expanded to a Central Composite Design (CCD) by adding star points and repeating the central point one more time (lower part of Table 2). Table 2: Parameters of the second experimental design. Static parameters: 5 mL HFIP + NEt3 (0.2 M), BDD electrodes, 40 °C. Standard Run Stirrer speed Concentration Amount of Current density NMR yield Order Order [min-1] [mol/L] charge [F] [mA/cm²] [%] 5 1 400 0.25 3.00 30 34.6% 7 2 400 0.35 3.00 20 33.4% 9 3 400 0.25 2.50 20 29.4% 15 4 400 0.35 3.00 20 32.1% 18 5 500 0.30 2.75 25 35.0% 2 6 600 0.25 2.50 30 36.9% 4 7 600 0.35 2.50 20 34.4% 12 8 600 0.35 2.50 20 31.6% 10 9 600 0.25 2.50 30 34.2% 17 10 500 0.30 2.75 25 33.4% 6 11 600 0.25 3.00 20 36.8% 16 12 600 0.35 3.00 30 29.0% 14 13 600 0.25 3.00 20 36.8% 8 14 600 0.35 3.00 30 30.3% 13 15 400 0.25 3.00 30 26.3% 1 16 400 0.25 2.50 20 31.5% 11 17 400 0.35 2.50 30 26.4% 3 18 400 0.35 2.50 30 26.6% 19 19 300 0.30 2.75 25 28.7% 20 20 700 0.30 2.75 25 31.0% 21 21 500 0.20 2.75 25 36.2% 22 22 500 0.40 2.75 25 34.6% 23 23 500 0.30 2.25 25 26.9% 24 24 500 0.30 3.25 25 28.9% 25 25 500 0.30 2.75 15 33.1% 26 26 500 0.30 2.75 35 27.3% 27 27 500 0.30 2.75 25 34.6% S16 CCD 24-1-Plan The resulting Response Surface Plots as well as a model summary are given below. It can be seen that a maximum was found regarding the stirrer speed, the current density and the amount of charge with the other factors held at their central settings. For the stirrer speed there is one exception to the maximum. The upper left plot suggests an increase in yield towards high stirrer speeds and low concentrations. Model Summary S R-sq R-sq(adj) R-sq(pred) 0,0212351 79,82% 62,52% 24,27% Using the Response Optimizer of Minitab 19.2 to maximize the NMR yield by the obtained non-linear model, we found that the best conditions would be at the corners of the investigated experimental space regarding the stirrer speed and concentration, while for the amount of charge and current density again a maximum was found. Using those S17 settings and isolating the product by column chromatography we achieved exactly 42% isolated yield as predicted by the model. The Response Optimizers output is given below. We tried to use even higher stirrer speeds with lower concentrations in a subsequent design, but this led to a significant number of failures since the stirring bars couldn t keep up with the high speeds and were only shaking after a while. Changing the Magnetic stirrer helped improve that but led to overall lower yields. Therefore, the conditions shown above were used for all following reactions. 3.3 First experimental design (23-Plan) on a 10 mmol scale in a temperable beaker type cell Since the stirrer speed was crucial, increasing the yield in the 5 mL-cells, we investigated on the distance of the electrodes and the temperature expecting them to influence diffusion and the availability of deprotonated HFIP to the oxidized caffeine species. In order to change the distance of the electrodes we turned the electrode mounting to the same direction, towards or away from each other. Furthermore, we used a bigger, temperable cell and charged it with 50 mL HFIP, 1.39 mL NEt3 (1.01 g, 10.0 mmol, 1 eq.) and 1.94 g caffeine (10.0 mmol). S18 Figure 6: Beaker type-cell used for electrolysis of 50 mL electrolyte. The inner diameter is 4.69 cm. The outer shell is used in combination with a thermostat to control the temperature. Left: fully assembled cell, a condenser was added at the open end on the right. Right: parts of the setup with a 1 coin for size comparison. To increase reproducibility, we cleaned the BDD electrodes by electrolyzing 70 mL diluted sulfuric (20 mM) acid with 900 mA until 200 C passed before starting the experiment. The used settings of the chosen 2³-plan are given in Table 3. S19 Table 3: Parameters of the third experimental design. Static parameters: 50 mL HFIP + NEt3 (0.2 M), caffeine 0.2 M, BDD electrodes (decentrally mounted), 2.61 F, 22.07 mA/cm². Standard Order Run Order Distance of electrodes [mm] Temperature [°C] Stirrer speed [min-1] NMR yield [%] 9 1 10,75 30 600 37.3% 8 2 17,00 40 700 43.0% 5 3 4,50 20 700 29.8% 10 4 10,75 30 600 37.0% 2 5 17,00 20 500 28.4% 3 6 4,50 40 500 36.5% 1 7 4,50 20 500 28.9% 6 8 17,00 20 700 31.6% 4 9 17,00 40 500 41.8% 7 10 4,50 40 700 37.3% Bearing in mind, that a parallel execution of experiments was not possible because of the changed setup, we tried to keep the number of experiments as little as possible and only repeated the central point. To be able to estimate the residues, despite the small number of degrees of freedom in this plan, we did a backwards elimination of the model s terms while evaluating the results, choosing an “ to remove of 5%. Doing so, the software will iteratively remove the term with the smallest p-value (least significant term) from the model and evaluate the data again. The resulting model s summary as well as a Pareto Chart, Residual Plots, the Main Effects Plot and the Interaction Plot of the fit for the NMR yield are given below: Model Summary S R-sq R-sq(adj) R-sq(pred) 0,0069778 99,22% 98,24% 94,46% S20 S21 S22 The setup used, allowed only the given distances of the electrodes. Therefore, we used the one that gave best results, which was 17 mm, for the following, final experimental design. 3.4 Final experimental design (22-Plan) Only the Temperature and the stirrer speed were left to optimize in the given setup. The used settings of the chosen 22-plan are given in Table 4. Table 4: Parameters of the fourth experimental design. Static parameters: 50 mL HFIP + NEt3 (0.2 M), caffeine 0.2 M, BDD-electrodes, 17 mm between the electrodes, 2.61 F, 22.07 mA/cm². Standard Order Run Order Temperature [°C] Stirrer speed [min-1] NMR yield [%] 1 1 40 500 44,7% 4 2 56 700 42,7% 3 3 40 700 39,5% 2 4 56 500 48,1% 5 5 48 600 49,2% 6 6 48 600 48,8% 7 7 48 600 47,5% The resulting model s summary as well as a Pareto Chart, Residual Plots, the Main Effects Plot and the Interaction Plot of the fit for the NMR yield are given below: Model Summary S R-sq R-sq(adj) R-sq(pred) 0,0086416 98,12% 94,35% * S23 S24 It can be seen from the Main Effects Plot as well as the Interaction Plot that the center point does not fit into the linear model. Indeed, it is way above the expected value from a S25 linear system. Therefore, we assume, that the center point is somewhere close to the maximum and isolated the product with these settings with 45% yield. S26 4 Gene al P o ocol 4.1 GP1 Electrochemical synthesis of HFIP ethers optimized by OVAT (conditions a) An undivided screening cell equipped with a stirring bar and heated to 40°C was charged with the respective purine or arene (1.25 mmol, 1.0 eq.), HFIP (5 mL) and NEt3 (51 mg, 70 µL, 0.50 mmol, 0.4 eq.). The solution was electrolyzed with BDD electrodes (distance: 4.5 mm, surface in the solution: 1.00 cm x 1.80 cm) applying a current density of 7.2 mA/cm² while stirring at 300 rpm until the required charge was applied. The reactions were monitored by TLC and GC-MS. HFIP was recovered in vacuo. Purification was performed using flash column chromatography. 4.2 GP2 Electrochemical synthesis of HFIP ethers optimized by DoE (conditions b) An undivided screening cell equipped with a stirring bar and heated to 40°C was charged with the respective purine or arene (1.00 mmol), HFIP (5 mL) and NEt3 (101 mg, 139 µL, 1.00 mmol, 1.0 eq.). The solution was electrolyzed with BDD electrodes (distance: 4.5 mm, surface in the solution: 1.00 cm x 1.80 cm) applying a current density of 22.1 mA/cm2 while stirring at 700 rpm until the required charge was applied. The reactions were monitored by TLC and GC-MS. HFIP was recovered in vacuo. Purification was performed using flash column chromatography. S27 5 S n he i 5.1 8-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)caffeine (2) Synthesis in 1.00 mmol scale The electrolysis of caffeine (149.2 mg, 1.00 mmol) was conducted according to GP2 until a charge of 2.61 F was applied. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0–60% in 60 min, then 60-100% in 20 min), yielding a crystalline colorless solid (152.0 mg, 0.422 mmol, 42%). Synthesis in 10.0 mmol scale An undivided beaker type-cell (see Figure 6) equipped with a stirring bar and heated to 48°C was charged with caffeine (1.942 g, 10.0 mmol, 1.0 eq.), HFIP (50 mL) and NEt3 (1.010 g, 1.390 mL, 10.00 mmol, 1.0 eq.). The solution was electrolyzed with BDD electrodes (distance: 17 mm, surface in the solution: 2.00 cm x 2.17 cm) applying a current density of 22.1 mA/cm2 while stirring at 600 rpm until the 2.61 F was applied. HFIP was recovered in vacuo. Purification was performed using flash column chromatography on silica gel eluting with ethyl acetate in cyclohexane (0–60% in 60 min, then 60-100% in 20 min), yielding a crystalline colorless solid (1.623 g, 4.51 mmol, 45%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 6.06 (hept, J = 6.0 Hz, 1H, H–2'), 3.77 (s, 3H, H– 14), 3.44 (s, 3H, H–11), 3.31 (s, 3H, H–13). S28 13C NMR (101 MHz, CDCl3): δ [ppm] = 154.8 (C–3), 152.1 (C–8), 151.3 (C–5), 144.7 (C– 1), 120.1 (qd, J = 283 Hz, 2.4 Hz, C–3'), 104.7 (C–2), 73.0 (hept, 35.7 Hz, C–2'), 30.2 (C– 14), 29.7 (C–11), 27.7 (C–13). 19F NMR (376 MHz, DMSO-d6): δ [ppm] = -73.89 (d, J = 6.1 Hz). Mp: 159.1 °C (crystallized from ethyl acetate). HRMS of ([C11H10F6N4O3]+H)+ (ESI+) [M+H]+: calculated: 361.0735, found: 361.0738. Crystal structure determination of 2: C10H10F6N4O3, Mr = 360.23 g/mol, colorless block (0.23 x 0.35 x 0.57 mm³), P 21/C (monocline), a = 13.3525(8) Å, b = 8.4536(4) Å, c = 13.1687(15) Å, V = 1444.06(15) Å3, z = 4, F(000) = 728, = 1.657 g/cm3, µ = 0.171 mm- 1, Mo-K graphite monochromator, -80 °C, 8332 reflections, 3436 reflections, wR2 = 0.1096, R1 = 0.0385, 1.06 eÅ-3, -0.24 eÅ-3, GoF = 1.03. (CCDC deposition number: 1988067) A suitable single crystal for structure determination was obtained by recrystallization from acetone at room temperature. Figure 7: left: molecular structure of 2; right: Packing of 2 in the solid state. The molecules interact amongst each other via - – stacking of the respective purine scaffolds. S29 5.2 8-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)theophylline (3) The electrolysis of theophylline (225.2 mg, 1.25 mmol) was conducted according to GP1 until a charge of 2.00 F was applied. The crude product was purified using flash chromatography on silica gel eluting with methanol in dichloromethane (0–5% in 45 min, then 5–10% in 25 min), yielding a crystalline colorless solid (135.8 mg, 0.393 mmol, 31%). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 13.76 (s, 1H, H–9), 7.05 (hept, J = 6.1 Hz, 1H, H–3'), 3.41 (s, 3H, H–12), 3.22 (s, 3H, H–10). 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 154.3 (C–6), 153.2 (C–8), 151.5 (C–2), 145.5 (C–4), 122.4 (qd, J = 283.0 Hz, 3.9 Hz, C–3'), 104.3 (C–5), 72.6 (hept, J = 33 Hz, C–2'), 30.44 (C–12), 28.2 (C–10). 19F NMR (376 MHz, DMSO-d6): δ [ppm] = -73.87 (d, J = 6.2 Hz). HRMS of ([C10H8F6N4O3]+H)+ (APCI+) [M+H]+: calculated: 347.0579, found: 347.0573. S30 5.3 1-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)naphthalene (6) The electrolysis of naphthalene (128.2 mg, 1.00 mmol) was conducted according to GP2 until a charge of 2.61 F was applied. The crude product was purified using flash chromatography on silica gel eluting with cyclohexane, yielding a crystalline colorless solid (174 mg, 0.591 mmol, 59%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.32 – 8.22 (m, 1H, H–8), 7.93 – 7.83 (m, 1H, H– 5), 7.66 (d, J = 8.0 Hz, 1H, H–4), 7.63 – 7.54 (m, 2H, H–6, H–7), 7.44 (t, J = 8.0 Hz, 1H, H–3), 7.05 (d, J = 8.0 Hz, 1H, H–2), 5.15 (hept, J = 5.7 Hz, 1H, H–2'). 13C NMR (101 MHz, CDCl3): δ [ppm] = 153.5 (C–1), 134.7 (C–4a), 127.6 (C–5), 127.2 (C– 6), 126.5 (C–7), 125.8 (C–8a), 125.2 (C–3), 124.2 (C–4), 121.0 (q, J = 283 Hz, C–3'), 121.6 (C–8), 108.1 (C–2), 76.1 (hept, J = 4 Hz, C–2'). 19F NMR (376 MHz, CDCl3): δ [ppm] = -74.46 (d, J = 5.9 Hz). Mp: 63.2 °C (crystallized from ethyl acetate). HRMS of [C13H8F6O]+ (APCI+) [M]+: calculated: 295.0479, found: 294.0479. S31 5.4 1,4-Bis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (5) The electrolysis of naphthalene (160.1 mg, 1.25 mmol) was conducted according to GP1 until a charge of 4 F was applied. The crude product was purified using flash chromatography on silica gel eluting with cyclohexane, yielding a crystalline colorless solid (104.1 mg, 0.226 mmol, 18%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.38 – 8.16 (m, 2H, H–5, H–8), 7.73 – 7.61 (m, 2H, H–6, H–7), 6.98 (s, 2H, H–1, H–4), 5.06 (hept, J = 5.7 Hz, 2H, H–2'). 13C NMR (101 MHz, CDCl3): δ [ppm] = 150.0 (C–1, C–4), 127.8 (C–5, C–8), 126.8 (C–4a, C–8a), 121.6 (C–6, C–7), 121.1 (q, J = 284.0 Hz, C–3'), 107.6 (C–2, C–3), 76.5 (C–2'). 19F NMR (376 MHz, CDCl3): δ [ppm] = -74.45 (d, J = 6.2 Hz). Mp: 149.8 °C (crystallized from ethyl acetate). S32 5.5 1,1,4,4-Tetrakis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,4- dihydronaphthalene (8) The electrolysis of naphthalene (128.2 mg, 1.00 mmol) was conducted according to GP2 until a charge of 7 F was applied. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0-3% in 2 h), yielding a highly viscous orange oil (208 mg, 0.262 mmol, 26%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 7.82 – 7.74 (m, 2H, H–6, H–7), 7.70 – 7.63 (m, 2H, H–5, H–8), 6.42 (s, 2H, H–2, H–3), 4.42 (hept, J = 5.5 Hz, 4H, H–2'). 13C NMR (101 MHz, CDCl3): δ [ppm] = 131.96 (C–5, C–8), 131.64 (C–4a, C–8a), 129.35 (C–2, C–3), 127.97 (C–6, C–7), 125.51 – 115.76 (m, C–3 ), 97.99 (C–1, C–4), 70.61 (hept, J = 33.8 Hz, C–2'). 19F NMR (376 MHz, CDCl3): δ [ppm] = -73.70 (d, J = 5.7 Hz). S33 5.6 N-(4-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)naphthyl)-acetamide (7) The electrolysis of N-(1-naphthyl)acetamide (185.23 mg, 1.00 mmol) was conducted according to GP2 until a charge of 2.61 F was applied. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0– 30% in 3 h), yielding a crystalline colorless solid (110 mg, 0.313 mmol, 31%). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 9.91 (s, 1H, H–4'), 8.17 – 8.02 (m, 2H, H–8, H– 5), 7.72 – 7.63 (m, 2H, H–7, H–6), 7.62 (d, J = 8.4 Hz, 1H, H–2), 7.41 (d, J = 8.4 Hz, 1H, H–3), 6.76 (hept, J = 6.0 Hz, 1H, H–2'), 2.18 (s, 3H, H–6'). 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 169.5 (C–5'), 149.7 (C–1), 130.2 (C–8a), 129.5 (C–4a), 127.4 (C–6), 127.1 (C–7), 125.5 (C–4), 123.6 (C–5), 122.2 (C–3), 122.0, (C–3') 121.3 (C–8), 108.9, 73.5 (hept, J = 33 Hz, C–2'), 23.8 (C–6') . 19F NMR (376 MHz, DMSO-d6): δ [ppm] = -74.04 (d, J = 6.4 Hz). HRMS of ([C15H11F6NO2]+H)+ (ESI+) [M+H]+: calculated: 352.0771, found: 352.0772. S34 5.7 N-(4-(tert-Butyl)-2-((1,1,1,3,3,3-hexafluoropropan-2- yl)oxy)phenyl)acetamide (4) The electrolysis of 4-(tert-butyl)acetanilide (238.9 mg, 1.25 mmol) was conducted according to GP1 until a charge of 2.00 F was applied. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0– 12% in 3 h), yielding a crystalline red solid (144.7 mg, 0.405 mmol, 32%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.24 (d, J = 8.6 Hz, 1H, H–3), 7.49 (s, 1H, H–4'), 7.21 (dd, J = 8.6, 2.0 Hz, 1H, H–4), 7.03 (d, J = 2.0 Hz, 1H, H–6), 4.84 (hept, J = 5.7 Hz, 1H, H–2'), 2.22 (s, 3H, H–7'), 1.32 (s, 9H, H–9'). 13C NMR (101 MHz, CDCl3): δ [ppm] = 168.2 (C–5'), 148.3 (C–5), 146.0 (C–1), 126.63 (C–2), 122.4 (C–4), 121.5 (C–3), 121.0 (C–3'), 112.1 (C–6), 77.0 (C–2'), 34.7 (C–8'), 31.2 (C–9'), 24.6 (C–7'). 19F NMR (376 MHz, CDCl3): δ [ppm] = -74.61 (d, J = 5.9 Hz). HRMS of ([C15H17F6NO2]+H)+ (ESI+) [M+H]+: calculated: 358.1242, found: 358.1243. S35 5.8 N-(2-((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)-4-methoxyphenyl)acetamide (9) The electrolysis of 4-(methoxy)acetanilide (165.2 mg, 1.00 mmol) was conducted according to GP2 until a charge of 2.61 F was applied. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0– 20% in 1.5 h), yielding a crystalline red solid (103 mg, 0.311 mmol, 31%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.19 (d, J = 9.0 Hz, 1H, H–3), 7.37 (s, 1H, H–4'), 6.71 (dd, J = 9.0 Hz, 2.6 Hz 1H, H–4), 6.60 (d, J = 2.6 Hz, 1H, H–6), 4.87 (hept, J = 4.9 Hz, 1H, H–2'), 3.81 (s, 4H, H–9'), 2.20 (s, 3H, H–7'). 