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Synthesis 2023; 55(18): 2911-2925
DOI: 10.1055/a-2039-1728
short review
Special Issue Electrochemical Organic Synthesis

Recent Advances in Electrochemical Cascade Cyclization Reactions

Cai Zhang∗
a   Department of Safety Supervision and Management, Chongqing Vocational Institute of Safety Technology, Wanzhou District, Chongqing 404020, P. R. of China
,
Demao Chen
b   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. of China
,
Jie-Ping Wan
b   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. of China
c   International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, P. R. of China
,
Yunyun Liu∗
b   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. of China
c   International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, P. R. of China
› Author Affiliations

This study has been supported by the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202104705), Human and Social Sciences Research Planning Project of Chongqing Municipal Education Commission in 2021 (21SKGH383).
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Abstract

This review highlights recent progress in electrochemical cascade cyclization reactions for the synthesis of carbon rings and heterocycles, such as pyridines, quinolines, phenanthridines, cinnolines, 1,4-dihydroquinolines, oxindoles, imidazo[1,5-α]pyridines, imidazoles, etc. The works included herein are introduced in two major sections of heterocycle construction and carbocycle construction reactions, covering the works reported from 2012 to 2022.

1 Introduction

2 Electrochemical Cascade Cyclization for the Synthesis of Heterocycles

2.1 Synthesis of Pyridines, Quinolines, Phenanthridines, and Cinnolines

2.2 Synthesis of 1,4-Dihydroquinolines, Hexacyclic Sulfonamides, and Thiazines

2.3 Synthesis of Hydroisoquinolinones and Hydroquinolinones

2.4 Synthesis of Quinazolin-4(3H)-ones

2.5 Synthesis of 4H-3,1-Benzoxazines

2.6 Synthesis of Oxindoles

2.7 Synthesis of Indolines and Indoles

2.8 Synthesis of Imidazo[1,5-α]pyridines and Imidazoles

2.9 Synthesis of Imidazolones, Imidazolidinones, Oxazolones, and Oxazolidinones

2.10 Synthesis of Benzoxazoles, Oxazolines, and Isoxazolines

2.11 Synthesis of Furans and Dihydrofurans

2.12 Synthesis of Indolizines, Pyrazoles, and Triazolium Inner Salts

2.13 Synthesis of Sulfonated Benzothiophenes, Thiazoles, Dihydrothiazoles, and 1,3,4-Thiadiazoles

2.14 Synthesis of Lactones

3 Electrochemical Cascade Cyclization for the Construction of Carbocycles

3.1 Synthesis of Carbon Polycycles and Spiroindenes

3.2 Synthesis of Difluoroacyl (Hetero)arenes and Sulfonated Indenones

4 Conclusion


#

Key words

electrochemical - cascade cyclization - heterocycle - carbocycle - green synthesis
1

Introduction

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Cai Zhang was born in Anhui Province, P. R. of China. He received his BSc degree from Huaibei Normal University (P. R. of China) in 2005, and obtained his M.Sc. degree at Southwest University, Chongqing, P. R. of China, in 2009. From 2009 to 2013, he conducted Active Pharmaceutical Ingredient (API) research, such as cholesterol absorption inhibitors, antiplatelet drugs, and antidiabetic drugs at pharmaceutical enterprises. In 2013, he moved to Chongqing Vocational Institute of Safety Technology, where he is engaged in teaching and scientific research. His current research interests focus on the development of novel synthetic methodologies, such as hypervalent iodine reagents for application in organic synthesis, C–H bond activation, total synthesis of natural products, and fluorine chemistry. Demao Chen was born in 1995 in Jiangxi Province, China. He obtained his Master’s degree from Qingdao Agricultural University in July 2021 under the supervision of Dr. Zuli Wang. He is currently studying as a Ph.D. student in the College of Chemistry and Chemical Engineering, Jiangxi Normal University under the guidance of Prof. Dr. Jie-Ping Wan. His present research interest in new synthetic methods and application of stable enamines. Prof. Dr Jie-Ping Wan studied chemistry during 2000–2004 in the Department of Chemistry, Nanchang University. After obtaining his B.Sc. degree in 2004, he moved to the Department of Chemistry, Zhejiang University in 2005 for postgraduate study under the guidance of Prof. Yuanjiang Pan. After receiving his Ph.D. degree therein in 2010. He joined the College of Chemistry and Chemical Engineering, Jiangxi Normal University as an assistant professor in the same year, and was promoted to full professor in 2017. He conducted postdoctoral research in RWTH Aachen University with Prof. Dieter Enders from Sept. 2011 to Aug. 2012. Dr. Wan has won the honor of the Thieme ­Chemistry Journal Award in 2014. His current research interests are ­diversity-oriented synthesis, discovery and application of platform ­synthons, and sustainable catalysis and synthesis. Dr. Yunyun Liu was born in Shandong Province, China. She obtained her B.Sc. degree from Qufu Normal University in 2005. She then moved to Zhejiang University to continue her postgraduate studies in the Department of Chemistry under the supervision of Prof. Weiliang Bao wherein she obtained her Ph.D. degree in 2010. Dr. Liu joined to the College of Chemistry and Chemical Engineering, Jiangxi Normal University as assistant professor in 2010, and was promoted to associate professor in 2013. She is currently interested in the research of metal-catalyzed organic synthesis and sustainable catalysis.

In the past decade, electrochemistry has gradually developed as a promising and powerful alternative to traditional organic synthesis.[1] As a green method, electrochemical synthesis is characterized by environmental friendliness, economy, minimum chemical consumption, and low byproduct output.[2] With this highly selective, relatively mild and tolerant electrochemical route, the use of many conventional chemical reagents such as metal catalysts, oxidants, etc. can be avoided.

