Electrifying Organic Synthesis

Abstract

The direct synthetic organic use of electricity is currently experiencing a renaissance. More synthetically oriented laboratories working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technology. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorganic transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the number of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochemical synthesis that will influence the future of this area.

Keywords: electrochemistry; oxidation; reduction; sustainable chemistry; synthetic methods.

Figure 1

Processes and parameters of electrosynthesis.

Scheme 1

Solvent effects in the anodic fluorination of 3‐phenylthiophthalide. Yields determined by ¹⁹F NMR analysis.20

Scheme 2

Influence of ether‐containing additives on the electrochemical fluorination of α‐(2‐pyrimidylthio)acetate.23

Scheme 3

Indirect anodic gem‐difluorination of dithioketals with para‐methoxyiodobenzene difluoride.25 SSCE=saturated sodium calomel electrode.

Scheme 4

Anodic fluorination with alkali‐metal fluorides.29

Scheme 5

Electrochemical C−H amination of activated arenes.41, 42, 43

Scheme 6

Electrochemical C−H amination of less activated alkylated arenes at BDD anodes.44

Scheme 7

Twofold electrochemical C−H amination of naphthalene.45

Scheme 8

Electrochemical amination of benzoxazoles through oxidative dehydrogenative couplings.48

Scheme 9

Anodic coupling of functionalized primary amines with aromatic compounds according to the heterocyclization approach.49

Scheme 10

Anodic coupling of N‐protected imidazoles with activated aromatic compounds.42,43,51 Ts=para‐toluenesulfonyl.

Scheme 11

Intramolecular anodic C−N functionalization yielding 2‐aminobenzoxazoles or ‐thiazoles.42,43,52

Scheme 12

Synthesis of 1,4‐benzoxazin‐3‐ones by electrochemical C−H amination.53

Scheme 13

Electrochemical benzylic C−H amination of toluene derivatives.56 NPhth=phthalimide.

Scheme 14

Electrochemically enabled nickel‐catalyzed amination of aryl halides.57 DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene, di‐^tBubpy=4,4′‐di‐tert‐butyl‐2,2′‐dipyridine, RVC= reticulated vitreous carbon.

Scheme 15

General steps of Kolbe electrolysis. Nu=nucleophile.

Scheme 16

Radical cascade reaction induced by a Kolbe electrolysis.68 Bn=benzyl.

Scheme 17

Kolbe dimerization of α‐silylacetic acids.69

Scheme 18

Non‐Kolbe conversion of an enantiomerically pure protected 4‐hydroxyproline.70 TBS=tert‐butyldimethylsilyl.

Scheme 19

Non‐Kolbe electrolysis for the generation of ketones from disubstituted malonic acids.71

Scheme 20

General reaction scheme for electrochemical coupling reactions of prefunctionalized arenes. For most reactions, R¹=R² and X=Y.

Scheme 21

Catalytic cycle for the reductive coupling of aryl halides by electrochemical regeneration of active Pd complexes.

Scheme 22

A selection of biaryls synthesized by electroreductive coupling reactions.79,80 sm=starting material.

Scheme 23

Electroreductive homo‐coupling with palladium nanoparticles electrochemically generated from solid palladium electrodes.82

Scheme 24

Heterobiaryls synthesized by reductive electrochemical cross‐couplings of aryl halides mediated by nickel complexes.87, 88, 89, 90

Scheme 25

Oxidative coupling of aryl boronic acids by electrooxidative regeneration of Pd^II species using TEMPO as a mediator.94

Scheme 26

A selection of biaryls synthesized by electrooxidative couplings of aryl boronic acids.93,94

Scheme 27

Mechanism for the electroreductive coupling of aryl halides with arenes, shown for the reaction of 4‐iodotoluene with benzonitrile.97

Scheme 28

General reaction scheme for the anodic coupling of aryl pyridines by C−H activation.100

Scheme 29

Mechanistic rationale for anodic aryl–aryl coupling reactions.

