Use of Electrochemistry in the Synthesis of Heterocyclic Structures

Review pubs.acs.org/CR

Use of Electrochemistry in the Synthesis of Heterocyclic Structures Yangye Jiang,†,§ Kun Xu,†,‡,§ and Chengchu Zeng*,† †

Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China ‡ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, China ABSTRACT: The preparation and transformation of heterocyclic structures have always been of great interest in organic chemistry. Electrochemical technique provides a versatile and powerful approach to the assembly of various heterocyclic structures. In this review, we examine the advance in relation to the electrochemical construction of heterocyclic compounds published since 2000 via intra- and intermolecular cyclization reactions.

tion and finding of specific properties of heterocycles are undoubtedly a cornerstone of organic chemistry. Of particular is the construction of a heterocyclic scaffold. On the one hand, the practical preparation of heterocyclic structures as efficiently and economically as possible has been the ultimate goal in industry. On the other hand, numerous complex heterocyclic structures display unusual molecular architectures and their synthetic approach represents an interesting challenge from an academic view. Starting from suitable acyclic precursors, the most frequently used processes for the creation of heterocycles include (1) the addition of a nucleophile (such as β-carbon of an enol, enoate, or enamine and appropriate heteroatom) to a carbonyl carbon, (2) a displacement of halides or other leaving groups by nucleophiles, and (3) electrocyclic reaction.2 However, most of these approaches involve the use of expensive reagents, harsh conditions, long reaction times, and yielding of large amounts of waste. Although much progress has been made during the last decades in the transition-metal-catalyzed cyclization of acyclic substrates, the expensive cost, toxicity, and air-moisture sensitivity of some of these catalysts are concerned. Consequently, new compatible and more sustainable synthetic approaches for the synthesis of heterocycles are continuously and highly required. Electrochemical technique provides an alternative to the assembly of various heterocyclic structures.3−7 With the use of electron as the mass-free reagent, organic electrosynthesis is regarded to be environmentally friendly since the usage of stoichiometric amount of chemical regents in conventional chemical transformations are taken over by catalytic employment or avoided completely, thereby eliminating the produce of waste. Besides, the electron transfer leads to polarity reversal (umpolung) of functional groups, which provides interesting opportunity that conventional chemistry may not have achieved.

CONTENTS 1. Introduction 2. Intramolecular Cyclization 2.1. C−C Bonds Formation 2.1.1. Oxidative Formation of C−C Bonds 2.1.2. Reductive Formation of C−C Bonds 2.2. C-Heteroatom Bonds Formation 2.2.1. Oxidative Formation of C−N Bonds 2.2.2. Reductive Formation of C−N Bonds 2.2.3. Oxidative Formation of C−O bonds 2.3. Heteroatom-Heteroatom Bond Formation 3. Intermolecular Cyclization 3.1. Reactions with Electrogenerated Benzoquinones and Analogues 3.2. Cycloaddition of Electrogenerated Active Species to Unsaturated Compounds 3.3. Electrogenerated Anions and Electrochemical Fixation of CO2 3.4. Homocoupling Reactions 3.5. Miscellaneous 4. Conclusion Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

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1. INTRODUCTION Heterocycles constitute by far one of the largest group of organic compounds. Various heterocyclic structures are widely found in biologically active nature products, organic materials, agrochemicals, and pharmaceuticals, and no one can ignore their importance when one notices that approximately more than 70% of all pharmaceuticals and agrochemicals bear at least one heterocyclic ring.1 Consequently, the preparation, transforma© 2017 American Chemical Society

Special Issue: Electrochemistry: Technology, Synthesis, Energy, and Materials Received: May 12, 2017 Published: October 17, 2017 4485

DOI: 10.1021/acs.chemrev.7b00271 Chem. Rev. 2018, 118, 4485−4540

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the electroauxiliary into an appropriate position of the starting material is not always easy. Therefore, other strategies without the use of electroauxiliaries are highly desired. In 2004, Fuchigami and co-workers reported an electroorganic synthesis of 3-oxotetrahydroisoquinolines using fluoride ion as a mediator under ultrasonic irradiation.15 As shown in Scheme 1,

When the electron-rich and nucleophilic character of a functional group change to be electrophilic or vice versa, unusual or unexpected reaction may occur. Electrolysis is preferred to be carried out in an undivided beaker-type cell under controlled potential (CPE) or constant current (CCE) conditions. If the active species electrogenerated at the working electrode undergoes undesirable reactions with species that electrogenerated simultaneously at the counter electrode, a divided cell having a membrane to separate the anodic and the cathodic compartments is necessary. Direct electrolysis leads to electron transfer occurring between a substrate molecule and the working electrode. Very often, the resulting active species, such as radical cation or radical anion, polymerize and cause passivation of the electrode. In this case, indirect electrolysis using a mediator is usually performed. There are several reviews on electrochemical synthesis of heterocycles. In 1997, Tabaković summarized a comprehensive overview on anodic synthesis of heterocycles.8 The electrochemical preparation and functionalization of heterocyclic compounds were also presented by Lund9 and Moinet,10 respectively, as a monography. Francke outlined the advances in the electrochemical construction of heterocycles until 2014.11 In this review, we intend to provide readers with more examples involving electrochemical heterocycle synthesis published in the range from 2000 to present (March 2017).

Scheme 1. Anodic Synthesis of 3-Oxotetrahydroisoquinolines Using a Fluoride Ion Mediator

electrolyzing 1 in CH3CN using 20 mol % of Et3N·3HF as the mediator and Pt plate as anode gave the cyclized products 2 in good to moderate yields. The control experiments showed that the cyclization reaction benefited greatly from the ultrasonic irradiation. A plausible mechanism for this reaction is shown in Scheme 2. One-electron oxidation of 1 affords radical cation 3, which is then Scheme 2. A Proposed Mechanism for the Anodic Oxidation of 1

2. INTRAMOLECULAR CYCLIZATION Electrochemical oxidation and reduction generate highly reactive intermediates, including radicals, radical ions, cations, anions, and electrophilic as well as nucleophilic groups. When one of the electrogenerated centers positions appropriately with another reactive unit within a molecule, an intramolecular cyclization reaction of the acyclic precursor occurs under the formation of a new chemical bond to give a cyclic compound. These intramolecular reactions may be classified in different ways, here they are treated according to the type of bond formed. For monocyclic compounds, only one new chemical bond formation is involved. When an acyclic precursor is initiated electrochemically to form two or more new chemical bonds, the reactions are placed in assortments according to the chemical bond formed first. Thus, the following intramolecular cyclization reactions are divided into carbon−carbon, carbon−heteroatom, and heteroatom−heteroatom bond formations, wherein, oxidative formation and then reductive formation of a new chemical bond are discussed. 2.1. C−C Bonds Formation

trapped by a fluoride ion to generate radical 4. Further oxidation of radical 4 followed by elimination of one molecule of HF yields intermediate 6, which undergoes intramolecular Friedel−Craftstype reaction to afford cyclic product 2. Meanwhile, intermediate 6 could also react with a fluoride ion to give fluorinated byproduct 7. In 2013, Yoshida and co-workers reported that alkoxysulfonium ions could mediate the integration of electrooxidative cyclization and chemical oxidation of 1,6-dinenes and 1,7dienes.16 As shown in Scheme 3, 1,6-dinenes and 1,7-dienes underwent intramolecular alkene−alkene couplings to give nitrogen-containing cyclic compounds in 45−90% yields. It is noteworthy that products 9a−9c were formed with exclusive diastereoselectivity. This protocol includes two continuous steps. First, the mixture of 8 and n-Bu4NB(C6F5)4 in DMSO/CH2Cl2 was electrolyzed using carbon felt as an anode in a H-type divided

2.1.1. Oxidative Formation of C−C Bonds. Electrooxidative intramolecular carbon−carbon bond formation has been proved to be a straightforward route to the formation of heterocyclic compounds. Traditionally, substrates containing heteroatoms are prefunctionalized with an electroauxiliary. Electroauxiliary is a group that is always installed onto a carbon center, such as stannanes, silanes,12 and organothio groups.13,14 Electroauxiliaries activate organic molecules toward electron transfer and control the fate of thus generated reactive intermediates. The substrates functionalized with electroauxiliaries first undergo anodic oxidation to fragment the electroauxiliary to generate carbocations. The in situ generated carbocations then trapped by a tethered carbon nucleophile would construct heterocyclic compounds under the formation of a new C−C bond. Although electroauxiliaries are able to facilitate the C−C bond formation at a specific position, the installation of 4486


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Conventional methods for indoles 15 synthesis need stoichiometric or excess amounts of oxidants such as Cu (II) salts,20 hypervalent iodine reagents,21 and N-bromosuccinimide (NBS)22 (Scheme 6). This electrocatalytic method provides an atom-economic and sustainable way to construct substituted indoles.

Scheme 3. Integrated Electrooxidative Cyclization Followed by Chemical Oxidation of 1,6- and 1,7-Dienes

Scheme 6. Intramolecular Dehydrogenative C−H/C−H Cross-Coupling for the Synthesis of Indoles cell. After the electrolysis was completed, Et3N was then added and the resulting mixture was heated at 35 °C for 1 h to give the crude mixture of product 9. A possible mechanism for the generation of carbonyl compound 9a is outlined in Scheme 4. One-electron oxidation Scheme 4. Possible Mechanism for the Formation of Cyclized Diketone 9a Recently, Xu and co-workers also developed an electrochemical CDC reaction to construct C3-fluorinated oxindoles in high efficiency (Scheme 7).23 Electrolyzing 20 in a mixed solvent Scheme 7. Oxidative Formation of 3-Fluorooxindoles 21

of MeOH/THF was performed using ferrocene, Fc, as the redox catalyst in an undivided cell equipped with a reticulated vitreous carbon (RVC) anode. The electrochemical cyclization proceeded smoothly to give oxindoles 21 in good-to-excellent yields with a broad substrate scope. A possible mechanism for the electrochemical CDC reaction is proposed as shown in Scheme 8. Initially, the anodic oxidation of Fc and the cathodic reduction of MeOH generate Fc+ and MeO−,

of 8a affords radical cation 10, which undergoes intramolecular coupling to generate cyclized radical cation 11. An attack of DMSO yields the cyclized alkoxysulfonium ion 12. Further oxidation followed by trapping with another molecule of DMSO gives a bisalkoxysulfonium ion 13. Treatment of 13 with Et3N generates the sulfur ylide, followed by the elimination of Me2S leading to the cyclic product 9a. For alkoxysulfonium ion 12 and bisalkoxysulfonium ion 13, a positive charge on sulfur atom raises the oxidation potential and therefore overoxidation is avoided. Cross-dehydrogenative coupling (CDC) reaction has proved to be a straightforward and economic way to construct C−C bonds by formally liberating one molecule of H2.17,18 Recently, Lei and co-workers reported an electrocatalytic intramolecular CDC reaction of N-aryl enamines 14 to give substituted indoles 15 with a broad substrate scope (Scheme 5).19 In each case, the intramolecular CDC reaction was accomplished in an undivided cell equipped with Pt anode and Pt cathode at a constant current of 7 mA.

Scheme 8. Possible Mechanism for the Formation of 3Fluorooxindoles

Scheme 5. Electrocatalytic Synthesis of Indoles

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respectively. The resulting MeO− then abstracts the malonyl proton from 20a to produce anion 22. One-electron oxidation of 22 by electrogenerated Fc+ gives radical 23. Subsequent intramolecular radical cyclization within 23 and rearomatization leads to the formation of 3-fluorooxindoles 21a. Radical chain reactions have been widely used for the construction of complex organic molecules. However, cationic chain reactions are not so widely used in organic synthesis.24 In 2008, Yoshida and co-workers reported an electrochemically initiated cation chain reaction to produce tetrahydropyran derivatives (Scheme 9).25 At −78 °C, excess amounts of ArSSAr

internal π-bond systems that tethered a heteroatom leading to the formation of heterocycles. 2.1.2.1. Electroreductive Intramolecular Coupling of Organic Halides, or Related Substrates with Unsaturated Functional Groups. The use of electroreductive C−C bonds formation to construct heterocycles can often be achieved in an indirect electrochemical way by using metal complexes or organic mediators to mediate the reactions. In 2002, Nédélec and co-workers reported a nickel-catalyzed electroreductive arylation of electron-deficient alkenes (Scheme 11).26 The electroScheme 11. Nickel-Catalyzed Electrochemical Arylation of Alkenes

Scheme 9. Intramolecular Oxidative C−C bond Formation Catalyzed by “ArS+”

was pre-electrolyzed in a H-type divided cell equipped with a carbon felt anode and a Pt cathode to generate Ar(ArSSAr)+, which then reacted with thioacetals to give tetrahydropyran derivatives in moderate-to-excellent yields (initiation method A). Further studies showed that the direct electrolysis of a mixture of ArSSAr and thioacetals was also effective in initiating the cyclization reaction with slightly lower yields (initiation method B). It is noteworthy that the products shown in Scheme 9 were formed in an exclusive cis-selective manner. This electrochemically initiated cation chain reaction adds a new dimension to organic cation chemistry. A proposed mechanism for this cation chain reaction is shown in Scheme 10. First, electrolysis of ArSSAr 25 generates “ArS+”,

reduction reaction was carried out in an undivided cell equipped with a nickel foam cathode and an iron rod anode using DMF/ pyridine as a mixed solvent at a constant current of 150 mA. With α, β-unsaturated carboxylic ester 29 as a substrate, 6-exocyclization product 30 was obtained in 20% yield. However, the electroreduction of acrylamide 31 underwent a 5-exo-cyclization to give product 32 in 40% yield. The nickel complex served as a mediator, which was initially reduced electrochemically in situ, and the resulting reduced complex carries out the following aryl radical-forming reaction. In 2004, Medeiros and co-workers reported the electroreductive cyclization of unsaturated 2-bromophenyl ethers catalyzed by nickel(II) or cobalt(II) complexes (Scheme 12).27 At a constant current density of 1.5−3 mA cm−2 in an undivided cell under an atmosphere of argon, 3,3-dimethylallyl-2bromophenyl ether 33 underwent electroreductive cyclization to give 3-isopropyl-dihydrobenzofuran 34 in 49% and 51% yields when the nickel-salen and cobalt-salen complexes were used as catalysts, respectively. In both cases, the cyclic product 35 with an unsaturated side chain was also formed. For major product 34, the highest enantiomeric excess was found to be 16%. This result reveals that the major route proceeds through Ni−C bond cleavage first and then undergoes a cyclization pathway to afford the cyclized product. Therefore, the chiral salen ligand is insufficient to control the enantiomeric outcome of the cyclized reaction. However, when allyl 2-bromophenyl ether 36 was subjected to electrolysis under the identical conditions, the cyclic product 37 could be obtained in 67% yield using a cobalt-salen complex as the catalyst, and the unsaturated compound 38 was not detected. In 2003, Peters and co-workers reported that [Ni(tmc)]+, electrogenerated at carbon cathode, could catalyze the cyclization of a bromo propargyloxy ester (Scheme 13).28 The reductive cyclization reaction was accomplished in a divided cell equipped with a RVC cathode and a Pt spiral anode, using 0.1 M tetraethylammonium tetrafluoroborate (TEABF4) in DMF as supporting electrolyte under a controlled potential. Cyclic

Scheme 10. Proposed Mechanism for the Electroinitiated Cation Chain Reaction

which reacts with thioacetal 24 to generate alkoxycarbenium ion 27 and ArSSAr. The following intramolecular cyclization affords cation 28, which reacts with ArSSAr to give tetrahydropyran 26, along with the regeneration of “ArS+” to initiate the next catalytic cycle. In the course of the electrochemically initiated cation chain reaction, the “ArS+” species acts as an initiator to activate thioacetal 24, hence the overall reaction should take place with a catalytic amount of “ArS+”. 2.1.2. Reductive Formation of C−C Bonds. Electroreduction of organic halides or related substrates,26−33 ketones,34−41 aromatic imines,42−44 cyclic imides,45−47 can generate carbon-centered radicals, which could be trapped by 4488


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Scheme 12. Nickel- or Cobalt-Catalyzed Electrochemical Arylation of Unsaturated 2-Bromophenyl Ethers

Scheme 13. Nickel-Catalyzed Electrochemical Cyclization of Bromo Propargyloxy Ester

voltammograms for reduction of [Ni(tmc)]2+ in the presence of 39 reveal that [Ni(tmc)]+ catalytically reduces 39 at potentials more positive than those required for direct reduction of 39. The results showed that the product distribution was significantly altered by adding HFIP as the additive. In 2008, Medeiros and co-workers reported that Ni(tmc)Br2 42 was a good electron carrier for indirect electrochemical cyclization of bromoalkoxylated derivatives 43 and 45.29 As shown in Scheme 14, the intramolecular electroreductive

A plausible mechanism for this transformation was shown in Scheme 15. First, [Ni(tmc)]+ was formed by one-electron Scheme 15. Possible Mechanism for the Electrochemical Cyclization of Alkynes

Scheme 14. Nickel-Catalyzed Electrochemical Cyclization of Alkynes

reduction of [Ni(tmc)]2+. Then, [Ni(tmc)]+ transfers one electron to the substrate 43 to cleave the C−Br bond. The radical-type intermediate 47 undergoes an intramolecular cyclization to afford radical 49, along with the regeneration of [Ni(tmc)]2+ species. Finally, protonation of radical 49 leads to the formation of corresponding tetrahydrofuran derivatives 44. In 2009, Medeiros and co-workers found that Ni(tmc)Br2 was also an effective catalyst for electroreductive cyclization of Nallyl-α-haloamides (Scheme 16).30 When N-allyl-N-methyl-2bromoethanamide 50 was employed as a substrate, cyclic product 51 was furnished in 18% yield; cyclized products 53 and 54 were obtained in 53% total yield from the electroreductive cyclization of 52. These reactions were accomplished in a single-compartment cell equipped with a sacrificial magnesium anode31 and a carbon fiber cathode using nBu4NBF4 as the supporting electrolyte.

cyclization of unsaturated bromoethers afforded the corresponding cyclic products 44 and 46 in excellent yields. In each case, the reductive cyclization reaction was accomplished in an undivided cell equipped with a glassy carbon rod cathode and a Pt spiral anode, using 0.1 M tetraethylammonium bromide (TEABr) in EtOH as a supporting electrolyte under a controlled potential of −0.9 V vs Ag/AgCl. 4489


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DMF solution containing 0.1 M n-Bu4NBF4 as a supporting electrolyte in the presence of CO2 at 0 °C. Besides, bromobenzene 61 with an N-allyl group and 2-(3butenyloxy)bromobenzene 63 were also compatible with the reaction conditions, leading to the formation of indoline-3ylacetic acid 62 and chroman-4-ylacetic acid 64 in 40% and 58% yields, respectively (Scheme 19).