Carbocycles and heterocycles are fundamental and ubiquitous structures in natural products, bioactive molecules, and related compounds in medicine[3] and a plethora of cyclization strategies, such as oxidative cyclizations,[4] carbonylative cyclizations,[5] radical cyclizations,[6] [4+2] cyclization,[7] etc., have been developed and applied to the construction of different carbon rings and heterocycle structures. Cascade reactions, which enable product formation via multiple chemical bond transformations, also constitute a pivotal tool in numerous ring formation reactions.[8] Following the requirement in developed synthetic methods with enhanced sustainability, electrochemically promoted cascade cyclization has emerged as a popular and reliable tool in the areas of cyclic molecule synthesis. This review is concerned with recent advances in electrochemical cascade cyclization reactions for the synthesis of both carbocyclic and heterocyclic compounds from 2012 to 2022 (Scheme [1]).


# 2

Electrochemical Cascade Cyclization for the Synthesis of Heterocycles

2.1

Synthesis of Pyridines, Quinolines, Phenanthridines, and Cinnolines

Effective syntheses of chromeno[2,3-b]pyridines 3 (2014)[9] and bis-pyrazolo[3,4-b:4′,3′-e]pyridines 6 (2022)[10] containing a pyridine ring were realized by the electrochemical promoted cascade cyclization reactions of two components (Scheme [2]). The experimental results showed that the electrocatalytic reactions between salicylaldehyde 1 and three molecules of malononitrile 2 in the presence of NaBr afforded chromeno[2,3-b]pyridines 3 in 83–90% yields.[9] The electrochemically promoted cyclization reactions of aromatic aldehydes 4 with pyrazol-5-amines 5 furnished bis-pyrazolo[3,4-b:4′,3′-e]pyridines 6 in 11–77% yields.[10]

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Scheme 1 Electrochemical cascade cyclization reactions
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Scheme 2 Electrochemical cascade cyclization for the synthesis of pyridines
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Scheme 3 Electrochemical cascade cyclization reactions for the synthesis of quinolines, phenanthridines, and cinnolines

Quinoline, phenanthridine, and cinnoline moieties are two of the most common heterocyclic compounds in many natural products and pharmaceutically active compounds.[11] Based on the importance of these blocks, from 2019 to 2022, the electrochemical synthesis of quinolines, phenanthridines, and cinnolines was developed via electrochemical cascade cyclization reactions by the groups of Sharma,[12] Liu and Sun,[13] Kong and Xu,[15] Lei and Gao,[16] Ackermann[17] Wen and Zhang,[18] and Liu and Guo[19] (Scheme [3]). The electrochemical coupling cyclization of 2-isocyanobiphenyls 8 with amines 7 [12] or the decarboxylative cyclization of α-aminooxy acids 10 [13] afforded phenanthridines 9 or 11. As an important organic fluorine reagent,[14] CF3SO2Na reacted with vinyl azides 12 in MeCN/H2O (10:1) in the presence of LiClO4 under the promotion of electrochemistry to give phenanthridines 13 in up to 63% yield.[15] In acetonitrile, three-component, electrochemically promoted cascade cyclization of isatins 14, alkynes 15, and alcohols 16 delivered 40–81% yields of quinolines 17.[16] Aza-polycyclic aromatic hydrocarbons 20 were obtained in 57–94% yields from the rhoda-electrocatalyzed cascade cyclization between amidoximes 18 and diphenylacetylene (19) in the presence of KOAc and AcOH in CH3OH at 35 °C.[17] The electrochemical cascade reactions of benzoxazinones 21 with arenesulfonyl hydrazides 22 directly generated 2-aryl-3-sulfonyl-substituted quinolines 23 with excellent regioselectivity in 31–87% yields.[18] Interestingly, when benzoxazinones 21 were replaced by alkynes 24, the reaction system gave cinnolines 25 in 54–79% yields in a two-step reaction.[19]

Xu, Kong, and co-workers provided a plausible reaction mechanism for the synthesis of 2,2,2-trifluoroethylated phenanthridines 13 (Scheme [4]).[15] First, CF3SO2Na is electrochemically anodized to give the CF3SO2 radical, which rapidly decomposes into SO2 and a CF3 radical A. Then, the CF3 radical A is captured by azide 12 and nitrogen is released to afford iminyl radical B, which cyclizes rapidly to intermediate C. Finally, intermediate C is anodized to cation D, which loses a proton and further generates phenanthridine 13.

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Scheme 4 A plausible mechanism for the synthesis of trifluoroethyl-substituted phenanthridines

Wen, Zhang, and co-workers proposed a possible mechanism of electrochemical cascade cyclization for the synthesis of 2-aryl-3-sulfonyl-substituted quinolines 23 (Scheme [5]).[18] Nitrogen radical A derived from arenesulfonyl hydrazide 22 through an electrochemical anodic oxidation process releases nitrogen to produce sulfonyl radical B, which reacts with benzoxazinone 21 to form intermediate C. Subsequently, intermediate C releases a proton and is cyclized to compound D, which finally generates quinoline 23 through a decarboxylation process.