Scheme 30

Anodic couplings of catechols to triphenyleneketals.103

Scheme 31

Template‐directed anodic phenol coupling sequence.104

Scheme 32

The radical cation pool method for C−H/C−H cross‐couplings of arenes.105

Scheme 33

Schematic illustration of the liquid–liquid parallel laminar flow in an electrochemical microflow reactor for arene–arene cross‐couplings. The dashed line represents the liquid–liquid border of the laminar flow.106

Scheme 34

Various electrochemical cross‐couplings enabled by C−H activation developed by Waldvogel and co‐workers.107, 108, 109, 110, 111, 112, 113, 114

Scheme 35

General cyclization of olefins with trapping nucleophiles.

Scheme 36

Exemplary competitive cyclizations with different bases.120b

Scheme 37

Anodic cyclization of amides to lactams.122 EDG=electron‐donating group.

Scheme 38

Aminooxygenation of non‐activated alkenes and redox‐neutral amination of substituted olefins.123,124 Cp=cyclopentadienide.

Scheme 39

Electrochemical amination of substituted olefins.125 DMA=N,N‐dimethylacetamide.

Scheme 40

Electrochemical formation of fused indoles.127

Scheme 41

Electrochemical formation of 3‐fluorooxindoles.128

Scheme 42

Electrochemical synthesis of pyrazolidine‐3,5‐diones.129

Scheme 43

Direct electrochemical formation of benzoxazoles from anilides.131

Scheme 44

TEMPO‐mediated synthesis of benzothiazoles.135

Scheme 45

Electrochemical generation of benzimidazoles and pyridoimidazoles.136

Scheme 46

Cobalt(III)‐mediated synthesis of benzimidazoles and benzothiazoles.137

Scheme 47

Iodine‐mediated synthesis of isatins.138

Scheme 48

Potentiostatic aziridine synthesis with N‐aminophthalamide.140

Scheme 49

Percarbonate‐ or persulfate‐mediated epoxidation.141,142

Scheme 50

Hypobromide‐mediated epoxidation for the synthesis of indinavir.143

Scheme 51

N−N dehydrodimerization reaction of xiamycin A to dixiamycin B.147

Scheme 52

Postulated mechanism for anodic cyclizations of olefins. The exact mechanism, order of steps, and rates of each step may vary for each substrate and different reaction conditions (X, Y=electron‐donating groups, e.g., OMe, SMe/S‐Alkyl). Synthesized natural product skeletons are shown on the right.148, 149, 150, 151, 152 TBDPS=tert‐butyldiphenylsilyl, TBS=tert‐butyldimethylsilyl.

Scheme 53

Synthesis of C‐glycosides by anodic olefin couplings.154

Scheme 54

Anodic synthesis of a spiro compound for the synthesis of heliannuol E.155

Scheme 55

Electrochemical synthesis of chromans and spiro chromans by intermolecular cycloadditions of terpenes and in situ generated ortho‐quinone methides.157

Scheme 56

Electrochemical synthesis of isocedrene by an anodic phenol–olefin coupling.159

Scheme 57

Electrochemical synthesis of licarin A by an anodic phenol–olefin coupling.160

Scheme 58

Electrochemical synthesis of the precursor for DZ‐2384 on multigram scale by anodic macrocyclization.164

Scheme 59

Synthesis of (+)‐N‐methylanisomycin by anodic cyclization of a δ‐alkenylamine.165 HMPA=hexamethylphosphoric acid triamide, MOM=methoxymethyl.

Scheme 60

Late‐stage functionalization of cyclic and noncyclic amides shown for one bicyclic lactam.166

Scheme 61

Electrochemical synthesis of enones by allylic C−H oxidation for the synthesis of several natural compounds.169

Scheme 62

Total synthesis of (+)‐2‐oxo‐yahazunone by C−H activation.171