Scheme 16. Nickel-Catalyzed Electrochemical Cyclization of N-Allyl-α-haloamides

Scheme 19. Synthesis of Acetic Acid Analogues

In 2012, Suga and co-workers reported that fluorene derivative 57 could serve as an efficient organic mediator for the cyclization of aryl halides 55 bearing an ethylene moiety (Scheme 17).32 In Scheme 17. Electrocyclization of Aryl Halides with an Ethylene Moiety A possible mechanism for this reaction is outlined in Scheme 20. One-electron reduction of methyl 4-tert-butylbenzoate leads to the formation of radical anion 65, which transfers one electron to substrate 58a to generate aryl radical 66. Radical cyclization followed by further one-electron reduction affords anion intermediate 68. Fixation of carbon dioxide to anion intermediate 68 gives carboxylate ion 69. Finally, acid treatment in workup furnishes the carboxylic acid 59a. In the course of their efforts to fix carbon dioxide under electroreductive conditions, the same group of Senboku developed an aryl radical cyclization with alkyne followed by tandem carboxylation mediated by methyl 4-tert-butylbenzoate 60.34 The reaction was carried out in an undivided cell equipped with a Pt plate cathode and a Mg rod anode in a DMF solution containing 0.1 M n-Bu4NBF4 as a supporting electrolyte in the presence of CO2 at −10 °C. As shown in Scheme 21, a wide range of aryl bromides 70 underwent radical cyclization followed by tandem carboxylation to give dicarboxylic acids 71 in up to 71% yield. The results reveal that internal alkyne is a suitable radical acceptor for aryl radicals. When more complex substrate 72 with an ene-yne unit was employed in this reaction, monocarboxylic acid 73 was formed through a 5-exo and 3-exo tandem cyclization (Scheme 22). For product 73a, the major and minor diastereoisomers could be separated by recrystallization. Substrate 72 first proceeds through a reduction reaction mediated by electrogenerated radical ion 65 to give radical 74, which undergoes tandem radical cyclizations to furnish radical 77. Radical 77 is reduced to yield anion intermediate 78, which is then captured by CO2 to afford the final product 73. In addition to aryl halides, diazonium salts were also suitable coupling partners of alkenes under electroreductive conditions. In 2002, Murphy and co-workers reported an elegant study on the cathodic cyclization of arenediazonium salts onto alkenes to synthesize indolines.35 The reactions were carried out in a divided cell equipped with a Pt cathode using 0.1 M NaClO4 in DMF as a electrolyte solution under a controlled potential at −1.1 V vs Ag/AgCl. With sulfide 79a and sulfoxide 79b as substrates, the corresponding diazonium tetrafluoroborates were prepared in situ and used for subsequent electroreductive couplings (Scheme 23). The corresponding vinylindoline 80 was

an undivided cell equipped with Mg anode and Pt cathode in the presence of 0.1 M Et4NClO4 under a constant current of 120 mA, the electroreductive cyclization proceeded smoothly to yield products 56 with exo-selectivity in 74−95% yields. However, the endo-cyclized products were not observed. It is noteworthy that aryl chlorides were also tolerated with the reaction conditions. In previous reports, electroreductive cyclization reactions were always restricted to aryl iodides and bromides. Electroreduction of aryl halides usually generates aryl radicals, which undergo cyclization reaction to give cyclized radicals. Further one-electron reduction of the cyclized radicals generates anion species. In previous reports, these anion species are usually terminated by protonation. To take advantage of these anion species, Senboku and co-workers reported that the introduction of one molecule of electrophilic CO2 could trap the anion species to afford carboxylic acids.33 As shown in Scheme 18, using methyl Scheme 18. Synthesis of 2,3-Dihydrobenzohuran-3-ylacetic Acids 59

4-tert-butylbenzoate 60 as an electron-transfer mediator, functionalized 2-allyloxybromobenzenes 58 underwent electroreductive cyclization reaction followed by fixation of carbon dioxide to give 2,3-dihydrobenzofuran-3-ylacetic acids 59 in up to 85% yields. The reactions were carried out in an undivided cell equipped with a Pt plate cathode and a Mg rod anode using a 4490


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Scheme 20. Proposed Mechanism for the Formation of 59a

This electroreductive cyclization protocol was also compatible with more complex substrates. As shown in Scheme 24, functionalized indoline 82a was obtained in 76% yield from the reaction of sulfide 81a, and indoline 82b was obtained in 65% yield from sulfoxide 81b. 2.1.2.2. Electroreductive Intramolecular Coupling of Ketones with Unsaturated Functional Groups. Electroreduction of ketones produces ketyl radicals efficiently, and hence a variety of electroreductive couplings of ketones with olefins,36,37 alkynes,38 and aromatic rings39−41 have been developed. If there is a heteroatom such as a nitrogen or a sulfur atom between the unsaturated group and the carbonyl group, an intramolecular reductive couplings would lead to the formation of heteroatomcontaining cyclic compounds. In 2003, Nishiguchi and coworkers reported an intramolecular electroreductive cyclization of heteroatom-containing nonconjugated enones and ynones. Electrolyzing enones 83, 85, and ynone 87 in an undivided cell equipped with an Al anode and an Al cathode with Et4NOTs as the supporting electrolyte under a constant current density of 10 mA cm−2 led to the regio- and stereoselective formation of heterocyclic products 84, 86, and 88 in moderate to good yields (Scheme 25).42 For sulfur-containing enones 83, the stereochemistry of two alkyl groups was exclusively cis-selective. However, some decrease in the stereoselectivity was observed during the electroreduction of nitrogen-containing enones 85. For this reaction, the solvent is the mixture of MeOH and dioxane, therefore, the ketone reduction and H2 evolution may take place simultaneously at the cathode. In 2008, Kise and co-workers reported an electroreductive intramolecular coupling of 1-indolealkanones and 3-methoxycarbonyl-1-indolealkanones (Scheme 26).43 The electroreduction of 1-indolealkanones 89 in a divided cell under a constant current at 100 mA gave trans-cyclized products 90 stereospecifically in 32−68% yields, while the electroreduction of 3methoxycarbonyl-1-indolealkanones 91 in an undivided cell gave a mixture of trans- and cis-cyclized products. These results reveal that the two kinds of substrates undergo different reaction pathways.

Scheme 21. Tandem Reaction of Radical Cyclization Followed by Tandem Carboxylation

Scheme 22. Tandem Radical Cyclization Followed by Carboxylation of Ene-yne

obtained in 90% yield from the reaction of sulfide 79a and 70% yield from sulfoxide 79b. Scheme 23. Electroreductive Preparation of Indolines

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Scheme 24. Electroreductive Preparation of Indolines with More Complex Structures

DFT calculations showed that the two radical anions had different natures. RA-1 has apparently the nature of a ketyl radical, while RA-2 has the character of a carbon-centered radical at the position next to the nitrogen (Scheme 27). The stereoselectivity in the electroreductive intramolecular coupling of 89a could be explained by the calculations.44 However, the reason for the stereoselectivity in the coupling of 91a is not clear at this stage. 2.1.2.3. Electroreductive Intramolecular Coupling of Aromatic Imines with Esters. Shono, Kise, and co-workers reported that electroreduction is a powerful tool for the reductive coupling of aromatic imines with a variety of carbonyl compounds.45 In the course of their studies on electroreductive couplings, in 2003, Kise and co-workers reported that intramolecular electroreductive coupling of chiral α-imino esters led to functionalized azetidines (Scheme 28).46 In the presence of

Scheme 25. Intramolecular Electroreductive Cyclization of Non-Conjugated Enones and Ynones

Scheme 28. Electroreductive Intramolecular Coupling of Chiral α-Imino Esters

Scheme 26. Electroreductive Intramolecular Coupling of 1Indolealkanones and 3-Methoxycarbonyl-1-indolealkanones chlorotrimethylsilane (CTMS), electrolyzing imino esters 94 in a divided cell equipped with a Pt cathode and a Pt anode under a constant current at 100 mA gave azetidines 95 as single stereoisomers with 85−99% ee values. However, the substrates were restricted to aromatic imines; aliphatic imines failed to give the corresponding products under the same conditions. A possible mechanism for this reaction is illustrated in Scheme 29. N-Silylation of 94 followed by one-electron reduction generates radical 97, which then undergoes further reduction leading to anion 98. The carbanion in 98 adds to the ester carbonyl followed by O-silylation resulting into the formation of Scheme 27. Possible Explanation for the Observed Stereoselectivity

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Scheme 29. Possible Mechanism for the Formation of 95

tricyclic products incorporating an isoindolinone ring are found widely in many alkaloids and biologically active compounds. A plausible mechanism for this cyclization is illustrated in Scheme 32. Two-electron reduction of phthalimide carbonyl

100. Treatment of 100 with acid during workup affords azetidine 95. Following a similar mechanism as described in Scheme 29, the electroreductive intramolecular coupling of β- and γ-imino esters was also performed in a divided cell using a Pt anode and a Pb cathode (Scheme 30).47 The resulting pyrrolidine and piperidine skeletons widely existed in many natural products and biologically active compounds.

Scheme 32. Proposed Mechanism for the Electroreductive Intramolecular Coupling of Phthalimides with α,βUnsaturated Esters

Scheme 30. Electroreductive Intramolecular Coupling of Chiral β- and γ-Imino Esters

group of 106 followed by O-silylation leads to the formation of an anion. The carbanion in the anion attacks the α,β-unsaturated ester moiety through transition state TS. Since TS-A is more favorable than TS-B due to the less steric repulsions between trimethylsilyloxy and ester enolate groups, trans-isomer of silyl ketene acetal 108 is furnished predominantly through subsequent desilylation of TS-A. Following a similar mechanism, the electroreductive intramolecular coupling of N-(oxoalkyl)phthalimides 109 was also carried out successfully (Scheme 33).49 For ketone substrates, the trans-cyclized products 110 were formed stereospecifically (>99%). Similarly, for aldehyde substrates, the five-, six-, and seven-membered trans-cyclized products were obtained with good to excellent stereoselectivities (75−93%). The electroreductive coupling of phthalimides with α,βunsaturated esters and ketones worked well in the presence of CTMS; however, these electroreductive conditions could not be

2.1.2.4. Electroreductive Intramolecular Coupling of Cyclic Imides with Unsaturated Functional Groups. As described in Schemes 28−30, electroreductive coupling of aromatic imines with esters in the presence of CTMS is a powerful tool for the construction of nitrogen-containing heterocycles. To extend the application of this electroreductive protocol, the same group of Kise reported an electroreductive intramolecular coupling of phthalimides with α,β-unsaturated esters.48 As shown in Scheme 31, the electroreductive coupling of N-substituted phthalimides 106 at Pt cathode in DMF containing 0.3 M Et4NOTs, followed by desilylation of resulting silyl ketene acetals 107 with TBAF gave trans-cyclized products 108 stereospecifically. These

Scheme 31. Electroreductive Intramolecular Coupling of Phthalimides with α,β-Unsaturated Esters

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Moeller et al. has developed a series of electrochemical protocols to construct cyclic amines by oxidative coupling of electron-rich olefins such as enol ethers, vinylsulfides, and ketene dithioacetals to nitrogen-based nucleophiles.51 The overall strategies were illustrated in Scheme 35. The reaction starts

Scheme 33. Electroreductive Intramolecular Coupling of Phthalimides with Carbonyl Groups

Scheme 35. Anodic Intramolecular Amination of ElectronRich Alkenes

applicable to reductive coupling of aliphatic cyclic imides with carbonyl compounds. To overcome this limitation, the intramolecular electroreductive coupling of succinimides with ketones and O-methyloximes was investigated by the same group, Kise (Scheme 34).50 The cyclization of N-(oxoalkyl)succinimides 111−112 gave pyrrolizidines 113 (n = 1) and indolizidines 114 (n = 2), which could be deoxygenated with NaB(CN)H3 to generate 115 and 116. Furthermore, this electroreductive method was also applicable to the coupling of succinimides with o-methyloximes to afford bicyclic products 120−122 in moderate to good yields. Similarly, bicyclic N,Oacetals 120−122 could also be reduced by NaB(CN)H3 to give deoxylated products 123−125. The reason for the unusual etherification to incorporate isopropyloxy groups into 113b, 114b, 120b, 121b, and 122b is not clear.

from initial deprotonation of I under basic conditions followed by an oxidation to produce intermediates II and III. These two intermediates are resonance forms of each other. Subsequently, the cyclization reactions proceed either by trapping a radical cation with a nitrogen anion or adding a nitrogen-centered radical to electron-rich olefin to generate radical IV, which is then oxidized to form cation V. Finally, the intermediate V is trapped by solvent methanol to afford the cyclic amine VI. To realize the proposal illustrated in Scheme 35, initial efforts of varying the substituents on the double bond of I to improve the yield were not encouraging, with the most successful example being shown in Scheme 36.52 Compound 126 underwent the reaction pathway as shown in Scheme 36 to afford cyclized product 127 in 37% yield. Neither varying the reaction conditions or changing the protecting group on the nitrogen could improve the yield. In the previous studies by the same group, the results showed that less polarized radical cations favor carbon-heteroatom bonds formation, while more polarized radical cations tend to favor carbon−carbon bonds formation. With these results in mind, the authors wondered if the use of a

2.2. C-Heteroatom Bonds Formation

2.2.1. Oxidative Formation of C−N Bonds. Anodic oxidation reactions can be used to generate reactive radical cations or radicals, which are potentially important intermediates to construct biologically important N-heterocycles. In general, electrosynthesis of N-heterocycles via an oxidative C−N bond formation can be classified as follows. For electron-rich olefins, one electron oxidation forms radical cations, which are then trapped with nitrogen nucleophile to produce N-heterocycles. Besides, nitrogen-centered radicals generated by anodic oxidation can undergo cyclization reactions onto unsaturated carbon−carbon bonds to afford N-heterocycles. Other representative methods also provide promising routes to N-heterocycles.

Scheme 34. Electroreductive Intramolecular Coupling of Succinimides with Ketones and o-Methyloximes

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The overoxidized product 130 may be due to the deprotonation from the initial cyclization intermediate 133. Then, oxidation of ketene acetal 134 and subsequent methanol trapping gave overoxidized product 130 (Scheme 38).

Scheme 36. Electrochemical Amination of Electron-Rich Olefin

Scheme 38. Possible Route to the Formation of Overoxidized Product 130

less polarized radical cation derived from electron-rich olefin might improve the cyclization. In order to test this idea, four substrates with different nature of the substituents on the radical cations were studied as outlined in Scheme 37.52,53 In each substrate, tosylamide was selected as Scheme 37. Electrochemical Amination of Different Types of Electron-Rich Alkenes

In order to avoid the elimination reaction, substrate 128d was subjected to the standard reaction conditions. The yield of cyclized product 129d improved slightly to 19%; however 24% yield of six-membered ring product 131 was also obtained. The six-membered ring product 131 formed by competitive trapping of the radical cation with methanol. The results show that intramolecular trapping reaction by tosylamide was not competing effectively with the intermolecular trapping reaction by methanol solvent. To solve this problem, increasing the nucleophilicity of the nitrogen trapping group would be an effective way. Therefore, the reactions were repeated under more basic reaction conditions (LiOMe as the base). As shown in Scheme 39, a series of enol ether, vinyl sulfide, and ketene dithioacetal were all well-compatible to give the corresponding cyclized products in good to excellent yields. Besides, the anodic oxidation of allylsilane, styrene, and diene moieties also yielded cyclic amines in good to excellent yields. The results described above prove that the reactions benefit greatly from the use of more basic reaction conditions. The use of LiOMe as an acid scavenger could increase the nuclophilicity of nitrogen trapping group, thus improve the yields greatly, while less basic 2,6-lutidine only led to much lower yields. In this procedure, LiOMe was either produced in situ by adding n-BuLi to MeOH solution or introduced as a commercially available THF solution. During the electrolysis, acid was produced at the anode, while an equal amount of methoxide was produced at the cathode. Therefore, LiOMe would not be consumed in the reaction, and the pH value of the reaction mixture remained the same. With the success of the cyclizations to construct fivemembered nitrogen-containing rings, attention was then turned toward six-membered N-heterocycles. When thioenol ether 135 was employed as the substrate, the corresponding cyclic product 136 was obtained in 27% yield along with the formation of fivemembered byproduct 137 in 8% yield (Scheme 40). The five-membered byproduct 137 might result from the elimination reaction followed by a nucleophilic amination reaction, as shown in Scheme 41. In order to avoid the elimination reaction involving the radical cation intermediate described in Scheme 41, the oxidation of substrates 138a and 138b were examined (Scheme 42). The results showed that gem-methyls in 138a effectively prevented

the trapping group for its propensity to serving as a nucleophile. The substrates were dissolved in 0.1 M Et4NOTs in 30% MeOH/THF solution containing 2,6-lutidine as a proton scavenger, and then the resulting mixtures were electrolyzed at a constant current of 6 mA with RVC as an anode and Pt as a cathode. For substrate 128a, the cyclization was not very successful, giving the corresponding product in only 20% yield. However, the cyclization yield improved dramatically when the vinyl sulfide substrate 128b was employed. The improvement in the yield benefited from the less polarized radical cation derived from the vinyl sulfide 128b compared with that of enol ether 128a. Further optimization showed that the anodic oxidation of ketene dithioacetal 128c only gave 14% yield of cyclic product 129c along with 4% of an overoxidized product 130. 4495


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Scheme 39. Electrochemically Intramolecular Trapping Reaction by Tosylamide