# 2.2

Synthesis of 1,4-Dihydroquinolines, Hexacyclic Sulfonamides, and Thiazines

The electrochemical synthesis of 1,4-dihydroquinolines 27, hexacyclic sulfonamides 29, and thiazines 31 through cascade cyclization was described by the research groups of Xu (2017),[20] Liao (2020),[21] and Sarkar (2021),[22] respectively (Scheme [6]). In the presence of Na2CO3 and catalyst Cp2Fe, the electrochemical cyclization of diynes 26 occurred in MeOH/THF (1:1) to generate 1,4-dihydroquinolines 27 in up to 82% yield.[20] Hexacyclic sulfonamides 29 were obtained in up to 64% yield depending on an electrochemical trifluoromethylation/SO2 insertion/cyclization process between N-aryl cyanamides 28 and CF3SO2Na in the presence of Bu4NBF4 using DCM/H2O (5:1) as the solvent.[21] The electro-oxidative cyclization between 2-(allylsulfanyl)benzimidazoles 30 and PhSeSePh delivered dihydro-benzimidazo[1,3]thiazines 31 in 81–96% yields.[22]

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Scheme 5 A plausible mechanism for the synthesis of 2-aryl-3-sulfonyl-substituted quinolines
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Scheme 6 Electrochemical cascade cyclization for the synthesis of 1,4-dihydroquinolines, hexacyclic sulfonamides, and thiazines
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Scheme 7 Electrochemical cascade cyclization for the synthesis of hydroisoquinolinones and hydroquinolinones

# 2.3

Synthesis of Hydroisoquinolinones and Hydroquinolinones

Hydroisoquinolines and hydroquinolinones exist widely in natural products and drug molecules,[23] showing potential biological activity. From 2019 to 2021, the electrochemical cascade cyclizations for the synthesis of hydroisoquinolinones and hydroquinolines, such as benzimidazo[2,1-a]isoquinolinones and indolo[2,1-a]isoquinolinones 34–37, isoquinoline-1,3-diones 39, and quinolinones 41, was successfully developed (Scheme [7]).[24] [25] [26] [27] [28] The electrochemical tandem cyclization of N-methacryloyl-2-arylbenzimidazole 32 and RB(OH)2 33 in the presence of Mn(OAc)3·2H2O in MeCN gave benzimidazo[2,1-a]isoquinolinones 34 in 52–80% yields.[24] Interestingly, electrochemical tandem cyclization of 2-aryl-N-acryloylindoles 35 and ArSO2NHNH2 in the presence of KI with THF/H2O (3:1) as the solvent gave sulfonyl-substituted indolo[2,1-a]isoquinolinones 36 in 25–76% yields,[25] while replacing KI with KBr in the absence of ArSO2NHNH2 gave brominated indolo[2,1-a]isoquinolinones 37 in 57–70% yields.[25] The electrochemical trifluoromethylation/cyclization of N-methacryloyl-benzamides 38 using CF3SO2Na or IMDN-SO2CF3 as the CF3 source in the presence of MnBr2·4H2O/H3PO4 or nBu4NBF4 provided trifluoromethyl dihydroisoquinoline-1,3-diones 39 in 41–69% or 38–78% yields.[26] [27] An effective electro-oxidative cascade azidation and cyclization of N-aryl-cinnamamides 40 catalyzed by MnBr2 in the presence of LiClO4 furnished quinolinones 41 in 49–83% yields.[28]

A plausible mechanism for the synthesis of sulfonyl-substituted indolo[2,1-a]isoquinolines 36 was proposed by Yang, Xia, and co-workers (Scheme [8]).[25] First, two iodide anions are anodized into molecular iodine, which can oxidize ArSO2NHNH2 to give ArSO2I A, with the release of nitrogen and hydrogen iodide. Compound ArSO2I rapidly decomposes into an iodine radical and arylsulfonyl radical B, which adds to the C=C of 2-aryl-N-acryloylindole 35 to give radical C. Then, radical C undergoes a 6-endo-trig cyclization process to afford radical D, which is oxidized by molecular iodine to give cationic intermediate E. Finally, intermediate E is protonated to form sulfonyl-substituted indolo[2,1-a]isoquinoline 36.

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Scheme 8 A plausible mechanism for the synthesis of sulfonyl-substituted indolo[2,1-a]isoquinolines

# 2.4

Synthesis of Quinazolin-4(3H)-ones

Quinazolin-4(3H)-one scaffolds 45 widely exist in natural products such as deoxyvasicinone, rutaecarpine, tryptanthrin, piriqualone, etc., which show potential antibacterial, anti-infective, anti-inflammatory, and antitumor properties.[29] Based on this, effective methods for the construction of quinazolin-4(3H)-ones have been developed.[30] An effective synthesis of quinazolin-4(3H)-ones 45 from the electro-oxidative tandem cyclization reactions between o-aminobenzamides 42 and aldehydes 43 or alcohols 44 was described by the research groups of Lu and Gong (2018),[31] Huang (2019),[32] and Sun and Ke (2021)[33] (Scheme [9]). The electrochemically promoted reactions of o-aminobenzamides 42 and aldehydes 43 catalyzed by p-TsOH·H2O in Bu4NClO4/MeCN solution (0.1 M) at room temperature afforded quinazolin-4(3H)-ones 45 in 15–88% yields.[31] Interestingly, when alcohols 44 replaced aldehydes 43 as reactants and 10 mol% TEMPO was added to similar reaction system, quinazolin-4(3H)-ones 45 were obtained in 25–90% yields.[31] In addition, in the presence of MnSO4·H2O/­LiClO4/TFA or K2S2O8, o-aminobenzamides 42 and alcohols 44 were converted into quinazolin-4(3H)-ones 45 with 50–90% or 54–95% yields, respectively.[32] [33]

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Scheme 9 Electrochemical cascade cyclization for the synthesis of quinazolin-4(3H)-ones
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Scheme 10 A plausible mechanism for the synthesis of quinazolin-4(3H)-ones

Huang and co-workers proposed a possible reaction mechanism for the synthesis of quinazolin-4(3H)-ones 45 (Scheme [10]).[32] First, Mn2+ is oxidized by the anode to give Mn3+, which oxidizes alcohol 44 to aldehyde 43. Then, an addition reaction between aldehyde 43 and o-aminobenzamide 42 affords intermediate A, which is cyclized rapidly to 2,3-dihydroquinazolinone B with the loss of H2O. Finally, 2,3-dihydroquinazolinone B is oxidized by Mn3+ to deliver quinazolin-4(3H)-one 45.