13C NMR (101 MHz, CDCl3): δ [ppm] = 167.1 (C–5'), 156.6 (C–5), 147.4 (C–1), 123.3 (C– 3), 122.4 (C–2), 120.9 (qd, J = 284.4, 3.0 Hz, C–3'), 109.0 (C–4), 102.6 (C–6), 77.4 (C– 3'), 55.7 (C–9'), 24.4 (C–7'). 19F NMR (376 MHz, CDCl3): δ [ppm] = -74.70 (d, J = 5.8 Hz). Mp: 82.7 °C (crystallized from ethyl acetate). HRMS of ([C15H17F6NO2]+H)+ (ESI+) [M+H]+: calculated: 332.0721, found: 332.0721. S36 5.9 8-Cyanocaffeine (10) 8-Cyanocaffeine was synthesized using nickel-catalysis (Method 1) and palladium- catalysis (Method 2) : Method 1: The nickel-catalyzed cyanation of HFIP caffeyl ether (81) was carried out using standard Schlenk techniques under argon atmosphere. HFIP caffeyl ether (81) (90.6 mg, 0.25 mmol, 1 eq.), KCN (65.1 mg, 1 mmol, 4 eq.), PPh3 (13.1 mg, 0.05 mmol, 20 mol%), NiCl2(PPh3)2 (16.4 mg, 0.025 mmol, 10 mol%), and Zn (16.3 mg, 0.25 mmol, 1 eq.) were added into a Schlenk tube, which was dried by heating under reduced pressure and backfilling with argon three times. The tube was sealed with a rubber septum and the reagents were dried for one hour at reduced pressure. Then dimethylformamide (1 mL) was added. The reaction mixture was stirred at 115 °C for 14 h and conversion monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0–15% in 1.5 h), yielding a crystalline yellow solid (21.0 mg, 0.096 mmol, 38%). Method 2: For the palladium-catalyzed cyanation of HFIP caffeyl ether (81) a round bottom flask was charged with HFIP caffeyl ether (81) (90.6 mg, 0.25 mmol 1 eq.), KCN (24.4 mg, 0.375 mmol, 1.5 eq.), XantPhos (14.5 mg, 0.025 mmol, 10 mol%), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 5 mol%), and dimethylformamide (1 mL). The reaction mixture was stirred at 85 °C for 14 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0– 15% in 1.5 h), yielding a crystalline yellow solid (33.2 mg, 0.15 mmol, 60%). S37 1H NMR (400 MHz, CDCl3): δ [ppm] = 4.19 (s, 1H, H–14), 3.59 (s, 1H, H–11), 3.44 (s, 1H, H–12). 13C NMR (101 MHz, CDCl3): δ [ppm] = 154.8 (C–1), 151.3 (C–5), 147.6 (C–3) , 124.9 (C– 8), 109.9 (C–2), 109.7 (C–15), 34.2 (C–14), 30.1 (C–11), 28.4 (C–12). Mp: 152.2 °C (crystallized from ethyl acetate). HRMS of ([C9H9N5O2]+H)+ (ESI+) [M+H]+: calculated: 220.0834, found: 220.0833. The analytical data match the literature.[7] S38 5.10 8-Morpholinocaffeine (11) Prep. 1: A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (100) (90.6 mg, 0.25 mmol 1eq.), morpholine (0.065 mL, 65.3 mg, 0.75 mmol, 3 eq.), XantPhos (14.5 mg, 0.025 mmol, 10 mol%), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 5 mol%), and dimethylacetamide (1.5 mL). The reaction mixture was stirred at 100 °C for 14 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0–15% in 1.5 h), yielding a crystalline beige solid (65.4 mg, 0.234 mmol, 94%). Prep. 2: A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (100) (90.6 mg, 0.25 mmol 1eq.), morpholine (0.065 mL, 65.3 mg, 0.75 mmol, 3 eq.), and dimethylacetamide (1.5 mL). The reaction mixture was stirred at 100 °C for 14 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with ethyl acetate in cyclohexane (0–15% in 1.5 h), yielding a crystalline beige solid (52.2 mg, 0.234 mmol, 75%). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.74 (dd, J = 6.6, 3.5 Hz, 1H, H–2'), 3.69 (s, 1H, H–14), 3.37 (s, 1H, H–13), 3.22 (dd, J = 6.6, 3.5 Hz, 1H, H–3'), 3.20 (s, 1H, H–12). 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 156.0 (C–8), 154.4 (C–4), 151.4 (C–2), 147.2 (C–6), 104.9 (C–5), 66.1 (C–2'), 49.9 (C–3'), 32.8 (C–14), 29.9 (C–13), 27.8 (C–12) Mp: 143.9 °C (crystallized from ethyl acetate). S39 HRMS of ([C12H17N5O3]+H)+ (ESI+) [M+H]+: calculated: 280.1410, found: 280.1409. The analytical data match the literature.[8] S40 5.11 (S)-8-((1-Phenylethyl)amino)caffeine (12) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (90.6 mg, 0.25 mmol 1eq.), (S)-1-phenylethanamine (0.097 mL, 90.8 mg, 0.75 mmol, 3 eq.), XantPhos (36.2 mg, 0.0625 mmol, 25 mol%), Pd(OAc)2 (2.8 mg, 0.0125 mmol, 5 mol%), and 1.5 mL dimethylacetamide. The reaction mixture was stirred at 100 °C for 14 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with methanol in dichloromethane (0–4% in 40 min), yielding a crystalline colorless solid (59.5 mg, 0.190 mmol, 76%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 7.42 (m, 2H, H–5'), 7.37 (m, 2H, H–6'), 7.30 (m, 1H, H–7'), 5.19 (pseudo-quintett, J = 6.8 Hz, 1H, H–2'), 4.57 (d, J = 6.8 Hz, 1H, H–1'), 3.68 (s, 3H, H–14), 3.51 (s, 3H, H–13), 3.36 (s, 3H, H–12), 1.65 (d, J = 6.8 Hz, 3H, H–3') 13C NMR (101 MHz, CDCl3): δ [ppm] = 154.3 (C–4), 152.6 (C–8), 151.8 (C–2), 148.6 (C– 6), 143.3 (C–4'), 128.7 (C–6'), 127.7 (C–7'), 126.2 (C–5'), 103.2 (C–5), 52.7 (C–2'), 29.8 (C–14), 29.6 (C–13), 27.6 (C–12), 22.5 (C–3') HRMS of ([C16H19N5O2]+H)+ (ESI+) [M+H]+: calculated: 314.1617, found: 314.1617. S41 5.12 8-Allylaminocaffeine (13) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (180 mg, 0.5 mmol 1eq.), allylamine (0.073 mL, 57 mg, 1.0 mmol, 2 eq.), XantPhos (28.9 mg, 0.05 mmol, 10 mol%), Pd(OAc)2 (5.6 mg, 0.025 mmol, 5 mol%), and 3 mL dimethylacetamide. The reaction mixture was stirred at 100 °C for 3 h and monitored was GC-MS. The crude product was purified using flash chromatography on silica gel eluting with methanol in dichloromethane (0–1% in 40 min), yielding a crystalline colorless solid (45 mg, 0.18 mmol, 36%). 1H NMR (400 MHz, CDCl3) 5.97 (ddt, J = 17.1, 10.2, 5.8 Hz, 1H), 5.28 (dq, J = 17.1, 1.4 Hz, 1H), 5.20 (dq, J = 10.2, 1.4 Hz, 1H), 4.13 (d, J = 5.8 Hz, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 3.36 (s, 3H). 13C NMR (101 MHz, CDCl3) 154.4, 153.0, 151.8, 148.2, 134.4, 117.3, 103.3, 77.5, 77.4, 77.2, 76.8, 46.0, 30.0, 29.8, 27.8. HRMS of ([C11H15N5O2]+H)+ (ESI+) [M+H]+: calculated: 250.1299, found: 250.1304. S42 5.13 8-Phenoxycaffeine (15) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (360 mg, 1.0 mmol 1 eq.), phenol (188 mg, 2.0 mmol, 2 eq.), cesium carbonate (977 mg, 3.0 mmol, 3 eq.) and 5 mL dimethylformamide. The reaction mixture was stirred at room temperature for 3 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with cyclohexane/ethyl acetate (0–25% in 45 min), yielding a colorless solid (40 mg, 0.14 mmol, 14%). HRMS of ([C14H14N4O3]+H)+ (ESI+) [M+H]+: calculated: 287.1139, found: 287.1139. 1H NMR (400 MHz, CDCl3) 7.47 – 7.39 (m, 2H), 7.31 – 7.23 (m, 3H), 3.88 (s, 3H), 3.46 (s, 3H), 3.41 (s, 3H). 13C NMR (101 MHz, CDCl3) 155.1, 153.6, 153.5, 151.8, 146.0, 129.9, 125.8, 119.5, 104.0, 76.8, 30.6, 30.0, 28.0. The analytical data match the literature.[9] S43 5.14 8-(Phenylsulfanyl)caffeine (14) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (360 mg, 1.0 mmol 1 eq.), thiophenol (0.204 mL, 220 mg, 2.0 mmol, 2 eq.), cesium carbonate (977 mg, 3.0 mmol, 3 eq.) and 5 mL dimethylformamide. The reaction mixture was stirred at room temperature for 3 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with cyclohexane/ethyl acetate (0–45% in 45 min), yielding a colorless solid (246 mg, 0.814 mmol, 81.4%). 1H NMR (400 MHz, CDCl3) 7.36 – 7.27 (m, 5H), 3.90 (s, 3H), 3.54 (s, 3H), 3.37 (s, 3H). 13C NMR (101 MHz, CDCl3) 155.0, 151.5, 148.1, 146.4, 130.9, 130.6, 129.7, 128.3, 109.6, 33.2, 30.0, 28.1. HRMS of ([C14H14N4O3]+H)+ (ESI+) [M+H]+: calculated: 303.0910, found: 303.0912. Mp: 146.5 °C (crystallized from ethyl acetate). The analytical data match the literature.[10] S44 5.15 8-Propyloxycaffeine (17) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (360 mg, 1.0 mmol 1 eq.), was dissolved in n-propanol (5 mL). A solution of NaOH (0.6 g, 15 mmol, 15 eq.) in 15 ml of water was added. The reaction mixture was stirred at 60 °C for 2 h. and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with cyclohexane/ethyl acetate (0–40% in 45 min), yielding a crystalline colorless solid (38.0 mg, 0.15 mmol, 15%). 1H NMR (400 MHz, CDCl3) 4.41 (t, J = 6.7 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 3H), 3.38 (s, 3H), 1.84 (dtd, J = 14.0, 7.4, 6.7 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) 156.0, 155.0, 151.9, 146.5, 103.5, 77.5, 77.2, 76.8, 72.8, 29.9, 29.8, 27.9, 22.4, 10.3. HRMS of ([C11H16N4O3]+H)+ (ESI+) [M+H]+: calculated: 253.1295, found: 253.1296. S45 5.16 8-Propylsulfanylcaffeine (16) A round bottom flask equipped with a reflux condenser was charged with HFIP caffeyl ether (102) (360 mg, 1.0 mmol 1eq.), propan-1-thiol (0.18 mL, 152 mg, 2.0 mmol, 2 eq.), potassium carbonate (415 mg, 3.0 mmol, 3 eq.) and 5 mL dimethylformamide. The reaction mixture was stirred at 65 °C for 2 h and monitored by GC-MS. The crude product was purified using flash chromatography on silica gel eluting with eluting with cyclohexane/ethyl acetate (0–35% in 45 min), yielding a crystalline colorless solid (213 mg, 0.794 mmol, 79.4%). 1H NMR (400 MHz, CDCl3) 3.81 (s, 3H), 3.52 (s, 3H), 3.35 (s, 3H), 3.22 (t, J = 7.3 Hz, 2H), 1.76 (h, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) 154.5, 151.5, 151.3, 148.4, 108.4, 77.4, 77.1, 76.8, 34.7, 32.1, 29.7, 27.8, 23.0, 13.2. HRMS of ([C11H16N4O2S]+H)+ (ESI+) [M+H]+: calculated: 269.1067, found: 269.1069. Mp: 130.9 °C (crystallized from ethyl acetate). The analytical data match the literature.[11] S46 6 Refe ence [1] C. Gütz, B. Klöckner, S. R. Waldvogel, Org. Process Res. Dev. 2016, 20, 26–32. [2] R. E. Sioda, B. Frankowska, E. B. Lesiak, Monatsh. Chem. 2008, 139, 513–519. [3] J. Heinze, Angew. Chem. Int. Ed. 1984, 23, 831–847; Angew. Chem. 1984, 23, 823–840. [4] M. Salihovic, H. , S. Spirtovic-Halilovic, A. Osmanovi , A. Dedi , Z. Asimovic, D. Zavrsnik, Glas. hem. tehnol. Bosne Herceg. 2014, 42. [5] B. N. Plakhutin, E. R. Davidson, J. Phys. Chem. A 2009, 113, 12386–12395. [6] B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Chem. Eur. J. 2015, 21, 12321–12325. [7] a) H.-Q. Do, O. Daugulis, Org. Lett. 2010, 12, 2517–2519; b) L.-L. Gundersen, K. Bechgaard, J. Songstad, M. Leskelä, M. Polamo, M. N. Homsi, F. K. H. Kuske, M. Haugg, N. Trabesinger-Rüf, E. G. Weinhold, Acta Chem. Scand. 1996, 50, 58–63. [8] S. Yoshikawa, E. Emori, F. Matsuura, R. Clark, H. Ikuta, N. Yasuda, T. Nagakura, K. Yamazaki, M. Aoki, EP1338595, 2003. [9] B. Strydom, J. J. Bergh, J. P. Petzer, Eur. J. Med. Chem 2011, 46, 3474–3485. [10] P. H. Gehrtz, V. Geiger, T. Schmidt, L. Sr an, I. Fleischer, Org. Lett. 2019, 21, 50– 55. [11] M. Jouffroy, C. B. Kelly, G. A. Molander, Org. Lett. 2016, 18, 876–879. S47 7 1H, 13C and 19F NMR pec a Figure 8: 1H NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)caffeine (2) in CDCl3 Figure 9: 13C NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)caffeine (2) in CDCl3 S48 Figure 10: 19F NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)caffeine (2) in DMSO-d6 Figure 11: 1H NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)theophylline (3) in DMSO-d6 S49 Figure 12: 13C NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)theophylline (3) in DMSO-d6 Figure 13: 19F NMR spectrum of 8-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)theophylline (3) in DMSO-d6 S50 Figure 14: 1H NMR spectrum of 1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (6) in CDCl3 Figure 15: 13C NMR spectrum of 1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (6) in CDCl3 S51 F F F F O F F -74.42 -74.46 -74.50 -74.54 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) Figure 16: 19F NMR spectrum of 1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (6) in CDCl3 F F F F O F F F F O F F F F 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 chemical shift (ppm) 5.15 5.10 5.05 5.00chemical shift (ppm) 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 chemical shift (ppm) Figure 17: 1H NMR spectrum of 1,4-bis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (5) in CDCl3 S52 8.28 8.28 8.27 8.26 8.25 8.25 8.24 8.23 7.70 -74.46 7.70 8.28 7.69 8.28 7.68 -74.488.27 7.67 8.26 7.66 8.25 7.66 8.25 7.65 8.24 7.28 CDC l3 8.23 7.70 7.70 6.98 7.69 -74.46 1.99 7.68 -74.48 7.67 2.00 7.66 7.66 1.98 7.65 7.28 CDC l3 6.98 5.11 5.09 2.00 5.08 5.06 5.05 5.03 5.11 5.02 5.09 5.08 5.06 5.05 5.03 1.59 HDO 5.02 F F F F O F F F F O F F F F 128 126 124 122 120 118 116 chemical shift (ppm) 77.0 76.5 76.0 chemical shift (ppm) 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 18: 13C NMR spectrum of 1,4-bis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (5) in CDCl3 F F F F O F F F F O F F F F -74.1 -74.2 -74.3 -74.4 -74.5 -74.6 -74.7 -74.8 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) Figure 19: 19F NMR spectrum of 1,4-bis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthalene (5) in CDCl3 S53 127.8 126.8 125.3 -74.44 -74.46 122.5 121.6 119.7 150.0 116.8 -74.44 127.8 -74.46 126.8 125.3 122.5 121.6 119.7 116.8 107.6 77.3 CDC l3 77.0 CDC l3 76.8 76.7 CDC l3 76.5 76.2 77.0 CDC l3 75.8 76.8 76.7 CDC l3 76.5 76.2 75.8 Figure 20: 1H NMR spectrum of 1,1,4,4-Tetrakis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,4- dihydronaphthalene (8) in CDCl3 Figure 21: 13C NMR spectrum of 1,1,4,4-Tetrakis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,4- dihydronaphthalene (8) in CDCl3 S54 Figure 22: 19F NMR spectrum of 1,1,4,4-Tetrakis((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,4- dihydronaphthalene (8) in CDCl3 O NH CH3 F F O F F F F 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 6.85 6.75 6.65 chemical shift (ppm) chemical shift (ppm) 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 chemical shift (ppm) Figure 23: 1H NMR spectrum of N-(4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthyl)acetamide (7) in DMSO-d6 S55 8.13 8.12 8.12 8.11 8.09 9.91 0.99 8.08 8.14 8.08 8.13 8.06 8.13 7.66 8.12 7.66 8.12 7.65 8.11 7.65 8.10 7.65 8.10 1.99 7.64 8.09 7.63 8.08 1.99 7.61 8.08 0.96 7.42 8.08 1.00 7.40 8.07 8.06 8.06 1.00 7.67 7.66 6.81 7.66 6.79 7.65 6.78 7.65 6.76 7.65 6.75 7.64 6.73 7.63 6.72 7.61 7.42 7.40 6.79 6.78 6.76 6.75 6.73 3.36 HDO 2.52 DMSO 2.51 DMSO 2.51 DMSO 2.50 DMSO 3.00 2.50 DMSO 2.18 O NH CH3 F F O F F F F 136 134 132 130 128 126 124 122 120 118 chemical shift (ppm) 76 74 72 chemical shift (ppm) 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 24: 13C NMR spectrum of N-(4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthyl)acetamide (7) in DMSO-d6 O NH CH3 F F O F F F F -73.85 -73.95 -74.05 -74.15 -74.25 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) Figure 25: 19F NMR spectrum of N-(4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)naphthyl)acetamide (7) in DMSO-d6 S56 130.19 129.49 -74.03 127.36 -74.05 127.11 125.47 123.64 123.37 169.54 122.22 121.29 149.65 120.56 130.19 129.49 127.36 -74.03 127.11 -74.05 125.47 123.64 123.37 122.22 121.29 120.56 108.86 73.82 73.82 73.50 73.50 73.18 73.18 40.59 DMSO 40.38 DMSO 3.21 40.17 DMSO 1.92 39.96 DMSO 1.74 39.75 DMSO 1.13 39.55 DMSO 39.34 DMSO 23.76 F F F F O F F NH CH3 H3C O H3 C CH3 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 4.85 4.80 chemical shift (ppm) chemical shift (ppm) 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) Figure 26: 1H NMR spectrum of N-(4-(tert-butyl)-2-((1,1,1,3,3,3-hexafluoropropan-2- yl)oxy)phenyl)acetamide (4) in CDCl3 F F F F O F F NH CH3 H3C O H3 C CH3 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 27: 13C NMR spectrum of N-(4-(tert-butyl)-2-((1,1,1,3,3,3-hexafluoropropan-2- yl)oxy)phenyl)acetamide (4) in CDCl3 S57 8.25 8.23 7.49 168.2 7.28 CDCl3 7.22 7.22 7.20 8.250.96 7.20 8.23148.3 7.49 146.0 7.03 7.02 7.28 CDC l3 0.94 7.22 1.02 7.22 1.08 126.6 7.20 122.4 7.20 121.5 7.03 7.02 112.1 4.89 4.87 4.89 4.86 4.87 4.84 4.86 1.07 4.83 4.84 4.82 4.83 77.3 4.80 4.82 4.80 34.6 3.05 2.22 31.2 24.6 1.63 HDO 1.50 HDO 9.00 1.32 F F F F O F F NH CH3 H3C O H3 C CH3 -74.50 -74.60 -74.70 -74.80 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) Figure 28: 19F NMR spectrum of N-(4-(tert-butyl)-2-((1,1,1,3,3,3-hexafluoropropan-2- yl)oxy)phenyl)acetamide (4) in CDCl3 F F F F O F F NH CH3 O O H3C 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 chemical shift (ppm) 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 chemical shift (ppm) Figure 29: 1H NMR spectrum of N-(2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4- methoxyphenyl)acetamide (9) in CDCl3 S58 8.20 8.18 7.37 7.28 CDCl3 6.72 6.72 8.20 6.70 8.18 6.69 7.37 6.69 7.28 CDC l3 1.00 6.61 6.72 6.60 6.72 1.02 6.70 6.69 1.08 1.02 6.69 6.61 