Scheme 41. Proposed Mechanism for the Formation of FiveMembered Byproduct 137

the elimination reaction to afford the desired product 139a in 81% yield. As mentioned above, 2-fold substitution on the allylic carbon of the substrate could avoid the elimination reaction and benefit the yielding of six-membered pipecolic acid derivative, the authors wondered if a single substituent on the allylic carbon of the substrate would accomplish the task. Consequently, substrates 141a and 141b were examined under anodic oxidation reaction conditions (Scheme 43). When a methyl group was placed on the allylic position, the corresponding product 142a was obtained in 44% yield, while 62% yield of 142b was obtained

if a larger t-butyldiphenylsiloxy group was attached to the allylic carbon of the substrate. The results reveal that a large substituent is beneficial to the cyclization to yield six-membered Nheterocycles. However, the need of a large group at allylic position of the substrate to increase steric effect would limit the applications of this protocol. After initial attempts, it was found that when a trisubstituted olefin 143 with an allylic methyl group was employed as the coupling partner, the cyclized product 144 was obtained in 71% yield. A plausible transition state model to explain the results was shown in Scheme 44. An A1,3-interaction in the transition state would force the allylic R group into a pseudoequatorial position and the allylic proton into a pseudoaxial position perpendicular to the radical cation. The poor overlap between the allylic proton and the radical cation could slow elimination reaction and leave more time for the cyclization step. Anodic coupling of enol ether, ketene dithioacetal, and vinyl sulfide to tosylamide has been demonstrated to be a direct route to functionalized proline and pipecolic acid type derivatives. However, the mechanism shown in Scheme 34 still has some uncertainty. The anodic oxidation of electron-rich olefins generates intermediates II and III, which undergo two different pathways to give cyclized intermediate IV. In principle, these two pathways should be distinguishable. A reaction that proceeds through intermediate II would involve a large polarity change moving from the zwitterionic intermediate to the neutral product. However, a reaction that proceeds through intermediate III would involve little change in polarity from neutral intermediate to the neutral product. Therefore, the reactions involved intermediate II would be favored by the use of less polar solvents, while the reactions involved intermediate III should not be sensitive to changes in solvent polarity. To probe the nature of oxidative cyclizations between electron-rich olefins and tosylamide, some competition studies were performed.54 The results showed that enol ethers and ketene dithioacetals likely underwent the radical cation type pathway, while vinyl sulfides favored the nitrogen-centered mechanism. In addition to tosylamides, Xu, Moeller, and co-workers found that O-benzyl hydroxamates and N-phenyl amides 145 were also suitable nucleophiles (Scheme 45).55 Under anodic oxidations,

Scheme 40. Attempts to Construction of Six-Membered N-Heterocycles

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Scheme 42. Attempts to Avoid the Elimination Reaction

Scheme 45. Electrosynthesis of γ- and δ-Lactams 146

Scheme 43. Electrochemical Amination of Thioenol Ether with a Single Substituent on the Allylic Carbon

amidyl radicals generated efficiently from amides. Subsequently, amidyl radicals underwent radical cyclization onto electron-rich olefins to afford γ- and δ-lactams 146, which are widely existent in biologically active natural products. The anodic coupling of electron-rich alkenes and tosylamides affords functionalized amino acid derivatives, which are potentially building blocks for the construction of alkaloids and peptidomimetics. However, the wide application of these protocols may be restricted by the need for the sulfonyl protecting group and its subsequent deprotection steps. This problem would be overcome if a free amine could be utilized as a nucleophile under this oxidative condition. However, at first glance, the oxidation potentials presented in Figure 1 indicates that this proposal is difficult to be carried out. As dithioketene acetal group has a lower potential than that of enol ether and vinyl sulfide group, amine tethered with dithioketene acetal group was selected as a substrate to overcome the free amine oxidation. For substrate 147, oxidation would take place first at the dithioketene acetal group instead of the amine group. Even with dithioketene acetal group tethered with amine, the oxidation potential of the secondary amine in compound 148 is much lower relative to that of either functional group in compound 147, which would lead to overoxidation of the product. However, this analysis neglects that cyclization itself may influence the oxidation potential of a substrate. Literature survey shows that rapid cyclization reactions could lower the oxidation potential of a substrate. Therefore, even the oxidation potential of 147 is much more positive than that of the product 148, as shown in Figure 1, and the reaction may still occur. After initial attempts, Xu and Moeller disclosed that the cyclization is fast enough to decrease substrate potential to such an extent that it is much lower than that of the corresponding product.56

Figure 1. Proposed intramolecular anodic coupling of an amine and a dithioketene acetal.

Consequently, the anodic coupling of free amines with dithioketene acetals could proceed efficiently to generate amino acid derivatives in good to excellent yields (Scheme 46). In each case, the anodic coupling was carried out by use of a RVC anode and a Pt cathode, LiOMe as a proton scavenger, and a constant current of 6 mA. It is possible that the use of the stronger base LiOMe leads to rapid deprotonation of the initial cyclic intermediate. Rapid deprotonation would facilitate the cyclization by slowing down the reverse reaction. These examples suggest that the simple analysis of oxidation potentials of isolated functional groups can be sometimes misleading in terms of the prediction of the success of an oxidation cyclization. Moeller’s protocols provide a straightforward route to nitrogen-containing cyclic compounds. However, the substrates are limited in utility to the use of electron-rich alkenes. To make electrochemical functionalization of alkenes more general, Xu and co-workers developed a series of anodic oxidative methods to generate nitrogen-centered radicals, which were then cyclized to a tethered unactivated alkenes/alkynes to afford functionalized nitrogen-containing cyclic compounds. In 2014, Xu and co-workers reported an electrochemical approach to the intramolecular aminooxygenation of unactivated

Scheme 44. Proposed Transition State to Explain the Observed Stereochemistry

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Scheme 46. Anodic Coupling of Amines and Dithioketene Acetals

revealed that N-aryl amides were also suitable substrates for this cyclization reaction (152u). Following the success with cyclic alkenes, a series of acyclic alkenes were tested under the standard reaction conditions (Scheme 48). As expected, acyclic alkenes 153 were welltolerated and led to the formation of cyclized products 154 in 58−97% yields.

akenes with TEMPO as an oxygen-atom donor, which provides an efficient access to the 1,2-aminoalcohol motif.57 The 1,2aminoalcohol motif is valued for its presence in many biologically important molecules and chiral reagents. The anodic aminooxygenation reaction was accomplished in an undivided cell equipped with a RVC anode and a Pt cathode at a constant current of 10 mA using n-Bu4NBF4 as the supporting electrolyte. As illustrated in Scheme 47, a series of functionalized carbamates

Scheme 48. Aminooxygenation of Acyclic Alkenes

Scheme 47. Aminooxygenation of Cyclic Alkenes

The reaction is believed to proceed through the addition of nitrogen-centered radicals to alkenes followed by trapping of the cyclized radical with TEMPO. The plausible mechanism for the formation of nitrogen-centered radical is shown in Scheme 49. TEMPO was used as a mediator to generate amidyl radicals 156 from carbamate. To expand the application scope of the anodically generated amidyl radicals, the same group reported an efficient intramolecular alkene hydroamidation reaction with Fc as the redox catalyst to produce amidyl radical from N-aryl amides.58 Preliminary studies showed that the combination of THF and MeOH as a mixed solvent could lower the oxidation potential of Scheme 49. Possible Mechanism for the Generation of Nitrogen Radicals

were well-tolerated to give cyclized products 152a−152n in 51− 97% yields. When trisubstituted olefins were employed as substrates, tetrasubstituted stereogenic centers were formed efficiently (152o−152q). Introduction of a nitrogen functionality into the cyclohexene ring led to the formation of a highly functionalized piperidine 152r in 89% yield. Cyclopentenyl carbamates were also tolerated to give the corresponding product 152s and 152t in slightly lower yields. Further investigations 4498


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available aldehyde 163 (Scheme 52). Notably, it was reported previously that 10 steps are required to construct 165 from aldehyde 163. Recently, Xu and co-workers developed a metal- and regentfree intramolecular oxidative amination of tri- and tetrasubstituted alkenes (Scheme 53).59 The constant current electrolysis

substrate 157 (Ep/2 = +0.61 V, vs SCE) and simultaneously increase that of Fc (Ep/2 = +0.55 V, vs SCE), so that their Ep/2 were much closer, which enables efficient electron transfer between substrate and electrochemically generated Fc+. With this concept in mind, the anodic hydroamidation of a series of carbamates, ureas, and amides were carried out in an undivided cell with 5 mol % Fc in a mixed solvent of THF/MeOH (5:1) (Scheme 50). The N-aryl group accommodated a wide range of

Scheme 53. Intramolecular Oxidative Amination of Alkenes

Scheme 50. Electrocatalytic Hydroamidation Reaction

of 166 in an undivided cell equipped with a RVC anode and a Pt plate cathode using a mixed electrolyte solution of Et4NPF6 in DMAC/HOAc yielded nitrogen-centered radical in situ, which then underwent radical cyclization to form the key C−N bond, allowing a variety of hindered tri- and tetrasubstituted alkenes to participate in the amination reactions. The resulting alkenebearing N-heterocycles are synthetically valuable, which could be transformed into many building blocks. Following the success of the hydroamidation of alkenes, hydroamidation of tethered alkynes with anodically generated amidyl radicals was also investigated (Scheme 54).60 Electro-

substituents with different electronic and/or steric properties. Substrates with mono- and multisubstituted alkenes with acyclic or cyclic structures were also tolerated. Moreover, the anodically generated amidyl radicals could trigger tandem cyclizations to afford polycyclic N-heterocycles. As shown in Scheme 51, diene substrates 159a and 159b Scheme 51. Tandem Reactions to Construct Polycyclic NHeterocycles

Scheme 54. Electrocatalytic Hydroamidation of Tethered Alkynes

lyzing of 168 in an undivided cell equipped with a RVC anode and a Pt cathode in the presence of 5 mol % of Fc under a constant current of 5 mA was carried out to generate amidyl radicals, which could trigger subsequent cyclization to give highly functionalized indoles and more challenging azaindoles. The reaction is similar to that of electrochemical alkene hydroamidation reaction but without the use of reducing reagent cyclohexa-1,4-diene (1,4-CHD). The synthetic utility of this method was demonstrated by the synthesis of isocryptolepine 172 in two steps, which is a bioactive natural product (Scheme 55).

underwent cyclization reactions smoothly to give tricyclic products 160a and 160b in 90% and 85% yields, respectively. When urea substrate 161 was employed in this transformation in the absence of H atom donor 1,4-cyclohexadiene (1,4-CHD), inoline 162 was formed in 65% yield. The synthetic utility of the electrochemical intramolecular hydroamidation reaction was demonstrated by the construction of androgen receptor modulator 165 in 4 steps from easily Scheme 52. Synthesis of Androgen Receptor Modulator 165

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Scheme 55. Electrosynthesis of the Natural Product Isocryptolepine

Scheme 56. Mechanistic Proposal for the Formation of 169a

A possible mechanism for this cyclization is shown in Scheme 56. First, Fc+ is generated by anodic oxidation of Fc, and methoxide (MeO−) is formed by cathodic reduction of MeOH simultaneously. The resulting methoxide deprotonates substrate 168a to form anion 173, and which after oxidization by Fc+ furnishes amidyl radical 174. Subsequently, radical 174 undergoes a 6-exo-dig cyclization to afford vinyl radical 175. Radical 175 then undergoes a second cyclization with the aryl ring to generate radical 176, followed by rearomatization to afford the final product 169a. Density functional theory calculations showed that the cascade cyclization is a descending and overall energetically favorable process from amidyl radical 174 to delocalized radical 176. Having established the applications of amidyl radicals, Xu and co-workers’ attention turned to the application of amidinyl radicals to construct polycyclic benzimidazoles, as well as pyridoimidazoles.61 The amidinyl radicals were obtained by the anodic cleavage of NH bonds in an undivided cell equipped with a RVC anode and a Pt cathode at a constant current of 5 mA. As shown in Scheme 57, the anodically generated amidinyl radicals undergo cyclizations with arenes, followed by rearomatization, to afford functionalized tetracyclic benzimidazoles in a highly straightforward manner. A series of polar functionalities, including alcohol, ester, carbamate, sulfonamide, and tertbutylcarbonyl (Boc)-protected amine or aminoester groups were found to be well-tolerated (178a−178h). Para-substituents with different electronic and steric properties on ring A were also well-tolerated (178i−178m). It is worth noting that all metasubstituted amidines afforded a 1:1 mixture of regioisomers (178n−178o). Further investigation showed that the C ring of

Scheme 57. Scope of Benzimidazole Formation

the bicyclic amidine was compatible with a halogen (178p, 178r, and 178s), a methyl group (178q), or a nitrogen atom (178t). Functionalized pyridoimidazole synthesis was much more challenging compared with the synthesis of benzimidazole, and the successful examples for the construction of functionalized pyridoimidazoles are limited. However, as revealed in Scheme 58, 4500


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Conventional electrochemically oxidative C−N bond formation proves to be a straightforward method to construct nitrogen-containing cyclic compunds; however, it often suffers from overoxidation when the oxidation potential of the products is similar or lower than that of the substrates. To solve this problem, Yoshida and co-workers found that integration of electrooxidative cyclization and chemical oxidation via alkoxysulfonium ions was an effective tool to avoid the problem of overoxidation.16 As shown in Scheme 61, tosylamide was a good nucleophile to trap the anodic-generated radical cation, leading to the formation of cyclic products 188 in 13−89% yields. A possible mechanism for this reaction is shown in Scheme 62. Anodic oxidation of 187a, followed by a nucleophilic attack by nitrogen atom of the tosylamine moiety and then deprotonation, affords the cyclized radical 189. Subsequently, radical 189 undergoes further oxidation to generate cation 190, which is then trapped by DMSO to generate cyclized alkoxysulfonium ion 191 as a cation tool. Finally, treatment of 192 with Et3N furnishes sulfur ylide, which then undergoes an elimination of Me2S to afford the cyclized ketone 188a. In 2015, Yoshida and co-workers reported a new electrochemically intramolecular C−H amination reaction of aromatic compounds.62 The anodic oxidation was carried out in a H-type divided cell equipped with a carbon felt anode and a Pt plate cathode under a constant current of 8.0 mA at room temperature or at 50 °C with magnetic stirring. After the electrolysis, piperidine was added to the anodic solution and stirred at 70 °C for 3 h to give the crude product mixture. This process proceeds through a cyclized cationic intermediate, which is electrooxidatively inactive under the conditions, to give a variety of functionalized benzoxazoles and benzothiazoles 194 with excellent regioselectivities (Scheme 63). A reasonable mechanism for the formation of 194a is outlined in Scheme 64. One-electron oxidation of 193a affords radical cation 195. Subsequently, the intramolecular attack of the nitrogen atom of the pyrimidine ring followed by oxidation and deprotonation generates cyclized cationic intermediate 197. The subsequent attack of piperidine followed by the ring opening and the nucleophilic attack of another molecule of piperidine on the resulting imine affords final product 2-aminobenzoxazole 194a. Hypervalent iodine(III) regents have been widely used in the construction of C−C, C-Het, and Het-Het bonds. Nishiyama and co-workers found that hypervalent iodine(III) regent 200 could be obtained by constant current electrolysis of PhI in trifluoroethanol (TFE) (Scheme 65) in an undivided cell equipped with a carbon anode and a Pt cathode in LiClO4/ TFE electrolyte solution.63 Electrochemically generated hypervalent iodine(III) regent 200 displayed a reactivity that is comparable to that of phenyliodine(III)bistrifluoroacetate (PIFA). When N-methoxyamide 201 was employed as a substrate with electrochemically generated 200 as an oxidant, azaspiro derivatives 202 were obtained in excellent yields (Scheme 66). However, the usual constant current electrolysis of 201 gave azaspiro derivative 202 in low to moderate yields. The oxidation of methoxyamides 203 carrying electrondonating group at the meta position to the methoxyamide side chain mediated by 200 led to the formation of quinolinone derivatives 204, as shown in Scheme 67.64 In order to furnish the cyclization reaction well, the X group should be installed as an electron-withdrawing group, such as AcO, Cl, Br, and CN. With electrochemically generated hypervalent iodine(III) regent 200 as an oxidant, amide 205a and nitrile 205b also

Scheme 58. Scope of Pyridoimidazole Synthesis

functionalized pyridoimidazoles could be prepared through the electrolysis of 4- and 3-aminopyridine-derived substrates. It is worth noting that the products were obtained with excellent regioselectivities. This electrochemical cross-coupling reaction was also carried out for the synthesis of other N-heterocycles (Scheme 59). With easily available amidines 181a−181c as substrates, medicinally important products 182a−182c were obtained in good to excellent yields. Scheme 59. Synthetic Extension of This Method

More recently, Lei and co-workers reported an intramolecular CDC reaction to construct C−N bond under electrocatalytic conditions (Scheme 60).19 When N-pyridyl enamines 183 and 185 were employed as the substrates, imidazo[1,2-a]-pyridines 184 and 186 were synthesized in up to 97% yield. Scheme 60. Electrocatalytic Synthesis of Imidazo[1,2-a]pyridines

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Scheme 61. Integrated Electrooxidative Cyclization Followed by Chemical Oxidation of Alkenes

Scheme 62. Proposed Mechanism for the Formation of 185a

Scheme 65. Anodically Generated Hypervalent Iodine

Scheme 66. Synthesis of 200 Using Electrochemically Generated 200 as an Oxidant

Scheme 63. Electrochemical Intramolecular C−H Amination Scheme 67. Synthesis of 204 Using Electrochemically Generated 198 as an Oxidant

underwent oxidative C−N formation reaction to afford the corresponding quinolinones 206a in 62% yield and 206b in 21% yield, respectively (Scheme 68).65 In 2016, our group developed an efficient electrochemically catalyzed amino-oxygenation of styrenes to construct indolines.66 With a suitable iodide salt as the redox catalyst, we envisaged that an electrochemically generated iodonium ion, “I+”, may undergo initial iodoamination of the alkene moiety to generate indoline 207, which is then trapped by solvent MeOH leading to the formation of 3-methoxy indolines 208 (Scheme 69). As a proof of the concept, a series of electrochemical aminooxygenation reaction of 209 were carried out in an undivided cell

equipped with a graphite anode and a graphite cathode with 50 mol % n-Bu4NI as the optimal redox catalyst in the presence of 0.1 M LiClO4. As shown in Scheme 70, a wide range of N-(2vinylphenyl)sulfonamides 209 were compatible with the reaction conditions to give indoline derivatives 210 in 28−78% yields. Moreover, this electrochemical amino-oxygenation reaction could also be carried out in the absence of additional supporting electrolyte. As demonstrated in Scheme 71, cyclized products

Scheme 64. Mechanistic Proposal for the Formation of Benzoxazole

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Scheme 68. Synthesis of 206 Using Electrochemically Generated 200 as an Oxidant