# 2.5

Synthesis of 4H-3,1-Benzoxazines

The 4H-3,1-benzoxazine skeleton, which widely exist in many drugs and natural products, has been effectively constructed by a large number of methods.[34] The effective synthesis of 4H-3,1-benzoxazines 48 and 51 (48: up to 76% yield, 51: 12–83% yields) was accomplished through electrochemical radical cascade cyclization of N-(2-vinylphenyl) amides 46 with arenesulfonyl hydrazides 47 and mercaptans 49 or disulfides (diselenides) 50 by the groups of Huang (2020)[35] and Lu and Lei (2021),[36] respectively (Scheme [11]).

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Scheme 11 Electrochemical cascade cyclization for the synthesis of 4H-3,1-benzoxazines
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Scheme 12 A plausible mechanism for the synthesis of 4H-3,1-benzoxazines

A possible mechanism for the electrochemical tandem sulfonylation/cyclization of N-(2-vinylphenyl) amides 46 and arenesulfonyl hydrazides 47 is showed in Scheme [12].[35] First, ArSO2 radical B is obtained from the oxidation of ArSO2NHNH2 47 by the anode. Then, ArSO2 radical B is captured by N-(2-vinylphenyl) amide 46 to give radical intermediate C, which is further oxidized by the anode to afford carbon cation D. Finally, cation D undergoes intramolecular nucleophilic attack and deprotonation to generate 4H-3,1-benzoxazine 48.


# 2.6

Synthesis of Oxindoles

Because oxindole motifs are widely present in many natural products and drugs and show potential biological activity, the functionalization and synthesis of oxindole scaffolds has aroused great interest in synthetic organic chemists.[37] Electrochemical tandem cyclization methods for the effective synthesis of oxindoles 53, 55, and 58 have also emerged (Scheme [13]).[26] [27] [28] , [38] [39] The oxidant-free electrochemical cascade trifluoromethylation/cyclization of N-phenylmethacrylamides 52 using CF3SO2Na in the presence of MnBr2·4H2O/H3PO4,[26] IMDN-SO2CF3 in the presence of nBu4NBF4,[27] or CF3SO2NHNHBoc in the presence of Et4NOTs[28] furnished trifluoromethyl-substituted oxindoles 53 in 30–83%, up to 67%, or 57–82% yields, respectively. Using N-phenylmethacrylamides 54 and replacing the trifluoromethylation reagent by NaN3 in a similar reaction system generated azide-substituted oxindoles 55 in 56–79% yields[28] while N-phenylmethacrylamides 56 and R4SeSeR4 57 gave selanyl-substituted oxindoles 58 in up to 93% yield.[39]

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Scheme 13 Electrochemical cascade cyclization for the synthesis of oxindoles

Pan and co-workers proposed a reaction mechanism for the synthesis of selanyl oxindoles 58 (Scheme [14]).[39] First of all, R4SeSeR4 57 is oxidized by the anode and rapidly decomposes into a R4Se radical A and R4Se cation B. Subsequently, the R4Se radical A adds to N-phenylmethacrylamide 56 to give radical intermediate C, which undergoes an intramolecular cyclization process to produce intermediate D. Finally, anodic oxidation of intermediate D gives cation E, which loses a proton and further generates selanyl-substituted oxindole 58.

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Scheme 14 A plausible mechanism for the synthesis of selanyl-substituted oxindoles
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Scheme 15 Electrochemical cascade cyclization for the synthesis of indolines and indoles

# 2.7

Synthesis of Indolines and Indoles

An efficient electrochemical cascade cyclization strategy for the synthesis of indolines and indoles was described by the groups of Zeng and Sun (2016)[40] and Huang (2022)[41] (Scheme [15]). The intramolecular amino-oxygenation of N-(2-vinylphenyl)sulfonamides 59 was performed in alcohol R2OH using n-Bu4NI as a redox catalyst in the presence of LiClO4 to afford the corresponding indolines 60 in 28–78% yields.[40] Huang and co-workers showed that reactions between 2-ethynylanilines 61 and arylamines 62 using 1.2 mA current with TEMPO and TBAI as the catalyst in the presence of LiClO4 at room temperature gave 2,3-diimino indolines 63 in 29–91% yields.[41] Interestingly, when the current of 1.2 mA was changed to 5 mA, the reaction system gave diamino indoles 64 in 41–75% yields.[41]

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Scheme 16 Electrochemical cascade cyclization for the synthesis of imidazo[1,5-a]pyridines and imidazoles

# 2.8

Synthesis of Imidazo[1,5-a]pyridines and Imidazoles

Imidazolo[1,5-a]pyridines are fused N-heterocyclic skeletons that are widely found in drugs.[42] In recent years, many synthetic methods have been developed to construct these compounds.[43] From 2018 to 2022, electrochemically promoted cyclization cascade reactions were also applied to the synthesis of imidazo[1,5-a]pyridines and imidazoles (Scheme [16]).[44] [45] [46] [47] [48] [49] [50] [51] The intramolecular electrochemical (3+2) cyclization reactions of pyridylamines with tethered internal alkynes 65 catalyzed by 66 in the presence of NaHCO3 and Et4NBF4 generated imidazo[1,5-a]pyridines 67 in up to 96% yield.[44] [45] Electrochemically promoted C–N formation/cyclization reactions between ketones 68 and pyridylamines 69 using HI as the redox mediator produced imidazo[1,5-a]pyridines 70 in moderate to excellent yields of 20–99%.[46] Likewise ketones 71 and pyridylamines 72 with NH4I as the redox mediator gave imidazo[1,5-a]pyridines 73 also in moderate to excellent yields of 31–90%.[47] NH4I-mediated tandem electrocyclizations of quinolines (or pyridines) 74 with amines 75 or amino acids 76 in an undivided cell at a constant current density of 15 mA/cm2 gave 1,3-disubstituted imidazo[1,5-a]quinolines 77 in up to 99% yield.[48] Interestingly, when both the reactants ketones 78 and amines 79 did not contain pyridine ring, the similar reaction system provided up to 95% or 62–81% yields of imidazoles 80.[49] [50] Three-component electrochemically promoted tandem cyclization amines 75, alkynes 81, and TMSN3 in DMSO at room temperature in the presence of KI and nBu4NBF4 gave imidazole derivatives 82 in up to 73% yield.[51]