6.60 4.91 4.89 1.16 4.88 4.86 4.85 3.81 4.84 4.82 3.81 3.16 2.20 1.44 HDO F F F F O F F NH CH3 O O H3C 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 30: 13C NMR spectrum of N-(2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4- methoxyphenyl)acetamide (9) in CDCl3 F F F F O F F NH CH3 O O H3C -74.60 -74.64 -74.68 -74.72 -74.76 -74.80 chemical shift (ppm) 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 chemical shift (ppm) Figure 31: 19F NMR spectrum of N-(2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4- methoxyphenyl)acetamide (9) in CDCl3 S59 167.1 156.6 147.3 125.1 125.1 123.3 122.4 122.3 122.3 119.5 119.4 116.6 109.0 102.6 76.4 55.7 24.4 O CH3 H3C N N N O N N CH3 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 chemical shift (ppm) 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) Figure 32: 1H NMR spectrum of 8-cyanocaffeine (10) in CDCl3 S60 4.19 3.59 3.44 7.28 CDC l3 3.00 4.19 3.00 3.59 3.00 3.44 1.73 HDO Figure 33: 13C NMR spectrum of 8-cyanocaffeine (10) in CDCl3 S61 O CH3 H3C N N N O O N N CH3 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 chemical shift (ppm) 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) Figure 34: 1H NMR spectrum of 8-morpholinocaffeine (11) in CDCl3 O CH3 H3C N N N O O N N CH3 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 35: 13C NMR spectrum of 8-morpholinocaffeine (11) in CDCl3 S62 3.75 3.75 3.74 3.73 3.69 156.0 3.37 154.4 3.33 HDO 151.4 3.24 147.2 3.23 3.22 3.21 3.20 104.9 3.75 3.75 3.74 3.73 3.69 3.37 3.33 HDO 66.1 4.00 3.24 3.02 3.23 3.05 3.22 4.01 2.97 3.2149.9 3.20 40.7 DMSO 2.52 40.6 DMSO 11.36 2.51 40.4 DMSO 2.51 DMSO 40.2 DMSO 2.50 40.0 DMSO 2.50 39.8 DMSO 39.6 DMSO 39.4 DMSO 32.8 29.9 27.8 O CH3 H3C N N NH O N N H CH 3 C 3 7.46 7.44 7.42 7.40 7.38 7.36 7.34 7.32 7.30 7.28 7.26 5.25 5.20 5.15 4.60 4.55 4.50 chemical shift (ppm) chemical shift (ppmch) emical shift (ppm) 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 chemical shift (ppm) Figure 36: 1H NMR spectrum of (S)-8-((1-Phenylethyl)amino)caffeine (12) in CDCl3 O CH3 H3 C N N NH O N N H C CH 33 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 chemical shift (ppm) Figure 37 1H NMR spectrum of (S)-8-((1-Phenylethyl)amino)caffeine (12) in CDCl3 S63 7.43 7.43 7.42 7.41 7.47 7.41 7.43 7.41 7.43 7.39 7.42 7.38 7.41 7.38 7.41 7.37 7.41 7.37 7.40 7.37 7.39 7.36 7.38 7.35 7.38 7.35 7.37 154.3 7.32 7.37 152.6 7.31 7.37 151.8 7.31 7.36 148.6 7.30 7.35 143.3 2.05 7.29 CDC l3 7.35 2.14 7.32128.7 1.38 7.31 127.7 7.31 126.2 7.30 5.22 7.30 5.21 7.29 CDC l3 5.19 7.29 5.17 103.2 5.225.15 5.21 5.19 1.03 5.17 5.15 77.4 CDC l3 4.58 4.581.00 77.0 CDC l3 4.56 4.56 76.7 CDC l3 3.08 3.68 3.05 3.51 3.06 3.36 52.7 29.7 1.82 HDO 29.6 3.11 1.6627.6 1.64 22.4 0.09 Figure 38 1H NMR spectrum of 8-allylaminocaffeine (13) in CDCl3 Figure 39 13C NMR spectrum of 8-allylaminocaffeine (13) in CDCl3 S64 Figure 40 1H NMR spectrum of 8-phenoxycaffeine (15) in CDCl3 Figure 41 13C NMR spectrum of 8-phenoxycaffeine (15) in CDCl3 S65 Figure 42 1H NMR spectrum of 8-(phenylthio)caffeine (14) in CDCl3 Figure 43 13C NMR spectrum of 8-(phenylthio)caffeine (14) in CDCl3 S66 Figure 44 1H NMR spectrum of 8-propyloxycaffeine (17) in CDCl3 Figure 45 13C NMR spectrum of 8-propyloxycaffeine (17) in CDCl3 S67 Figure 46 1H NMR spectrum of 8-propylthiocaffeine (16) in CDCl3 Figure 47 13C NMR spectrum of 8-propylthiocaffeine (16) in CDCl3 S68 MINIREVIEW Electrosynthesis 2.0 in 1,1,1,3,3,3-Hexafluoroisopropanol / Amine mixtures Johannes L. Röckl,[a,b] Maurice Dörr,[a] Siegfried R. Waldvogel*[a,b] In the memory of Prof. Dr. Dennis G. Peters. Frontispiece Graphic (18.5 cm in diameter) 1 MINIREVIEW [a] J. L. Röckl, M. Dörr, Prof. Dr. S. R. Waldvogel Department of Chemistry Johannes Gutenberg University Mainz Duesbergweg 10 14, 55128 Mainz (Germany) E-mail: waldvogel@uni-mainz.de Homepage: https://www.aksw.uni-mainz.de [b] J. L. Röckl, Prof. Dr. S. R. Waldvogel Graduate School Materials Science in Mainz Staudingerweg 9, 55128 Mainz (Germany) Abstract: The intention of this survey is to highlight the innovative be employed without loss of selectivity and reactivity. Here, HFIP electrolyte combination of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) based electrolytes seem to play an outstanding role.[26] The with tertiary nitrogen bases in electro-organic synthesis. This easy avoidance of chemical reagents minimizes the amount of reagent applicable and promising mixture is not yet well established in electro- waste produced by the process. Thus, many of the green organic synthesis but expands the various possibilities in the latter. chemistry principles may be fulfilled by applying electro-organic Combinations of fluorinated alcohols with nitrogen bases form highly methods.[26,27] A common drawback in electrochemistry is the conductive electrolyte systems which can be evaporated completely. need for supporting electrolytes, which are often salts with Consequently, no additional supporting electrolyte is required and significant environmental impact.[28] The subsequent workup is work-up procedures are tremendously simplified. With this electrolyte complicated due to difficult removal or recovery of the salt. mixture carbon-carbon homo- and cross-coupling reactions of arenes Noteworthy, perchlorates can lead to explosive events and and phenols have been established with substrates, which have not symmetric tetraalkylammonium salts strongly affect the been previously susceptible to the anodic dehydrogenative coupling wastewater treatment.[29] When applying a combination of base reaction. The intermediate installation of highly fluorinated alkoxy with acidic HFIP (pK = 9.3[15]a ) to electro-organic synthesis, a moieties can be exploited for subsequent conversions as well as supporting electrolyte is formed in-situ, eliminating the need for various benzylic functionalization, including asymmetric additional supporting electrolyte. Avoiding the use of salts transformations. These transformations show unique selectivity and simplifies the workup procedure, facilitating easy removal of the functional group tolerance making them highly applicable to the electrolyte by distillation, simplifying downstream processing and synthesis of sophisticated structural motifs, including natural products. recycling of the electrolyte. Additionally, the lack of salts allows the coupling with mass spectrometry for real-time reaction monitoring in, for example, automated synthesis. In addition, the Introduction enhanced nucleophilicity of deprotonated HFIP allows trapping of reactive intermediates, which can be submitted to different coupling reactions to open new pathways in organic synthesis. Fluorinated alcohols have emerged as excellent choices for a For example, in 2013 Tajima et al. first described the use of a broad range of applications in organic chemistry, due to their high solid-supported base in HFIP in a one-pot sequence of hydrogen-bond donor ability,[1,2] high polarity,[2,3] outstanding alkoxylation followed by the reaction with allyltrimethylsilane (electro-)chemical stability,[4,5] and micro-heterogeneity.[6 8] This (Scheme 1).[30] Subsequently, our group first used a simple is illustrated by their use as solvents, co-solvents or promoters in tertiary amine base without additional salt or reagents in a formal organic syntheses.[2,5,9,10] Several examples have showcased the benzyl-aryl cross-coupling reaction, demonstrating the potential utility of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in transition of this approach (Scheme 3).[31] Many more seminal applications metal-catalyzed,[10,11] and metal-free reactions.[12] In combination of this powerful combination have been recently published and with bases, HFIP promotes unusual transformations like the will be discussed within this review.[32 36] generation of aza-oxyallyl cationic intermediates from - haloamides[13] or HFIP-promoted nucleophilic substitutions[9,14]. These unique features of HFIP make it particularly well-suited as Johannes L. R ckl finished his a solvent for electrochemical reactions, especially its ability to apprenticeship as a laboratory technician in stabilize radical intermediates.[15,16] HFIP has demonstrated 2013 at BASF SE, Ludwigshafen and superior effects compared to other solvents when it comes to received his B.Sc. from Johannes improving selectivity and yield of various electrochemical Gutenberg University in a collaboration with transformations.[17 21] In particular, the solvate formation BASF SE working on the total synthesis of modulates nucleophilicity and oxidation potential.[7,17] The unusual natural product derivatives under electrochemical stability of HFIP is ensured as long as inert supervision of Prof. Dr. Siegfried R. anodes are employed for direct electrode processes,[22] whereas Waldvogel and Dr. Joachim Dickhaut in hypervalent iodine mediators are capable to convert HFIP to 2016. Afterwards, he was appointed as a highly toxic hexafluoroacetone.[23] scientist in insecticide science working on early stage projects for BASF. Upon acceptance as a fast-track Ph.D. Electrochemistry has experienced a renaissance in recent years candidate, he started working on electro-organic synthesis in the since it offers benefits over classical synthetic methodologies.[18 Waldvogel lab. After working as a visiting researcher at ETH, Zurich under 20,24] Electric current, as an inexpensive and inherently safe the supervision of Prof. Dr. Bill Morandi in 2019, he returned to Mainz to reagent, facilitates sustainable synthetic pathways, and is conclude his Ph.D. in electro-organic synthesis. compatible with renewable energy sources.[25] A direct contribution for the stabilizing of the electric grid is provided, when the electro-conversions are robust and fluctuating electricity can 2 MINIREVIEW Electro-organic Formation of Nitrogen Maurice Dörr received his B.Sc. degree in Heterocycles using Ammonia in HFIP chemistry from Johannes Gutenberg University Mainz working on anodic C C The ubiquity of nitrogen moieties in natural products, cross-coupling reactions in 2016 and his pharmaceutically active compounds, and advanced materials M.Sc. working on anodic C N cross- highlights the necessity for sustainable formation of nitrogen coupling reactions in 2018 supervised by heterocycles.[37] Several approaches have been described along Prof. Dr. Siegfried. R. Waldvogel. Currently, with electro-organic C N bond construction.[38] A regioselective he is engaged in the application of Design of anodic approach towards phenanthridines and pyridine-fused Experiments (DoE) towards electro-organic polycyclic structures exploits ammonia as an inexpensive and synthesis as a graduate student in the stable nitrogen donor and base with high atom economy in HFIP Waldvogel lab. (Scheme 2).[39] Ammonia (pK +a(NH4 ) = 9.2)[40] is used as a reagent and additive for ensuring sufficient conductivity by an acid-base Siegfried R. Waldvogel studied chemistry in equilibrium with the solvent HFIP. This galvanostatic protocol was Konstanz and received his Ph.D. in 1996 also performed in a decagram-scale towards 4 in 81% yield to from University of Bochum/Max Planck highlight the utility in organic synthesis. In addition, access to the Institute for Coal Research with Prof. Dr. M. natural product nonitidine 8 could be accomplished in 72% yield. T. Reetz as supervisor. After Postdoctoral research at Scripps Research Institute in La Jolla, CA (Prof. Dr. J. Rebek, jr.), he started his own research career in 1998 at University of Münster. After his professorship in 2004 at University of Bonn, he became full professor for organic chemistry at Johannes Gutenberg University Mainz in 2010. His research interests are novel electro-organic transformations including bio-based feedstocks, from electrosynthetic screening to scale-up in flow electrolyzers and innovative cell concepts. In 2018, he cofounded ESy- Labs GmbH, which provides custom electrosynthesis and contract R&D. Anodic Alkoxylation promoted by Solid- supported Base as Part of a One-Pot Sequence Scheme 2. Electro-organic access to phenanthridines and related structures The Tateno group developed an elegant anodic alkoxylation of using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and ammonia. lactams followed by allylation in a one-pot sequence using HFIP in combination with a solid-supported amine base.[30] This gives rise to allylated five- and six-membered lactams (1) and (2) in Benzyl-Aryl Cross-coupling reaction via yields up to 82% over both steps (Scheme 1). After electrolysis Anodic C H Functionalization by HFIP the silica-supported piperidine can be easily removed by filtration. In case of a 7-membered ring (3) the intermediate N-acyliminium A selective dehydrogenative electrochemical functionalization of ion was not formed and therefore no reaction took place. benzylic positions with HFIP has been developed by Waldvogel et al.[31] These electro-generated HFIP ethers are versatile intermediates for subsequent functionalization, as they act as masked benzylic cations, which can be easily activated. Best results were obtained in combination with N,N- diisopropylethylamine (DIPEA). Liberation of the benzylic cation was accomplished by acidic treatment. These cations can readily react with aromatic nucleophiles to provide valuable diarylmethanes. Overall, 28 examples in yields up to 93% (9) over both steps have been accessed (Scheme 3). Various heterocycles could be alkylated by this way, such as 1,3- benzodioxoles (10), benzo[b]furanes (11), thiophenes (12) and Scheme 1. One-pot sequence enabling allyl-substituted lactams utilizing a indoles (13) in high yields up to 78% over 2 steps. solid-supported amine base in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). 3 MINIREVIEW free electrochemical cyanation reaction (Scheme 5). It consists of a two-step sequence and the HFIP ether generated in-situ can be used without further purification. The reaction is selective with yields up to 90% over 2 steps and methoxy groups (18), multiple alkyl groups (19), propyl moieties (20) and halogens (21) being tolerated (Scheme 5). Phenols can be converted in a protective group-free manner, shortening the usual synthetic route by one or two steps. Additionally, only a small excess of cyanide source is used and therefore less toxic reagent waste is generated. The HFIP released during the reaction can be recovered and redistilled, improving the sustainability of this reaction. Scheme 3. Benzyl-aryl cross-coupling of phenols with various nucleophiles after anodic activation with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Even late-stage functionalization of a variety of natural products and pharmaceutically active ingredients was possible in yields up to 44% (17a and 17b) with slight alteration of the protocol employing Lewis acids instead of 2,2,2-trifluoroacetic acid for HFIP ether cleavage (Scheme 4). Bergapten (14), hymecromone (15) and even phenylethylamines (16) could be converted in this reaction in yields up to 37%. Scheme 5. Scope of the benzylic anodic activation with 1,1,1,3,3,3- hexafluoroisopropanol (HFIP) and subsequent cyanation reaction. Asymmetric Lewis Acid-catalyzed Alkylation in a toluene/HFIP/quinuclidine Electrolyte Inspired by the benzyl-aryl coupling via HFIP ethers by Waldvogel et al., the Guo group developed an outstanding asymmetric nickel-catalyzed electrochemical alkylation.[35] Asymmetric induction is achieved through the radical radical coupling of a chiral Ni(II) complex chelated radical with an electrochemically formed benzylic radical. The resulting alkylation products could be isolated in yields up to 85% (22) and enantiomeric excess up to 97% (23) (Scheme 6). However, the well conductive nature of the HFIP/amine mixture was not exploited, since an additional supporting electrolyte was employed. Scheme 4. Lewis acid-directed late-stage functionalization of natural products and pharmaceutically active compounds. Benzylic anodic C H Functionalization with HFIP and subsequent Cyanation to generate 2-Phenylacetonitriles The HFIP ether concept has been expanded to other valuable building blocks by the Waldvogel group. It was found that liberation of the benzylic cation is not necessary to achieve selective bond formation when stronger nucleophiles are used.