Scheme 70. Indoline Synthesis in the Presence of Electrolyte

were obtained in almost the same yields as that in the presence of 0.1 M LiClO4. This procedure avoids the separation of additional supporting electrolyte from the reaction mixture after the reaction, thus representing a sustainable means by which to achieve intramolecular amino-oxygenation. To make electroorganic synthesis more environmentally benign, Moeller and co-workers demonstrated that electrolysis can derive the energy it needs from renewable sources such as sunlight.67,68 As shown in Scheme 72, using the photovoltaic cell as the source of current, the anodic oxidation of 211 led to the formation of nitrogen-containing cyclic product 212 in a yield comparable to that conducted with the traditional electrochemical apparatus.67 Electroorganic synthesis is recognized as a safe and environmentally friendly methodology since it obviates the use of stoichiometric quantities of chemical oxidants and expensive noble-metal catalysts. However, electroorganic synthesis has its own disadvantages. In most cases, excess amounts of supporting electrolyte are necessary. Thus, after the completion of electrolysis, the supporting electrolyte needs separation from the reaction mixture. Unless it is recovered and reused, it represents a source of waste. To address these limitations, Francke and co-workers developed a recyclable mediatorelectrolyte system based on ionically tagged phenyl iodide and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP).69 The structure of this redox-active supporting electrolyte 213 is shown in Scheme 73. In this structure, 4-iodophenyl moiety serves as redox-active unit based on the iodine(I)/iodine(III) redox couple; the quaternary ammonium group not only provide ionic conductivity but also facilitate recovery and reuse after the reaction. The supporting electrolyte could be obtained in three scalable steps from easily available starting materials without the use of column chromatography. This mediator-salt concept could be successfully applied to the intramolecular construction of C−N bonds, as shown in Scheme 74. The electrolysis of 216 in 10 mL of pre-electrolyzed solution of 214 in HFIP (0.2 M) led to formation of N-acetyl carbazoles 217 in 66−94% yields. After the reaction, HFIP was removed by distillation, while the mediator was recovered by dissolving the remaining solid in acetone and precipitation upon cooling and addition of ether. 2.2.2. Reductive Formation of C−N Bonds. In comparison with the well-established electrochemically oxidative C−N bonds formation, there are only a few examples of electro-

Scheme 71. Indoline Synthesis in the Absence of Electrolyte

Scheme 72. Sunlight Driven Electrochemical Oxidation of 211

Scheme 73. Concept for the Electrochemical Generation of an Iodine(III) Species and the Subsequent Use for Chemical Transformations

chemical syntheses of heterocycles via a single reductive C−N bond formation. Tallec and co-workers reported that onitrophenoxyacetic acid or its methyl ester (218a−218b) and 2-(o-nitrophenylthio)-acetic acid or its methyl ester (219a− 219b) could be reduced to form phenylhydroxylamines (220− 221) under electrochemical conditions, which then underwent cyclization to give 4-hydroxy-2H-1,4-benzoxazin-3(4H)-one 222 and 4-hydroxy-2H-1,4-benzothiazin-3(4H)-one 223 (Scheme

Scheme 69. Reaction Proposal with Iodide as the Redox Catalyst

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Scheme 74. Intramolecular C−N Bonds Forming Reactions Using Electrolyzed Salt 213

Scheme 75. Electrochemical Reduction of o-Substituted Nitro Aromatic Compounds

groups renders double bonds (normally serving as nucleophiles) into highly reactive radical cations with character of electrophilicity, which can be subsequently trapped by alcohol nucleophiles. In this way, a series of anodic umpolung reactions open up new routes to the construction of oxygen containing heterocycles. In 2000, Moeller and co-workers reported that enol ether radical cations could be trapped by alcohols to generate tetrahydrofuran and tetrahydropyran rings.72,73 The anodic oxidation reaction was accomplished in an undivided cell equipped with a RVC anode and a Pt cathode under a constant current of 8 mA in the presence of 2,6-lutidine as a proton scavenger. As illustrated in Scheme 77, the cyclization reactions

75). Theoratically, the average number of electrons required to reduce one molecule of substrate was essentially 4.70 Recently, Peters and co-workers developed an efficient method for the electrosynthesis of 1H-indoles 225 from onitrostyrene 224 (Scheme 76).71 These electrochemical Scheme 76. Electrochemical Synthesis of 1H-Indoles 223

Scheme 77. Anodic Construction of Tetrahydrofurans and Tetrahydroprans

reductions were carried out at carbon cathodes in DMF with tetramethylammonium tetrafluoroborate (TMABF4) as the supporting electrolyte. The key to the success of these reactions was the use of 10-fold molar excess of a proton donor (phenol or methyl 3-oxobutanoate). This protocol represents a valuable and competitive alternative to the construction of 1H-indoles under mild reaction conditions. 2.2.3. Oxidative Formation of C−O bonds. The intramolecular anodic oxidative C−O bonds formation can serve as a powerful tool for the construction of oxygen containing heterocycles. Generally, there are three reaction pathways for the anodic oxidative formation of oxygen containing heterocycles. First, Moeller and co-workers developed a series of anodic couplings of electron-rich olefins with alcohols. The oxidation of electron-rich olefins affords radical cations, which are then trapped by alcohol nucleophiles to generate oxygen-containing heterocycles.72−84 Second, anodic oxidation of amides or tertiary amines generates reactive N-acyliminium cations or iminium cations, which are then trapped by alcohol nucleophiles to afford oxygen containing heterocycles.85−87 Other intramolecular nucleophilic attack of Schiff bases or unactivated alkenes by oxygen nucleophiles reported by Zeng,89−91,93 and other groups88,92,94 also provide straightforward routes to construct oxygen-containing heterocycles. 2.2.3.1. Intramolecular Trapping of Electron-Rich Radical Cations with Oxygen Nucleophiles. As demonstrated above, anodic oxidation of electron-rich alkenes with electron-donating

of 226 proceeded smoothly to give five- and six-membered products 227a−227d in good to excellent yields with the transproduct predominating. However, the cyclization reaction of 226e failed to give seven-membered products. Then, the authors examined the compatibility of the cyclization reaction with the formation of a quaternary carbon. As shown in Scheme 78, the cyclization originating from 228a gave the desired tetrahydrofuran ring 229a in 74% yield as a 3:1 mixture of trans- and cis-isomers. The reaction was also compatible with the formation of tetrahydropyran rings 229b in 56% yield. However, a 1:1 ratio of stereoisomers was formed. 4504


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dithioacetal 237 was subjected to the anodic cyclization reaction to give cyclized products 238 and 239 as a 3:1 ratio of diastereomers, which could be converted into (+)-nemorensic acid 240 after a 3-step synthesis. Following the success of anodic coupling of ketene dithioacetals with alcohols, Moeller and co-workers extended the methodology to the synthesis of lactone rings by anodic coupling of a ketene dithioacetal with an amide (Scheme 83).75 The optimization studies showed that the cyclization reaction benefits greatly from the addition of water to the reaction medium. In the absence of water, the furanone 242 was obtained in 67% yield, while 83% yield of 242 was obtained after adding 10 mol % of water to the solvent mixture. To determine the stereochemical preferences for this reaction, amide 243 with a methyl substituent at allylic position was employed as the substrate (Scheme 84). The anodic cyclization gave furanone 244 in 76% yield as a single isomer. The results show that the direction of selectivity for the cyclization is the same as that obtained for the analogous cyclizations described in Scheme 81. In connection with the efforts to explore the synthetic utility of anodic coupling of ketene dithioacetals with alcohols, Moeller and co-workers reported a total synthesis of (−)-crobarbatic acid by utilizing the anodic coupling of vinyl-substituted ketene dithioacetal with alcohol.76 As illustrated in Scheme 85, the vinyl substituent did not interfere with the anodic cyclization reaction, and the corresponding product 246 was obtained in 72% yield as a 5:1 ratio of diastereomers. With 246 in hand, (−)-crobarbatic acid 247 was successfully synthesized after 6 steps. In 2010, Moeller and co-workers reported an anodic synthesis of C-glycosides by taking advantage of anodic coupling of enol ether or vinyl sulfide with alcohols (Scheme 86).77 With enol ethers 248 as the substrates, furanoses 249a and 249b were obtained in 85% and 62% yields, respectively. In each case, a mixture of diastereomers were formed. The major diastereomer had the acetal group trans to the neighboring methoxy at C3 of the ring. Further studies showed that substrates having differently protected hydroxyl groups were also compatible with the anodic oxidative conditions, giving furanose-derived C-glycosides in moderate yields (Scheme 87). For substrate 250b, the cyclized product 251b was obtained as a mixture of the monothioacetal and the dimethoxyacetal. With the success of construction of furanose-derived Cglycosides, attention was then turned to the synthesis of pyranose derivatives (Scheme 88). For enol ethers 252a and 252b, the cyclization reaction only gave low yields. However, with vinyl sulfide as the initiating group, pyranose derivative 253c was obtained in 68% yield. The results reveal that vinyl sulfide derived radical cation might accelerate the cyclization. To test this hypothesis, fully methoxylated vinyl sulfide 254a was subjected to the anodic electrolysis conditions (Scheme 89).

Scheme 78. Anodic Functionalization of Tri-Substituted Alkenes

The utility of these cyclization reactions was demonstrated by the synthesis of natural product linalool oxide (Scheme 79).73 With enol ether 230 as the substrate, dimethoxyacetal 231 was obtained in 80% yield as a 7:1 ratio of stereoisomers. By taking advantage of a hydrolysis reaction, aldehyde was obtained in 80% yield. Finally, linalool oxide 232 was furnished from aldehyde with a Wittig reaction. This type of cyclization reactions could also be initiated by the oxidation of a ketene acetal equivalent 233 (Scheme 80). With 2,6-lutidine as a proton scavenger, the corresponding product 234 was obtained in 69% yield in a completely trans-selective manner. The use of a trimethylsilyl substituted enol ether indeed improves the diastereoselectivity of the cyclized product due to the steric hindrance between ketane acetal group and benzylic group. However, substrates having an vinylic methyl group on the β-carbon of the enol ether (R = Me) could not be synthesized. This limitation excluded the possibility of generating a quaternary carbon from this cyclization reaction. To overcome this limitation, the authors presumed that the use of a ketene dithioacetal as the initiating group would also improve the diastereoselectivity of these reactions. As shown in Figure 2, compared with transition state TS I, the transition state TS II having the olefin in a pseudoaxial position makes the sterically hindrance larger. Therefore, TS I is favorable, and the use of a ketene dithioacetal initiating group might improve the diastereoselectivity in the construction of quaternary carbon center.74 With this idea in mind, substrates 235 were synthesized and electrolyzed under the same conditions described above. As illustrated in Scheme 81, the oxygen nucleophiles proved to be effective trapping groups for the ketene acetal based radical cations. For substrates 235c and 235d, only single isomers were formed. The results show that the use of ketene dithioacetal group increase the preference for the radical cation moiety to occupy a pseudoequatorial position in the transition state for the cyclization, as shown in Figure 2. By taking advantage of the above-mentioned methodology, (+)-nemorensic acid was efficiently obtained after a 11-step synthesis.73 As shown in Scheme 82, with (R)-(+)-3-methylglutarate as the starting material, ketene dithioacetal 237 was synthesized as a 3:1 mixture of diastereomers. Then, ketene Scheme 79. Synthetic Application

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Scheme 80. Anodic Cyclization of a Ketene Acetal Equivalent 233

Scheme 83. Anodic Coupling of Ketene Dithioacetal with an Amide

Figure 2. Transition states accounting for the observed stereoselectivity.

Scheme 81. Intramolecular Anodic Cyclization of 235

Scheme 84. Determination of the Stereochemical Preference

bromostyrene derivative 259 as the substrate, intramolecular anodic coupling gave C-glycoside 260 in 85% yield as a 1:2 ratio of α/β-isomers. The subsequent Pd-catalyzed coupling reaction delivered the final product 261 in 61% yield. By taking advantage of the anodic coupling reaction, protected C-glycoside 261 could be obtained from mannose 258 in only 4 steps. In addition to alcohol and amide, Moeller and co-workers demonstrated that carboxylic acids could also trap electron-rich radical cations to generate lactones.79 As shown in Scheme 92, anodic coupling of ketene dithioacetals and carboxylic acids gave lactones 263a and 263b in 87% and 72% yields, respectively. Other electron-rich olefins were also well-tolerated to give the corresponding lactones 265a and 265b in moderate yields (Scheme 93). Kolbe decarboxylation did not appear to be a significant competing pathway. The success of intramolecular C−O bonds formation for ketene dithioacetal, vinyl sulfide, and enol ether substrates 262 and 264 reveals that the initial oxidation occurs at the olefin moiety instead of at the carboxylate. Then, attention turned to the coupling of carboxylate with styrene derivatives with higher

It was observed that 71% isolated yield of corresponding product 255a was obtained. However, polymethoxy ether substrate 254b failed to give the corresponding product 255b. These control experiments suggest that vinyl sulfide is a better coupling partner than enol ether for the synthesis of pyranose derivatives. Having established the anodic methodology for the construction of C-glycosides, the same group of Moeller extended this methodology for the synthesis of aryl-substituted Cglycosides (Scheme 90).78 Different from the previously developed strategies using polar enol ether or vinyl sulfide as the initiating groups, the present method employs nonpolar alkene as the initiating group. In general, substituted styrene derivatives were well-tolerated under the anodic conditions, giving the aryl-substituted C-glycosides in 36−86% yields. To demonstrate the utility of this methodology, mannose inhibitor of FimH 261 was synthesized (Scheme 91). With

Scheme 82. Synthetic Application in the Synthesis of (+)-Nemorensic Acid

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Scheme 85. Synthetic Application

to give the corresponding lactones 267 in 33−76% yields. For ortho and para substituents, the cyclization reaction proceeded well, while meta substitutent led to a lower yield of product 267d. The oxidation potential is widely used as a guide for what will happen in preparative oxidation reactions. However, its use sometimes would lead to misleading conclusions. For example, for compound 268 as shown in Scheme 95, the dithioketal has a half-wave potential of Ep/2 = +1.1 V versus Ag/AgCl, while the enol ether has a half-wave potential of Ep/2 = +1.4 V versus Ag/ AgCl.80 Theoretically, the coupling reaction would not occur because the anodic oxidation of 268 would be expected to oxidize the dithioketal in preference to the enol ether. However, experimental results showed that this transformation could be carried out to yield product 271 in 70% yield. The main reason is the intramolecular electron transfer between a sulfur radical 269 and the enol ether 270, and then a Curtin-Hammet controlled reaction would occur. The intramolecular electron-transfer reaction allows for the anodic coupling of an enol ether to an oxygen nucleophile in spite of the presence of a dithioketal with a lower oxidation potential than that of enol ether. For substrate 272 with two enol ether moieties, the cyclized product 273 was obtained in 52% yield, and no evidence was found for oxidation of the second enol ether (Scheme 96). The selective oxidation of the enol ether proximal to the thioacetal in 272 was clearly consistent with a mechanism that involved an initial oxidation of the thioacetal followed by an intramolecular electron transfer to form the enol ether radical cation that led to the cyclization. Besides, Curtin-Hammet controlled reaction was also compatible for the synthesis of seven-membered oxygencontaining heterocycle 275a (Scheme 97).81 However, an oxidation of the eight-membered substrate 274b failed to give the corresponding product 275b. Intramolecular anodic coupling of electron-rich radical cation with alcohol provides a straightforward route to construct oxygen-containing heterocycle. However, radical cation are very reactive intermediates. If the cyclization step is too slow then elimination reaction or other alternative pathways would occur. In 2013, Moeller and co-workers reported a new strategy of controlling the course of a radical cation-derived reaction with the use of a second nucleophile.82 The oxidation of electron-rich olefins gave radical cations, which were trapped by a second nucleophile to form a radical intermediate. The generation of the radical intermediate slows down the competitive “cationic” decomposition pathways and could then go on to complete the desired cyclization reaction. To test the utility of this hypothesis, three trapping groups were selected for the cyclization. As illustrated in Scheme 98, trapping both ends of enol ether radical cations is an effective strategy for completing oxidative cyclization reactions, giving oxygen-containing heterocycles 277, 279, and 281 in 61−85% yields. To further demonstrate the utility of this methodology, a control experiment was carried out (Scheme 99). In the presence

Scheme 86. Intramolecular Anodic Cyclization

Scheme 87. Furanose-Derived C-Glycosides Synthesis

Scheme 88. Pyranose Synthesis

Scheme 89. Effects of Coupling Partner on the Cyclization Reaction

Scheme 90. Anodic Coupling of Alcohol with Substituted Styrene

oxidation potentials. As illustrated in Scheme 94, substituted styrene derivatives 266 underwent the anodic coupling reactions 4507


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Scheme 91. Total Synthesis of FimH 261

kinetically favored pathway and is reversible, while trapping with the sulfonamides leads to the thermodynamic product (Scheme 100).83 With 286 and 288 as model substrates, the relative reactivity of enol ether and allylsilane coupling partners toward ketene dithioacetal derived radical cations were also examined (Scheme 101).84 With the enol ether trapping group, the chemoselectivity of the competition study favored C−C bond formation, and the enol ether trapping of the radical cation gives rise to the kinetic product from the reaction. With the allysilane trapping group, the chemoselectivity of the competition study favored C−O bond formation. CV data show that enol ether trapping of the ketene dithioacetal radical cation is much faster than allylsilane trapping of the radical cation. 2.2.3.2. Intramolecular Trapping of Iminium Cations or NAcyliminium Cations with Oxygen Nucleophiles. Anodic oxidation of tertiary amine or amide could generate the corresponding iminium cations or N-acyliminium cations. These reactive intermediates are intramolecularly trapped by hydroxyl groups to yield oxygen-containing heterocycles.81−83 In 2006, Okimoto and co-workers reported that hydroquinolyl 290 and hydroisoquinolyl 292 were electrochemically oxidized in the presence of KI to give tricyclic products 291 and 293 in moderate to good yields (Scheme 102).85 Following the same procedure, a series of N-benzylpiperidine alcohols 294 were subjected to the anodic oxidative conditions in the presence of a catalytic amount of KI. As shown in Scheme 103, the cyclization reactions gave the corresponding products 295 in 60−67% yields.86 The electrooxidation of 2-benzyl(methyl)aminoethanol 296 under similar reaction conditions afforded cyclized product in 78% yield as a 51:49 mixture of 297 and 298 (Scheme 104). This result suggests that alkyl carbon atoms can also undergo intramolecular attack by the tethered hydroxy group. Consequently, a series of tertiary amines 299 with a hydroxyl group at their benzylic carbon position were subjected to the oxidative conditions in the absence of iodide ions. As illustrated in Scheme 105, the corresponding bicycle products 300 were obtained in 55−82% yields. In 2009, Lee and co-workers reported a method for the intramolecular anodic oxidation of ω-hydroxyl amides to afford oxygen-containing heterocycles in acceptable yields.87 First, (1S)-ketopinic acid derived chiral substrate 301 was used, and cyclic products 302 were obtained in 62−86% yields (Scheme 106). For substrates 301a and 301d, the corresponding products

Scheme 92. Anodic Coupling of Ketene Dithioacetals and Carboxylic Acids

Scheme 93. Extension to Other Electron-Rich Olefins

Scheme 94. Anodic Coupling of Acids to Styrene Derivatives

of a second nucleophile, the cyclization reaction of 282 gave product 283 in 65% yield; however, anodic oxidation of 284 under similar conditions failed to give the desired cyclized product 285. These results indicate that the presence of a second nucleophile could push the reaction toward the desired cyclization. In addition to the exploration of the synthetic utility of radical cations for construction of heterocycles, Moeller and co-workers also performed a series of mechanistic studies to investigate the reactivity of radical cations. With dithioketal as a model substrate, the studies reveal that alcohol-trapping of the radical cation is the 4508


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Scheme 95. Curtin-Hammet Controlled Reaction

Scheme 96. Selective Oxidation of the Enol Ether

Scheme 98. Compatibility of the Cyclization with Alternative Trapping Groups

Scheme 97. Synthesis of Seven-Membered OxygenContaining Heterocycle

302a and 302d were obtained as single isomers. However, acyclic amides 301b and 301c underwent the cyclization reaction to give products 302b and 302c as a mixture of diastereomers. When ethyl (S)-lactate and ethyl (S)-3-hydroxy butyrate derived chiral substrates 303 were used, different products were obtained (Scheme 107). For substrate 303b, the intramolecular C−O bond formation was faster than intermolecular C−O bond formation, thereby leading to the formation of cyclic product 304 in 40% yield. However, for substrate 303a, the intramolecular C−O bond formation was much slower than intermolecular C− O bond formation, and therefore giving acyclic product 305 in 74% yield. 2.2.3.3. Intramolecular Trapping of CN or Unactivated CC Bonds with Oxygen Nucleophiles. In 2013, the first anodic coupling between an imine carbon and a phenol oxygen was developed by Huang and co-workers.88 As shown in Scheme 108, the Schiff base could couple with phenol to yield benzoxazole 307 in 83% yield (condition 1). Further investigation showed that the cyclization reaction benefits from the addition of catalytic amount LiOMe (condition 2). CV studies showed that initial oxidation potential decreased when phenol was deprotonated to phenoxide, which may increase the efficiency of the cyclization.

