Electrocatalysis as an enabling technology for organic synthesis

Abstract

Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry. Electrochemistry's unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a number of new electrochemical methodologies for the preparation of valuable chemical motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chemical methods, allowing for the subversion of kinetic and thermodynamic obstacles encountered in conventional organic synthesis. This review highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.

Fig. 1

Number of publications per year (indexed in SciFinder since 2000) in the research areas of organic electrochemistry and organic electrocatalysis.

Fig. 2

(A and B) Iodide-mediated aminooxygenation of alkenes.

Fig. 3

(A and B) Hypervalent Iodine-mediated difluorination of alkenes.

Fig. 4

(A and B) Iodide-mediated cyclization.

Fig. 5

(A and B) Iodide-mediated oxidation of methylketones.

Fig. 6

(A and B) Iodide-mediated oxidation of lignin model compounds.

Fig. 7

(A and B) Oxidative cleavage of alkenes using electrochemical generated periodate.

Fig. 8

(A and B) Radical cyclization triggered by electrochemical generated sulfur centered radicals.

Fig. 9

(A and B) Hypervalent iodine-mediated fluorodesulfurization of dithiolanes.

Fig. 10

(A and B) Iodide-mediated synthesis of 2-aminobenzoxazoles.

Fig. 11

(A and B) Nitrate-mediated oxidation of alcohols.

Fig. 12

(A–C) Nitrate-mediated C(sp³)–H fluorination.

Fig. 13

Minteer and Sigman’s model for nitroxyl mediators. This figure has been reproduced from ref. with permission from American Chemical Society, copyright 2015.

Fig. 14

(A and B) Nitroxyl-mediated oxidation of alcohols and aldehydes to carboxylic acids.

Fig. 15

Cooperative copper-nitroxyl system for oxidation of alcohols to aldehydes.

Fig. 16

(A–C) Nitroxyl-mediated oxidation of carbamates.

Fig. 17

(A and B) Radical cyclization triggered by electrochemical generated nitrogen centered radicals.

Fig. 18

(A–C) Nitroxyl-mediated diazidation of alkenes.

Fig. 19

(A–C) N-hydroxy phthalimide-mediated allylic oxidation.

Fig. 20

(A and B) N-hydroxy phthalimide-mediated benzylic iodination.

Fig. 21

(A–C) Quinuclidine-mediated C(sp³)–H oxidation.

Fig. 22

(A and B) DDQ-mediated generation of benzoxazoles.

Fig. 23

(A and B) Different stability profiles of triarylamine cation-radicals.

Fig. 24

(A and B) Triarylamine-mediated oxidation of alcohols and ethers.

Fig. 25

(A and B) Triarylimidazole-mediated oxidation of chalcone epoxides mediated by TAI cation-radical.

Fig. 26

Cyclic voltammogram of TAI 26–1 and its cyclized analogue 26–2. This figure has been adapted from ref. with permission from American Chemical Society, copyright 2014.

Fig. 27

(A and B) Tetraarylhydrazine-mediated synthesis of imidazo-fused N-heterocycles.

Fig. 28

(A–C) Phenothiazine-mediated synthesis of substituted pyrrolidines.

Fig. 29

(A and B) Modes of electrochemical transition metal-catalyzed C–H functionalization.

Fig. 30

(A–D) Manganese-catalyzed electrocatalytic diazidation and dichlorination of alkenes.

Fig. 31

(A–D) Manganese-catalyzed electrocatalytic heterofunctionalization of alkenes.

Fig. 32

(A–C) Synthesis of chlorotrifluoromethylated pyrrolidines via electrocatalytic radical ene–yne cyclization.

Fig. 33

(A–C) Manganese-mediated electrochemical trifluoromethylation for the synthesis of azaheterocycles.

Fig. 34

(A–C) Manganese-catalyzed electrochemical cyclization reaction of N-substituted 2-arylbenzoimidazoles with alkylboronic acids.

Fig. 35

(A–C) Manganese-catalyzed oxidative azidation of C(sp³)–H bonds under electrophotocatalytic conditions.

Fig. 36

(A and B) Manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols via alkoxy radicals.

Fig. 37

(A–C) Manganese-catalyzed electrochemical synthesis of quinazolinones.

