Chapter 1: Redox-mediated Electrochemical Cyclization Reactions

More than 90% of common organic compounds contain rings.^1,2  As a result, the search for efficient means for the construction of cyclic structures has been constantly pursued in the field of organic synthesis.

Organic electrochemistry employs electric current to drive organic synthetic reactions and is attracting renewed interest in the past decade.^3,4  Since electrons do not produce reagent-related waste and are among the cheapest reagents for chemical synthesis, organic electrochemistry holds great promise in developing green and sustainable synthetic methods.⁵  While the majority of the reported organic electrosynthetic reactions rely on direct electrolysis, indirect electrolysis with mediators has been increasingly explored, especially in the past few years.^6–9  The use of mediators not only allows the reactions to proceed under mild electrode potentials to reduce energy consumption and increase selectivity^10,11  but also significantly expands the scope of organic electrosynthesis to many redox inactive compounds through atom transfer catalysis¹²  or C–H bond activation.^13–16  In addition, electrolysis with a redox mediator allows the generation of radical intermediates in the bulk solution away from the electrode surface to avoid electrode passivation and reduce their local concentration.⁹  Key to the success of indirect electrosynthesis is the development of mediators that can function under electrochemical conditions. Efforts in the past few years have significantly expanded the list of mediators, some of which are listed in Scheme 1.1A, leading to the rapid development of indirect electrosynthesis. The mediators promote electrochemical reactions through an outer-sphere or inner-sphere mechanism (Scheme 1.1B). In the latter case, a transient adduct is formed between the mediator and substrate either after or before electron transfer on the electrode. In this context, many redox-mediated electrochemical cyclization reactions have been disclosed for the synthesis of various hetero- and carbocycles and will be the focus of this chapter (Scheme 1.1C). These reactions proceed mainly through radical or ionic cyclization to forge the ring structures.

Radical cyclization reactions are effective for the synthesis of ring structures because of the versatile reactivity of radical species and the possibility for cyclization cascades.^17,18  In this context, several redox strategies have been developed for the electrochemical generation of various heteroatom- and carbon-centered radical species. These reactive species react to form several classes of hetero- and carbocycles by cyclization onto the tethered π-systems, 1,5-hydrogen atom transfer, or intermolecular addition to alkenes or alkynes to induce cyclizations.

Nitrogen-centered radicals (NCRs) are attractive intermediates for the construction of C–N bonds.^19–22  These reactive species are commonly produced through the cleavage of a weak N–heteroatom bond.²³  The current trend is to generate NCRs from stable and easily available N–H precursors.^24–28 

The Xu group reported in 2014 an early example of redox-mediated electrochemical generation of NCRs from anilides using 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) as the mediator (Scheme 1.2A).²⁹  Mechanistically, the anilide 1d is deprotonated by hydroxide generated at the cathode and then oxidized to amidyl radical 3 via single electron transfer (SET) by anodically generated oxoammonium salt (TEMPO⁺). Intermediate 3 undergoes 5-exo-trig cyclizations to give carbon-centered radical 4, which is trapped with TEMPO to generate the final aminooxygenation product 2d. A similar aminooxygenation reaction was later achieved using a continuous flow electrochemical microreactor by Wirth and coworkers.³⁰  Although the use of TEMPO as the mediator limits the reaction to aminooxygenation,³¹  this work proves that redox catalysis can be an effective strategy in developing electrochemically driven radical reactions. Importantly, the electrode potentials needed for these mediated electrochemical reactions are much lower than those for the anilide substrates. In addition, the continuous generation of the requisite base at the cathode to promote the oxidation reaction obviates the need to add stoichiometric strong bases and avoids base-induced side reactions.

The Xu group then went on to develop several new catalytic systems for the oxidative generation of NCRs from anilides employing ferrocene (Cp₂Fe), cobalt salen complex 5, tetraarylhydrazine 6, or phenothiazine 7 as the catalysts (Scheme 1.2B).²⁶  All these mediators catalyze the anilide oxidation through outer-sphere electron transfer except for 5, which oxidizes the anilides through inner-sphere electron transfer.³²  These electrophilic NCRs generated under the electrocatalytic conditions undergo monocyclization or cyclization cascades onto tethered alkenes (Scheme 1.3A–C)^33–35  or alkynes (Scheme 1.3D–E)^36–38  to form several types of useful N-heterocycles. Note that ferrocene is not a good catalyst for anilide oxidation in aqueous solutions because of its reduced stability and oxidation potential in these solvents. As a result, organic mediators such as 7 or 6 are used for the cyclizations of 12 and 24, respectively.^34,38  The use of redox catalysis allows the formation of heterocyclic products that are oxidized at lower potentials than the starting anilides. Direct electrolysis can also be employed to promote NCR formation and cyclizations but often requires an increase in oxidation potential from substrate to product.^39–42  Otherwise, further oxidation of the product can occur.⁴³ 