[33] Scheme 6. Quinuclidine in toluene/1,1,1,3,3,3-hexafluoroisopropanol (HFIP) With cyanides, a direct substitution reaction is observed to yield mixture as electrolyte in a Lewis acid-catalyzed asymmetric alkylation. 2-phenylacetonitriles, which represent important building blocks in organic synthesis. This structural feature is a precursor to many biologically active molecules such as 2-phenylethylamines[41] or pharmaceuticals, such as the calcium ion channel blocker verapamil or the fungicide mandipropamid.[42] This procedure allows a simple, sustainable, easily scalable, reagent- and metal- 4 MINIREVIEW Anodic C–H Functionalization towards fluorinated Orthoesters from 1,3- Benzodioxoles In contrast to benzylic anodic oxidation of phenols, anisoles and anilides, 1,3-benzodioxoles were found to exhibit unexpected reactivity at complete conversion.[32] Functionalization of 24 occurred at position 2 (26), even in the presence of benzylic methyl groups. This is in contrast to previous work, wherein the benzylic position was functionalized (25) (Scheme 7). Scheme 7. Selectivity of the anodic C H functionalization of 1,3-benzodioxoles Scheme 9. Scope of electrochemically accessible fluorinated orthoesters. with HFIP. Higher yields and improved selectivity were observed with These orthoesters exhibit unusual and unique properties. increasingly larger -systems (31 and 34). This can be explained Surprisingly, 26 proved to be extraordinarily stable towards acids by stabilization of the respective cations after twofold oxidation and bases and does not undergo substitution reactions, even and deprotonation. Halo substituents (29, 32, 36), as well as a when transition metals are present within the reaction mixture. substitution pattern in position 2 and 5 were tolerated (33, 34, 35). Therefore, it was possible to perform a bromination on 26, The logP-values of 1,3‐benzodioxoles and the corresponding followed by a Pd-catalyzed Suzuki coupling to give 28 in 64% orthoesters were calculated and compared, to determine the yield, in the presence of the HFIP orthoester (Scheme 8). lipophilicity of the orthoesters in comparison to the respective 1,3-benzodioxoles (see SI of ref.[32]). Remarkably, these values increased by a factor of 1.5 to 2 when fluorinated side chains were installed. Such an enhancement of lipophilicity is very unusual. This transformation could boost the potency of bioactive compounds and impact target selectivity tremendously by influencing pKa, modulating conformation, and hydrophobic interactions of the 1,3-benzodioxole moiety.[44] Dehydrogenative anodic C C Coupling of Scheme 8. Bromination reaction under acidic conditions followed by Suzuki Phenols bearing electron-withdrawing Groups coupling at elevated temperatures in the presence of fluorinated orthoesters. Electron-rich phenols and related substrates such as arenes, anilides or heterocycles could be selectively cross-coupled due to It was also possible to install various fluorinated alkoxy moieties, the solvent effect of HFIP.[6,17,45] However, the method failed when allowing the modulation of the bioactive properties of the the components were not electron-rich enough. Interestingly, pharmaceutically relevant 1,3-benzodioxole moiety in 28 phenols carrying electron-withdrawing groups (EWG) in position examples in yields up to 60% (31) (Scheme 9).[43] 2 undergo dehydrodimerization reaction instead of HFIP ether formation. To the best of our knowledge, this represents the first selective electrochemical coupling of phenols bearing EWGs,.[34] The reaction is highly selective and yields 2,2 -biphenols in up to 64% yield (Scheme 10). This reaction showed a high tolerance to functional groups like ketones (37 and 40), halogens (37), sulfoxides (38), as well as esters (39). 5 MINIREVIEW the Waldvogel group[53] because of the technical relevance. A novel approach surmounting the laborious recovery of supporting electrolyte using a HFIP-pyridine system (Scheme 12) was established.[54] Scheme 10. First selective homo-coupling of phenols bearing electron- withdrawing groups. Scheme 12. Electro-organic synthesis of 3,3 ,5,5 -tetramethyl-2,2 -biphenol using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)/supporting electrolyte and These types of structures are used as ligands in the synthesis of HFIP/pyridine system as electrolyte. several binuclear boron[46] and aluminum complexes,[47] for application in optoelectronic devices and as catalysts in polymerization reactions[48] and most of them need sophisticated The straightforward removal of HFIP and pyridine after multi-step syntheses.[49] Cross-coupling reactions were also electrolysis by simple distillation is a major advantage of this investigated in the HFIP/amine electrolyte system. Co-electrolysis synthetic protocol. This is of particular interest when scalability of with naphthalene unexpectedly yielded polycyclic structures (41), the electro-conversion in a technical range is intended. Scale-up which were unequivocally analyzed by X-ray analysis, NMR and in continuous flow-electrolysis cells[55] using a glassy carbon (GC) ESI/MS techniques (Scheme 11). The aromatic system was anode gives the desired ligand precursor in yields up to 58% in a intercepted by the nucleophilic attack of the phenolic oxygen, 12 cm² and 59% a 48 cm2 flow-cell. High current densities of 60 which is quite unusual. It was also found that these are in mA/cm2 and high flow rates in a cascade electrolysis result in a equilibrium with the common cross-coupled products (42). This high time efficiency. Numbering up of flow-cells and a simple equilibrium is influenced by the pH, which poses a new type of work-up strategy make this process viable for a technical scale. isomerism. Further oxidation with DDQ provided dibenzofurans (43) in yields up to 83%. Therefore, it is possible to obtain both, Table 1. Optimized parameters of the different flow cells and yields obtained. 2,4-Dimethylphenol c = 1.25 mol/L and pyridine (5 vol %) in HFIP, cathode: the simple cross-coupled or polycyclic product selectively. stainless steel, anode: glassy carbon, cascade electrolysis with 8 steps of 0.1 F, total applied charge: 0.8 F 2 cm x 6 cm-flow cell 4 cm x 12 cm-flow cell Anode surface 12 cm2 48 cm2 Current density 60 mA/cm2 60 mA/cm2 Flow rate 3.58 mL/min 14.33 mL/min Temperature 20 °C 0 °C Isolated yield (44) 58% 59% Scheme 11. Cross-coupling of phenols bearing electron-withdrawing groups with naphthalene discovery of a new form of isomerism. Anodic C–H Functionalization of Purine Scalable S he i f 2,2 -Biphenols using derivatives and subsequent Cross-coupling HFIP/pyridine as Electrolyte reaction (sp2) 2,2 -Biphenols are important ligand building blocks for the After developing benzylic activation reactions and isolating aryl transition metal-catalyzed hydroformylation as a major branch of HFIP ethers as side components, it was considered to use the transition metal catalysis.[50] The synthesis of this particular HFIP moiety attached to aryls as a leaving group in metal- structural motif either requires economically and ecologically catalyzed cross-coupling reactions. A selective, scalable, and unfavorable transition metal catalysis or can be performed in an sustainable electrochemical synthesis of HFIP aryl ethers was electro-organic transformation which requires supporting thus developed. [56] Of particular interest is the electrochemical electrolytes.[51] The use of HFIP is vital to avoid undesired C O modification of bioactive purine derivatives, such as theophylline coupling reactions and formation of polycyclic products.[52] The (45) and caffeine (48) derivatives (Scheme 13). Anilides (46, 50) electrochemical synthesis of 44 was major research topic within as well as naphthalene (47 and 49) could be converted successfully in yields up to 59%. 6 MINIREVIEW Electron-releasing groups lowered the yield significantly down to 22%, as seen for a methoxy group in ortho position (57). Scheme 15. N,N-Diisopropylethylamine (DIPEA) as C2 feedstock and base promoting conductivity in the anodic formation of cinnamaldehydes. Scheme 13. One variable at a time (OVAT) and Design of Experiment (DoE) optimized reaction conditions of the anodic oxidation of purines and other arenes to 8-(1,1,1,3,3,3-hexafluoro-2-propoxy)-arenes in the presence of a Electrosynthesis of Alkyl Arylsulfonates in a base. OVAT optimized a) 7.2 mA/cm2, 2.0 F, 300 rpm (stirrer velocity), 0.25 M Multi-Component Reaction caffeine, 0.1 M NEt3, yield of 48 33%; DoE optimized b) 22.1 mA/cm2, 2.61 F, 700 rpm (stirrer velocity), 0.2 M caffeine, 0.2 M NEt3, yield of 48 42%; The combination of DIPEA and HFIP has also been applied in the concise electrochemical synthesis of alkyl arylsulfonates by direct The optimization to increase the yield for the electrosynthesis of anodic oxidation of electron-rich arenes in a multi-component HFIP caffeyl ether (48) was conducted via a Design of Experiment reaction (Scheme 16, A). The combination of SO2, an alcohol, and (DoE) approach. Optimal reaction conditions were successfully DIPEA leads to an in-situ generation of monoalkyl sulfites (B) with applied to a variety of aryl substrates to extend the scope to non- bifunctional purpose. Firstly, this species functions as nucleophile purine derivatives. Furthermore, the HFIP caffeyl ether was and secondly, excellent conductivity is provided. Several primary successfully used as the electrophile in transition metal-catalyzed and secondary alcohols and electron-rich arenes are and transition metal-free reactions with cyanides (51) and amines implemented in this reaction to generate the alkyl arylsulfonates with excellent yields up to 94% (52) (Scheme 14). Even under in yields up to 73% with exquisite selectivity (C). A competition metal-free conditions most of the conversions worked, accessing reaction was observed between 1,1,1-trifluoroethanol and HFIP thioethers (53) and ethers (54) in yields up to 81%. resulting in a product mixture (D). BDD electrodes are employed in divided cells at galvanostatic conditions, separated by a simple commercially available glass frit.[57] Scheme 14. Derivatization of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) caffeyl ether with various nucleophiles. Anodic formation of Cinnamaldehydes with DIPEA as reagent The Chiba group recently identified a novel mode of reactivity and reported a HFIP/DIPEA-based aldol reaction, whereby the ethyl group of DIPEA additionally serves as a C2 source.[36] Mechanistic Scheme 16. Electrochemical synthesis of alkyl arylsulfonates in a multi- studies revealed that DIPEA and HFIP play a significant role component reaction. within this reaction. DIPEA forms not only an electrolyte with HFIP, but also generates acetaldehyde in-situ. A broad scope of benzaldehyde derivatives and heteroarene-aldehydes could be Summary and Perspectives employed in this reaction, forming the cinnamaldehydes in yields up to 76% (55) (Scheme 15). Even selective reaction of only one Within this review, the outstanding impact and unique reactivity of of two aldehyde groups was achieved in yield of 70% (56). organic substrates in HFIP/amine electrolytes during electrolysis are surveyed. The important advantage of this approach in 7 MINIREVIEW comparison to conventional electro-organic synthesis using [15] L. Eberson, M. P. Hartshorn, O. Persson, J. Chem. Soc., Perkin Trans. 2 additional salts as supporting electrolytes is the simple purification 1995, 1735. process, which can mostly be performed by distillation of the [16] a) L. Eberson, M. P. Hartshorn, O. Persson, J. Chem. Soc., Chem. electrolyte. The direct evaporative recovery of the HFIP/amines Commun. 1995, 1131; b) L. Eberson, O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. 1995, 34, 2268 2269; Angew. Chem. 1995, 107, mixtures and subsequent reuse diminishes the environmental 2417 2418. footprint. Although, besides aryls several aliphatic compounds [17] B. Elsler, A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. have been transformed and a large functional group tolerance has Waldvogel, Chem. Eur. J. 2015, 21, 12321 12325. been demonstrated. Moreover, the scope of most electrosynthetic [18] A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R. Waldvogel, transformations is significantly expanded by using HFIP/amines Angew. Chem. Int. Ed. 2018, 57, 5594 5619; Angew. Chem. 2018, 130, instead of the traditional HFIP electrolytes. The successful 5694 5721. conversion of and towards natural products and pharmaceutically [19] S. Möhle, M. Zirbes, E. Rodrigo, T. Gieshoff, A. Wiebe, S. R. Waldvogel, active compounds is of exceptional importance and underlines Angew. Chem. Int. Ed. 2018, 57, 6018 6041; Angew. Chem. 2018, 130, 6124 6149. the versatility for the application of this technique. This [20] J. L. Röckl, D. Pollok, R. Franke, S. R. Waldvogel, Acc. Chem. Res. 2020, development will open a new field in electro-organic synthesis and 53, 45 61. should encourage scientists towards novel processes using these [21] L. Schulz, S. Waldvogel, Synlett 2019, 30, 275 286. particular HFIP/amine mixtures in sustainable electrosynthesis [22] a) T. Gieshoff, D. Schollmeyer, S. R. Waldvogel, Angew. Chem. Int. Ed. protocols. 2016, 55, 9437 9440; Angew. Chem. 2016, 128, 9587 9590; b) T. Gieshoff, A. Kehl, D. Schollmeyer, K. D. Moeller, S. R. Waldvogel, J. Am. Chem. Soc. 2017, 139, 12317 12324; c) T. Gieshoff, A. Kehl, D. Acknowledgements Schollmeyer, K. D. Moeller, S. R. Waldvogel, Chem. Commun. 2017, 53, 2974 2977; d) A. Kehl, T. Gieshoff, D. Schollmeyer, S. R. Waldvogel, Chem. Eur. J. 2018, 24, 590 593; e) B. Elsler, D. Schollmeyer, K. M. J. L. Röckl is a recipient of a DFG fellowship through the Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2014, 53, Excellence Initiative by the Graduate School Materials Science in 5210 5213; Angew. Chem. 2014, 126, 5311 5314; f) S. Lips, A. Wiebe, Mainz (GSC 266). Funding by the DFG in frame of FOR 2982 B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, UNDODE (Wa1276/23-1) is highly appreciated. Support by the Angew. Chem. Int. Ed. 2016, 55, 10872 10876; Angew. Chem. 2016, 128, 11031 11035; g) L. Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. Advanced Lab of Electrochemistry and Electrosynthesis M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, ELYSION (Carl-Zeiss-Stiftung) is gratefully acknowledged. 4877 4881; Angew. Chem. 2017, 129, 4955-4959; h) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 11801 11805; Angew. Chem. 2016, 128, 11979-11983; Conflict of Interest i) L. Schulz, R. Franke, S. R. Waldvogel, ChemElectroChem 2018, 5, 2069 2072; j) A. Wiebe, S. Lips, D. Schollmeyer, R. Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 14727 14731; Angew. 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Schollmeyer, Chem. Eur. J. 2020, DOI: 10.1002/chem.202001171. 9 MINIREVIEW Entry for the Table of Contents Electrosynthesis 2.0: The well conductive electrolyte system based on HFIP and amines offers not only intriguing features for practically performing the electrosynthesis, but also novel reactivity and expansion of the scope of the well-established HFIP electrolytes. With an almost complete recovery of the HFIP-amine mixtures a substantial contribution to greener electrosynthesis is established and might lead to a new area in electrosynthesis. 10 Title: Merging shuttle reactions and paired electrolysis: e-shuttle enables the reversible interconversion of alkenes and vicinal dihalides Authors: Xichang Dong1,3, Johannes L. Röckl1,2,3, Siegfried R. Waldvogel2* & Bill Morandi1* 1Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. 2Department of Organic Chemistry, Johannes Gutenberg-University Mainz, Germany. 