Fig. 38

(A–C) Electrochemical difluoromethylarylation of alkynes.

Fig. 39

(A–C) Electrochemical dehydrogenative cyclization of 1,3-di-carbonyls.

Fig. 40

(A–C) Electrochemical synthesis of 7-membered carbocycles through cascade 7-endo-trig radical cyclization.

Fig. 41

(A and B) Electrochemistry-driven iron-catalyzed C–H arylation.

Fig. 42

(A–C) Electro-oxidative generation of diaza-oxy-allyl cation toward the synthesis of diamine.

Fig. 43

(A and B) Electrochemical access to benzimidazolone and quinazolinone via in situ generation of isocyanates.

Fig. 44

(A–C) Enantioselective electrocatalytic cyanophosphorylation of vinylarenes.

Fig. 45

(A–C) Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes.

Fig. 46

(A–C) Copper-catalyzed alkyne annulation.

Fig. 47

Cu(II)/TEMPO-coatalyzed enantioselective C(sp³)–H alkynylation of tertiary cyclic amines.

Fig. 48

(A–C) Copper-catalyzed electrochemical C–H amination of arenes with secondary amines.

Fig. 49

(A–C) Formal aza-Wacker cyclization by tandem electrochemical oxidation and copper catalysis.

Fig. 50

(A) Electrochemical palladium-catalyzed ortho-oxygenation of 2-phenylpyridines with perfluorocarboxylic acids. (B) Electrochemical palladium-catalyzed phosphonation of pyridines.

Fig. 51

Electrochemical palladium-catalyzed chlorination of N-quinolinylbenzamide derivatives.

Fig. 52

(A and B) Palladium-catalyzed electrooxidative C–C bond formation of oximes.

Fig. 53

Electrochemical palladium-catalyzed methane monofunctionalization.

Fig. 54

(A–C) Electrochemical oxidative aminocarbonylation of terminal alkynes.

Fig. 55

(A–C) Electrochemical palladium-catalyzed C(sp³)–H bond acetoxylation.

Fig. 56

(A–C) Electrochemical ruthenium-catalyzed alkyne annulations of arylcarbamates.

Fig. 57

(A and B) Ruthenaelectro-catalyzed three-component alkyne annulation.

Fig. 58

(A–C) Ruthenium-catalyzed Electrochemical dehydrogenative alkyne annulation.

Fig. 59

(A–C) Cooperative iridium-catalyzed electrooxidative C–H alkenylations.

Fig. 60

(A–C) Electrochemistry-enabled Ir-Catalyzed vinylic C–H Functionalization for alkyne annulation.

Fig. 61

(A–C) Electrochemistry-enabled cobalt-catalyzed C–H/N–H Activation. PyO = 2-pyridyl N-oxide.

Fig. 62

Cobalt-catalyzed electrooxidative C–H amination of arenes with alkylamines.

Fig. 63

(A–C) Electrochemistry-enabled cobalt-catalyzed [4+2] annulation for the synthesis of sultams.

Fig. 64

Electrochemical oxidative C–H/N–H intramolecular annulation with isocyanides for iminoisoindolinone synthesis.

Fig. 65

Nickellaelectro-catalyzed C–H alkoxylation with secondary alcohols.

Fig. 66

(A–C) Electrooxidative rhodium-catalyzed C–H/C–H activation for dehydrogenative alkenylation.

Fig. 67

(A and B) Electrochemical C–C bond activation C–C bond alkenylation by rhodium(III) catalysis.

Fig. 68

(A–C) Rhodium(III)-catalyzed aryl C–H phosphorylation enabled by anodic oxidation induced reductive elimination.

Fig. 69

(A–C) Nickel-catalyzed electrochemical homocoupling reaction.

Fig. 70

(A and B) Nickel-catalyzed electrochemical enantioselective homocoupling reaction.

Fig. 71

Nickel-catalyzed electrochemical cross coupling reaction. X = Br or Cl.

Fig. 72

(A–C) Nickel-catalyzed electrochemical Mizoroki–Heck coupling reaction.

Fig. 73

Nickel-catalyzed electrochemical cross coupling of aryl, heteroaryl or vinyl halides with activated alkyl chlorides.