Aza-Wacker-type cyclization reactions, which are commonly achieved with Pd-catalysis, are attractive transformations for the preparation of N-heterocycles.⁴⁴  To expand the scope of these types of cyclization reactions and avoid the use of noble metals, several alternative methods based on radical cyclizations have been developed.^32,45–49  For example, the Xu group has developed radical-based aza-Wacker-type cyclization reactions of anilides employing Cu-catalysis in the presence of stoichiometric hypervalent iodide as the terminal oxidant.⁴⁵  The same group has also developed similar types of cyclization reactions through direct electrolysis without using any catalysts or external chemical oxidants.^46,47  While these transformations are effective for the cyclization of various unactivated alkenes, relatively high electrode potentials are needed to generate the radical intermediates. Hu and coworkers have developed electrochemical aza-Wacker-type cyclizations of anilides employing a catalytic amount of Cu(ii) salt as the mediator.⁵⁰  These reactions are conducted in a divided cell to avoid the cathodic reduction of the Cu(ii) salt to copper. The Xu group has recently achieved cobalt-catalyzed electrochemical aza-Wacker-type cyclizations of various di-, tri-, and tetrasubstituted alkenes in an undivided cell (Scheme 1.4).³²  Besides function as an electron transfer mediator for amidyl radical formation, the cobalt catalyst (5) also serves as a hydrogen atom transfer agent to convert the carbon radical 32 to the alkene product. The low oxidation potential of the cobalt-based catalyst ensures high functional group tolerance of the electrocatalytic method. Other easily oxidized nucleophiles such as sulfonyl hydrazine (29f) and oxime (29e) are also suitable for electrocatalytic cyclization. The oxidation of oximes produces iminoxy radicals that are reactive to both oxygen and nitrogen atoms.⁵¹  The electrocatalytic oxidation of oximes to iminoxy radicals can also be accomplished with TEMPO as the catalyst.⁵² 

Halides are widely employed mediators for organic electrosynthesis and have been utilized for the generation of NCRs from acidic amides or sulfonamides.^53–55  The anodic oxidation of iodide and bromide generates the corresponding dihalogen, which reacts with the nitrogen anions to produce N–halogen species (Scheme 1.5). These intermediates are converted to NCRs through the cleavage of the N–halogen bond facilitated by heating, cathodic reduction, or light irradiation.

Chen and coworkers have reported that the electrolysis of N-aryl sulfonamide 33 in the presence of a catalytic amount of iodide-afforded carbazole 35 (Scheme 1.6A).⁵⁶  On the other hand, Zheng and coworkers have disclosed that the electrooxidation of N-acetoxy amide 36 with 1 equiv. of NaBr as the mediator produces phenanthridinone 38 via NCR cyclization (Scheme 1.6B).⁵⁷  The less acidic N-alkyl amide (36b) fails to afford any desired cyclization product. For both reactions, the C–N bond is formed through cyclization of NCRs onto the tethered benzene ring. Analogous electrochemical cyclization reactions have also been achieved with other mediators such as aryliodides⁵⁸  and Pd⁵⁹  or through direct electrolysis.^60,61 

Shono and coworkers have shown in the late 1980s that the electrolysis of N-alkyl tosylamides upon heating with substoichiometric KBr or KI as the mediator and Pt electrodes promotes Hofmann–Loffler–Freytag-type cyclizations to produce pyrrolines.⁶²  The Rueping group has recently reported that these useful transformations can be conducted under basic conditions at rt with 2 equiv. of KBr as the mediator and graphite and stainless steel as the anode and cathode, respectively (Scheme 1.7A).⁶³  Notably, the reaction has been scaled up to gram and decagram scale using batch reactors or a continuous flow microreactor. Since iodide is oxidized at a lower potential than bromide, the use of iodide as the mediator can increase functional group tolerance. But the homolytic cleavage of the N–I bond is more difficult than that of the N–Br bond. To address this issue, Stahl and coworkers have developed a photoelectrochemical method by merging electrochemistry with photochemistry to accomplish iodide-mediated dehydrogenative cyclization of 45 in the absence of bases (Scheme 1.7B).⁶⁴  Here, the intermediate N–I species 47 undergoes photoassisted bond fission at rt to generate the key NCR 48. The photoelectrochemical method^65–67  is also suitable for the cyclization of imidates (51). Similar electrochemical C–H amination reactions without mediators are also known.^68,69 

In analogous to anilides, N-aryl thioamides are oxidized electrocatalytically with TEMPO as the catalyst to produce thioamidyl radicals (Scheme 1.8).⁷⁰  But these reactions are suggested to proceed through an inner-sphere pathway to produce the key radical intermediate 55. The weak S–O bond of the adduct 54 allows its homolytic cleavage at rt. Unlike the anilide-derived NCR, which reacts on the nitrogen atom, thioamidyl radicals such as 55 undergo cyclization reactions on the sulfur atom. The cyclization reactions of thioamides can also be achieved in the absence of mediators in batch⁷¹  or continuous flow electrochemical microreactors^72–74  but require higher electrode potentials.