A possible reaction pathway for the formation of imidazole derivatives 82 through a three-component reaction was proposed by Chen and co-workers (Scheme [17]).[51] First, the addition reaction between amine 75 and alkyne 81 gives enamine A, which reacts with an iodine radical (derived from iodide by anodic oxidation) to afford intermediate B. Then, the iodine in intermediate B is replaced by N3 – to give azide C, which is further oxidized to radical D. The radical D releases nitrogen to form imine radical E, which undergoes a [1,5]-H shift and oxidation process to obtain cationic intermediate F. Finally, cationic intermediate F is cyclized to imidazole derivative 82 by loss of a proton.

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Scheme 17 A plausible mechanism for the synthesis of imidazole derivatives
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Scheme 18 Electrochemical cascade cyclization for the synthesis of imidazolones, imidazolidinones, oxazolones, and oxazolidinones

# 2.9

Synthesis of Imidazolones, Imidazolidinones, Oxazolones, and Oxazolidinones

Imidazolone, imidazolidinone, oxazolone, and oxazolidinone scaffolds, which are present in some drugs such as droperidol, chlorzoxazone, domperidone, etc.,[52] have been effectively constructed in recent years.[53] Between 2018 and 2020, various electrochemical tandem cyclization strategies were also used to synthesize these heterocyclic units (Scheme [18]).[15] , [54] [55] [56] The electrochemical fluoroalkylation/dearomatization of 2-azido-N-(4-methoxyphenyl)acrylamides 83 was carried out in MeCN/H2O (10:1) in the presence of LiClO4 using RFSO2Na as the fluoride source to afford fluoroalkylated 1,4-diazaspiro[4.5]decatrienediones 84 in up to 64% yield.[15] Electrochemical dehydrogenative cyclization cascade of arylamine-tethered 1,5-enynes 85 or 87 in the presence of Et4NPF6 and trifluoroacetic acid (or AcOH) using DMF or TFE gave benzimidazolones 86 and benzoxazolones 88 in 20–78% and 44–88% yields, respectively.[54] The ureas 89 (X = N) and carbamates 89 (X = O) containing an unconjugated diene can be effectively converted into imidazolidinones or oxazolidinones 90, respectively, in up to 75% yield in the presence of nBu4NBF4, Na2CO3, and cyclohexa-1,4-diene (1,4-CHD) under the catalysis of ferrocene (Cp2Fe).[55] The Cu(OAc)2-catalyzed aza-Wacker electrochemical cyclization of N-allyl-N′-phenylureas 91 (X = N) or allyl N-phenylcarbamates 91 (X = O) in the presence of ­NaOPiv and LiClO4 afforded imidazolidinones or oxazolidinones 92, respectively, in 38–81% yields.[56]


# 2.10

Synthesis of Benzoxazoles, Oxazolines, and Isoxazolines

Oxazolines and isoxazolines are the key scaffolds for many active molecules,[57] and can also be used as protectants and chiral ligands in asymmetric synthesis and materials science.[58] In 2020–2021, electrochemical syntheses of benzoxazoles, oxazolines, and isoxazolines via cascade cyclization were successfully developed in a one-pot fashion (Scheme [19]).[36] , [59] [60] [61] The NaI/NaCl-catalyzed electrochemical cyclization between 2-aminophenols 93 and isothiocyanates 94 using EtOH/H2O (1:1) as a mixed solvent afforded 2-aminobenzoxazoles 95 in 13–97% yields.[59] 4-Methylbenzenethiol (97) reacted with N-allyl amides 96 in the presence ofnBu4NBF4 under electrochemical conditions to give 5-((4-tolylsulfanyl)methyl)oxazolines 98 in 66–82% yields.[36] N-Allyl amides 99 and diselenides 101a (X = Se) or disulfides 101b (X = S) underwent smooth electrochemical cyclization reactions in the presence of LiClO4 at room temperature to form the selanyl- or sulfanyl-substituted oxazolines 102 in good yields (X = Se: 62–91%, X = S: 59–75%).[60] Under the same reaction conditions, oximes 100 were effectively converted into isoxazolines 103 in 68–88% or 47–68% yields.[60] The electrochemical oxidative cascade cyclization of but-3-en-1-one oximes 104 with diselenides 101a using nBu4NBF4 as electrolyte and HFIP/CH3CN (1:9) as mixed solvent gave selanyl-substituted isoxazolines 105 in 38–98% yields.[61]

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Scheme 19 Electrochemical cascade cyclization for the synthesis of benzoxazoles, oxazolines, and isoxazolines

As for the formation process of selanyl-substituted oxazolines 102a, Sarkar and co-workers proposed two reaction mechanisms via free radicals and cations, however, only one of these is shown (Scheme [20]).[60] Similar to the initial reaction mechanism in Scheme [14], ArSe cation A and ArSe radical B are obtained from ArSeSeAr 101a under anodic oxidation. ArSe radical B is further oxidized to ArSe cation A by the anode. Then, ArSe cation A adds to N-allyl amide 99 to form intermediate C, which undergoes intramolecular nucleophilic cyclization by the amide oxygen to afford selanyl-substituted oxazoline 102a.