Fig. 74

(A–C) Nickel-catalyzed electrochemical cross-electrophile coupling reactions of unactivated alkyl halides.

Fig. 75

(A–C) Nickel-catalyzed electrochemical cathodically coupled electrolysis.

Fig. 76

Nickel-catalyzed chain-walking cross-electrophile coupling reaction.

Fig. 77

(A–C) Nickel-catalyzed electroreductive electrophile cross coupling reaction via redox shuttles.

Fig. 78

(A and B) Nickel-catalyzed electrochemical enantioselective cross coupling reaction.

Fig. 79

Nickel-catalyzed electroreductive alkene fuctionalization.

Fig. 80

(A and B) Electroreductive pyridylation of electron-deficient alkenes. The anodic reaction is not discussed by the authors.

Fig. 81

(A–C) Electrochemical nickel-catalyzed coupling between aryl halides and amines.

Fig. 82

(A–C) Electrochemical nickel-catalyzed thiolation of aryl halides and heteroaryl halides.

Fig. 83

Electrochemical nickel-catalyzed carbon–sulfur bond formation.

Fig. 84

(A and B) Electrochemical nickel-catalyzed phosphorination of aryl halides and heteroaryl halides.

Fig. 85

(A–C) Electrochemical nickel-catalyzed carbon–phosphine bond formation.

Fig. 86

(A and B) Electrochemically enabled, NiCl₂-catalyzed reductive decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with quinoxalinones.

Fig. 87

Electrochemical C–H activation of benzamides.

Fig. 88

(A and B) Nickel-catalyzed reductive electrochemical decarboxylation.

Fig. 89

Cobalt-catalyzed aryl halides coupling: early contributions from Gosmini, Nedéléc and co-workers.

Fig. 90

(A and B) Co(salen)-catalyzed alkylation. W = electron-withdrawing group (EWG).

Fig. 91

(A–C) Co(salen)-catalyzed debromination. GC = glassy carbon. DSA = Dimensionally Stable Anodes, titanium mesh with metal oxides (RuO₂, IrO₂ or PtO₂). The anodic reaction was not discussed.

Fig. 92

(A and B) Co(salen)-catalyzed enantioselective carboxylation.

Fig. 93

(A–C) Cobalt-catalyzed allylic carboxylation.

Fig. 94

Vitamin B₁₂-catalyzed cyclopropanation of styrene.

Fig. 95

(A and B) Vitamin B₁₂-catalyzed ester/amide synthesis.

Fig. 96

Cobalt-catalyzed reductive ketone dimerization via CPET. Boron-doped diamond (BDD) electrode is used as cathode and glassy carbon is used as counter electrode.

Fig. 97

(A and B) Titanocene-catalyzed dehalogenation and epoxide opening. The anode [XX(+)] in the epoxide ring-opening reaction was not disclosed.

Fig. 98

(A and B) Titanium-catalyzed amination of arenes.

Fig. 99

Titanium-catalyzed epoxide ring-opening arylation.

Fig. 100

(A–C) Zinc-mediated allylation of aldehydes.

Fig. 101

(A and B) Zinc catalyzed allylation of aldehydes and sulfonimines. TCO glass = transparent conductive oxide glass, indium tin oxide.

Fig. 102

(A) Palladium catalysed homocoupling of aryl halides; (B and C) palladium catalysed Heck type reaction.

Fig. 103

(A and B) Palladium-catalyzed allylic halide coupling.

Fig. 104

(A–C) Palladium-catalyzed carboxylation of allyl ethers. DPPPH = 1,2-bis(diphenylphosphino)benzene; (R)-MeO-BIPHEP = (R)-(+)-2,2″-bis(diphenylphosphino)-6,6″-dimethoxy-1,1″-biphenyl.

Fig. 105

(A–D) Samarium-mediated coupling reactions.

Fig. 106

(A and B) Samarium-catalyzed reductive coupling of nitroarenes.

Fig. 107

(A and B) Tin-catalyzed allylation of ketones/aldehydes.

Fig. 108

(A–C) Tin-catalyzed ketone allylation in one pot.

Fig. 109

(A–C) Tin-catalyzed synthesis of oximes.