While P-centered radicals have been extensively studied for the synthesis of organophosphorus compounds,^75–77  electrochemical methods for the generation of these intermediates have remained underdeveloped.⁷⁸  Suga and Mitsudo and coworkers reported an electrosynthesis of five- and six-membered phosphacycles with DABCO (1,4-diazabicyclo[2.2.2]octane) as the mediator via phosphinyl radical cyclization (Scheme 1.9). The anodic oxidation of DABCO produces amine radical cation 58, which abstracts a hydrogen atom from diarylphosphine oxide 56a to generate P-centered radical 59. The latter undergoes cyclization and rearomatization to generate the final phosphacycle 57a.

Redox catalysis is also an effective strategy for the electrochemical oxidation of 1,3-dicarbonyl carbon compounds to electrophilic carbon-centered radicals.^32,79–82  Like the electrocatalytic generation of NCRs from anilides, deprotonation of the acidic C–H precursor with base generated at the cathode produces carbanions that can be oxidized by the catalyst to carbon-centered radicals (Scheme 1.10A). This method has been applied for the synthesis of 3-fluorinated 2-oxoindoles 62 through the dehydrogenative cyclization of malonate amides 61 (Scheme 1.10B).⁷⁹  3-Alkyl 2-oxoindoles are also accessible with this strategy under modified conditions.⁸⁰  Cobalt salen complex 68 has been employed as a catalyst by the Xu group for the intramolecular allylic alkylation reactions (Scheme 1.10C). The electrocatalytically generated carbon-centered radical 66 undergoes cyclization onto the tethered alkene to generate alkyl radical 67. The latter loses an H atom to the Co(ii) catalyst to produce the alkene product 65. Note that these types of cyclizations are traditionally achieved with stoichiometric metal salts such as Cu(OAc)₂ and Mn(OAc)₃.⁸³ 

Radical addition to alkynes and alkenes generates new carbon-centered radicals, which can undergo cyclizations with appropriately positioned π-systems. The Xu group has reported that difluoromethylsulfonylhydrazine 70 is an easily available precursor for difluoromethyl radical (Scheme 1.11).^84,85  The electrochemical oxidation of difluoromethylsulfonylhydrazine 70 with ferrocene as the catalyst generates difluoromethyl radical through oxidative dehydrogenation to diazene 75 followed by its decomposition. The addition of difluoromethyl radical to alkyne 69 initiates a radical cascade cyclization to produce fluorinated dibenzazepine 71.

Indirect electrolysis of sulfinic acids or sulfinates with bromide or iodide as a mediator generates sulfonyl radicals through inner-sphere electron transfer.⁸⁶  The sulfonyl radicals can add to alkenes and alkynes or undergo C–S bond scission to release SO₂ and generate CF₃ radical in the case of trifluoromethylsulfonate. For example, the Lei group has reported an iodide-mediated electrochemical synthesis of sulfonated indenones 78 via the addition of aryl/alkyl sulfonyl radicals to alkynones 76 (Scheme 1.12A).⁸⁷  Mechanistic experiments revealed that stoichiometric oxidants such as N-chlorosuccinimide (NCS) can also promote the same reaction but not I₂. Based on these observations, the authors propose that iodide is oxidized on the anode to generate I⁺, which promotes the oxidation of sulfinic acid 77a to sulfonyl radical 79. The addition of this radical to alkynones 76a followed by cyclization and rearomatization generates the indanone product 78a. On the other hand, Zeng and coworkers have shown that electrochemically generated bromine reacts with aryl and alkyl sulfinates 84 to generate the sulfonyl bromide 86, which undergoes heat-induced homolytic bond scission to generate sulfonyl radical 87 (Scheme 1.12B).⁸⁸  The addition of 87 to acrylate amides 83 generates sulfonated 2-oxoindoles 85. The use of sodium trifluoromethylsulfonate 91 (Langlois reagent) produces trifluoromethylated 2-oxoindoles 92 (Scheme 1.12C). This latter reaction has also been achieved with MnBr₂ as the mediator by Mo and coworkers.⁸⁹ 