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Scheme 20 A plausible mechanism for the synthesis of selanyl-substituted oxazolines

# 2.11

Synthesis of Furans and Dihydrofurans

As furans and dihydrofurans are important heterocyclic scaffolds that widely exist in many bioactive molecules and natural products, the synthesis of these scaffolds has been developed to a certain extent in recent years.[62] In the period 2016 to 2022, the effective synthesis of furans and dihydrofurans through electrochemical cascade cyclization was reported by various groups (Scheme [21]).[36] , [63] [64] [65] [66] Lei, Lu, and co-workers showed that the electrochemical oxidative radical cascade cyclization reactions of 2-(1-phenylvinyl)benzamides 106 with 4-methylbenzenethiol (97) using nBu4NBF4 as electrolyte and MeCN as solvent at 40 °C generated 1-iminoisobenzofurans 107 in 14–81% yields.[36] Under similar reaction conditions, 2-vinylbenzamides 108 and diselenides 57 were effectively converted into 3-(selanylmethyl)-1-iminoisobenzofurans 109 in 34–94% yields.[63] Electrochemical aryl radical cyclization reactions of 1-bromo-2-(propargyloxy)benzenes 110 with carbon dioxide in the presence of 0.5 equivalent of 4-t-BuC6H4CO2CH3 using DMF as solvent containing 0.1 M nBu4NBF4 at –10 °C gave 3-carboxy-2,3-dihydrobenzofuran-3-ylacetic acids 111 in 39–62% yields.[64] In addition, a series of homopropargyl alcohols 112 were reacted with various diaryl diselenides 101a promoted by electrochemistry using MeCN/TFE (20:1) solution of 0.1 M LiClO4 to provide the corresponding 3-(arylselanyl)furans 113 in 54–84% yields.[65] However, when homopropargyl alcohols 112 were replaced with γ,δ-unsaturated carbonyls 114 and nBu4NBF4 was used as electrolyte, a similar reaction system generated 2-((phenylselanyl)methyl)-2,3-dihydrofurans 115 in 26–93% yields.[66]

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Scheme 21 Electrochemical cascade cyclization for the synthesis of furans and dihydrofurans

A reaction mechanism for the synthesis of 3-carboxy-2,3-dihydrobenzofuran-3-ylacetic acids 111 via electrochemical aryl radical cyclization was proposed by Senboku and co-workers (Scheme [22]).[64] At the cathode, methyl 4-tert-butylbenzoate is reduced to the corresponding free radical anion, which reacts with aryl bromide 110 resulting in C–Br bond cleavage and provides aryl radical A. Then aryl radical A undergoes intramolecular cyclization to further provide cyclized vinyl radical B, which undergoes one-electron reduction to give vinyl anion C. The α,β-unsaturated carboxylate ion D, derived from the reaction between vinyl anion C and carbon dioxide, also undergoes one-electron reduction to afford radical anion E, which combines with the magnesium cation to furnish stable enolate F. Finally, one-electron reduction of stable enolate F generates benzylic anion G, which reacts with carbon dioxide again to give dicarboxylate ion H, followed by acid treatment to afford dicarboxylic acid 111.

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Scheme 22 A plausible mechanism for the synthesis of 3-carboxy-2,3-dihydrobenzofuran-3-ylacetic acids

# 2.12

Synthesis of Indolizines, Pyrazoles, and Triazolium Inner Salts

Heterocyclic units, such as indolizines, pyrazoles, and 1,2,4-triazoles, are often encountered in various bioactive natural products and drugs, so the construction of these units is very important and has been developed to a certain extent.[67] The electrochemical synthesis of indolizines (119 and 123), pyrazoles (126 and 128), and triazolium inner salts 130 via cascade intermolecular cyclization was reported by the groups of Sharma (2022),[68] Baell and Huang (2022),[69] and Feng and Ruan (2021)[70] (Scheme [23]). The electro-oxidative cascade cyclization reactions between 2-methylquinazolin-4(3H)-ones 116, pyridines 117, and chalcones 118 in the presence of NH4I and nBu4NPF6 at 90 °C for 8 h gave heterocyclic-substituted indolizines 119 in 51–83% yields.[68] Heterocycles 120, pyridines (or isoquinolines) 121, and 5-styrylisoxazoles 122 were also effectively converted into indolizines 123 in 43–84% yields using the same reaction system.[68] Sulfonyl hydrazides 125 reacted with enaminones 124 or N,N-dimethyl enaminones 127 under electrochemical promotion using KI or TBAI as the redox reagent to afford sulfonated pyrazoles 126 or 128 in up to 81% or 43–72% yields, respectively.[69] Triazolium inner salts 130 were obtained in 48–90% yields from the electrochemical thiocyanation/cyclization between aldehyde hydrazones 129 and NaSCN in MeCN at 23 °C.[70]

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Scheme 23 Electrochemical cascade cyclization for the synthesis of indolizines, pyrazoles, and triazolium inner salts

Sharma and co-workers proposed a possible reaction mechanism for the synthesis of indolizines 123 (Scheme [24]).[68] First, iodide is oxidized by the anode to give an iodine radical, which reacts with methyl-substituted heteroarene 120 to afford iodomethyl-heteroarene A. Then, the reaction between iodomethyl-heteroarene A and pyridines (or isoquinolines) 121 generates ylide B, which reacts rapidly with 5-styrylisoxazole 122 to provide dihydroindolizine C through an intermolecular cyclization process. Finally, dihydroindolizine C is oxidized by the anode to afford indolizine 123 with loss of protons.