In the same year, the first example of the indirect electrochemical synthesis of benzoxazoles was reported by our group (Scheme 109).89 In this efficient transformation, a catalytic amount of NaI was used as a redox catalyst, which could be recycled by anodic oxidation in a two-phase system. Remarkably, no additional supporting electrolyte or oxidant was required since sodium iodide serves an electrolyte and a source of the oxidant. With respect to the mechanism, a plausible catalytic cycle, involving a nucleophilic cyclization and a subsequent oxidation of in situ generated hypervalent iodine species, was proposed according to the control experiments and the related reports. Very recently, an organocatalyst 2,3-dichloro-5,6-dicyano-phydroquinone (DDH) was also explored as our ongoing work in the electrochemical synthesis of benzoxazoles 312 (Scheme 110).90 The organocatalyst DDH as the precursor of oxidant 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was readily recycled by the anode oxidation. This novel protocol provided 4509


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Scheme 99. Control Experiments

Scheme 100. Competition Study

Scheme 102. Electrooxidative Cyclization

Scheme 103. Electrooxidative Coupling of NBenzylpiperidine Alcohols

a facile and direct route to a broad range of 2-substituted benoxazoles 312. Inspired by the previous work, an electrochemical amination of benzoxazole was reported in 2014 (Scheme 111).91 Mechanistically, this intermolecular amination reaction was considered as a stepwise reaction involving nucleophilic C−N Scheme 101. Substrates for the Competition Experiments

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Scheme 104. Extension to Other Type of Amino Alcohol

Scheme 109. Indirect Electrochemical Synthesis of 2Substituted Benzoxazoles

Scheme 105. Electrooxidative Cyclization of 3-Dialkylamino1-phenylpropanols

Scheme 106. Intramolecular Electrocyclization of Amide 301 In 2013, Singh and co-workers reported an electrochemical synthesis of substituted 1,3,4-oxadiazoles by trapping of CN with oxygen nucleophiles (Scheme 112).92 With benzohydrazone derivatives 318 as substrates, 2,5-disubstituted 1,3,4oxadiazoles 319 were obtained in 61−94% yields under controlled potential at room temperature. To further demonstrate the utility of the oxidative C−O bond formation strategy, our group developed an electrochemical synthesis of 3,5-disubstituted isoxazoles 321 starting from chalcone derived oximes 320 (Scheme 113).93 This electrosynthesis was proposed to proceed through an iminoxy radical intermediate that undergoes cyclization, further oxidation and deprotonation. In the key step of forming oxime anion, the EGB resulted from the cathodic reduction of CH3OH is suggested to play an important role. With this electrochemical method, a gram-scale synthesis of isoxazolewas also achieved. In 2015, Hilt and co-workers reported an electrochemical cyclization of hydroxyl-functionalized 1,4-dienes to afford tetrahydrofuran and pyran derivatives.94 First, the cyclization of 326 mediated by Ph2Se2 was investigated (Scheme 114). For aryl-substituted substrates 326a−326g, the cyclization reaction afforded furan derivatives 327a−327g in 42−90% yields. For simple methyl-substituted substrate 326i, the corresponding tetrahydrofuran 327i was obtained in 86% yield. When multisubstituted 1,4-dienols 326j and 326k were used as the substrates, the formation of tetrahydrofuran and pyran derivatives 327j−327k and 328j−328k were observed. The reaction may proceed through a tandem pathway shown in Scheme 115. First, PhSe+ cation interacts with the 1,1disubstituted double bond to generate intermediate 329, which then undergoes intramolecular nucleophilic attack to afford product 327 and 328. Subsequently, a similar approach of the iodonium-mediated cyclization of 1,4-dienols was examined (Scheme 116). With aryl substituted 1,4-dienols 330 as substrates, iodoalkoxylated tetrahydrofurans 331 were obtained in 40−82% yields as single regio- and diastereomers. Following a similar mechanism involving a swern-Moffatt-type oxidation described in Schemes 3 and 61 for C−C and C−N bonds formation,16 Yoshida and co-workers also realized the intramolecular trapping of unactivated alkene 332 with carboxylate to yield lactone 333 in 61% yield (Scheme 117).

Scheme 107. Competition Study Between Intra- and Intermolecular C−O Bond Formation

Scheme 108. Intramolecular Electrooxidative Coupling of Schiff Base with Phenol

formation and oxidative C−O formation. Consequently, this direct amination reaction was classified into the oxidative C−O bond formation. More importantly, only catalytic amount of a tetraalkylammonium halide was used as a redox catalyst in this reaction. Under the optimized conditions, a large number of secondary amines could react smoothly with benzoxazoles providing an efficient and general approach to 2-aminobenzoxazoles. 4511


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Scheme 110. Electrochemical Synthesis of Benzoxazoles Mediated by DDH

Scheme 111. Electrochemically Initiated Oxidative Amination of Benzoxazoles

to afford product 335. For the conventional oxidation, PhI(OAc)2 was always used. The oxidation of 334 by PhI(OAc)2 invariably gave comparable amounts of spirocyclohexadienones 339, which complicated its purification.96 In 2017, Waldvogel and co-workers reported a new approach to employ amidyl radical intermediates to synthesis of benzoxazoles from anilides (Scheme 119).97 In an undivided cell equipped with a RVC or graphite anode and a Pt cathode with TBAPF6/HFIP as the supporting electrolyte solution, anilides 340 underwent cyclization to give benzoxazoles 341 with up to 80% yield.

Scheme 112. Electroorganic Synthesis of Substituted Oxadiazoles

In 2015, Harran and co-workers reported efficient electrolytic macrocyclizations (Scheme 118).95 The macrocyclization was carried out in an undivided cell equipped with a graphite anode and a graphite cathode at constant potential of 1.6 V with Et4NBF4/DMF/H2O as the supporting electrolyte solution. Electrolyzing 334 gave diastereoisomers 335a and 335b in 35% total yield, and the dr value was measured to be 2.3:1. Compound 335a is a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. The electrochemical oxidation of 334 initiated at the indole rather than the phenol to give radical cation 336, which loses one molecule of H+ to yield radical 337. Radical 337 subsequently undergoes 5-exo-trig cyclization to give radical 338, which undergoes further oxidation

2.3. Heteroatom-Heteroatom Bond Formation

In comparison with the construction of heterocycles via intramolecular C−C and C-Het bonds formation, there are very few reports on the intramolecular Het-Het bonds formation. Recently, Waldvogel’s group developed a novel access to pyrazolidin-3,5-diones 343 through anodic oxidation of 2,2dimethylmalonic dianilides 342 (Scheme 120).98 The constant current electrolysis of malonic dianilides 342 were carried out in an undivided cell using 0.01 M TBAPF6/HFIP as supporting electrolyte. It was observed that best yield was obtained when the

Scheme 113. Electrochemical Synthesis of 3,5-Disubstituted Isoxazoles

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Scheme 114. Electrochemical Selenoalkoxylation of 1,4Dienols

Scheme 116. Electrochemical Iodoalkoxylation Reaction

Scheme 117. Intramolecular Coupling of Unactivated Alkene with Carboxylate

(Scheme 121). In the pathway 1, two-electron anodic oxidation of two amido groups generates nitrogen-centered radical 344, which undergoes N−N coupling reaction to give the products 343. The formation of pyrazolidin-3,5-diones 343 may also start from anodic oxidation of one of the amido groups leading to nitrogen centered radical 345, which after further oxidation gives nitrogen cation 346. Meanwhile, the cathodic reduction of solvent generates alcoholate anion, which abstracts a proton of the other amido group to give intermediate 347. The product 343 is finally generated by the formation of N−N bond.

3. INTERMOLECULAR CYCLIZATION Electrochemically intermolecular cyclization for the synthesis of heterocycles involves the creation of two bonds simultaneously via a concerted mechanism or in a stepwise pattern. In the latter case, electrochemically generated active species first react with a stable molecule to afford an adduct under an intermolecular new chemical bond formation. The resulting adduct then cyclizes via further electron transfer or cascade reaction to produce the desired heterocyclic structure.

reaction was performed in 1,1,1,3,3,3-hexafluoroisopanol (HFIP) as solvent and using platinum as the cathode. The acidic character of HFIP in combination with the low overpotential for hydrogen evolution at Pt cathode facilitates the generation of alcoholate anions, which benefits the anodic oxidation of amide nitrogen. Compared with conventional chemical methods, this pathway avoids the utilization of highly carcinogenic hydrazine and overcomes the drawback that only simple hydrazine derivatives are commercially available. Employing easily accessible and inexpensive starting materials, a broad substitution pattern is tolerated and nonsymmetrical substrates can also be converted to give corresponding pyrazolidin-3,5diones in yields up to 89%. The conventional approach to pyrazolidin-3,5-diones employs an activated malonic acid derivative and an N,N’-diarylhydrazine as the substrates.99 Although this approach is effective for the construction of simple pyrazolidin-3,5-diones, this approach has two major drawbacks. First, most hydrazine derivatives are highly carcinogenic. Therefore, extra safety arrangements are always required, and up-scaling is problematic. Second, only simple hydrazine building blocks are commercially available. Although detailed mechanism is not clear, two potential routes for the N−N bond formation are postulated by the authors

3.1. Reactions with Electrogenerated Benzoquinones and Analogues

Anodic oxidation of catechols generates o-benzoquinones, which are stable but reactive and very prone to Michael addition reaction with various nucleophiles to afford substituted catechols VII. Then VII, having the catechol moiety, can further be oxidized anodically prior to a second Michael reaction. In this way, the anodic oxidation of catechol in the presence of a dinucleophile provides a powerful and versatile approach to form the catechol-fused heterocycles VIII (Scheme 122). Similar reactions might also occur with 1,4-hydroquinone, the isomer of catechol, and their azo-analogues wherein one (or two) phenolic oxygen atom is replaced by nitrogen atom(s). These compounds include o-aminophenol, o-benzenediamine, paminophenol, and p-benzenediamines (Figure 3).

Scheme 115. Plausible Reaction Pathway

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Scheme 118. Electrochemical Macrocyclization of 334

In the course of the electrolysis, the enolate subunit of 4hydrocoumarin undergoes subsequent inter- and intramolecular Michael addition reactions with in situ electrogenerated obenzoquinone moiety, first leading to the C−C bond and then to the C−O bond formation, to finally afford the benzoxazole heterocycle. In this way, Tabaković and other scientists from Iran have employed a variety of enolates, such as 350−355 as the C,O-doubly nucleophiles to construct various benzoxazole derivatives.101−107 We have been interested in the synthesis of polyhydroxylated indoles, known as potential HIV integrase inhibitors, through anodic oxidation of catechols in the presence of C,N-doubly nucleophiles.108−113 It was observed that polyhydroxylated fused indole derivatives 356 and 357 could be generated one-pot in reasonable yields from both ketene N,O-acetals 358108,109 and N,S-acetals 359,110 respectively (Scheme 124). However, the anodic oxidation reaction stops at the intermolecular Michael addition step, exclusively leading to α-arylated products 360 and 361, when ketene N,N-acetals 362111,112 or enaminones 363113 were used as the potential C,N-doubly nucleophilic species, respectively. Moreover, the further anodic oxidation of isolated α-arylated products 360 and 361 as starting materials only gives a decomposed mixture, rather than the desired corresponding indoles, under the same electrolytic conditions applied for the formation of indoles. These results indicate that the formation of either indole or α-arylated products is dependent on the nature of the starting N,C-doubly nucleophiles. Similar to the electrochemical formation of benzoxazole heterocycle, the electrochemical formation of polyhydroxylated indoles is believed to proceed via an intermolecular Michael addition of

Scheme 119. Synthesis of Benzoxazoles from Anilides

Scheme 120. Oxidative Formation of N−N Bond of 2,2Dimethylmalonic Dianilides

Tabaković and co-workers first studied the anodic oxidation of catechol in the presence of 4-hydrocoumarin, 348, a formal C,Odoubly nucleophile, to construct the benzoxazole cycle.100 The reaction was performed in a phosphate buffer or NaOAc buffer solution under potentiostatic or galvanostatic electrolysis conditions using carbon rod as a working electrode. In order to improve the solubility of the nucleophiles employed in the electrolytic medium, a small amount of organic solvent (such as CH3CN) was added. The process is synthetically simple and efficient; the resulting 6H-benzofuro[3,2c]benzopyran-6-one 349 was produced in 95% yield after simple filtration and washing (Scheme 123). 4514


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Scheme 121. Possible Mechanism for the Formation of 339

Scheme 122. Anodic Oxidation of Catechol in the Presence of a Dinucleophile

Figure 3. Precursors for Electrochemical Generation of Benzoquinones and Azo-Analogues.

Scheme 123. Anodic Oxidation of Catechols in the Presence of Enolates as C,O-Doubly Nucleophiles

Scheme 124. Anodic Oxidation of Catechols in the Presence of C,N-Doubly Nucleophile

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Scheme 125. Anodic Oxidation of Catechols in the Presence of N,S-Doubly Nucleophile

the N,C-doubly nucleophiles to the in situ generated obenzoquinone, leading to α-arylated products under the formation of an intermolecular C−C bond. Followed by a second anodic oxidation and an intramolecular cyclization, the indole cycles are finally constructed.102,103 Other dinucleophiles have been also employed in the anodic oxidation of catechols for the formation of heterocycles. As shown in Scheme 125, the electrochemical oxidation of catechol in the presence of 2-thiouracil 364 as a N,S-doubly nucleophile reagent gave 6,7-dihydroxy-9-thiafluoren-2-one 365 in 88% yield.114 In the case of 2-mercaptobenzimidazole 366, the corresponding catechol-fused tetracyclic imidazo[2,1-b]thiazoles 367 were afforded in 82−97% yields.115 The products 365 and 367 themselves have catechol subunits, and in principle, further anodic oxidation could also occur. However, such overoxidation was circumvented during the preparative reaction due to their lower solubility in the water/acetonitrile medium. However, when 2-imidazolidine thione 368 was used as the N,S-doubly nucleophile reagent, overoxidation of the resulting imidazo[2,1b]thiazole intermediate occurred under the formation of tricyclic imidazo[2,1-b]thiazole-6,7-diones 365 in 76−89% yields.116 When N,N′-diisopropylethylenediamine was used as the N,Ndoubly nucleophilic reagent to react with cathchols, tetrahydroquinoxaline-6,7-diones 370 were generated in 25−40% yields (Scheme 126). Notably, the yield of 370 was lower if the reaction was performed under conventional chemical conditions using K3Fe(CN)6 as the chemical oxidant.117

(S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine 373 as the organocatalyst gave rise to 5-hydroxy 2,3-disubstituted dihydrobenzofuran 372a in 30% yield. When N-Boc-4-aminophenol 371b was used as the starting material, the resulting adduct 372b was obtained with less than 30% conversion, whereas 75% yield and excellent enantioselectivity (96% ee) of 372c was afforded in the case of N-tosyl-4-aminophenol 371c. Under exactly the same conditions, the reaction to form 372d did not occur at all. The protocol proves to be general; linear aliphatic and the nonconjugated unsaturated aldehydes all work well with 371c under the standard conditions described above, to give selectively m-products 372e−372h relative to the amino substituent in good yields (75−87%) and excellent enantioselectivities of 81− 91% ee (Scheme 128). To demonstrate the synthetic utility of this protocol, optically active dihydrofuran 375 was synthesized from 372b in two steps. Wittig reaction of lactol 372b and subsequent spontaneous intramolecular cyclization led to the formation of trans-2,3disubstituted dihydrobenzofuran 374 in 78% and 98% ee. Removal of the N-tosyl group using SmI2 as a reductant afforded 5-amino-2,3-disubstituted dihydrobenzofuran 375 in 73% yield, which is a versatile building block in the synthesis of more elaborated products (Scheme 129). The electrochemical preparation of 2,3-disubstituted dihydrobenzofurans 372 is believed to start from the oxidation of 371b giving p-azobenzoquinone 376, which after reaction with the Michael donor, the electron-rich enamine 377 generated by condensation of aldehyde and organocatalyst 373, leads to intermediate 378. Hydrolysis of 378, followed by a series of proton transfers affords the dihydrobenzofuran 372 and regenerates the organocatalyst 373 simultaneously (Scheme 130). As typical Michael donors, compounds with active methylene groups are able to react with the electrogenerated benzoquinones and aza-analogues. Nematollahi and co-workers reported that the anodic oxidation of 4-aminophenol (or 1,4-benzenediamine) in the presence of malononitrile led to symmetric and asymmetric indoles 379a and 379b, in good yields (74−80%) (Scheme 131).119 The reaction was performed in an undivided cell, equipped with carbon rod electrodes and phosphate buffer, under controlled potential electrolysis at 0.15 V versus Ag/AgCl. Scheme 132 illustrates the mechanism for the synthesis of 379a. Analogous to the anodic oxidation of catechol, the twoelectron oxidation of 4-aminophenol leads to the corresponding p-quinone imine, which after reaction with malononitrile gives adducts 380. Further anodic oxidation followed by a second intermolecular Michael addition results in the formation of adduct 382. The indole derivative 379a is finally obtained