3These authors contributed equally: Xichang Dong, Johannes L. Röckl. ✉e-mail: bill.morandi@org.chem.ethz.ch; waldvogel@uni-mainz.de Abstract (Nature format): Polyhalogenated molecules have found widespread applications as flame retardants, pesticides, polymers and pharmaceuticals1,2. Moreover, they serve as versatile synthetic intermediates in organic chemistry due to the inherent reactivity of carbon-halogen bonds3 , 4 . Despite these attractive features, the preparation of polyhalogenated molecules still relies on the use of highly toxic and reactive halogenating reagents, such as Cl2 and Br2, which are hazardous compounds to transport, store, and handle4,5. Moreover, the use of such highly reactive reagents inherently prevents the possibility to perform the reverse reactions, retro-dihalogenations, despite their potential for the recycling of persistent halogenated pollutants. Here, we introduce an electrochemically-assisted shuttle (e-shuttle) paradigm for the facile and scalable interconversion of alkenes and halogenated molecules, a class of reactions which can be used to either synthesize useful polyhalogenated molecules from simple alkenes or recycle waste material. The power of this reaction is best highlighted by an example, in which an inexpensive persistent environmental pollutant (Lindane), can be used as a donor reagent for the functionalization of simple feedstock alkenes, merging a recycling process with a synthetically relevant dichlorination reaction. We further demonstrate that this paired electrolysis-enabled shuttle protocol, which uses a simple setup and inexpensive electrodes, is applicable to four different, synthetically useful transfer halogenation reactions, and can be readily scaled up to decagrams of product. The synthetic potential offered by the reaction’s reversibility was further demonstrated in a unique e- shuttle-mediated alkene protection/deprotection sequence and an intramolecular transfer dibromination. In a broader context, the symbiotic merging of shuttle reactions and electrochemistry introduced in this work opens new horizons for safe transfer functionalization reactions that will address important challenges across the molecular science. Main text: Transfer hydrofunctionalization proceeding through a shuttle catalysis6 paradigm has emerged as a powerful strategy to reversibly functionalize and defunctionalize organic molecules without employing or releasing hazardous reagents7,8,9,10,11,12, such as HCN7. However, catalytic and reversible transfer reactions have so far been limited to alkene monofunctionalization reactions which usually involve the transfer of an HX molecule6,12. In contrast, the synthetically appealing, simultaneous transfer of two functional groups, in a catalytic reversible transfer difunctionalization process, has so far remained elusive, despite the vast synthetic potential of these reactions in organic synthesis. In particular, reactions involving the formal transfer of extremely hazardous molecules, such as Cl 132 or Br2, from inexpensive and non-toxic bulk chemicals, such as dichloro- and dibromoethane, would be highly desirable because of the widespread synthetic applications of polyhalogenated molecules in flame retardants, pesticides, materials and natural products1,2,14, (Scheme 1). The inherent reversibility of a shuttle reaction would further unlock the retro- dihalogenations of waste compounds, such as flame retardants and pesticides, providing a new entry into a circular economy approach to these products. The challenge in developing transfer difunctionalizations originates from the catalytic approach generally employed in shuttle catalysis. Transfer hydrofunctionalizations, such as hydrocyanation7, rely on the intermediacy of an alkyl-M complex which readily undergoes fast and reversible -hydride elimination, thus triggering the transfer of an H group alongside the desired functional group12. Unfortunately, the ease of -hydride elimination makes the selective, competitive elimination of other synthetically useful groups extremely challenging15. Furthermore, while -hydride elimination is a fast and reversible process, the subsequent migratory re-insertion of an alkene into the M−X bond is often kinetically and thermodynamically disfavored due to the high stability of metal-halogen bonds16. Thus, a mechanistically distinct approach to favor X- cleavage over H cleavage is crucial to unlock this important class of transfer difunctionalization reactions. Electrochemistry has recently experienced a renaissance in organic chemistry, as it utilizes inexpensive and readily available electrical current from renewable resources as a sustainable and inherently safe redox reagent17,18,19. Notable advances have been made in halogenation reactions, as illustrated by an elegant example of dichlorination reaction from Lin et al20. However, this reaction, as well as the vast majority of other electrochemical reactions, has to be coupled to another sacrificial half reaction at the counter-electrode. Besides this limitation, current protocols can often be further limited by the use of complex reaction setups including expensive metal electrodes, or the generation of hazardous/flammable by-products (e.g. hydrogen gas) 21 . Moreover, they are inherently irreversible processes and thus cannot be easily used for other synthetically useful applications, such as the degradation of waste molecules, as well rearrangement reactions and new protecting strategies which rely on a process’ reversibility. We envisaged that paired electrolysis22,23, a class of ideal yet extremely rare electrochemical reactions wherein all electrons are employed in the desired transformation, could provide a totally unexplored path to reversible electrochemically-mediated shuttle reactions (e-shuttle). We surmised that the reversible cleavage of two strong C X bonds through a controlled electron transfer process initiated by simple reduction and/or oxidation of key intermediates at the anode and cathode, simultaneously and respectively, would unlock this new class of reactions. More specifically, the single-electron reduction of the dihalide at the cathode releases the X anion and generates the carbon radical Z, which is almost instantly reduced again to an anion24. As a central design, the following selective departure of anion X instead of the hydride breaks the second C X the bond, releasing the alkene simultaneously. Considering that a halide anion is a much better leaving group than a hydride, the competing undesired –H elimination, which is often the preferred pathway with transition metal intermediates, can be effectively suppressed by this electrochemical approach. The subsequent oxidation of the anion X at the anode followed by reaction with the alkene delivers the desired product, which closes the cycle by rebuilding the C X and C Y bonds in a fully isodesmic process. The highly precise control of the potential applied on the electrode and the highly tunable cell potential would make this strategy extremely versatile with regard to the group transferred, opening new horizons for further shuttle reaction development. This is a great advantage over the organometallic strategy, where each shuttle reaction relies on a completely different combination of metal and catalyst requiring tedious optimization campaigns12. At the outset of our investigations, a transfer dibromination was uniformly optimized in an undivided cell using inexpensive isostatic graphite as the electrode material under a constant current conditions at room temperature, a reaction setup easily accessible to non-specialized laboratories. 1,2-Dibromoethane (DBE) was selected as a formal Br2 donor because it is an inexpensive reagent, produced on a bulk scale, that would solely release benign ethylene as a by-product. It is also notable that most commercial suppliers offer this reagent at an even lower price (per mol of Br2) than Br2 itself, probably reflecting additional costs occurring during transportation and storage of toxic and volatile Br 252 . Optimal results were obtained with 5 equiv. of 1,2-dibromoethane as the Br2 donor, as little as 1 vol% HFIP as the key additive, and 2 equiv. of Et4NBF4 as electrolyte, providing the targeted 1,2-dibromide XX in 84% NMR yield when 3.0 F of electricity with respect to alkene XX was applied. As indicated by cyclic voltammetry (CV) studies, the HFIP additive plays a key role in facilitating the reduction of the DBE donor and suppressing the undesired and unproductive cathode reductive oligo/polymerization of alkene acceptors (see Scheme 2 and SI for more details). Using this protocol, a broad range of inactivated terminal alkenes (XX−XX) were readily converted to the corresponding dibromide product in good to excellent yields, in which a large variety of functional groups such as amide (XX), ester (XX), free carboxylic acid (XX), alcohol (XX), and bromide (XX) were well tolerated. Activated alkenes, such as styrene (XX-XX) and vinyl silane (XX-XX), proved to be suitable substrates as well, albeit giving slightly lower yields. This protocol was also applicable to the natural products camphene (XX) and Betulin (XX), both of which underwent desired dibromination reaction. Notably, the acid-sensitive silyl ether was well- accommodated, exhibiting an advantage over the previously reported electrochemical oxidative 1,2-dibromination of alkenes under acidic conditions21. While the hexa-1,5-diene (XX) underwent two-fold 1,2-dibromination to yield the tetra brominated product XX in decent yield, selective mono 1,2-dibromination was observed for several other unconjugated dienes (XX-XX). To demonstrate the easy scalability and robustness of this e-shuttle process, the dibromination of Betulin was readily scaled up to a 1.5 L beaker cell from a 10 mL reaction vial to give 33 g of product under otherwise indentical reaction conditions. Taking advantage of the reversible elimination of a -SR group, we could next also develop a transfer bromothiolation of alkenes to access 1,2-bromothioether derivatives which are valuable synthetic intermediates usually accessed through multistep synthesis involving toxic R-SBr reagents 26 , 27 . Several terminal alkenes were successfully converted to the targeted bromothioether product with excellent regioselectivity (XX-XX), under otherwise identical conditions, taking 2-bromoethyl phenyl sulfide (10 equiv.) as the PhS−Br donor (Scheme 2). The carboxylic acid (XX) and ester (XX) functional groups were well tolerated. Interestingly, an interrupted shuttle reaction took place when pent-4-en-1-ol (XX) and pent-4-enoic acid (XX) were employed as the substrates, delivering the cyclic ether or lactam derivatives (XX-XX) via subsequent intramolecular nucleophilic attack, demonstrating the method´s potential for the development of new cascade reactions. 1,2-dichloroethane 1,1,2-trichloroethane 1,1,2,2-tetrachloroethane 1,1,1,2-tetrachloroethane 1,1,1,2,2,2-hexachloroethane lindane 70 20 -2 -1,8 -1,6 -1,4 -1,2 -1 -0,8 -0,6 -30 -80 -130 -180 -230 In order to further demonstrate the modularity of this conceptually new approach to shuttle catalysis, we next developed a transfer dichlorination reaction. 1,2-Dichloroethane (DCE) was selected as the donor, because it is an inexpensive bulk chemical (20 million ton/year) produced with the excess of Cl2 gas generated during the Chlor-alkali electrolysis process28. After initial fruitless attempts, the desired dichloride XX was obtained in 39% yield when 5 mol% of a Mn(II) salt (e.g. MnCl2 4H2O) was introduced as a mediator20, and the yield was further increased to 70% when DCE (ca. 125 equiv.) was used as the solvent. While this procedure was efficient for a wide set of terminal alkenes, it failed for more challenging 1,1,2-trisubstituted alkene XX, a feature largely attributed to the undesired 1,2-dechlorinative decomposition of the product XX and alkene oligomerization of the starting material via cathodic reduction. We reasoned that these two challenges could be smoothly resolved by choosing a suitable dichloride donor, as they could not be resolved by adding an additive, such as HFIP. Among all of the polychloride donors examined, 1,1,1,2-tetrachloroethane (XX, 10 equiv.) turned out to be the best option in terms of atom economy and reaction efficiency, affording the dichloride product XX in 90% NMR yield. This can be rationalized by the low redox potential of 1,1,1,2-tetrachloroethane (Scheme 3, blue curve) and the high stability of the extruded 1,1-dichloroethene. Using this procedure, various styrene- derived alkenes were converted to the corresponding 1,2-dichlorides in good to excellent yield (XX-XX), leaving the Br, Cl, CHO, COOH and CN functional groups untouched. The indene (XX) was diastereoselectively transformed into trans-1,2-dichloride XX (d.r. > 19:1). The 1,2-dichloride compound XX, bearing a reactive benzylic tertiary C Cl bond, was prepared in good yield from α–methylstyrene. Several other activated alkenes proved viable acceptors as well (XX-XX), in particular, methyl cinnamate was converted to the 1,2-dichloride XX in an excellent d.r. ratio (9:1). A series of mono- and disubstituted alkenes participated smoothly in the 1,2-dichlorination reaction, with the Boc and Ts protected amine well tolerated. To our delight, preliminary experiments show that this protocol can be readily extended to the 1,2-chlorothiolation transfer reaction using the commercially available 2-chloroethyl phenyl sulfide (10 equiv.) as the donor. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00 Applied charge in F Intermediate I dialkene Starting material Desired product Intermediate II dibromide An intriguing advantage of the reaction’s reversibility is the possibility to perform an intramolecular rearrangement reaction through a shuttle reaction. Indeed, taking advantage of conjugation as a driving force, we could selectively transfer a dibromide from an internal position to a terminal one (Scheme 4). The reaction´s reversibility further inspired us to design a new protecting group strategy for alkenes. As shown in the figure (Scheme 4), the selective bromination of the unconjugated diene XX taking DBE as Br2 donor leads to protected compound X, which can subsequently undergo site selective asymmetric dihydroxylation of the terminal alkene to generate the intermediate XX while the dibromide moiety remained untouched. A final retro- dibromination of XX using a sacrificial alkene (1,4-cyclohexadiene) as acceptor produces the desired dihydroxylated product XX bearing an internal alkene29. Lindane, which was once widely used as an effective insecticide in crop protection, is classified as a persistent organic pollutant due to its high toxicity and high persistency in the environment. We thus questioned whether this waste material, which can only be inefficiently degraded through normal electrochemical recycling approaches30,31,32, could instead serve as an efficient Cl2 donor in a synthetically useful transfer dichlorination. Remarkably, lindane served, through three GC conversion in % successive retro-dichlorination events, as an excellent donor in this reaction generating the desired dichlorinated product alongside benzene, the fully dechlorinated by-product of lindane. These results provide a conceptual blueprint for the development of ideal shuttle reactions, in which the synthetically relevant functionalization of a substrate is coupled with the recycling of a persistent environmental pollutant. In conclusion, we have reported a scalable e-shuttle strategy to unlock previously elusive transfer difunctionalization reactions. Using an easily accessible electrochemical setup involving paired electrolysis, we have been able to take advantage of single electron transfer processes to develop four distinct, synthetically relevant transfer reactions using this unified strategy. The utility of the reaction’s reversibility is demonstrated in an intramolecular rearrangement, a new protecting group strategy for alkenes and a strategy involving the concomitant degradation of a waste molecule to functionalize simple feedstocks. In a broader context, we believe that these results lay the groundwork for the development of countless new reversible reactions which take advantage of the merger between shuttle reactions and electrochemistry. Acknowledgements: This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Shuttle Cat, Project ID: 757608). We also thank the ETH Zürich for support. X. D. acknowledges the Marie Skłodowska-Curie Action (HaloCat, Project ID: 886102) for a postdoctoral fellowship. J.L.R. is a recipient of a DFG fellowship through the Excellence Initiative by the Graduate School Materials Science in Mainz(GSC 266). Author contributions: X. D. and J. 