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Scheme 24 A plausible mechanism for the synthesis of indolizines 123
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Scheme 25 Electrochemical cascade cyclization for the synthesis of sulfonated benzothiophenes, thiazoles, dihydrothiazoles, and 1,3,4-thiadiazoles

# 2.13

Synthesis of Sulfonated Benzothiophenes, Thiazoles, Dihydrothiazoles, and 1,3,4-Thiadiazoles

In 2021–2022, green and practical electrochemical cascade cyclization methods were developed for the synthesis of sulfonated benzothiophenes 133, thiazoles 136, dihydrothiazoles 138, and 1,3,4-thiadiazoles 141 (Scheme [25]).[71] [72] [73] [74] The electrochemical sulfonylation/cyclization reactions between 2-alkynylthioanisoles 131 and sodium sulfinates 132 using nBu4NBF4 or nBu4NBr as electrolyte delivered sulfonated benzothiophenes 133 in 43–87% or up to 86% yield.[71] [72] The electrochemical reactions of thiourea (135) with enamines 134 or enaminones 137 in the presence of HCl (aq) in MeOH or trifluoromethanesulfonic acid (TfOH) in R4OH gave thiazoles 136 and dihydrothiazoles 138 in 31–96% yields and up to 93% yield, respectively.[73] Under the catalysis of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the electrochemical reaction of isothiocyanates 139 and hydrazones 140 afforded 2-amino-1,3,4-thiadiazoles in 40–84% yields.[74]

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Scheme 26 A plausible mechanism for the synthesis of sulfonated benzothiophenes
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Scheme 27 Electrochemical cascade cyclization for the synthesis of lactones

A plausible mechanistic pathway for the electrochemical synthesis of sulfonated benzothiophenes 133 was depicted by Liu, Fang, and co-workers as shown in Scheme [26].[71] First of all, sodium sulfinate 132 is oxidized by the anode to give radical A or B, which is captured by 2-alkynylthioanisole 131 to afford vinyl radical intermediate C. Then, vinyl radical intermediate C is cyclized to sulfonated benzothiophene 133 with the release of a methyl radical.


# 2.14

Synthesis of Lactones

In 2022, a series of lactones 144, 146, and 148 were synthesized by electrochemical tandem cyclizations (Scheme [27]).[75] [76] Chen and co-workers showed that the electrochemical reactions between 2-vinylbenzoic acids 142 and sulfonyl hydrazides 143 in CH3CN/H2O (10:1) in the presence of AcOH and LiClO4 at room temperature gave sulfonyl phthalides 144 in up to 97% yield.[75] The electrochemical oxidative palladium-catalyzed cascade carbonylation-carbocyclization of enallenols 145 or 147 in the presence of benzoquinone (BQ), HOAc, and LiClO4 at room temperature gave γ-lactones 146 in up to 83% yield or spirolactones 148 in 57–85% yields.[76]


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# 3

Electrochemical Cascade Cyclization for the Synthesis of Carbocycles

3.1

Synthesis of Carbon Polycycles and Spiroindenes

The synthesis of polycyclic is one of the major goals of cyclization reactions.[8c] [77] In 2020, Matsumoto and co-workers developed an electrochemical method for the synthesis of carbon polycycles 150 in 23–57% yields through the tandem cyclization of epoxyolefins 149 using 0.1 M Bu4NB(C6F5)4 as the electrolyte (Scheme [28]).[78] The electrochemical three-component cyclization of 1,5-enyne-containing para-quinone methides 151, sulfonyl hydrazides 125, and potassium iodide afforded spiroindenes 152 in up to 95% yield.[79]

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Scheme 28 Electrochemical cascade cyclization for the synthesis of carbon polycycles and spiroindenes

# 3.2

Synthesis of Difluoroacyl (Hetero)arenes and Sulfonated Indenones

In 2017, an effective electrochemical tandem cyclization for the synthesis of difluoroacyl (hetero)arenes 155 and sulfonated indenones 158 was developed by the groups of Médebielle and Lei (Scheme [29]).[80] [81] Médebielle and co-workers showed that electrochemically promoted reactions between chlorodifluoromethyl vinyl ketones 153 and alkenes 154 in the presence of PhNO2 and Et4NBF4 at room temperature provided difluoroacyl (hetero)arenes 155 in 8–68% yields.[80] Enynones 156 reacted with sulfinic acids 157 driven by electrochemistry using TBAI as redox reagent to afford sulfonated indenones 158 in 48–95% yields.[81]

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Scheme 29 Electrochemical cascade cyclization for the synthesis of difluoroacyl (hetero)arenes and sulfonated indenones

A plausible mechanism for the synthesis of sulfonated indenones 158 was illustrated by Lei and co-workers (Scheme [30]).[81] First, the iodine anion is continuously oxidized by the anode to give an iodine cation, which reacts with sulfinic acid 157 to afford sulfonyl radical A. Then, sulfonyl radical A is quickly captured by enynone 156 to form radical B, which undergoes intramolecular cyclization to deliver intermediate C. Finally, intermediate C loses a hydrogen free radical to produce sulfonated indenone 158.

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Scheme 30 A plausible mechanism for the synthesis of sulfonated indenones

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# 4

Conclusion

This review highlights the progress in the electrochemical cascade cyclization reactions over the past 10 years. The reactions enabling the synthesis of diverse organic products via the formation of both carbocycles and heterocycles have been presented and discussed. The examples collected in this article show the increasing application of electrochemical methods in annulation reactions as green and efficient protocols. Whilst playing an increasingly important role in organic synthesis, the application of the electrochemical approach to enantioselective synthesis or the combination of electrochemical conditions with transition metal catalysis both remain challenges because scarce examples of such catalytic reactions are available. To address these challenges and further promote the application of electrochemical synthesis, extensive efforts are yet highly desired.