The Lin group has developed a series of Mn-catalyzed electrochemical transformations employing easily available heteroatom and carbon nucleophiles as the radical precursors.⁹⁰  In one example, they achieved the electrocatalytic synthesis of chlorotrifluoromethylated pyrrolidines 94 by cyclization of enyne 93 (Scheme 1.13).⁹¹  Here, CF₃SO₂Na and [Mn^II]–Cl are oxidized on the anode to generate CF₃ radical and [Mn^III]–Cl. Regioselective addition of CF₃ radical to the alkene moiety of 93 followed by cyclization produces vinyl radical 96. The latter reacts with [Mn^III]–Cl to produce the final pyrrolidine product.

Manganese salt has also been employed to promote the cyclization of N-substituted 2-arylbenzoimidazoles 97 by Lei and coworkers (Scheme 1.14).⁹²  They propose that anodic oxidation of alkylboronic acids 98a generates alkyl radical 100, which reacts with Mn^II to produce Mn^III complex 101. The latter reacts with 97a to initiate radical cyclization to ultimately generate the cyclized product 99a.

Anodically generated electrophilic halogen species have been employed for the promotion of ionic cyclizations of alkenes, ketones, and arenes. Hypervalent iodine species, which are common reagents in organic synthesis, can be generated in situ through anodic oxidation of iodobenzenes.^93–96 

Zeng and coworkers have reported that electrolysis of 2-vinylanilide 104 in alcoholic solvents in the presence of 0.5 equiv. of nBu₄NI produced indoline 105 (Scheme 1.15A). The cyclization of the iodonium intermediate 106 to generate 3-iodoindoline 107 is proposed as the key step for this process. Analogous electrochemical cyclization reactions have been reported by Wang and coworkers for the synthesis 3-azido (109)⁹⁷  and 3-aminoindolines (111)⁹⁸  (Scheme 1.15B).

Anodic oxidation of iodobenzenes in the presence of Et₃N·xHF (x = 3 or 5) generates the corresponding difluoroiodobenzenes.⁹⁹  Waldvogel and coworkers employed 4-iodotoluene 114 as the mediator to promote the fluorocyclization of N-allylcarboxamides 112 to 2-oxazolines 113 (Scheme 1.15C).¹⁰⁰  The authors proposed that the difluoroiodotoluene 115 generated on the anode reacted with the alkene moiety of 112a to produce iodonium species 116, which cyclized on the amidyl oxygen atom to afford hypervalent iodine species 117. The latter was converted into the final oxazoline product after nucleophilic substitution with fluoride.

Vincent and coworkers have developed an electrochemical halocyclization of tryptamine, tryptophol, and tryptophan derivatives 118 for the synthesis of 3-haloindolines 119 with MgBr₂ or MgCl₂ as the halogen sources (Scheme 1.15D).¹⁰¹  The mechanism for the bromination reaction involves the cyclization of the bromonium intermediate 120, which is generated through the reaction of the indoline moiety with Br⁺ generated on the anode. Similar transformations have been disclosed by Lei and coworkers but with lithium halides as the mediators.¹⁰² 

Electrochemically generated I₂ reacts with ketones to produce α-iodoketones, which can undergo intramolecular substitution reaction with an appropriately positioned nucleophile. For example, Xu, Zhang, and Tan and coworkers have reported the iodide-mediated electrochemical dehydrogenative cyclizations of ketoacids 121 (Scheme 1.16A)¹⁰³  and ketoamides 124 (Scheme 1.16B)¹⁰⁴  for the synthesis of lactones 122 and 2-oxazolines 125, respectively. α-Iodoketones 123 and 126 are proposed as the key intermediates for these cyclization reactions. Interestingly, ketones 127 that bear a carbamate group at the β-position produce aziridines 128 as the final products (Scheme 1.16C).¹⁰⁵  Here, the reactions are proposed to proceed through the cyclization of N–I species 129.

The past few years have witnessed tremendous progress in mediated electrosynthesis. The application of this strategy in cyclization reactions has led to the development of exciting methodologies for the preparation of various heterocycles and carbocycles. The development of new redox mediators and the discovery of new mechanisms for the mediated activation of small molecules have significantly expanded the scope of electrosynthesis in ring constructions. Most of these electrochemical transformations are oxidative reactions but do not require stoichiometric sacrificial chemical oxidants, providing sustainable entries into ring structures. Future efforts in expanding the repertoire of mediators will further increase the synthetic utility of electrochemistry in promoting cyclization reactions.

The authors acknowledge the financial support of this research from NSFC (No. 21971213) and Fundamental Research Funds for the Central Universities.