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Hill, Safety Review of Bromine-Based Electrolytes for Energy Storage Applications, Report 1 http://energystorageicl.com/wp-content/uploads/2018/04/DNV-GL-Safety-Review-of-Bromine- Based-Electrolytes-for-Energy-Storage-Applications.pdf (2018). 26. Schneider, E., Darstellung & Eigenschaften von Alkylschwefelhalogeniden, Chem. Ber. 84, 911– 916 (1951). 27. Drabowicz, J., Kiełbasiński, P., & Mikołajczyk, M. Synthesis of sulphenyl halides and sulphenamides (eds. Patai, S.) 221–292 (John Wiley & Sons, Ltd., 1990) 28. Hoffmann, C., Weigert, J., Esche, E., & Repke, J. U. Towards demand-side management of the chlor-alkali electrolysis: Dynamic, pressure-driven modeling and model validation of the 1, 2- dichloroethane synthesis. Chem. Eng. Sci. 214, 115358 (2020). 29. Husstedt, U, & Schäfer, H. Selective Monoprotection of the Less Alkylated Double Bond in Dienes, Synthesis 964−966 (1979). 30. Rondinini, S. & Vertova, A. Electroreduction of halogenated organic compounds. 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Inhalt 1 General Methods .................................................................................................................................. 2 1.1 Gas Chromatography (GC/GC-MS) ................................................................................................ 2 1.2 Liquid Chromatography ................................................................................................................ 2 1.3 High Resolution Mass Spectrometry ............................................................................................. 2 1.4 NMR Spectroscopy ........................................................................................................................ 3 1.5 Melting Point ................................................................................................................................. 3 1.6 Cyclic voltammetry........................................................................................................................ 3 1.7 Mechanistic experiments .............................................................................................................. 4 1.8 Optimization ................................................................................................................................ 8 Optimization of Br2 shuttle conditions .......................................................................... 8 1.9 Electrolysis setup ..................................................................................................................... 11 1.10 General procedures .................................................................................................................... 13 GP1: Electrolytic shuttle dibromination of alkenes ............................................................ 13 GP2: Electrolytic shuttle dichlorination of alkenes ............................................................. 13 GP3: Electrolytic shuttle bromothiolation of alkenes ......................................................... 14 GP4: Electrolytic shuttle chlorothiolation of alkenes ......................................................... 14 1.11 Characterization .......................................................................................................................... 15 1.12 Spectra ........................................................................................................................................ 63 1 1 Gene al Me hod 1.1 Gas Chromatography (GC/GC-MS) Crude reaction mixtures and purified products were analyzed by gas chromatography (GC) with a GC-2010 (Shimadzu K ō o Japan A q a capilla col mn ZB-5 (length: 30 cm, inner diameter: 0.25 mm, layer thickness of stationary phase: 0.25 µm, carrier gas: hydrogen, stationary phase: (5%-phenyl)- methylpolysiloxane (Phenomenex, Torrance, USA) was used. The carrier gas rate was 45.5 cm -1 and the injection temperature 250 °C. A flame ionization detector (FID) with an inlet temperature of 310 °C was used. Further analysis by gas chromatography mass spectra (GC-MS) using a GC-2010 with a similar column, combined with a GC MS-QP2010 (Shimadzu K ō o Japan de ec o i h an injec ion empe a e of 250 °C and detection inlet temperature of 310 °C was conducted. All ch oma og aphic da a a eco ded ing he me hod hart hich a a °C with a heating rate of 15 C min-1 to 290 °C which is held for 8 min. 1.2 Liquid Chromatography Thin la e ch oma og aph TLC a pe fo med i h DC Kie elgel F254 Merck KGaA, Darmstadt, Germany) on aluminum plates and an UV lamp ( = 254 nm, NU-4 KL, Benda, Wiesloch, Germany). No stain was utilized as all starting materials and products absorbed in the UV light at = 254 nm. An automatic silica flash column chromatography system with a control unit C-620, a fraction collector C-666 and a UV photometer C 635 (Büchi, Flawil, Switzerland) was used for all isolations. Silica gel 60 M (0.040 0.063 mm, Macherey-Nagel GmbH & Co., Düren, Germany) was used as the stationary phase. Cyclohexane and ethyl acetate or dichloromethane and methanol were used as eluents. The system connected to a computer and controlled with the software BÜCHI Sepacore Control 1.2 Standard Edition. 1.3 High Resolution Mass Spectrometry High resolution electrospray ionization mass spectrometry (HR-ESI) and high resolution atmospheric pressure chemical ionization (HR-APCI) was performed using an Agilent 6545 QTOF-MS (Agilent, Santa Clara, USA). The data given displays the mass-charge-ratio (m/z) of the corresponding compounds. 2 1.4 NMR Spectroscopy Nuclear magnetic resonance spectroscopy (NMR) was measured using a multi nuclear magnetic resonance spectrometer Bruker Avance III HD 400 (400 MHz) (5 mm BBFO-SmartProbe with z gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). The chemical shifts (δ) are reported in parts per million (ppm) relative to the residue signal of the deuterated solvent (CDCl3 or DMSO-d6) used for the measurements by the solvent data chart from Cambridge Isotopes Laboratories, USA. For the 19F pec a e h l fl o oace a e e ed a e e nal anda d ppm The evaluations of 1H and 13C were executed using the software MestReNova 10.0.1-14719 (Mestrelab Research S.L., Spain) with the assistance of H,H–COSY, C,H–HSQC and C,H–HMBC experiments. The multiplicity of the signals were abbreviated in the following manner: s (singlet), d (doublet), t (triplet), hept (heptet) pseudo-quart (pseudo-quartet), pseudo-quint (pseudo-quintet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets). The coupling constants J have been given in Hertz (Hz). 1.5 Melting Point The melting ranges of purified products were measured using M-565 (Büchi, Flawil, Switzerland) with a heating rate of 2 C min-1. The given melting ranges are not further corrected. 1.6 Cyclic voltammetry C clic ol amme CV a pe fo med i h a Me ohm VA S and eq ipped i h a A olab pe III potentiostat (Metrohm AG, Herisau, Switzerland). Working electrode: for Br2 shuttle graphite electrode tip, 2 mm diameter; for Cl2 shuttle Pt electrode tip, 2 mm diameter; counter electrode: glassy carbon rod; reference electrode: Ag/AgCl in saturated LiCl/EtOH. Solvent: MeCN, scan rate (unless stated otherwise) v = 100 mV/s, T = 20 °C, c = 5 mM, supporting electrolyte (if used): Et4NBF, c(Et4NBF,) = 1 M. 3 2 Mechani ic e e imen 4 2.1 Cyclic voltammetry 5 6 7 3 O imi a ion Optimization of Br2 – shuttle conditions conv. 99% yield = 84% anode cathode j (mA/cm2) donor screening (20eq.) BDD (traces) Platinum (23%) 1.6 (25%) 8.3 (48%) 1,2-dibromoethane (50%) 5 eq. (50%) Glassy carbon (traces) Graphite (50%) 3.3 (31%) 10 (50%) 1,2-dibromopropane (20%) Graphite (50%) Zinc (ND) 5.3 (49%) 15 (46%) 2,3-dibromobutane (6%) Magnesium (ND) 1,2-dibromoethylbenzene 1.eq (42%) atmosphere solvent additive (5 vol%) supp. electrolyte (0.2 M) air (74%) CH3CN (49%) - (49%) - nitrogen (84%) 1,2-dibromoethane (22%) HFIP (82%) 1 vol% (84%) NBu4BF4 (40%) argon (84%) MeOH (traces) MeOH (76%) NEt4BF4 (50%) HFIP (ND) water (messy) applied charge (F) temperature additional exp.: (conversion in %) r.t. (50%) Slow addition (23%) 2.0 (63%) 2.6 (87%) 40 °C (50%) Excell (4%) 2.2 (75%) 2.8 (95%) 60 °C (36%) 2.4 (80%) 3.0 (>99%) 8 Optimization of Cl2 – shuttle conditions 9 10 4 Elec ol i e Electrasyn cell-setup (5 and 10 mL) https://www.ika.com/electrasyn/Echem-Platform.html Beaker-type cell (200 mL) The beaker-type cell (200 mL) consists of a simple glass beaker and a glass adapter, closed by a PTFE plug. This cap allows precise arrangement of the electrodes. Total dimension of the electrodes are 14 cm x 3.5 cm x 0.3 cm. Figure X: 200 mL beaker-type cell; left: assembled; right: individual parts. For size comparison e 2 c i (dia e e 25.75 1.01 i che ) i laced i f f he glass cell. 11 Beaker-type cell (1.5 L). The undivided 1.5 L vessel is equipped with a heating jacket, bottom outlet and thermometer. A bipolar stacked electrode setup of 8 isostatic graphite electrodes (d = 5 mm) with a total surface area of 374 cm² anodic and cathodic sites was used. For power supply, a TDK La bda Ge e GEN 30-50 was used providing a maximum of 1500 W at 30 V/50A. Figure X: Double-jacketed 1500 mL beaker-type cell; left: assembled; right: Electrode arrangement. 12 5 Gene al oced e GP1: Electrolytic shuttle dibromination of alkenes Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) was added to an oven-dried undivided ElectraSyn® vial (10 mL) equipped with a Teflon-coated magnetic stir bar. Two graphite electrodes (0.8 x 0.2 x 3.25 cm, SIGRAFINE®V2100, SGL Carbon, Bonn-Bad Godesberg, Germany) were adapted to the ElectraSyn® vial cap. The vial was capped and connected to the Schlenk line via a canula and purged with a gentle flow of N2 (the gentle flow was maintained during the whole electrolysis). The respective alkenes (1 mmol, 1 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 2.5 mmol, 5 equiv.), HFIP (100 µL, 1 vol%) and dry MeCN (ca. 9.5 mL) were added to the reaction mixture to reach 10 mL (0.1 M). Pre-stir the reaction mixture until a clear solution was obtained. The reaction mixture was subjected to a constant current electrolysis with a current density of 10.0 mA/cm2 at room temperature. The progress of the reaction was monitored by GC or TLC and the electricity was turned off until completion of the reaction (typically after 2.5 10 F per mole). Then, the volatile solvent was removed in vacuo. The residue was purified by column chromatography using silica gel and cyclohexane/ethyl acetate as eluent to afford the desired product. GP2: Electrolytic shuttle dichlorination of alkenes MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.) and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) was added to an oven-dried undivided ElectraSyn® vial (5 mL) equipped with a Teflon-coated magnetic stir bar. Two graphite electrodes (0.8 x 0.2 x 3.25 cm, SIGRAFINE®V2100, SGL Carbon, Bonn-Bad Godesberg, Germany) were adapted to the ElectraSyn® vial cap. The vial was capped and connected to the Schlenk line via a canula, which was then evacuated and backfilled with N2 for five times. The respective alkenes (0.5 mmol, 1 equiv.), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.) and dry MeCN (ca. 4.5 mL) was added to the reaction mixture to reach 5 mL (0.1 M). The reaction mixture was stirred until a clear solution was obtained. The reaction mixture was subjected to a constant current electrolysis with a current density of 2.0 mA/cm2 at 50 °C. The progress of the reaction was monitored by GC or TLC and the electricity was turned off until completion of the reaction (typically after 2.5 5 F per mole). Then, the volatile solvent was removed in vacuo. The residue was purified by column chromatography using silica gel and n-pentane/diethyl ether or cyclohexane/ethyl acetate as eluent to afford the desired product. 13 GP3: Electrolytic shuttle bromothiolation of alkenes Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) was added to an oven-dried undivided ElectraSyn® vial (5 mL) equipped with a Teflon-coated magnetic stir bar. Two graphite electrodes (0.8 x 0.2 x 3.25 cm, SIGRAFINE®V2100, SGL Carbon, Bonn-Bad Godesberg, Germany) were adapted to the ElectraSyn® cap. The vial was capped and connected to the Schlenk line via a canula and purged with a gentle flow of N2 (the gentle flow was maintained during the whole electrolysis). The respective alkenes (0.5 mmol, 1 equiv.), and (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and dry MeCN (ca. 4.5 mL) were added to the reaction mixture to reach 5 mL (0.1 M). Pre-stir the reaction mixture until a clear solution was obtained. The reaction mixture was subjected to a constant current electrolysis with a current density of 10.0 mA/cm2 at room temperature. The progress of the reaction was monitored by GC or TLC and the electricity was turned off until completion of the reaction (typically after 2.5 10 F per mole). Then, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography using MeCN/water (Millipore + 0.1% formic acid) acetate as eluent to afford the desired product. GP4: Electrolytic shuttle chlorothiolation of alkenes To an oven-dried undivided ElectraSyn® vial (5 mL) equipped with a Teflon-coated magnetic stir bar, MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.) and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) was added. Two graphite electrodes (0.8 x 0.2 x 3.25 cm, SIGRAFINE®V2100, SGL Carbon, Bonn- Bad Godesberg, Germany) were adapted to the ElectraSyn® vial cap. The vial was capped and connected to the Schlenk line via a canula, which was then evacuated and backfilled with N2 for five times. The respective alkenes (0.5 mmol, 1 equiv.), (2-chloroethyl)(phenyl)sulfane (864 mg, 738 µL, 5 mmol, 10 equiv.) and dry MeCN (ca. 4.2 mL) was added to top-up the reaction mixture to reach 5 mL (0.1 M). The reaction mixture was stirred until a clear solution was obtained. The reaction mixture was subjected to a constant current electrolysis with a current density of 2.0 mA/cm2 at 50 °C. The progress of the reaction was monitored by GC or TLC and the electricity was turned off until completion of the reaction (typically after 2.5 5 F per mole). Then, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography using MeCN/water (Millipore + 0.1% formic acid) acetate as eluent to afford the desired product. 14 6 Cha ac e i a ion 1,2-dibromododecane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of dodec-1-ene (168 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 84%, 276 mg, 0.84 mmol). Scale-up 25x in 250 mL cell: yield: 80%, 6.57 g, 20 mmol 1H NMR (400 MHz, Chloroform-d) 4.24 4.12 (m, 1H), 3.86 (dd, J = 10.2, 4.4 Hz, 1H), 3.64 (t, J = 10.2 Hz, 1H), 2.15 (dddd, J = 14.6, 10.2, 5.6, 3.3 Hz, 1H), 1.80 (dtd, J = 14.4, 9.7, 4.6 Hz, 1H), 1.65 1.51 (m, 1H), 1.31 (m, 18H), 0.91 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) 53.2, 36.4, 36.0, 31.9, 29.6, 29.5, 29.4, 29.3, 28.8, 26.7, 22.7, 14.1. Long, Jin; Chen, Jia; Li, Rong; Liu, Zhuo; Xiao, Xuan; Lin, Jin-Hong; Zheng, Xing; Xiao, Ji-Chang[Synlett, 2019, vol. 30, # 2, p. 181 - 184] 15 Methyl 10,11-dibromoundecanoate (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of Methyl 10-undecenoate (198 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 62%, 222 mg, 0.62 mmol). 1H NMR (400 MHz, Chloroform-d)) 4.15 ( dd, J = 9.5, 4.4, 3.3 Hz, 1H), 3.84 (dd, J = 10.2, 4.4 Hz, 1H), 3.66 (s, 3H), 3.62 (t, J = 10.2 Hz, 1H), 2.29 (t, J = 7.5 Hz, 2H), 2.12 (dddd, J = 14.7, 10.2, 5.6, 3.3 Hz, 1H), 1.83 1.71 (m, 1H), 1.65 1.57 (m, 2H), 1.30 (m, 9H). 13C NMR (101 MHz, Chloroform-d) 174.4, 53.2, 51.60, 36.4, 36.1, 34.2, 29.3, 29.2, 29.2, 28.8, 26.79, 25.0. HRMS for C12H22Br2O2 (ESI+) [M]+: calc.: 357.0059, found: 357.0065. Kabalka; Yang; Reddy; Narayana[Synthetic Communications, 1998, vol. 28, # 5, p. 925 - 929] 16 10,11-dibromoundecan-1-ol (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of Methyl 10-undecen-1-ol (170 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 37%, 122 mg, 0.37 mmol). 