Fig. 110

(A and B) Naphthalene-mediated detosylation.

Fig. 111

Fluorene mediated: (A) dechlorination, FN = 9-fluorenone; (B) radical cyclization of aryl halides, ETFN = 9,9-diethyl-9H-fluorene.

Fig. 112

(A and B) PDI-catalyzed C–H arylation of pyrroles.

Fig. 113

(A and B) Benzoate-catalyzed radical cyclization carboxylation.

Fig. 114

Carborane-catalyzed debromination. The anodic reaction was not discussed.

Fig. 115

(A–C) Palladium/viologen catalyzed aryl halides coupling.

Fig. 116

(A–C) Electrochemical nickel-catalyzed direct arylation of benzylic C–H bonds.

Fig. 117

Ni-Catalyzed C–O cross coupling via microfluidic cell.

Fig. 118

(A and B) Nickel-catalyzed electrochemical cross-coupling reactions of benzyl trifluoroborate and organic halides.

Fig. 119

(A and B) Electrochemically induced nickel catalysis for oxygenation reactions with water.

Fig. 120

Paired electrolysis of aldehyde condensation and carbon dioxide reduction.

Fig. 121

Paired electrolysis of epoxide and dibromide synthesis.

Fig. 122

Paired electrolysis of alcohol oxidation with Pd-mediated hydrogenation of alkynes.

Fig. 123

(A–C) TEMPO-catalyzed aryl C-N bond construction.

Fig. 124

Electrochemical decarboxylation of phenylacetic acid with different anode materials.

Fig. 125

Electrochemical cyclization with different anode materials.

Fig. 126

(A–C) Electrochemical difunctionalization of alkenes with hydroxamic acid using different anode materials.

Fig. 127

Electrochemical epoxidation of alkenes with nanoparticles coated anode.

Fig. 128

(A and B) Electrochemical cross-electrophile coupling with nanoparticles coated cathode.

Fig. 129

Nanowiring of redox enzymes by a gold nanoparticle. a = 1 or 2, b = 0 or 1. FAD = flavin adenine dinucleotide, GOx = glucose oxidase. The author did not specify the role of the glassy carbon cathode.

Fig. 130

(A and B) Bioelectrocatalytic N₂ fixation: from N₂ to chiral amine intermediates. The platinum anode generates protons and O₂ from water.

Fig. 131

NADH regeneration by a redox polymer-immobilized enzymatic system. DH = diaphorase, ADH = alcohol dehydrogenase. The platinum-wire anode generates O2 from water.

Fig. 132

Biphasic bioelectrocatalytic synthesis of chiral β-hydroxy nitriles. DH = diaphorase, ADH = alcohol dehydrogenase HHDH = halohydrin dehalogenase. A platinum mesh serves as the anode. The authors do not specify the anodic reaction.

Fig. 133

Resting E. coli as a chassis for microbial electrosynthesis: production of chiral alcohols. MtrA, STC and CymA: proteins of the electron transfer pathway in Shewanella oneidensis. MR-1, LbADH: An alcohol dehydrogenase from Lactobacillus brevis. The graphite anode generates O₂ from water.

Fig. 134

(A–C) Electrophotochemical oxidation of alcohols mediated by riboflavin tetraacetate.

Fig. 135

(A–C) Electrophotochemical alkylation of heteroarenes mediated by chloride.

Fig. 136

(A and B) Electrophotochemical trifluoromethylation of arenes.

Fig. 137

Electrophotochemical alkylation of benzothiazole.

Fig. 138

(A–C) Electrophotochemical coupling of arenes with azoles mediated by trisaminocyclopropenium cation.

Fig. 139

Electrophotocatalytic deamination of vicinal C–H bonds.

Fig. 140

Electrophotocatalytic azolation of arenes. TdCBPA = tris(2′,4;-dicyano-[1,1′-biphenyl]-4-yl)amine.

Fig. 141

(A–C) Electrophotochemical reduction of aryl halides mediated by dicyanoanthracene.

Fig. 142

(A and B) Electrophotochemical reduction of aryl halides mediated by naphthalene-based imide.

Fig. 143

(A–C) Electrophotochemical synthesis of pyrrolidines mediated by iodide. CFL = compact fluorescent lamp.