Scheme 126. Anodic Oxidation of Catechols in the Presence of N,N-Doubly Nucleophile

Eelectrogenerated p-benzoquinone and azobenzoquinones can also serve as Michael acceptors for the synthesis of heterocycles. In 2010, Jørgensen and co-workers combined the anodic oxidation and organocatalysis to achieve a direct regioand stereoselective electrochemical synthesis of m-substituted anilines 372 by α-arylation of 3-methylbutanal (Scheme 127).118 The reaction was carried out at carbon rod anode in a mixed solution of CH3CN and water and NaClO4 as the supporting electrolyte, in an undivided cell under galvanostatic electrolysis at 10 mA cm−2. As shown in Scheme 127, the anodic oxidation of 1,4-hydroquinone 371a with 3-methylbutanal in the presence of 4516


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Scheme 127. Anodic Oxidation of p-Hydroquinone and Its Azo-Analogues in the Presence of 3-Methylbutanal, Activated by Organocatalyst 373

Scheme 128. Anodic Oxidation of p-Hydroquinone and Its Azo-analogues in the Presence of Aldehydes Activated by Organocatalyst 371

Scheme 129. Utilization of 372b in the Synthesis of Optically Active 5-Amino-2,3-Disubstituted Dihydrobenzofuran 375

Scheme 130. Proposed Mechanism for the Electrochemical/Organocatalytic Sequence to Form Products 370

385 in good yields (80−90%).120 However, when 4-aminodiphenylamine 388 was subjected to electrolysis with malononitrile under the same conditions, 2-amino-1-phenylindole-3carbonitrile 389 was formed (Scheme 133). For substrate 383, electrochemical oxidation leads to o-diazoquinone 386, which then undergoes nucleophilic addition with electrogenerated base

through intramolecular cyclization initiated from nucleophilic attack of CN group and imine-enamine tautomerization.119 Besides, controlled potential electrolysis of a mixture of 2aminodiphenylamine 383 and active methylene compounds 384 in carbonate buffer (pH = 9) with ethanol in an undivided cell led to the formation of 6H-pyrrolo [3,2,1-de]phenazine derivatives 4517


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Scheme 131. Anodic Oxidation of 4-Aminophenol (or 1,4-Benzenediamine) in the Presence of Malononitrile

Scheme 132. Proposed Mechanism for the Synthesis of 379a

Scheme 133. Anodic Oxidation of Benzenediamines 383 and 388 in the Presence of Active Methylene Compounds

Scheme 134. Cycloaddition of Electrogenerated N-Acyliminium Ion 391 and Unsaturated Hydrocarbons

3.2. Cycloaddition of Electrogenerated Active Species to Unsaturated Compounds

to yield 387. Subsequently, intramolecular tandem cyclization gives product 385. However, for substrate 388, the condensation

The Diels−Alder (D−A) reaction, one of the most powerful methods to construct six-membered cyclic systems, has been well-documented in organic synthesis.121 For efficient formation of cyclic scaffold, an electron-poor dienophile and an electronrich diene are normally required. In contrast, inverse-electrondemand D−A reactions are less studied due to the lack of readily

of 4-aminodiphenylamine with electrogenerated p-diazobenzoquinone is postulated to proceed prior to the addition with malononitrile. The antibacterial activity of these compounds has been evaluated. 4518


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Scheme 135. Proposed Mechanism for the Synthesis of 1,3-Oxazinan-2-ones

Scheme 136. Suggested Mechanism for the Inverse-Electron-Demand D-A Reaction of Electrogenerated o-Azoquinone and Enamines

alkyl-substituted alkenes as dienophiles indicate that the heterocyclic addition involves a concerted mechanism. In contrast to the reaction with alkyl-substituted alkenes, the arylsubstituted alkenes seem to undergo a stepwise reaction via a cationic intermediator 393. The stepwise pathway involving the aryl-substituted alkenes is further confirmed by the formation of a significant amount of polymer through the reaction of Nacyliminiums with styrene (Scheme 135). In addition to the reaction with nucleophiles, electrochemically generated o-azoquinones can also serve as heterodienes in the cycloaddition reactions. Largeron et al. found that oaminophenol 394 is an efficient redox mediator to promote the autorecycling oxidation of homobenzylamine, giving the corresponding alkylimines 395 (top, Scheme 136). However, in the case of unactivated primary aliphatic amines, the catalytic process ceases after few turnovers.125−128 Further experiments demonstrate that it is due to an inverse electron-demand D−A reaction between o-azobenzoquinone 396, the oxidized form of the mediator 394, and an alkylenamine 397, generating from tautomerization of the electrogenerated alkylimines 395.125 The reaction is of synthetic interest since the unstable diene 396 and dienophile 397 are simultaneously electrogenerated at room temperature. In addition, the resulting polyfunctionalized 1,4benzoxazine adducts 398 are complete regiospecific; the more electron-rich carbon atom of 397 (β-carbon of the enamine

accessible electron-deficient dienes. However, heterodienes can be easily generated electrochemically, thereby providing an alternative to inverse-electron-demand D−A reactions for the synthesis of heterocycles. N-Acyliminium ions are versatile intermediates in inverseelectron-demand D−A reactions as electron-deficient heterodienes.122 Yoshida and co-workers reported that N-acyliminium ion 391, electrochemically generated in situ from anodic oxidation of N-methoxycarbonyl-N-(trimethylsilylmethyl)-butylamine 390 via the so-called “cation pool method”, undergoes cycloaddition reaction with alkenes and alkynes to give the corresponding 1,3-oxazinan-2-ones 392 in good to excellent yields (Scheme 134).123 In the cation pool method,124 carbocations are generated and accumulated in relatively high concentration by the low-temperature electrochemical oxidation of the corresponding precursor. The electrolysis is usually carried out at low temperature in order to avoid decomposition of carbocations. The starting material 390 was electrolyzed in a divided cell equipped with a carbon felt anode and a platinum plate cathode using n-Bu4NBF4/CH2Cl2, as supporting electrolyte at −78 °C under constant current conditions, to generate the corresponding N-acyliminium 391, which was accumulated in a solution (cation pool). At the end of the electrolysis, the dienophiles were added to generate the corresponding cycloadducts 392. DFT calculation and complete stereospecificity of the reaction using 4519


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Scheme 137. Electrosynthesis of 1,4-Benzoxazine Derivatives from Electrogenerated o-Azoquinone and Enamines

Scheme 138. Electrochemical Aziridination of Alkenes

Scheme 139. Proposed Mechanism for the Direct Electrochemical Aziridination

subunit) adds to the nitrogen atom of the heterodiene system, 396. Optimized conditions were achieved in a divided cell equipped with a mercury or platinum sheet anodes, tetraethylammonium perchlorate as supporting electrolyte in methanol, and 1:20 ratio of o-aminophenol 394 to amine substrate. The reaction was performed at room temperature under controlled potential conditions. The catalytic oxidation of amine R1R2CHCH2NH2 in the presence of a second type of amine R3NH2 was also investigated (Scheme 137). It was observed that steric and electronic effects exerted by the substituents R1, R2, and R3 play important roles: of the two amines, generally the more nucleophilic one was oxidized anodically, unless steric hindrance prevented it. The multistep one-pot electrochemical procedure represents the first synthesis of 1,4-benzoxazine derivatives 400, being potential novel neuroprotective agents. Electrochemically initiated transfer of a nitrene fragment to alkenes provides an efficient method for the synthesis of threemembered nitrogen-containing heterocycle, which is widely present in natural products bearing various biological activities, as well utilized as potential building blocks for the synthesis of other

nitrogen-containing compounds. Yudin and co-workers reported electrochemical aziridination of olefins through controlled potential electrolysis of a mixture of N-aminophthalimide 401 and alkenes (Scheme 138, top).129,130 The synthesis was performed in a divided cell using Pt as a working electrode and controlled potential at 1.8 V vs Ag wire. A wide range of structurally variable alkenes could be transformed into the corresponding aziridines 402 in good to excellent yields. The anodic oxidation of N-aminophthalimide generates the corresponding nitrene intermediate 403 (Scheme 139). In the absence of alkenes, the nitrene intermediate insert into the N−H σ-bond of another N-aminophthalimide molecule to generate tetrazene 404. Followed by further anodic oxidation and decomposition, the tetrazene 404 finally transfers to phthalimide by extrusion of N2. The presence of acetate anion is indispensable for the electrochemical aziridination reaction, which forms Nacetoxyamino intermediate 405 with the nitrene 403 and prevents the unwanted nitrene dimerization pathway. In the presence of alkenes, the N-acetoxyamino intermediate 405 undergoes concerted addition with olefin to afford corresponding aziridines 402. 4520


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Scheme 140. Proposed Mechanism for Electrochemical Aziridination of Alkenes Mediated by n-Bu4NI

Scheme 141. Asymmetric Epoxidation of Alkenes Using Cl−/Optically Active Mn-Salen Complex Double Mediatory System

Control experiments demonstrated that the reaction could involve a radical route where molecular iodine is a possible active species. Furthermore, since the aziridination reaction was suppressed in the dark, the indirect electrochemical reaction is suggested to involve two reactive intermediates, I• and I2−•, and that it is promoted by ambient laboratory light. The loss of alkene stereochemistry in the mediated electrochemical aziridination demonstrates that the reaction is stepwise, rather than a concerted one, involving the formation of a nitrene. This is supported by the observation that the aziridination of an alkene via a singlet nitrene occurs stereoselectively, while we observed the loss of alkene stereochemistry. The iodide-mediated electrochemical aziridination mechanism is depicted in Scheme 140. Initially, the anodic oxidation of iodide generates molecular iodine, which then reacts with nBu 4 NI to generate ammonium triiodide (n-Bu 4 NI3 ) in equilibrium with I2 and n-Bu4NI. Upon excitation by visible light, I• and I2−• are formed. Hydrogen atom abstraction from Phth-NH2 by I• forms the aminyl radical 406, which is trapped by the alkene to form radical 407. The homolytic cleavage of the N− H bond of 407 is assisted by I2−• via the abstraction of a H atom and is followed by intramolecular cyclization to furnish the aziridine products 402. Simultaneously, iodide is regenerated and re-enters the catalytic cycle. Efficient construction of an oxirane moiety is of significance since compounds containing this structure are found in several biologically active natural products. In addition, these compounds are versatile intermediates in organic synthesis and play an important role in industry. Torii et al. reported electrochemical asymmetric epoxidation of olefins by using Cl−/ optically active Mn-salen complex double mediatory system (Scheme 141).132 The electrochemical epoxidation of alkenes

The crucial role of acetate in the electrochemical aziridination is evidenced by the correlation between aziridine yields and acetate concentration, as well as by a control experiment, that anodic oxidation of N-aminaphthalimide in the presence of cyclohexene with supporting electrolytes other than triethylammonium acetate afford no aziridine, while phthalimine was isolated in high yields (80−85%). The concerted mechanism is further demonstrated by comparing the stereochemical outcomes of electrochemical and Pb(OAc)4-mediated aziridinations. Similar to the chemical formation of stereospecific aziridines, the electrochemical version also afforded stereospecifically aziridines 402. Notably, this direct electrochemical aziridination was found to be efficient only when proceeded in a divided cell utilizing controlled-potential electrolysis technique; aziridination attempts in an undivided cell resulted in significant amounts of byproducts from the reduction of alkene. In addition, the aziridination reaction did not take place when platinum anode was replaced by carbon. We recently improve the methodology and developed an efficient indirect electrochemical protocol for the aziridination of alkenes using n-Bu4NI as a mediator (Scheme 138, bottom).131 The modified procedure employed constant current electrolysis technique and was performed in an undivided cell equipped with a GC anode and an iron plate cathode, 0.1 equiv of n-Bu4NI to serve as the redox catalyst and CF3CH2OH as the solvent. All styrenes and aliphatic cycloalkenes are useful partners; the corresponding aziridines were formed in moderate to good yields. In addition, the mediated electrochemical aziridination can also proceed without additional supporting electrolyte, although the yields are a little lower than that using LiClO4 as supporting electrolyte. 4521


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was performed in an undivided cell by using a CH2Cl2/aqueous NaCl two-phase solution at 0 °C. Notably, when Br− or I− was used as one of the mediators of the double mediatory system, the epoxidation reaction failed since the generated Br+ and I+ could not efficiently oxidize the Mn-salen complex. In these cases, 1,2dihalogen products were obtained. It is proposed that the Cl− in the aqueous phase is anodically oxidized to afford active chlorine species Cl+, such as ClO−, which migrates to the organic phase and operates as a co-oxidant to generate optically active Mn-oxo complex 410. Subsequently, the Mn-oxo complex could react with alkene to give the corresponding epoxide 409, and simultaneously regenerate the Mn-salen complex 408 (Scheme 142).

Scheme 143. Epoxidation of Alkenes in BDMIN-BF4 Using in Situ Generated H2O2

Scheme 142. Proposed Mechanism for the Asymmetric Epoxidation of Alkene

3.3. Electrogenerated Anions and Electrochemical Fixation of CO2

Organic anions, such as carbanions and heteroanions, are important intermediates in organic synthesis as nucleophiles and base. Electrochemistry provides a unique method via cathodic reduction, to generate organic anions under mild conditions without the addition of stoichiometric amount of chemical base. The electrogenerated anions afford an excellent control of the base strength if a solvent is used as the precursor of an EGB. Furthermore, the amount of the EGB is a function of the applied current density and the duration of the electrolysis which could also be tuned. Typically, the EGB can be formed by either two-electron reductive cleavage of a C−X bond in a halogen compound, or one-electron cleavage of an activated elementhydrogen bond of C−H, N−H, O−H, P−H, and S−H acids. The generation and applications of EGB have been welldocumented in several reviews and monographs,142 and readers are encouraged to refer to them for detailed insight. Here we will examine only some of the more recent papers. Electrogenerated gem-dichloro carbanions from electrochemical reduction of trichloroacetate can undergo electrophilic attack of some reagents, such as proton,143 α,β-unsaturated compounds,144 and carbonyl compounds.145,146 Nishiguchi et al. reported a stereoselective and facile synthesis of 2-chloroepoxyester 412 through electroreductive cross-coupling of methyl trichloroacetate 411 with aliphatic aldehydes (Scheme 144).147 With tetraethylammonium p-toluenesulfonate (Et4NOTs) in DMF as supporting electrolyte, constant current electrolysis of 411 with aldehydes in the presence of trimethylsilyl chloride was performed in an undivided cell equipped with a Zn rod as the sacrificial anode and cathode. It was observed that sec- or tertaliphatic aldehydes gave good yields of corresponding αchloroepoxyesters, whereas complex mixture was obtained from reaction with primary aliphatic aldehydes. In addition, because the produced α-chloroepoxyesters have three different active functional groups (a chloro atom, an epoxide ring, and an ester group), these compounds are useful synthetic intermediates. For example, its condensation with o-phenylenediamine gave quinoxaline derivative 413 in 60% yield. It is proposed that the dichlorocarbanion 414 is first cathodically generated. Followed by a nucleophilic attack on the carbonyl carbon of the aliphatic aldehyde and ionic interaction with zinc cation, generated electrochemically from the anode, the adduct intermediate 415 is afforded. Subsequently, the oxygen anion of the adduct 415 attacks the adjacent carbon atom intramolecularly to eliminate chloride ion, giving the epoxide product 412. Notably, only (Z)-αchloroepoxyesters are obtained in the stereoselective manner,

The epoxidation of alkenes using electrogenerated hydroperoxide as oxidant is another method for the synthesis of epoxide. Hydroperoxide can be electrochemically generated in aqueous133−136 and biphasic system.137,138 Chan et al. reported the electrogeneration of H2O2 in 3-butyl-1-methylimidazolium tetrafluoroborate, an ionic liquid, and demonstrated that the electrogenerated H2O2 could be used in situ for the epoxidation of electrophilic alkene in alkaline medium.139 However, this system is found to be applicable only for the epoxidation of electrophilic alkenes. To widen the scope and extend its application to other classes of alkenes, the authors integrated the electrogeneration of H2O2 with manganese/bicarbonateactivated epoxidation system.140 In this modified procedure,141 the cathodic reduction of oxygen in a divided cell using RVC as the cathode and a platinum-coated titanium plate anode in the ion liquid generates O2−•, which is activated by water resulting in further reduction to H2O2 or HO2−. Once H2O2 is electrogenerated, the mixture of [BDMIN][BF4]/NaOH(aq)/H2O2 was transferred to a separated reaction vessel charged with alkene while bubbling CO2 to afford the desired epoxide (Scheme 143). Since the concentration of H2O2 (∼ 0.08 M) prepared by electrogeneration in this study is much lower than 35 wt % H2O2 that is commonly used, the hazards associated with the handling of concentrated H2O2 are greatly reduced. During the electrolysis, OH− was produced at the anode. Therefore, CO2 was used to generated the bicarbonate, which could lower the pH of the reaction mixture to the optimal range for epoxidation. 4522


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Scheme 144. Epoxidation of Electrogenerated gem-Dichloro Carbanion with Aldehydes

although two types of stereoisomers would be expected for the reaction (Scheme 145).