1H NMR (400 MHz, Chloroform-d) 4.23 4.15 (m, 1H), 3.87 (dd, J = 10.2, 4.4 Hz, 1H), 3.72 3.58 (m, 1H), 2.16 (dddd, J = 14.6, 10.2, 5.6, 3.2 Hz, 1H), 1.86 1.73 (m, 1H), 1.59 (dq, J = 9.6, 6.6 Hz, 4H), 1.51 1.42 (m, 2H), 1.40 1.31 (m, 10H). 13C NMR (101 MHz, Chloroform-d) 63.2, 53.3, 36.5, 36.1, 32.9, 29.5, 29.4, 28.9, 26.9, 25.8. HRMS for C11H14Br2 (ESI+) [M]+: calc.: 328.0037, found: 328.0038. Camps, F.; Chamorro, E.; Gasol, V.; Guerrero, A.[Journal of Organic Chemistry, 1989, vol. 54, # 18, p. 4294 - 4298] 17 10,11-dibromoundecanoic acid (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 10-undecenoic acid (184 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 61%, 210 mg, 0.61 mmol). 1H NMR (400 MHz, Chloroform-d) 4.21 4.12 (m, 1H), 3.85 (dd, J = 10.2, 4.4 Hz, 1H), 3.63 (t, J = 10.0 Hz, 1H), 2.35 (t, J = 7.5 Hz, 2H), 2.13 (dddd, J = 14.6, 10.3, 5.6, 3.3 Hz, 1H), 1.85 1.71 (m, 1H), 1.70 1.50 (m, 2H), 1.43 1.25 (m, 10H). 13C NMR (101 MHz, Chloroform-d) 178.4, 52.3, 36.5, 36.1, 34.0, 29.3, 29.2, 29.1, 28.9, 26.8, 24.8. HRMS for C11H19Br2O2 (ESI-) [M-H]-: calc.: 340.9457, found: 340.9450. Nishio, Yuya; Yubata, Kotaro; Wakai, Yutaro; Notsu, Kotaro; Yamamoto, Katsumi; Fujiwara, Hideki; Matsubara, Hiroshi[Tetrahedron, 2019, vol. 75, # 10, p. 1398 - 1405] 18 10,11-dibromo-N,N-dimethylundecanamide (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of N,N-dimethylundece-10-ene amid (212 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 65%, 242 mg, 0.65 mmol). 1H NMR (400 MHz, CDCl3) 4.20 4.11 (m, 1H), 3.83 (dd, J = 10.2, 4.5 Hz, 1H), 3.62 (t, J = 10.2 Hz, 1H), 2.97 (s, 6H), 2.36 2.26 (m, 2H), 2.11 (dddd, J = 14.6, 10.2, 5.6, 3.3 Hz, 1H), 1.84 1.70 (m, 1H), 1.67 1.48 (m, 3H), 1.45 1.25 (m, 9H). 13C NMR (101 MHz, CDCl3) 173.41, 53.16, 36.39, 36.01, 33.28, 29.43, 29.30, 29.22, 28.74, 26.72, 25.17. HRMS for C13H25Br2NO (ESI+) [M+H]+: calc.: 370.0376, found: 370.0382. 19 (3,4-dibromo-3-methylbutyl)benzene (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of (3-methylbut-3- en-1-yl)benzene 146 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 5.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (n-pentane : diethyl ether = from 100:0) yielding the product as a colorless solid (yield: 60%, 184 mg, 0.60 mmol). 1H NMR (400 MHz, Chloroform-d) 7.40 7.26 (m, 5H), 4.02 (d, J = 10.3 Hz, 1H), 3.93 (d, J = 10.2 Hz, 1H), 2.91 2.87 (m, 2H), 2.28 2.24 (m, 2H), 1.96 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 141.0, 128.7, 128.6, 67.3, 44.4, 42.2, 32.3, 30.8. HRMS for C11H14Br2 (ESI+) [M]+: calc.: 303.9457, found: 303.9458. The analytical data are in accordance with those reported.[XX] Ref: W. Chen, H.Tao, W. Huang, G. Wang, S. Li, X. Cheng, G. Li, Chem. Eur. J. 2016, 22, 9546 9550. 20 (3,4-dibromobutyl)benzene (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of but-3-en-1- ylbenzene (132 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (n-pentane : diethyl ether = from 100:0) yielding the product as a colorless solid (yield: 60%, 184 mg, 0.60 mmol). 1H NMR (400 MHz, Chloroform-d) 7.41 7.36 (m, 2H), 7.31 7.27 (m, 3H), 4.21 4.15 (m, 1H), 3.93 3.90 (m, 1H), 3.74 3.68 (m, 1H), 3.05 2.98 (m, 1H), 2.86 2.79 (m, 1H), 2.59 2.50 (m, 1H), 2.21 2.11 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 140.3, 128.7, 128.6, 126.4, 52.2, 37.8, 36.3, 33.1. HRMS for C10H12Br2 (ESI+) [M]+: calc.: 289.9300, found: 289.9298. Xia, Xuanshu; Toy, Patrick H.[Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 1397 - 1405] 21 (1,2-dibromoethyl)dimethyl(phenyl)silane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of dimethyl(phenyl)(vinyl)silane (162 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 4.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (n-pentane : diethyl ether = from 100:0) yielding the product as a colorless solid (yield: 48 %, 154 mg, 0.48 mmol). 1H NMR (400 MHz, Chloroform-d) 7.60 7.58 (m, 2H), 7.49 7.40 (m, 3H), 3.94 3.86 (m, 1H), 3.68 3.61 (m, 2H), 0.56 0.54 (m, 6H). 13C NMR (101 MHz, Chloroform-d) 134.46, 134.14, 130.23, 128.27, 42.56, 36.97, -3.24, -4.65. HRMS for C10H14BrSi (ESI+) [M Br]+: calc.: 241.0043, found: 241.0042. 22 4-(1,2-dibromoethyl)benzaldehyde (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 4-vinylbenzaldehyde (134 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 5.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 18 %, 52.2 mg, 0.18 mmol). 1H NMR (400 MHz, Chloroform-d) 10.03 ( , 1H), 7.92 7.89 (m, 2H), 7.59 7.57 (m, 2H), 5.16 (dd, J = 11.1, 5.1 Hz, 1H), 4.11 3.99 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 191.5, 145.0, 136.8, 130.3, 128.6, 49.1, 34.3. HRMS for C9H8Br2NaO (ESI+) [M+Na]+: calc.: 312.8834, found: 312.8833. 23 4-tert-butyl-1,2-dibromoethylbenzene (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 4-tert- butylstyrene (160 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 42%, 134 mg, 0.42 mmol). 1HNMR 400 MHz, Chloroform-d) =7.40-7.31(m,4H),5.15 (dd, J1= 10.2 Hz, J2= 5.8 Hz, 1H), 4.09- 4.00 (m, 1H), 1.32 (s, 9H). 13C NMR (100 MHz, Chloroform-d) = 152.5, 135.8, 127.5, 126.1, 51.5, 35.4, 35.0, 31.5. HRMS for C H 79 +12 16 Br (APCI+) [M-Br] : calc.: 239.0430, found: 239.0434. 24 4-(1,2-dibromoethyl)benzonitrile (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 4-vinylbenzonitrile (130 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 5.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 30:1) yielding the product as a colorless oil (yield: 40 %, 116 mg, 0.40 mmol). 1H NMR (400 MHz, Chloroform-d) 7.70 7.67 (m, 2H), 7.53 7.50 (m, 2H), 5.12 (dd, J = 11.2, 5.0 Hz, 1H), 4.07 (dd, J = 10.4, 5.0 Hz, 1H), 3.99 3.93 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 143.7, 132.8, 128.7, 118.3, 113.1, 48.5, 34.0. HRMS for C H Br NNa (ESI+) [M+Na]+9 7 2 : calc.: 309.8837, found: 309.8837. Chinese Academy Of Sciences Lanzhou Chemical Physics Institute; Qian Bo; Li Weihe - CN110862292, 2020, A 25 1,2,5,6-tetrabromohexane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of hexa-1,5-diene (83 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 7 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless solid (yield: 35 %, 138.9 mg, 0.35 mmol). 1H NMR (400 MHz, Chloroform-d) 4.23 4.16 (m, 2H), 3.91 3.86 (m, 2H), 3.67 3.61 (m, 2H), 2.57 2.47 (m, 1H), 2.40 2.30 (m, 1H), 2.15 2.03 (m, 1H), 1.97 1.85 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 51.6, 51.2, 35.9, 35.8, 33.8, 33.7. HRMS for C6H9Br2 (ESI+) [M Br2H]+: calc.: 238.9066, found: 238.9066. 26 tert-butyl(3,4-dibromobutoxy)diphenylsilane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of (but-3-en-1- yloxy)(tert-butyl)diphenylsilane (311 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 6.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n- pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 75 %, 352.6 mg, 0.75 mmol). 1H NMR (400 MHz, Chloroform-d) 7.77 7.72 (m, 4H), 7.51 7.41 (m, 6H), 4.59 4.52 (m, 1H), 3.96 3.87 (m, 3H), 3.77 3.72 (m, 1H), 2.55 2.47 (m, 1H), 1.97 1.89 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 135.7, 135.7, 133.6, 133.5, 129.9, 129.9, 127.9, 61.2, 49.8, 39.1, 37.0, 27.0, 19.6. HRMS for C20H26Br2NaOSi (ESI+) [M+Na]+: calc.: 491.0012, found: 491.0009. 27 1,2,5-tribromopentane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 5-bromopent-1- ene (149 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a slightly yellow oil (yield: 64%, 306.4 mg, 0.64 mmol). 1H NMR (400 MHz, Chloroform-d) 4.21 4.14 (m, 1H), 3.87 (dd, J = 10.3, 4.4 Hz, 1H), 3.63 (t, J = 10.1 Hz, 1H), 3.50 3.41 (m, 2H), 2.42 2.34 (m, 1H), 2.23 2.13 (m, 1H), 2.06 1.88 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 51.6, 36.0, 34.8, 32.5, 30.1. HRMS for C5H9Br3 (ESI+) [M-Br]+: calc.: 228.9045, found 228.9046. 28 N-allyl-N-(2,3-dibromopropyl)-4-methylbenzenesulfonamid (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of N,N- diallyltosylamide (251 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 8.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 60%, 247 mg, 0.60 mmol). 1H NMR (400 MHz, Chloroform-d) 7.76 7.69 (m, 2H), 7.37 7.31 (m, 2H), 5.56 (ddt, J = 16.8, 10.0, 6.6 Hz, 1H), 5.24 5.16 (m, 2H), 4.51 (qd, J = 6.9, 4.9 Hz, 1H), 3.96 (ddt, J = 15.1, 6.9, 1.4 Hz, 1H), 3.89 3.74 (m, 3H), 3.68 (dd, J = 15.1, 6.9 Hz, 1H), 3.34 (dd, J = 15.1, 7.1 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 144.1, 135.9, 132.4, 130.1, 127.6, 120.5, 53.4, 52.9, 52.3, 50.2, 35.1, 21.7. HRMS for C13H17Br2NO2S (ESI+) [M+H]+: calc.: 409.9420, found: 409.9421. 29 (1,2-dibromoethyl)trimethylsilane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of trimethyl(vinyl)silane (100 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 22 %, 56.7 mg, 0.22 mmol). 1H NMR (400 MHz, Chloroform-d) 3.97 (dd, J = 11.1, 4.5 Hz, 1H), 3.73 3.65 (m, 1H), 3.48 (dd, J = 10.4, 4.5 Hz, 1H), 0.20 (s, 9H). 13C NMR (101 MHz, Chloroform-d) 43.05, 36.68, -2.36. MS for C5H1Br2Si EI m/z (%): 139 (37), 136 (39), 109 (4), 85 (7), 75 (4), 74 (8), 73 (100), 59 (10), 45 (13), 44 (3), 43 (10). Billups; Saini, Rajesh K.; Litosh, Vladislav A.; Alemany, Lawrence B.; Wilson, William K.; Wiberg, Kenneth B.[Journal of Organic Chemistry, 2002, vol. 67, # 13, p. 4436 - 4440] 30 E-1,2-dibromo-4-vinylcyclohexane (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 4- vinylcyclohexane (108 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 2.6 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 58%, 154 mg, 0.58 mmol). 1H NMR (400 MHz, Chloroform-d) 5.83 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.10 (dt, J = 17.0, 1.4 Hz, 1H), 5.05 (dt, J = 10.4, 1.4 Hz, 1H), 4.75 4.67 (m, 2H), 2.69 2.46 (m, 3H), 2.02 (ddq, J = 14.9, 3.3, 1.7 Hz, 2H), 1.79 1.66 (m, 2H). 13C NMR (101 MHz, CDCl3) 142.0, 127.0, 53.2, 52.3, 35.6, 29.6, 27.0, 21.3. MS for C8H12Br2 EI m/z (%): 189 (4), 187 (2), 119 (6), 108 (48), 107 (48), 105 (38), 91 (13), 80 (100), 79 (64), 77 (11), 54 (16), 53 (13), 41 (13), 39 (17). Husstedt,U.; Schaefer,H.J.[Synthesis, 1979, p. 966 - 968] 31 E-4,5-dibromo-7,8-dihydroxyvinylcyclohexane (XX) According to the standard procedure reported by Sharpless et. al. 2 mmol of E-1,2-dibromo-4- vinylcyclohexane was dehydroxylated (Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. (1994). "Catalytic Asymmetric Dihydroxylation". Chem. Rev. 94 (8): 2483–2547) using AD-mix alpha. The desired product was isolated in 66% yield in a d.r. of 9:9:1:1. 1H NMR (400 MHz, CDCl3) 4.75 4.69 (m, 1H), 4.66 (m, 1H), 3.72 (m, 1H), 3.62 3.52 (m, 2H), 2.55 2.42 (m, 1H), 2.40 2.21 (m, 2H), 2.18 1.83 (m, 2H), 1.80 1.51 (m, 3H). 13C NMR (101 MHz, CDCl3) 75.4, 75.3, 64.8, 53.2, 53.2, 53.2, 53.1, 34.7, 34.6, 31.1, 30.5, 28.23, 28.2, 23.0, 22.0. 32 4-vinylcyclohexene-1,8-diol (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of XX (300 mg, 1 mmol, 1.0 equiv.), HFIP (100 µL, 1 vol%) Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) and 1,4- cyclohexadiene (801 mg, 10 mmol, 10. equiv.) as acceptor in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 51%, 72 mg, 0.51 mmol). 1H NMR (400 MHz, CDCl3) 5.75 5.54 (m, 2H), 4.13 3.38 (m, 3H), 1.92 1.23 (m, 7H). 13C NMR (101 MHz, CDCl3) 127.8, 126.1, 74.5, 68.3, 36.8, 27.9, 25.0, 21.1. MS for C8H14O2 EI m/z (%): 166 (4), 124 (2), 111 (6), 106 (48), 91 (48), 78 (38), 77 (13), 43 (100). 33 E-4,5-dibromocyclohex-1-ene (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of cyclohexa-1,4- diene (80 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 55%, 131 mg, 0.55 mmol). 1H NMR (400 MHz, Chloroform-d) 5.67 5.66 (m, 2H), 4.53 4.51 (m, 2H), 3.23 3.18 (m, 2H), 2.63 2.57 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 122.3, 48.7, 31.2. MS for C6H8Br2 EI m/z (%): 242 (1), 240 (2), 238(1), 161 (6), 159 (6), 80 (13), 79 (100), 77 (43), 51 (12), 39 (13). 34 diBr2 camphene (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of 2,2-Dimethyl-3- methylen-norbornan (136 mg, 1 mmol, 1.0 equiv.), 1,2-dibromoethane (939 mg, 433 µL, 5.0 mmol, 5 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 33%, 98.5 mg, 0.33 mmol). 1H NMR (400 MHz, CDCl3) 4.26 (dd, J = 8.7, 4.6 Hz, 1H), 3.77 (d, J = 9.9 Hz, 1H), 3.48 (d, J = 9.9 Hz, 1H), 2.43 (dtd, J = 14.4, 4.6, 3.3 Hz, 1H), 2.16 (dd, J = 14.4, 8.6 Hz, 1H), 2.00 1.88 (m, 2H), 1.84 1.74 (m, 1H), 1.56 (ddd, J = 13.4, 9.5, 4.1 Hz, 1H), 1.21 (s, 3H), 1.20 1.14 (m, 1H), 0.94 (s, 3H). 13C NMR (101 MHz, CDCl3) 56.8, 53.2, 49.5, 48.5, 42.2, 37.3, 34.6, 26.5, 21.1, 20.5. MS for C8H14O2 EI m/z (%): 217 (23), (2), 215 (22), 175 (4), 173 (4), 161 (15), 159 (15), 135 (100), 121 (4), 107 (27), 93 (67), 79 (34), 77 (21), 43 (18), 41 (39). 35 Intra SM (XX) Prep. 1H NMR (400 MHz, CDCl3) 7.45 7.31 (m, 5H), 5.85 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.34 (d, J = 11.8 Hz, 1H), 5.26 5.10 (m, 2H), 4.84 (d, J = 11.8 Hz, 1H), 4.36 (td, J = 6.7, 1.9 Hz, 2H), 2.51 (qt, J = 6.7, 1.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) 168.0, 137.7, 133.5, 129.5, 129.0, 128.2, 117.9, 65.7, 50.8, 47.1, 32.8. MS for C8H14O2 EI m/z (%): 217 (23), (2), 215 (22), 175 (4), 173 (4), 161 (15), 159 (15), 135 (100), 121 (4), 107 (27), 93 (67), 79 (34), 77 (21), 43 (18), 41 (39). 36 Intra P (XX) A mixture of 2,2-Dimethyl-3-methylen-norbornan (136 mg, 1 mmol, 1.0 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 6.2 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0) yielding the product as a colorless oil (yield: 33%, 98.5 mg, 0.33 mmol). 1H NMR (400 MHz, CDCl3) 7.72 (d, J = 16.0 Hz, 1H), 7.54 (ddd, J = 5.9, 4.2, 2.7 Hz, 3H), 7.40 (dtt, J = 5.9, 4.2, 1.9 Hz, 4H), 6.45 (d, J = 16.0 Hz, 1H), 4.49 (ddd, J = 10.9, 5.9, 4.8 Hz, 1H), 4.42 4.29 (m, 2H), 3.92 (dd, J = 10.4, 4.2 Hz, 1H), 3.70 (dd, J = 10.4, 9.7 Hz, 1H), 2.64 (dddd, J = 15.0, 8.7, 5.9, 3.1 Hz, 1H), 2.14 (ddt, J = 15.0, 9.7, 4.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) 168.0, 137.7, 133.5, 129.5, 129.0, 128.2, 117.9, 65.7, 50.8, 47.1, 32.8. MS for C8H14O2 EI m/z (%): 217 (23), (2), 215 (22), 175 (4), 173 (4), 161 (15), 159 (15), 135 (100), 121 (4), 107 (27), 93 (67), 79 (34), 77 (21), 43 (18), 41 (39). 37 30-Bromoallobetulin (XX) According to the GP1 for the electrochemical Br2 shuttle of alkenes, a mixture of betulin (222 mg, 0.50 mmol, 1.0 equiv.), 1,2-dibromoethane (1880 mg, 854 µL, 10.0 mmol, 20 equiv.), HFIP (100 µL, 1 vol%), and Et4NBF4 (434 mg, 2.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (10 mL). After 10 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: cyclohexane : ethyl acetate = from 100:0 to 80:20) yielding the product as a colorless solid (yield: 48 %, 145 mg, 0.24 mmol). Scale-up in 1.5 L beaker cell (x140): yield 44%, 17.8 g, 30.8 mmol. 1H NMR (400 MHz, CDCl3) 3.86 3.74 (m, 1H), 3.54 3.28 (m, 2H), 3.19 (dd, J = 11.2, 5.0 Hz, 1H), 1.71 (dt, J = 13.0, 3.7 Hz, 1H), 1.65 1.18 (m, 20H), 1.10 (ddd, J = 14.3, 6.6, 3.3 Hz, 1H), 0.99 0.90 (m, 13H), 0.86 0.74 (m, 8H), 0.72 0.67 (m, 1H). 13C NMR (101 MHz, CDCl3) 88.1, 83.8, 79.1, 77.5, 77.4, 77.2, 76.8, 71.7, 71.4, 55.6, 51.2, 51.2, 47.1, 46.9, 46.2, 41.7, 41.6, 40.9, 40.8, 40.7, 40.4, 39.1, 39.0, 37.4, 36.9, 36.6, 36.4, 34.3, 34.2, 34.0, 32.8, 30.4, 28.9, 28.1, 27.5, 27.0, 26.6, 26.5, 26.4, 26.1, 24.7, 21.2, 21.1, 21.0, 18.4, 16.6, 15.8, 15.5, 13.6. HRMS for C +30H50Br2O2 (ESI+) [M-Br] : calc.: 520.2915, found: 520.2916. Melting point: Mp = 217 220 °C. 38 2-thiophenylmethyl-tetrahydrofuran (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of 4-penten-1- ol (43 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless liquid (yield: 67 %, 130 mg, 0.33 mmol). 1H NMR (400 MHz, Chloroform-d) 7.40 7.34 (m, 2H), 7.30 7.25 (m, 2H), 7.20 7.14 (m, 1H), 4.06 (qd, J = 6.9, 5.8 Hz, 1H), 3.91 (ddd, J = 8.3, 6.9, 6.0 Hz, 1H), 3.80 3.72 (m, 1H), 3.16 (dd, J = 13.1, 5.8 Hz, 1H), 2.97 (dd, J = 13.1, 6.9 Hz, 1H), 2.07 (dddd, J = 12.0, 8.5, 6.9, 5.3 Hz, 2H), 1.97 1.85 (m, 1H), 1.67 (ddt, J = 12.0, 8.5, 6.9 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 136.5, 130.4, 129.4, 129.0, 126.1, 77.8, 68.5, 39.0, 31.1, 25.9. MS: EI m/z (%): 195 (2), 194 (15), 125 (2), 124 (19), 123 (7), 77 (5), 71 (100). 45 (9), 43 (35). Marset, Xavier; Guillena, Gabriela; Ramón, Diego J.