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#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Cai Zhang
Department of Safety Supervision and Management, Chongqing Vocational Institute of Safety Technology
Wanzhou District, Chongqing 404020
P. R. of China   

Yunyun Liu
College of Chemistry and Chemical Engineering, Jiangxi Normal University
Nanchang 330022
P. R. of China   

Publication History

Received: 20 December 2022

Accepted after revision: 20 February 2023

Accepted Manuscript online:
20 February 2023

Article published online:
23 March 2023

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Cai Zhang was born in Anhui Province, P. R. of China. He received his BSc degree from Huaibei Normal University (P. R. of China) in 2005, and obtained his M.Sc. degree at Southwest University, Chongqing, P. R. of China, in 2009. From 2009 to 2013, he conducted Active Pharmaceutical Ingredient (API) research, such as cholesterol absorption inhibitors, antiplatelet drugs, and antidiabetic drugs at pharmaceutical enterprises. In 2013, he moved to Chongqing Vocational Institute of Safety Technology, where he is engaged in teaching and scientific research. His current research interests focus on the development of novel synthetic methodologies, such as hypervalent iodine reagents for application in organic synthesis, C–H bond activation, total synthesis of natural products, and fluorine chemistry. Demao Chen was born in 1995 in Jiangxi Province, China. He obtained his Master’s degree from Qingdao Agricultural University in July 2021 under the supervision of Dr. Zuli Wang. He is currently studying as a Ph.D. student in the College of Chemistry and Chemical Engineering, Jiangxi Normal University under the guidance of Prof. Dr. Jie-Ping Wan. His present research interest in new synthetic methods and application of stable enamines. Prof. Dr Jie-Ping Wan studied chemistry during 2000–2004 in the Department of Chemistry, Nanchang University. After obtaining his B.Sc. degree in 2004, he moved to the Department of Chemistry, Zhejiang University in 2005 for postgraduate study under the guidance of Prof. Yuanjiang Pan. After receiving his Ph.D. degree therein in 2010. He joined the College of Chemistry and Chemical Engineering, Jiangxi Normal University as an assistant professor in the same year, and was promoted to full professor in 2017. He conducted postdoctoral research in RWTH Aachen University with Prof. Dieter Enders from Sept. 2011 to Aug. 2012. Dr. Wan has won the honor of the Thieme ­Chemistry Journal Award in 2014. His current research interests are ­diversity-oriented synthesis, discovery and application of platform ­synthons, and sustainable catalysis and synthesis. Dr. Yunyun Liu was born in Shandong Province, China. She obtained her B.Sc. degree from Qufu Normal University in 2005. She then moved to Zhejiang University to continue her postgraduate studies in the Department of Chemistry under the supervision of Prof. Weiliang Bao wherein she obtained her Ph.D. degree in 2010. Dr. Liu joined to the College of Chemistry and Chemical Engineering, Jiangxi Normal University as assistant professor in 2010, and was promoted to associate professor in 2013. She is currently interested in the research of metal-catalyzed organic synthesis and sustainable catalysis.
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Scheme 1 Electrochemical cascade cyclization reactions
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Scheme 2 Electrochemical cascade cyclization for the synthesis of pyridines
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Scheme 3 Electrochemical cascade cyclization reactions for the synthesis of quinolines, phenanthridines, and cinnolines
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Scheme 4 A plausible mechanism for the synthesis of trifluoroethyl-substituted phenanthridines
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Scheme 5 A plausible mechanism for the synthesis of 2-aryl-3-sulfonyl-substituted quinolines
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Scheme 6 Electrochemical cascade cyclization for the synthesis of 1,4-dihydroquinolines, hexacyclic sulfonamides, and thiazines
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Scheme 7 Electrochemical cascade cyclization for the synthesis of hydroisoquinolinones and hydroquinolinones
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Scheme 8 A plausible mechanism for the synthesis of sulfonyl-substituted indolo[2,1-a]isoquinolines
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Scheme 9 Electrochemical cascade cyclization for the synthesis of quinazolin-4(3H)-ones
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Scheme 10 A plausible mechanism for the synthesis of quinazolin-4(3H)-ones
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Scheme 11 Electrochemical cascade cyclization for the synthesis of 4H-3,1-benzoxazines
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Scheme 12 A plausible mechanism for the synthesis of 4H-3,1-benzoxazines
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Scheme 13 Electrochemical cascade cyclization for the synthesis of oxindoles
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Scheme 14 A plausible mechanism for the synthesis of selanyl-substituted oxindoles
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Scheme 15 Electrochemical cascade cyclization for the synthesis of indolines and indoles
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Scheme 16 Electrochemical cascade cyclization for the synthesis of imidazo[1,5-a]pyridines and imidazoles
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Scheme 17 A plausible mechanism for the synthesis of imidazole derivatives
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Scheme 18 Electrochemical cascade cyclization for the synthesis of imidazolones, imidazolidinones, oxazolones, and oxazolidinones
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Scheme 19 Electrochemical cascade cyclization for the synthesis of benzoxazoles, oxazolines, and isoxazolines
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Scheme 20 A plausible mechanism for the synthesis of selanyl-substituted oxazolines
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Scheme 21 Electrochemical cascade cyclization for the synthesis of furans and dihydrofurans
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Scheme 22 A plausible mechanism for the synthesis of 3-carboxy-2,3-dihydrobenzofuran-3-ylacetic acids
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Scheme 23 Electrochemical cascade cyclization for the synthesis of indolizines, pyrazoles, and triazolium inner salts
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Scheme 24 A plausible mechanism for the synthesis of indolizines 123
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Scheme 25 Electrochemical cascade cyclization for the synthesis of sulfonated benzothiophenes, thiazoles, dihydrothiazoles, and 1,3,4-thiadiazoles
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Scheme 26 A plausible mechanism for the synthesis of sulfonated benzothiophenes
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Scheme 27 Electrochemical cascade cyclization for the synthesis of lactones
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Scheme 28 Electrochemical cascade cyclization for the synthesis of carbon polycycles and spiroindenes
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Scheme 29 Electrochemical cascade cyclization for the synthesis of difluoroacyl (hetero)arenes and sulfonated indenones
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Scheme 30 A plausible mechanism for the synthesis of sulfonated indenones