Scheme 147. Electrocatalytic Chain Cyclization of Tetracyanocyclopropanes with Alcoholate Anion

Scheme 145. Proposed Mechanism for the Electrochemical Synthesis of α-Chloroepoxyesters

Scheme 148. Proposed Mechanism for the Electrocatalytic Formation of 416

Analogously, the aziridine analogues 416 were synthesized when aromatic imine derivatives 417 were used as substrates for the electrochemically reductive cross coupling (Scheme 146).148 Cathodic reduction of solvent alcohol generates alcoholate anion, RO−, which is among the most important EGBs. Using a catalytic amount of this EGB, Elinson and co-workers have developed a novel and efficient electrocatalytic chain transformation of organic compounds for the synthesis of complex structure.149−154 The chemistry is generally performed in an undivided cell in alcohol containing alkali metal halides, such as NaBr or KBr as supporting electrolyte. The procedure is synthetically valuable, especially for large-scale processes, since it utilizes catalytic amount of electron as reagent and performs in an undivided cell using graphite anode under galvanostatic conditions. The first example of the process involves the electrocatalytic chain cyclization of tetracyanocyclopropanes 418 with in situ generated alcoholate anion into substituted 2-amino-4,4dialkoxy-1,5-dicyano-3-azabicyclo[3,1,0]hex-2-enes 419 (Scheme 147).149 The mechanistic illustration of the electrocatalytic chain reaction for the formation of 419 is shown in Scheme 148. The electrogenerated alcoholate anion undergoes addition to tetracyanocyclopropanes 418 leading to iminium anion 420. Followed by heterocyclization and protonation, intermediate 421 was generated. After a second addition of alcoholate anion to intermediate 421, the 2-amino-4,4-dialkoxy-1,5-dicyano-3azabicyclo[3,1,0]hex-2-enes 419 are finally produced. Under similar conditions, 2,2-dicyanocyclopropane-1,1-dicarboxylates 422 undergo stereoselectivly electrocatalytic chain transformation, leading to 4,4-dialkoxy-5-cyano-2-oxo-3azabicyclo[3,1,0]hexane-1-carboxylates 423 (Scheme 149).143

Scheme 149. Electrocatalytic Chain Cyclization of Dicyanocyclopropane-1,1-dicarboxylates with Alcoholate Anion

The electrocatalytic methodology is further extended to baseactivated multicomponent reactions for the synthesis of medicinally privileged 2-amino-4H-chromene scaffold. For example, electrolysis of a mixture of salicylaldehydes and two equivalents of either malononitrile or alkyl cyanoacetate accomplishes cyano-functionalized 2-amino-4H-chromene 424 (Scheme 150).151,152 When one molecule of the necessarily cyano-functionalized C−H acid is replaced by another C−H acid, 425, similar multicomponent transformation occurs (Scheme 151).153 The electrocatalytic multicomponent transformation of salicylaldehydes and two different C−H acids is proposed to start from the cathodic reduction of solvent alcohol, giving alkoxide anion. Subsequent reaction of alkoxide anion with the strongest acid 426 in the system gives rise to the corresponding

Scheme 146. Aziridination of Electrogenerated gem-Dichloro Carbanion with Aromatic Imines

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conditions, high yields, and separation of products through simple filtration. In addition to electrogenerated alcoholate anion, cyanomethyl anion, NCCH2−, generated from the reduction of CH3CN/ supporting electrolyte solution is also one of the widely used EGBs for the synthesis of heterocycles. Massa, Palombi, and coworkers reported the synthesis of isoindolinone 444 from 2cyanobenzaldehyde and 1,3-dicarbonyl compounds or malononitrile induced by the electrogenerated cyanomethyl anion (Scheme 157).160,161 The electrolysis of 2-cyanobenzaldehyde was carried out in a divided cell using TEABF4 in CH3CN as supporting electrolyte and platinum spirals as electrodes (anode and cathode) under galvanostatic conditions. At the end of electrolysis, the reaction was stirred at room temperature until TLC disappearance of 2-cynobenzaldehyde. This one-pot twostep synthesis gave the corresponding isoindolines 444 in 52− 98% yields. Next, a one-pot procedure to synthesis of isoindoline derivatives 445 and 446 containing quaternary carbon centers also succeed. Active 1,3-dicarbonyl compounds were electrolyzed in the presence of Michael acceptors. After the electrolysis, Michael acceptors were subsequently added to the cathodic compartment. Compared with the conventional chemical methods, the electrochemical approach allows for only catalytic amount electricity (0.04 F/mol) and shorter reaction time (0.75 h vs 18 h). The mechanistic illustration of the tandem reaction is shown in Scheme 158. The electrogenerated cyanomethyl anion initiates an aldol addition of active methylene compounds to the 2cyanobenzaldehyde leading to intermediate 447. Followed by heterocyclization and rearrangement via an aza-Michael reaction, 3-functionaized isoindolinone 444 is finally afforded. Since the electrogenerated cyanomethyl anion is a strong base (pKa ∼ 31), it is reactive and generally prepared in situ in a divided cell. The preparation and accumulation of active cyanomethyl anion can also occur in an undivided cell through stabilization as Grignard-type species using sacrificial anode electrolysis. For example, Mekni et al. reported the electrosynthesis of thiazolidine-2-thiones 448 promoted by the in situ generated NCCH2− (Scheme 159).162 The chemistry was carried out by initial generation of NCCH2− in an undivided cell using nBu4NBF4 as supporting electrolyte in acetonitrile and Mg rod as anode and stainless steel cathode under galvanostatic conditions. At the end of the electrolysis, secondary β-amino alcohols and carbon disulfide were added to the EGB solution to afford the desired thiazolidine-2-thiones 448 in good yields. Arcadi, Rossi, and co-workers reported an electrochemicalmediated annulation of 2-alkynylanilines 449 to functionalized indoles 450 with the aid of electrogenerated base (Scheme 160).163 The authors found that electrogenerated cyanomethyl anion, which was obtained by electrochemical reduction of 0.1 M tetraethylammonium tetrafluoroborate (TEABF4)/MeCN sol-

Scheme 150. Electrocatalytic Synthesis of 2-Amino-4Hchromene Scaffold

anion 429, which undergoes Knoevenagel condensation with 427 affording the key intermediate 430. Once the Knoevenagel adduct 430 is formed, it may undergo three reaction pathways. As shown in Scheme 152, the hydroxide-promoted Michael addition of C−H acid 426 to the adduct 430 followed by intramolecular cyclization leads to corresponding 4H-chromene 432 (pathway A). The following uptake of the stronger C−H acid 426 and based-promoted addition of weaker C−H acid 425 affords the desired 2-amino4H-chromene 428. On the other hand, 2-amino-4H-chromene 428 may generate from the intramolecular cyclization of Knoevenagel adduct 430, leading to the reactive intermediate 433, and its subsequent base-promoted Michael addition with weaker C−H acid 425 (pathway B). The pathway C shown in Scheme 152 seems to be less probable since it involves the addition of the anion of the weaker C−H acid 425 to Knoveneagel adduct 430 in the presence of stronger acid 423 under the formation of intermediate 435. Besides, a combination of cyclic 1,3-diketones, aldehydes, and malononitrile catalyzed by the electrogenerated alkoxide anion also gives chromene-3-carbonitrile derivatives 437 (Scheme 153).154,155 When cyclic 1,3-diketones is replaced by barbituric acid, similar reaction occurs. For example, Islamnezhad reported electrochemical reaction of barbituric acid, and aldehyde and malononitrile afforded substituted pyrano[2,3-d]pyrimidinones 438 in 65−85% yields (Scheme 154).156 Under similarly electrocatalytic conditions, cyclic 1,3diketones, isatins, and malononitrile were transformed into functionalized spirocyclic (5,6,7,8-tetrahydro-4H-chromene)4,3′-oxindoles 439 (Scheme 155).157 When N-alkyl barbiturates 440 were used as 1,3-diketones to react with isatins and malononitrile, the corresponding adducts 441 were generated.158 The electrochemical multicomponent reaction has also been used for synthesis of fused pyridines.159 When a mixture of 6aminouracil, various aromatic aldehydes and malonotrile or dimedone was subjected to electrolysis in an undivided cell using NaBr/EtOH as supporting electrolyte at 40 °C under constant current, pyrido[2,3-d]pyrimidine derivatives 442 and 443 were generated in excellent yield, respectively (Scheme 156). The protocol is attractive for the synthesis of fused pyridines because of using of inexpensive starting materials, nonhazardous reaction

Scheme 151. Electrocatalytic Multicomponent Reaction for the Synthesis of 2-Amino-4H-chromene Scaffold

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Scheme 152. Possible Catalytic Pathways for the Formation of 2-Amino-4H-chromene

fore, this electrochemical approach provides an appealing complementary to the reported procedures. As a main contributor to the greenhouse effect and highly abundant carbon source, fixation of carbon dioxide into organic compounds has been paid increasing interest in chemistry. EGBs provide a convenient and less energy input approach for the fixation of CO2. Inesi and co-workers pioneeringly use the electrogenerated NCCH2− for the fixation of CO2 into organic compounds. For example, chiral cyclic carbamates 451 was afforded in good yields through electrolysis of a solution of 1,2-amino alcohol in CH3CN containing Et4NClO4 as electrolyte prior to bubbling of CO2 and subsequent addition of TsCl (Scheme 161).164 The electrogenerated NCCH2− was also used to promote the fixation of CO2 to propargyl amines 452 for the synthesis of 5methylene-1,3-oxazolidine-2-ones 453 (Scheme 162).165 Similarly, CH3CN/Et4NPF6 solution containing acetylenic amines 452 was electrolyzed in a divided cell. After passing 2 F/mol

Scheme 153. Electrocatalytic Multicomponent Reaction for the Synthesis of 2-Amino-4H-chromene Scaffold

utions at 0 °C in a divided cell using a Pt cathode, could act as a base to promote the annulation of 2-alkynylanilines 449. This methodology was compatible with a large variety of functional groups, regardless of internal or terminal alkynes. To further demonstrate the practicability of this protocol, a large-scale experiment (10 mmol) was also performed without significant loss of reaction efficiency. After the reaction, simple evaporation of the solvent and filtration through silica gel afforded the corresponding products without any extractive workup. There-

Scheme 154. Electrocatalytic Multicomponent Reaction of Barbituric Acid, Aldehyde, and Malononitrile

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Scheme 155. Electrocatalytic Multicomponent Reactions

Scheme 156. Electrocatalytic Multicomponent Reaction of 6-Aminouracil, Aldehydes, and Malonotrile or Dimedone

Scheme 157. Electrosynthesis of Isoindolinone from 2-Cyanobenzaldehyde and Active Methylenes Induced by Electrogenerated Cyanomethyl Anion

5-exo-dig cyclization of the corresponding intermediate propargylic carbamate anion gives the 5-methylene-1,3-oxazolidine-2ones 453 (Scheme 163). This hypothesis is supported by the observation of ethane evolution at the electrode during the electrolysis. N-Heterocyclic carbenes (NHCs), generated from a direct single electron cathodic reduction of imidazolium cations, are well-known organocatalysts. These electrogenerated NHCs have found numerous applications as organocatalysts in Henry reaction,166 benzoin condensation,167 synthesis of β-lactams,168 and anodic oxidation of aldehydes to esters and thioesters.169,170

charge, CO2 was bubbled into the catholyte and then the mixture was heated to reflux. During the electrolysis, gas evolution at the electrode was observed. In addition, when lithium salt, instead of a R4N+ salt was used as the supporting electrolyte, the expected 5methylene-1,3-oxazolidine-2-ones 453 were not isolated. On the basis of these facts, the pathway for the synthesis of the product is proposed to start from electrochemical reduction of tetraethylammonium cation at the cathode generating a carbanion, which then abstracts a proton from the solvent acetonitrile to form the NCCH2−. Deprotonating the NH group of propargyl amine by NCCH2− followed by carboxylation and a 4526


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Scheme 158. Possible Mechanism for the Formation of 3Functionaized Isoindolinone 444

Scheme 161. Synthesis of Chiral Cyclic Carbamates Induced by Electrogenerated Cyanomethyl Anion

Scheme 162. Synthesis of 5-Methylene-1,3-oxazolidine-2ones Induced by Electrogenerated Cyanomethyl Anion

Scheme 159. Synthesis of Thiazolidine-2-thiones Induced by Electrogenerated Cyanomethyl Anion Scheme 163. A Proposed Mechanism for the Synthesis of 5Methylene-1,3-oxazolidine-2-ones

Orsini, Inesi, and co-workers reported the synthesis of γbutyroactones from α,β-unsaturated aldehydes and ketones induced by the electrogenerated NHCs (Scheme 164).171 The imidazolium salt 454 was initially electrolyzed in a divided cell under N2 atmosphere in molecular solvents or in ionic liquids to generate the corresponding NHCs. After 0.5 Faradays consumed per mol of aldehyde, the electrolysis was stopped. Then, α,βunsaturated aldehydes and ketones were added into the catholyte to afford the desired γ-butyroactones 455. It was observed that the nature of the ionic liquids plays an important impact on the reaction; best yield of γ-butyroactones 455 was obtained employing BnMIMBF4 as the solvent and precatalyst. The electrogenerated NHC plays as a catalyst by umpolung of α,βunsaturated aldehyde. NHCs can also be used for the fixation of CO2 to organic compounds. Deng and co-workers first reported the electrochemical activation of CO2 in ionic liquid for the synthesis of cyclic carbonates (Scheme 165).172 Using Mg or Al rod as sacrificial anode and Cu plate as cathode in an undivided cell, epoxides and CO2 dissolved in ionic liquid were electrolyzed at the controlled potential of the reduction potential of CO2 (−2.4 V vs Ag/AgCl) to give the corresponding cyclic carbonates 456 in good to excellent yields. It was observed that both the cation and anion of the ion liquid have a relatively stronger impact on the addition reaction; with BMIMBF4 as the solvent and

Scheme 164. NHCs-Induced Synthesis of γ-Butyroactones

Scheme 165. NHCs-Induced Synthesis of Cyclic Carbonates

electrolyte, 54−92% of conversion and 69−100% of selectivity were achieved.

Scheme 160. Intramolecular Cyclization of 2-Alkynylanilines to Indoles

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A conversion of CO2 and diols to cyclic carbonate 457 was also achieved by the NHC generating from electrochemical reduction of BMIMBF4 in a divided cell using inert electrodes (Scheme 166).173 The control experiment revealed that K2CO3 instead of

Scheme 168. Mechanism for the Direct Conversion of CO2 with Alkenes and Water

Scheme 166. NHCs-Induced Synthesis of Cyclic Carbonates

NHCs acts as a base to deprotonate proton of diols. However, the role of CH3I is not clear. This work provides a new procedure for synthesis of cyclic carbonates, as well as expands the function of NHCs. Employing EGB and I2, Yuan, Jiang, and co-workers have developed a simple and highly efficient electrochemical protocol for the direct conversion of CO2 with alkenes 458 into cyclic carbonates 459.174 As shown in Scheme 167, with NH4I as the

dehyde using NaI as a mediator (Scheme 169).175 The electrolysis was carried out in an undivided cell with a Ni foil cathode and a graphite rod anode at room temperature. The process avoids the use of toxic phosgene or CO, which is usually used in traditional methods, thus providing an environmentally friendly and efficient route to the 1,3,4-oxadiazol-2(3H)-one derivatives. The chemistry is proposed to start from the reaction of electrogenerated molecular I2 with 1-methylene-2-phenylhydrazine, generated in situ from the condensation of aryl hydrazines and paraformaldehyde, to give N-(α-iodomethylene)-N’-phenylhydrazine 462. Meanwhile, the cathodic reduction of MeOH generates hydrogen and methoxylic anion, an EGB. Deprotonation by either MeO− or t-BuOK, 462 is converted to corresponding anion 463. The anion 463 undergoes intermolecular nucleophilic attack to CO2, giving the desired 1,3,4oxadiazol-2(3H)-one derivatives 461, along with the regeneration of iodide ion (Scheme 170). In addition to using EGB for the fixation of CO2, the direct electrochemical reduction of CO2 is also an important pathway for the application of CO2. Recently, Buckley, Wijayantha, and co-workers reported the electrosynthesis of cyclic carbonates from epoxides and atmospheric pressure carbon dioxide in the absence of expensive catalysts (Scheme 171).176 The reaction was carried out in an undivided cell equipped with acetonitrile as solvent, n-Bu4NBr as electrolyte, and a 60 mA current. Excellent conversion to cyclic carbonate was achieved using copper cathode/magnesium anode combination. In addition, the use of tetrabutylammonium bromide is essential for the reaction; only 17% conversion to the cyclic carbonate was observed if the bromide counterion was replaced by tetrafluoroborate. Without passing current, the reaction did not occur. A wide range of substrates are suitable for the approach; excellent yields of cyclic carbonate were produced, including electron-rich and poor aromatic and aliphatic epoxides. The approach is easy to set up, reliable, requires no expensive catalyst, and runs under atmospheric CO2 pressure and ambient temperature. In the same pattern, but using chiral epoxides as the starting material, enantiomerically pure cyclic carbonates were electrochemically produced.177 The reaction was performed using stainless steel as cathode and Mg as anode. Scheme 172 illustrates the possible mechanism. Mg rod as sacrificial anode is oxidized to generate Mg2+. Simultaneously, CO2 is reduced to anion radical and stabilized by the Mg2+ ion to form complex 464. Further reaction with epoxide and nucleophilic attachment of Br anion to β-C atom leads to the formation of 465. Upon a following intramolecular nucleophilic attack of oxygen atom on epoxide and electron transfer with a second CO2 molecule, 466 is formed

Scheme 167. Direct Electrochemical Conversion of CO2 with Alkenes into Cyclic Carbonates

supporting electrolyte, graphite anode/Ni cathode and DMSO as solvent in an undivided cell, cyclic carbonates were afforded from electrochemical reaction of CO2 and alkenes. A wide range of alkenes 458, including styrene derivatives, vinylnaphthalene, and aliphatic (cyclic or heterocyclic) alkenes, could be converted into the corresponding cyclic carbonates in good to excellent yields. Besides, the present approach could be applicable to a largerscale process; the yield did not decrease dramatically in a 100 mmol scale. Compared with the synthesis of cyclic carbonates from CO2 and epoxide using sacrificial metal anode, from the viewpoint of synthesis, this direct conversion of CO2 with olefins to carbonates is of significance, since the synthesis and isolation of epoxides is not required. In addition, the sacrificial anode is avoided, which suffers from the utilization of stoichiometrical metal anode and difficulty in separation of products. Since related intermediate, iodohydrin 460, is confirmed by GC/MS and NMR spectra, in addition to the observation of I2 and NH3, the authors postulated a mechanism shown in Scheme 168 for the synthesis of cyclic carbonates 459. With NH4I as supporting electrolyte, I2 and NH3 are formed simultaneously at the anode and cathode, respectively. In the presence of water, the in situ generated I2 reacts with alkenes to generate the important intermediate, iodohydrin 460. Deprotonated by NH3, iodohydrin further reacts with CO2, followed by the intramolecular cyclization to give products 459. In accordance with the mechanism, the formation of cyclic carbonates 459 is proceeded via a synergistic action of electrochemical generated NH3 (a base) and I2, therefore it is a reaction using NH4I as the redox catalyst, which in principle can be used catalytically. Recently, Yuan et al. further extended this protocol to the one-pot electrochemical synthesis of 1,3,4oxadiazol-2(3H)-one derivatives 461 via a three-component coupling reaction of CO2 with aryl hydrazines and paraformal4528


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Scheme 169. Electrochemical Conversion of CO2 with Aryl Hydrazines and Paraformaldehyde to 1,3,4-Oxadiazol-2(3H)-one Derivatives