[Chemistry - A European Journal, 2017, vol. 23, # 44, p. 10522 - 10526] 39 5-[(phenylsulfanyl)methyl]dihydrofuran-2(3H)-2-on (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of 4-pentenoic acid (50 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless liquid (yield: 65%, 68 mg, 0.32 mmol). 1H NMR (400 MHz, Chloroform-d) 7.45 7.39 (m, 1H), 7.37 7.30 (m, 1H), 7.29 7.23 (m, 1H), 4.70 4.58 (m, 1H), 3.37 (dd, J = 13.9, 4.8 Hz, 1H), 3.06 (dd, J = 13.9, 7.7 Hz, 1H), 2.68 2.36 (m, 2H), 2.12 1.97 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 175.7, 134.8, 131.1, 129.3, 127.2, 78.7, 38.7, 28.6, 27.1. MS: EI m/z (%): 209 (6), 208 (46), 125 (5), 124 (21), 123 (77), 110 (18), 86 (5), 85 (100), 77 (12), 57 (15), 45 (31), 39 (10). HRMS for C11H12O2S (ESI+) [M+H]+: calc.: 209.0631, found: 209.0633. Marset, Xavier; Guillena, Gabriela; Ramón, Diego J.[Chemistry - A European Journal, 2017, vol. 23, # 44, p. 10522 - 10526] 40 (2-bromododecyl)(phenyl)sulfane (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of 1-dodecene (84 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil in a mixture of regioisomers (ratio 7:1) (yield: 30 %, 54 mg, 0.15 mmol). 1H NMR (400 MHz, Chloroform-d) 7.45 7.39 (m, 1H), 7.37 7.30 (m, 1H), 7.29 7.23 (m, 1H), 4.70 4.58 (m, 1H), 3.37 (dd, J = 13.9, 4.8 Hz, 1H), 3.06 (dd, J = 13.9, 7.7 Hz, 1H), 2.68 2.36 (m, 2H), 2.12 1.97 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 175.7, 134.8, 131.1, 129.3, 127.2, 78.7, 38.7, 28.6, 27.1. MS: EI m/z (%): 356 (9), 358 (9), 277 (17), 207 (14), 188 (8), 190 (8), 123 (35). 110 (100), 97 (49), 83 (52), 69 (60), 55 (78), 41 (63). 41 Methyl 10-bromo-11-benzylsulfanyl-undecanoate (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of methyl 10-undecenoate (99 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After X.X F was applied, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil in a mixture of regioisomers (ratio 7:1) (yield: 33%, 64 mg, 0.16 mmol). 1H NMR (400 MHz, CDCl3) 7.39 7.20 (m, 5H), 4.05 (tdd, J = 8.9, 5.1, 3.3 Hz, 1H), 3.66 (s, 3H), 3.53 (dd, J = 13.8, 5.1 Hz, 1H), 3.25 (dd, J = 13.8, 9.3 Hz, 1H), 2.30 (t, J = 7.6 Hz, 1H), 2.08 (dddd, J = 14.5, 10.0, 5.7, 3.3 Hz, 1H), 1.77 (dddd, J = 14.5, 10.0, 9.3, 4.5 Hz, 1H), 1.66 1.57 (m, 2H), 1.55 1.47 (m, 1H), 1.28 (m, 10H). 13C NMR (101 MHz, CDCl3) 173.7, 135.8, 132.4, 130.2, 129.2, 126.9, 54.4, 51.5, 42.6, 36.7, 34.1, 29.2, 29.1, 29.1, 28.8, 27.1, 24.9. MS: EI m/z (%): 388 (4), 386 (3), 307 (7), 291 (14), 253 (5), 207 (36), 191 (6), 165 (16), 123 (45). 110 (98), 109 (40), 83 (29), 74 (66), 69 (39), 55 (100), 41 (62). 42 10-bromo-11-benzylsulfanyl-undecanoic acid (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of 10-undecanoic acid (92 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After X.X F was applied, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil and a mixture of regioisomers 7 : 1 (yield: 41%, 76.5 mg, 0.21 mmol). 1H NMR (400 MHz, CDCl3) 7.48 7.21 (m, 5H), 3.68 (dtt, J = 10.5, 7.5, 3.8 Hz, 1H), 3.17 (d, J = 13.1 Hz, 1H), 2.87 (dd, J = 13.7, 8.7 Hz, 1H), 2.36 (td, J = 7.5, 2.4 Hz, 2H), 1.69 1.60 (m, 2H), 1.54 (dt, J = 8.1, 5.8 Hz, 2H), 1.48 1.26 (m, 10H). 13C NMR (101 MHz, CDCl3) 179.5, 135.3, 130.1, 129.1, 129.0, 126.6, 69.4, 42.2, 36.1, 34.0, 29.5, 29.3, 29.1, 29.0, 25.6, 24.6. 43 4-hydroxy-5-phenylsulfonylcyclohexene (XX) According to the GP3 for the electrochemical SPhBr-shuttle of alkenes, a mixture of 1,4- cyclohexadiene (40 mg, 0.5 mmol, 1.0 equiv.), (2-bromoethyl)(phenyl)sulfane (543 mg, 2.5 mmol, 5 equiv.) and Et4NBF4 (217 mg, 1.0 mmol, 2 equiv.) in dry MeCN (0.1 M) was electrolyzed at room temperature with a current density of 10.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by reversed phase column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil (yield: 29%, 30 mg, 0.15 mmol). 1H NMR (400 MHz, Chloroform-d) 7.52 7.46 (m, 2H), 7.36 7.27 (m, 3H), 5.63 5.52 (m, 2H), 3.78 3.64 (m, 1H), 3.21 3.08 (m, 1H), 2.66 2.50 (m, 2H), 2.26 2.09 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 133.5, 129.0, 127.8, 125.5, 124.6, 68.8, 52.1, 33.2, 32.0. MS: EI m/z (%): 206 (4), 153 (1), 129 (1), 136 (11), 110 (100), 95 (11), 79 (32), 67 (17), 45 (7), 41 (18). Ingle, Gajendrasingh; Mormino, Michael G.; Antilla, Jon C.[Organic Letters, 2014, vol. 16, # 21, p. 5548 - 5551] 44 1,2-dichlorododecane (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1-dodecene (84 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 65 %, 66.0 mg, 0.33 mmol). 1H NMR (400 MHz, Chloroform-d) 4.07 3.95 (m, 1H), 3.78 3.58 (m, 2H), 2.02 1.89 (m, 1H), 1.75 1.62 (m, 1H), 1.44 1.18 (m, 16H), 0.86 (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) 61.3, 48.3, 35.1, 31.9, 29.6, 29.56, 29.4, 29.3, 29.0, 25.8, 22.7, 14.1. 45 (3,4-dichlorobutyl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), but-3-en-1-ylbenzene (67 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 65 %, 66.0 mg, 0.33 mmol). 1H NMR (400 MHz, Chloroform-d) 7.38 7.34 (m, 2H), 7.29 7.25 (m, 3H), 4.08 4.01 (m, 1H), 3.82 (dd, J = 11.3, 5.1 Hz, 1H), 3.71 (dd, J = 11.3, 7.4 Hz, 1H), 3.00 2.93 (m, 1H), 2.85 2.77 (m, 1H), 2.40 2.32 (m, 1H), 2.13 2.03 (m, 1H). 13C NMR (101 MHz, Chloroform-d) 140.5, 128.7, 128.6, 126.4, 60.4, 48.4, 36.8, 32.1. HRMS for C10H12Cl2 (ESI+) [M]+: calc.: 202.0311, found: 202.0305. 46 rac-1,2-dichloro-2,3-dihydro-1H-indene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1H-indene (58 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 61.4%, 57.7 mg, 0.31 mmol). 1H NMR (400 MHz, Chloroform-d) 7.48 7.45 (m, 1H), 7.38 7.28 (m, 3H), 5.36 (d, J = 3.0 Hz, 1H), 4.67 (dt, J = 6.3, 3.4 Hz, 1H), 3.71 (dd, J = 16.8, 6.0 Hz, 1H), 3.19 (dd, J = 16.8, 3.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 140.0, 129.8, 128.1, 125.6, 125.2, 67.8, 64.6, 40.9. HRMS for C9H8Cl2 (ESI+) [M]+: calc.: 185.9998, found: 185.9997. 47 (3,4-dichloro-3-methylbutyl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), (3-methylbut-3-en-1-yl)benzene (74 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 70%, 76.5 mg, 0.35 mmol). 1H NMR (400 MHz, Chloroform-d) 7.36 7.32 (m, 2H), 7.29 7.23 (m, 3H), 3.87 3.76 (m, 2H), 2.87 2.82 (m, 2H), 2.27 2.12 (m, 2H), 1.74 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 141.2, 128.7, 128.6, 126.3, 71.1, 52.5, 42.7, 30.9, 28.3. HRMS for C11H14Cl2 (ESI+) [M]+: calc.: 216.0467, found: 216.0470. 48 2,3-dichloro-3-methylbutyl benzoate (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 3-methylbut-2-en-1-yl benzoate (96 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 9.0 F was applied, the volatile solvent was removed in vacuo. After 2.5 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 30:1) yielding the product as a colorless oil (yield: 87%, 113.9 mg, 0.44 mmol). 1H NMR (400 MHz, Chloroform-d) 8.10 8.06 (m, 2H), 7.61 7.57 (m, 1H), 7.49 7.44 (m, 2H), 5.00 (dd, J = 11.9, 3.1 Hz, 1H), 4.57 (dd, J = 11.9, 8.4 Hz, 1H), 4.35 (dd, J = 8.4, 3.1 Hz, 1H), 1.81 (s, 3H), 1.73 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 166.3, 133.5, 129.9, 129.8, 128.6, 69.3, 67.3, 66.2, 31.9, 28.0. HRMS for C12H14Cl2NaO2 (ESI+) [M+Na]+: calc.: 283.0263, found: 283.0262. 49 1,2-dichloroethyl benzoate (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), vinyl benzoate (75 mg, 0.5 mmol, 1.0 equiv,), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 7.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 30:1) yielding the product as a colorless oil (yield: 64%, 70.5 mg, 0.32 mmol). 1H NMR (400 MHz, Chloroform-d) 8.12 8.09 (m, 2H), 7.66 7.61 (m, 1H), 7.51 7.47 (m, 2H), 6.77 (dd, J = 8.0, 3.6 Hz, 1H), 4.08 3.95 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 164.09, 134.29, 130.30, 128.79, 128.32, 81.37, 46.10. HRMS for C +9H8Cl2NaO2 (ESI+) [M+Na] : calc.: 240.9794, found: 240.9791. 50 1-(tert-butyl)-4-(1,2-dichloroethyl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1-(tert-butyl)-4-vinylbenzene (81 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 69%, 80.2 mg, 0.35 mmol). 1H NMR (400 MHz, Chloroform-d) 7.43 7.40 (m, 2H), 7.35 7.32 (m, 2H), 5.00 (t, J = 7.3 Hz, 1H), 4.02 3.91 (m, 2H), 1.33 (s, 9H). 13C NMR (101 MHz, Chloroform-d) 152.4, 135.1, 127.2, 125.9, 66.0, 48.6, 34.8, 31.4. HRMS for C12H16Cl2 (ESI+) [M]+: calc.: 230.0624, found: 230.0622. 51 (1,2-dichloroethyl)dimethyl(phenyl)silane (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), dimethyl(phenyl)(vinyl)silane (82 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 60%, 70 mg, 0.30 mmol). 1H NMR (400 MHz, Chloroform-d) 7.57 7.54 (m, 2H), 7.46 7.38 (m, 3H), 3.86 (dd, J = 11.1, 2.5 Hz, 1H), 3.70 3.60 (m, 2H), 0.50 0.49 (m, 6H). 13C NMR (101 MHz, Chloroform-d) 134.4, 134.2, 130.3, 128.3, 51.2, 48.6, -4.1, -5.3. HRMS for C9H10ClSi (ESI+) [M CH Cl]+4 : calc.: 181.0235, found: 181.0231. 52 rac-methyl-2,3-dichloro-3-phenylpropanoate (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), methyl cinnamate (82 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 7.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 30:1) yielding the product as a colorless solid (yield: 42%, 48.2 mg, 0.21 mmol, d.r. = 9 : 1). 1H NMR (400 MHz, Chloroform-d) 7.45 7.36 (m, 5H), 5.19 (d, J = 10.7 Hz, 1H), 4.63 (d, J = 10.7 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 168.1, 136.5, 129.6, 128.9, 128.2, 61.2, 58.9, 53.5. HRMS for C10H10Cl2NaO2 (ESI+) [M+Na]+: calc.: 254.9950, found: 254.9949. 53 N-(2,3-dichloropropyl)-4-methyl-N-phenylbenzenesulfonamide (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), N-allyl-4-methyl-N-phenylbenzenesulfonamide (144 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 9.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography yielding the product as a white solid (yield: 58%, 105 mg, 0.29 mmol). 1H NMR (400 MHz, Chloroform-d) 7.48 7.45 (m, 2H), 7.36 7.33 (m, 3H), 7.29 7.26 (m, 2H), 7.10 7.07 (m, 2H), 4.27 4.19 (m, 1H), 3.99 (dd, J = 14.2, 7.3 Hz, 1H), 3.88 3.87 (m, 2H), 3.82 (dd, J = 14.2, 6.6 Hz, 1H), 2.45 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 144.1, 139.6, 134.4, 129.7, 129.4, 128.7, 128.5, 127.9, 58.2, 54.7, 46.4, 21.7. HRMS for C H Cl NNaO S (ESI+) [M+Na]+16 17 2 2 : calc.: 380.0249, found: 380.0245. 54 1-bromo-4-(1,2-dichloroethyl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1-bromo-4-vinylbenzene (92 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n- pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 79%, 99.7 mg, 0.39 mmol). 1H NMR (400 MHz, Chloroform-d) 7.55 7.51 (m, 2H), 7.31 7.26 (m, 2H), 4.95 (dd, J = 8.4, 6.1 Hz, 1H), 3.98 (dd, J = 11.3, 6.1 Hz, 1H), 3.88 (dd, J = 11.3, 8.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 137.1, 132.1, 129.3, 123.4, 60.8, 48.1. HRMS for C8H +7BrCl2 (ESI+) [M] : calc.: 251.9103, found: 251.9104. 55 1-chloro-4-(1,2-dichloroethyl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1-chloro-4-vinylbenzene (70 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 74%, 77.9 mg, 0.37 mmol). 1H NMR (400 MHz, Chloroform-d) 7.39 7.34 (m, 4H), 4.97 (dd, J = 8.4, 6.2 Hz, 1H), 3.99 (dd, J = 11.3, 6.2 Hz, 1H), 3.88 (dd, J = 11.3, 8.4 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 136.64, 135.20, 129.18, 128.98, 60.81, 48.18. HRMS for C8H7Cl3 (ESI+) [M]+: calc.: 207.9608, found: 207.9608. 56 4-(1,2-dichloroethyl)benzonitrile (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 4-vinylbenzonitrile (70 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 4.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 50:1) yielding the product as a colorless oil (yield: 80%, 80.2 mg, 0.40 mmol). 1H NMR (400 MHz, Chloroform-d) 7.72 7.69 (m, 2H), 7.56 7.53 (m, 2H), 5.01 (dd, J = 8.7, 5.8 Hz, 1H), 4.01 (dd, J = 11.4, 5.8 Hz, 1H), 3.89 (dd, J = 11.4, 8.7 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 143.0, 132.7, 128.5, 118.3, 113.3, 60.1, 47.7. HRMS for C9H7Cl2NNa (ESI+) [M+Na]+: calc.: 221.9848, found: 221.9846. 57 (1,2-dichloropropan-2-yl)benzene (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), prop-1-en-2-ylbenzene (60 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2- tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 100:0) yielding the product as a colorless oil (yield: 56%, 53.1 mg, 0.28 mmol). 1H NMR (400 MHz, Chloroform-d) 7.59 7.55 (m, 2H), 7.43 7.32 (m, 3H), 4.08 3.99 (m, 2H), 2.11 (s, 3H). 13C NMR (101 MHz, Chloroform-d) 141.6, 128.6, 128.5, 126.6, 70.7, 54.7, 28.4. HRMS for C9H8Cl +2 (ESI+) [M H2] : calc.: 185.9998, found: 186.0001. 58 tert-butyl 4-chloro-4-(chloromethyl)piperidine-1-carboxylate (XX) According to the GP2 for the electrochemical Cl2 shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), tert-butyl 4-methylenepiperidine-1-carboxylate (99 mg, 0.5 mmol, 1.0 equiv.), 1,1,1,2-tetrachloroethane (840 mg, 546 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 7.5 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: n-pentane : diethyl ether = from 10:1) yielding the product as a colorless oil (yield: 57%, 76.3 mg, 0.29 mmol). 1H NMR (400 MHz, Chloroform-d) 4.07 (m, 2H), 3.74 (s, 2H), 3.12 (m, 2H), 1.96 1.88 (m, 2H), 1.83 1.78 (m, 2H), 1.45 (s, 9H). 13C NMR (101 MHz, Chloroform-d) 154.7, 80.0, 71.1, 54.0, 39.6, 35.8, 28.53. HRMS for C11H19Cl2NNaO2 (ESI+) [M+Na]+: calc.: 290.0685, found: 290.0686. 59 (1-chlorododecyl)(phenyl)sulfane (XX) According to the GP4 for the electrochemical SPhCl-shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1-dodecene (84 mg, 0.5 mmol, 1.0 equiv.), (2- chloroethyl)(phenyl)sulfane (863 mg, 738 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil and a mixture of regioisomers (ratio 2:1) (yield: 30%, 47 mg, 0.15 mmol). 1H NMR (400 MHz, Chloroform-d) 7.48 7.29 (m, 5H), 3.72 (dd, J = 11.0, 4.0 Hz, 1H), 3.52 (dd, J = 11.0, 9.3 Hz, 1H), 3.28 (tt, J = 8.6, 4.0 Hz, 1H), 2.05 1.97 (m, 1H), 1.73 (ddt, J = 14.3, 9.3, 5.0 Hz, 1H), 1.59 1.49 (m, 2H), 1.36 1.26 (m, 12H), 0.92 (m, 4H). 13C NMR (101 MHz, Chloroform-d) 133.8, 132.5, 130.1, 129.2, 127.6, 126.8, 50.4, 47.5, 31.9, 31.2, 29.6, 29.5, 29.4, 29.0, 26.6, 26.1, 22.7, 15.0. HRMS for C +18H29ClS (ESI+) [M+HO] : calc.: 329.1700, found: 329.1706. 60 Methyl 11-chloro-10-benzylsulfanyl-undecanoate (XX) According to the GP4 for the electrochemical SPhCl-shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), methyl 10-undecenoate (99 mg, 0.5 mmol, 1.0 equiv.), (2- chloroethyl)(phenyl)sulfane (863 mg, 738 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil and a mixture of regioisomers (ratio 2:1) (yield: 32%, 55 mg, 0.16 mmol). 1H NMR (400 MHz, Chloroform-d) 7.46 7.27 (m, 5H), 3.71 (dd, J = 11.0, 4.0 Hz, 1H), 3.69 (s, 3H), 3.51 (dd, J = 11.0, 9.2 Hz, 1H), 3.30 3.23 (m, 1H), 2.33 (td, J = 7.5, 3.4 Hz, 3H), 2.03 1.95 (m, 1H), 1.68 1.60 (m, 1H), 1.32 (dd, J = 14.7, 3.1 Hz, 10H). 13C NMR (101 MHz, Chloroform-d) 174.9, 133.7, 132.5, 130.1, 129.2, 127.6, 126.8, 51.5, 50.3, 47.4, 34.1, 31.2, 29.2, 29.16, 29.11, 26.5, 26.0, 24.9. HRMS for C18H27ClO2S (ESI+) [M-Cl]+: calc.: 307.1726, found: 307.1720. 61 4-hydroxy-5-phenylsulfonylcyclohexene (XX) According to the GP4 for the electrochemical SPhCl-shuttle of alkenes, a mixture of MnCl2 4H2O (5.0 mg, 25 µmol, 0.05 equiv.), 1,4-cyclohexadiene (40 mg, 0.5 mmol, 1.0 equiv.), (2- chloroethyl)(phenyl)sulfane (863 mg, 738 µL, 5 mmol, 10 equiv.), and Et4NBF4 (109 mg, 0.5 mmol, 1 equiv.) in dry MeCN (0.1 M) was electrolyzed at 50 °C and a current density of 2.0 mA/cm2 using graphite electrodes in an undivided ElectraSyn® vial (5 mL). After 3.0 F was applied, the volatile solvent was removed in vacuo. The residue was purified by column chromatography (gradient: MeCN : water (0.1% HOAc) = from 70:30 to 100:0) yielding the product as a colorless oil (yield: 19%, 21.5 mg, 0.10 mmol). 1H NMR (400 MHz, Chloroform-d) 7.52 7.46 (m, 2H), 7.36 7.27 (m, 3H), 5.63 5.52 (m, 2H), 3.78 3.64 (m, 1H), 3.21 3.08 (m, 1H), 2.66 2.50 (m, 2H), 2.26 2.09 (m, 2H). 13C NMR (101 MHz, Chloroform-d) 133.5, 129.0, 127.8, 125.5, 124.6, 68.8, 52.1, 33.2, 32.0. MS: EI m/z (%): 206 (4), 153 (1), 129 (1), 136 (11), 110 (100), 95 (11), 79 (32), 67 (17), 45 (7), 41 (18). HRMS for C12H14OS (ESI+) [M-OH]+: calc.: 189.0732, found: 189.0737. Ingle, Gajendrasingh; Mormino, Michael G.; Antilla, Jon C.[Organic Letters, 2014, vol. 16, # 21, p. 5548 - 5551] 62 6.1 Spectra 63 64 65 66 v 67 68 69 70 71 4 diastereomers. Mix of trans bromination and cis hydroxylation 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156