Scheme 170. Proposed Reaction Mechanism for the Synthesis of 1,3,4-Oxadiazol-2(3H)-one Derivatives

Scheme 171. Synthesis of Cyclic Carbonates from Direct Electroreduction of Carbon Dioxide

Scheme 173. Electrochemical Synthesis of Cyclo[n]pyrrole

and regenerates the stabilized complex. The cyclic carbonate 467 is finally produced from intramolecular nucleophilic replacement of the bromide anion by the carboxylic oxygen anion. The proposed mechanism explains the important role of Mg2+ and bromide ion.

oxidation methods but avoiding the use of harsh conditions (1 N acid and iron(III) or chromium(VI) oxidant), therefore providing an environmentally friendly approach. Notably, the choice of anionic species within the supporting electrolyte influenced the oxidation potential of starting substrate and the efficiency of the cyclization reaction; the yield of 469 spans in a range from close to 0% with tetrabutylammonium fluoride as the electrolyte to almost 70% when tetrabutylammonium hydrogensulfate was used for this purpose. Under the same conditions, but using bispyrrolylthiophene 470 as a substrate, tris-thiophen nonaphyrin [4H6]2+SO42− 471, bearing 6 pyrrole and 3 thiophene subunits directly connected

3.4. Homocoupling Reactions

Homocoupling of electrogenerated species also gives heterocycles. Bucher, Sessler, and coworkers developed an efficient electrochemical process for the synthesis of cyclo[n]pyrrole (Scheme 173).178 The electrochemical oxidation of 3,3’,4,4’tetraethylbipyrrole 468 at Pt anode in CH2Cl2 containing tetrabutylammonium salt as supporting electrolyte was performed in a divided cell under controlled-potential conditions. The resulting cyclo[8]pyrrole 469 was afforded in a yield competitive with that obtained by using the best chemical

Scheme 172. Proposed Mechanism for the Synthesis of Cyclic Carbonates from Direct Electroreduction of Carbon Dioxide

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Scheme 174. Electrochemical Synthesis of Thiophene-Containing Cyclo[9]pyrrole

Scheme 175. Electrochemical Synthesis of Cyclo[7]- and Cyclo[8]pyrrole

Scheme 176. Possible Reaction Mechanism for the Formation of 464

through their respective α-position in a fully symmetric arrangement, was isolated in 6% yield (Scheme 174).179 This novel compound could not be obtained using standard chemical oxidative coupling procedure. A 34 π-electron aromatic system is assigned for the compound based on 1H NMR spectroscopic measurements. A mixture of cyclo[7]pyrrole, 472, and cyclo[8]pyrrole 473 from anodic oxidation of 3,4-diethylpyrrole under the electrochemical conditions was generated and the two species were found to range from 1% to 3% yields (Scheme 175).180 Although not yet fully understood, the radical coupling of the cyclo[n]pyrrole formation is believed to start from anodic oxidation of pyrrole subunit giving a radical cation. As shown in Scheme 176, the one-electron oxidation of bipyrrole 468

generates corresponding cation radical 474. The resulting cation radical undergoes radical homocoupling and deprotonation leading to tetrapyrrole 475. Through an anion-assisted cyclization process, further oxidation and deprotonation finally affords the cyclo[8]pyrrole 469. A complex heterocylic scaffold containing five-membered Oheterocycles from direct anodic oxidation of 2,4-dimethylphenol using Pt electrodes in an undivided cell was produced by Waldvogel and co-workers (Scheme 177).180 It was observed that four pentacyclic compounds were simultaneously generated in notable quantities, in addition to the o,o-homocoupling dimer 476 and so-called Pummerer’s ketone 477. The nature of the electrolyte had a severe impact on the reaction outcome. When Ba(OH)2 in methanol was used as the supporting electrolyte, the 4530


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Scheme 177. Electrochemical Oxidation of 2,4-Dimethylphenol

polycyclic structures containing typical structural elements of bioactive compounds.182 A novel highly oxygenated heterocycle 483 was also produced in 60% yield from anodic oxidation of 2,3-dihydroxypyridine in aqueous phosphate buffer solution.183 On the basis of cyclic voltammetry, controlled potential coulometry and spectroscopic data of the isolated product, the reaction mechanism is assumed. As shown in Scheme 179, anodic two-electron oxidation of each 2,3-dihydroxypyridine leads to pyridine-2,3-dione. It undergoes ring cleavage in the acidic buffer solution giving intermediate 484. Followed by an intermolecular and then intramolecular Michael addition, compound 485 containing a dihydropyrazine cycle unit is constructed. After a sequence of enolization, cyclization, and oxidation, the final product 483, 3,8-dihydroxy5,10-dihydrodipyrano[2,3-b:2′,3′-e]pyrazine-2,7-dione, was formed.

pentacyclic compound 478 was generated with diastereometrically pure in 18% yield. In addition, compound 479 was isolated in 5% yield as a single diastereoisomer; 480 and 481 were obtained in about 2% yield each. Notably, during the electrolysis, the major pentacyclic scaffold 478 precipitated, and thereby were easily prepared by this electrochemical method. The construction of these spiropentacyclic structure most likely involves Pummerer’s ketone 477 as a synthetic intermediate. In a follow-up study, it was demonstrated that spiropentacyclic compound 482 is the actual electrolysis product, which converts to compound 478 via thermal rearrangement under loss of a phenol unit during purification of the crude products.181 A further optimization of electrolytic conditions achieved to give 482 in 52−60% yields when it was performed in Ba(OH)2/ MeOH electrolyte in combination with Pt as electrodes and a current density of 12.5 mA cm−2 (Scheme 178).

3.5. Miscellaneous

Scheme 178. Electrochemical Oxidation of 2,4Dimethylphenol

Several major types of intermolecular cyclization methods for the synthesis of heterocycles are classified and reviewed in the preceding sections. Besides, some other interesting examples involve intermolecular cyclization under electrochemical conditions are examined as follows. It is well-documented that oxidation of electron-rich cyclopropanes in the presence of dioxygen produces cyclic peroxides. Six and Buriez reported an environmentally friendly and efficient procedure for the synthesis of α-aminoendoperoxides from the electrochemical aerobic oxidation of aminocyclopropanes (Scheme 180).184 The preparative-scale electrolysis were carried out at gold grids electrodes with TBABF4 in CH3CN as supporting electrolyte in a divided cell. The potential applied was controlled at a value that corresponds roughly to the peak potential of the starting aminocyclopropane 486, which ensures

Since spiropentacyclic structure of 482 resembles the core moieties of several natural products, this electrolysis protocol is therefore used as a key-step for the generation of a variety of

Scheme 179. Electrochemical Homo-Coupling of 2,3-Dihydroxypyridine

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Scheme 180. Electrochemical Synthesis of αAminoendoperoxides

Scheme 183. Proposed Mechanism for the Synthesis of Endoperoxides 492

good yields and selectivity. During the electrolysis, 0.5 F/mol is consumed, which indicates that the process is an electronchemically initiated chain reaction. The substituent, R3, on the dioxolane ring played an important role not only in determining the stability of the product but also in directing the equilibrium between the cyclopropyl cation radical 488 and the ring-opened iminium radical 489 shown in Scheme 181. When R3 is not a Scheme 181. A Proposed Mechanism for the Electrochemical Synthesis of α-Aminoendoperoxides

leads to corresponding aminyl cation radical 493, which undergoes isomerization and ring-opening giving carboncentered radical 494. Trapping with molecular oxygen, an oxygen-centered radical 495 is formed. A 5-exo-trig cyclization with the olefinic unit followed by homogeneous electron transfer with the starting azabicyclos 491 affords the desired products 492, simultaneously regenerate the aminyl cations 493. Owing to the analogy of the synthesized endoperoxide with some of the antimalarial drugs, several of the stable products were subjected to antimalarial and cytotoxicity activity assays.186 In addition to the concerted oxirane process using electrogenerated peroxide described in section 3.2, epoxide can also be prepared from indirect electrochemical halohydrine process.187 The chemistry proceeds in an undivided cell using CH3CN/H2O (4/1) as solvent and sodium bromide as the mediator at platinum electrode (Scheme 184). It was observed that the concentration of NaBr and current density influenced the epoxidation reaction. Under the optimal conditions, the epoxidation of styrene produced the epoxide in 79% yield, together with bromohydrin (10%) and dibromo (11%) derivatives as byproducts. Other synthetic alkenes and some natural terpenes can also be epoxidized by the route in yields ranging from 23% to 79%. This NaBr-mediated epoxidation of alkenes is proposed to start from the anodic oxidation of bromine and cathodic reduction of water (Scheme 185). Subsequently, the generated molecular bromide reacts with alkene to form unstable bromonium intermediate 496, which undergoes nucleophilic addition of a hydroxide ion to form adduct bromohydrin 497. Finally, the bromohydrin consumes another hydroxide ion and produces the epoxides 498. In the above case, the bromonium ion intermediate 496 is generated by the reaction of molecular bromine and alkene. Actually, the most straightforward method to form such halonium ion intermediate can be achieved by reaction of alkene with halogen cations such as Br+ and I+. Yoshida and co-workers found that DMSO can effectively stabilize halogen cations, thereby the unstable halogen ion can be accumulated in solution

hydrogen atom, the ring-opened iminium radical 489 is more stable since the carbon-centered radical is secondary rather than primary. Besides this, due to the geometrical alignment of the bond being broken with the orbital of the aminyl cation radical, the cyclopropane undergoes a regioselective ring-opening leading exclusively to [3,3,0] rather than [3,2,1]. The mechanism probably involves a one-electron oxidation of the starting aminopropane to form aminyl cation radical 488, which undergoes ring-opening reaction with the formation of a carbon-centered iminium radical 489. Trapped by dioxygen and followed by a 5-exo-trig cyclization reaction, dioxolane cation radical 490 was generated. This species undergoes homogeneous electron transfer with the starting aminopropane to give the desired endoperoxides 487 and simultaneously regenerate the aminyl cation radical 488, thereby only catalytic amount of electricity is required to complete the transformation. On the basis of this observation, the authors expanded the electrochemical oxidation process to more complex 3-azabicyclo[4,1,0]hept-4-ene derivatives 491.185 Under similar electrolytic conditions, as shown in Scheme 182, the corresponding endoperoxides 492 were generated, although in low yields. The pathway for the formation of 492 is depicted in Scheme 183. The single-electron anodic oxidation of azabicyclos 491

Scheme 182. Synthesis of Endoperoxides from Electrochemical Oxidation of 491

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Scheme 184. Electrochemical Epoxidation of Styrene Mediated by NaBr

Benzazoles can also be synthesized electrochemically from alcohols and o-substituted anilines (Scheme 188).190 The electrochemical reaction was carried out in the presence of TFA at room temperature in CH3CN containing 0.1 M LiClO4 as supporting electrolyte using an undivided cell equipped with Pt anode and cathode under constant current conditions. It was observed that transition metal salt could promote this reaction; and CoSO4·7H2O gave the best yields. In addition, the presence of a small amount of water was beneficial to the formation of benzazoles 502. On the basis of several control experiments, cyclic voltammetrical analysis, the authors proposed a possible mechanism for the electrosynthesis of benzazoles from alcohols and osubstituted anilines. As shown in Scheme 189, benzylic alcohol is oxidized by electrochemically generated Co(III) ion to benzaldehyde, which undergoes condensation and cyclization to give benzazolines 503. Further oxidative dehydrogenation of 503 affords the desired products 502 by the combined effects of Co(III), anodic oxidation, and O2. Wang and co-workers demonstrated that oxadiazoles could be efficiently synthesized from benzoylhydrazines via anodic oxidation (Scheme 190).191 The electrochemical reaction was carried out at room temperature in MeOH containing 0.1 M KI as catalyst and supporting electrolyte using an undivided cell equipped with Pt anode and cathode under constant current conditions. With substituted benzoylhydrazines 504 as substrates, structurally diverse 2,5-disubstituted-1,3,4-oxadiazoles 505 were obtained in good yields.

Scheme 185. Proposed Mechanism for the Electroepoxidation of Natural and Synthetic Alkenes Mediated by Sodium Bromide

as a “halogen ion pools” (Scheme 186).188 Therefore, anodic oxidation of Bu4NX (X = Br, I) in DMSO/CH2Cl2 (1:9 v/v) was performed at −78 °C in a divided cell using Bu4NBF4 as supporting electrolyte to generate halogen ion which was stabilized by DMSO. After addition of alkenes, the mixture changes to β-haloalkoxysulfonium 499, which can be switched to give different products by changing the base. Treatment of 499 with sodium methoxide gave epoxides 495 in excellent yield. In this case, the methoxide ion attacks the sulfur atom and cleave the S−O bond under formation of an alkoxide ion. The latter intramolecularly attacks the carbon atom bearing the halide substituent to give epoxide. The mechanism is confirmed by control experiment using 18O-labled DMSO since the oxygen atom in the product is found to originate from DMSO. Compounds containing benzazole moiety are widely present in natural products, pharmaceutical argents, and functional materials. Therefore, efficient methods to construct the benzazole cycle are highly desired. Huang et al. reported electrochemical synthesis of 2-substituted benzimidazole via decarboxylative coupling of α-keto acids with o-phenylenediamines (Scheme 187).189 The reaction was carried out in an undivided cell equipped with Pt electrodes using DMSO/H2O containing NH4ClO4 as supporting electrolyte at room temperature. Good to excellent yields of benzazoles 501 were obtained for most of the phenylenediamines or 2-aminobenzenethiol, including substrates bearing electron-deficient and electron-rich substituents on the aromatic ring. Besides the aromatic keto acids, the aliphatic keto acids also underwent decarboxylative coupling with phenylenediamine to afford the desired benzimidazoles in moderate to good yields. Notably, the presence of trifluoacetic acid (TFA) and diisopropylethylamine (DIPEA) is necessary; lower yields of 2-phenyl benzimidazole was afforded respectively in the absence of TFA (40%) and DIPEA (48%).

4. CONCLUSION The use of electrochemical techniques in the synthesis of heterocycles has been reviewed. We restrict our investigation on the progress made since Tabaković’s review appeared in 1997, particularly after 2000. In the review, our focus is on how to use the electrochemical method to construct various heterocyclic moieties and how it achieves the target. Consequently, to some extent, the synthetic procedures to construct various cyclic structures are illustrated in most of the reactions. In addition, the possible mechanisms to form the heterocycles are discussed. Although we have not yet exhausted advances that have been made since 2000, we do try our best to include most of the important and interesting examples involving electrosynthesis of heterocycles. The above reactions demonstrate that electrochemistry has emerged as a versatile and efficient tool to construct heterocycles. Especially, with the increasing pressure of environmental problems, organic electrosynthesis is being paid increasing attention since it uses mass-free electron as reagents to achieve

Scheme 186. Epoxidation of Alkenes via “Halogen Ion Pools” Method

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Scheme 187. Electrochemical Decarboxylative Coupling of α-Keto Acids with o-Phenylenediamine or o-Aminophenthiol

Scheme 188. Electrosynthesis of Benzazoles from Alcohols and o-Substituted Anilines

Scheme 189. Proposed Mechanism for the Electrosynthesis of Benzazoles from Alcohols and o-Substituted Anilines

Notes

Scheme 190. Electrosynthesis of Oxadiazoles from Benzoylhydrazines

The authors declare no competing financial interest. Biographies Yangye Jiang obtained his bachelor’s degree from Beijing University of Technology (BJUT) in 2014 and obtained his master’s degree from the same university in 2017. Now, he is a Ph.D. student in Dr. Zeng’s group. His research mainly focuses on the development of new electrocatalytic organic reactions.

the conversion of functional group, formation, and cleavage of new chemical bonds, thereby avoiding the utilization of chemical redox reagents. On the other hand, electrochemical oxidation or reduction results in umpolung of functional groups (i.e., electron-rich groups to be electrophilic and electron-deficient group nucleophiles). This umpolung character will significantly furnish the toolbox of organic chemists to provide more opportunities in organic synthesis and especially may lead to unexpected results. Definitely, we believe that the incentives of environmentally friendly and synthetically versatile transformations will lead to expanded scope and application of organic electrochemistry in synthesis of heterocycles. Meanwhile, it is a fact that the necessity for excess amounts of supporting electrolyte constitutes a severe drawback for largescale electrosynthesis. By taking advantage of the flow chemistry, we believe that this problem will be solved in the near future.

Dr. Kun Xu obtained his Ph.D. degree from University of Science and Technology of China in 2014, supervised by Prof. Zhiyong Wang. From 2012 to 2013, he was a visiting Ph.D. student, supervised by Prof. Xumu Zhang, at Rutgers University, United States. Dr. Xu started his independent research at Nanyang Normal Univeristy as an associate professor in 2014. Now he is a postdoctoral researcher in Dr. Zeng’s group. His research mainly focuses on electroorganic synthesis. Dr. Chengchu Zeng was born in Jiangxi Province, China. He graduated from Ji’an Teacher’ College (now Jinggangshan University) in 1991, where he studied Chemistry and Biology. After working as a middle school teacher, he moved to Central China Normal University (CCNU), Wuhan, and earned his Master’s degree in Organic Chemistry in 1998 with prof. Zhao-jie Liu. He was awarded his Ph.D. degree in Organic Chemistry at Institute of Chemistry, Chinese Academy of Science (ICCAS), with Prof. Zhi-tang Huang in 2001. From 2011− 2013, Dr. Zeng worked with Prof. James Y. Becker as a postdoctoral researcher at Department of Chemistry, Ben-Gurion University in Israel. During that period, he had the opportunity to learn Organic Electrochemistry. Dr. Zeng began his independent career at BJUT in August 2003 and was promoted to Associate professor in November 2003 and full professor in 2010. He also joined Prof. R. D. Little’s group as a visiting scholar in April 2011 through August 2011. Dr. Zeng’s research interests focus on the interface of organic chemistry and electrochemistry and in particular on electrosynthesis of fine chemicals.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Chengchu Zeng: 0000-0002-5659-291X Author Contributions §

Y.J. and K.X. contributed equally to this work. 4534


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ACKNOWLEDGMENTS The authors acknowledge financial support from the National Natural Science Foundation of China (Grants 21472011, 21272021, and 20772010) and the National Key Technology R&D Program (Grant 2011BAD23B01 and 2017YFB0307502). C.C.Z. would like to sincerely thank Prof. J. Y. Becker in BenGurion University (Israel) for leading him to this special and exciting research area. Special thanks are due to Prof. R. D. Little in University of California, Santa Barbara, for continuous encouragement and spiritual support.

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Use of Electrochemistry in the Synthesis of Heterocyclic Structures

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