Electrochemical Late-Stage Functionalization

Abstract

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical or biological activities. LSF can thus greatly accelerate the development of medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical molecular synthesis has emerged as an environmentally friendly platform for the transformation of organic compounds. Over the past decade, electrochemical late-stage functionalization (eLSF) has gained major momentum, which is summarized herein up to February 2023.

Scheme 1. Opportunities for Electrochemical Late-Stage Functionalization Strategies in Drug Discovery

Scheme 2. Electrochemical Rhodium-Catalyzed Late-Stage C(sp²)–H Methylation

Scheme 3. Electrochemical Rhodium-Catalyzed Late-Stage C(sp²)–H Alkylation

Scheme 4. Electrochemical Controlled C(sp²)–H Late-Stage Trifluoromethylation and Difluoromethylation

Scheme 5. Electrochemical Iridium-Catalyzed Late-Stage C(sp²)–H Alkynylation

Scheme 6. Electrochemical Late-Stage C(sp²)–H Carboxylation with CO₂

Scheme 7. Electrochemical Late-Stage C(sp²)–H Hydroxylation

Scheme 8. Electrochemical Late-Stage C–H Acyloxylation of Tyrosine-Containing Peptides

Reproduced with permission from ref (162). Copyright 2022, Royal Society of Chemistry.

Scheme 9. Electro-oxidative C–H Alkoxylation of Arenes with Secondary Alcohols

Scheme 10. Electrochemical Late-Stage Aminations

Scheme 11. Electrochemical Late-Stage Nitrogenation

Scheme 12. Electrochemical Peptide and Protein Modification at Tyrosine

Scheme 13. Selective Peptide Modification at Tyrosine Using N-Methyl Luminol and 1-Methyl-4-Phenylurazole

Scheme 14. Electrochemical Late-Stage C–H Nitrogenation of Tyrosine-Containing Peptides

Reproduced with permission from ref (182). Copyright 2019, Royal Society of Chemistry.

Scheme 15. Electrocatalytic Coupling Reactions of Caffeine with Dialkylphosphites

Scheme 16. Electrochemical Rhodium-Catalyzed C(sp²)–H Phosphorylation

Scheme 17. Electrochemical Late-Stage C(sp²)–H Phosphorylation in Continuous Flow

Scheme 18. Ruthenaelectro-Catalyzed meta-C–H Bromination with HBr

Scheme 19. Electrochemical Late-Stage Bromination of Drug Molecules with NaBr

Scheme 20. Paired Electrocatalysis for the Preparation of Aryl Chlorides Using DCE

Scheme 21. Electrochemical Late-Stage C(sp²)–H Iodination of Tyrosine-Containing Protein

Scheme 22. Rhodaelectro-Catalyzed Peptide Late-Stage Labeling via Formyl C–H Activation

Reproduced with permission from ref (221). Copyright 2021, Springer Nature.

Scheme 23. Tandem Electrochemical Oxidative Azidation/Heterocyclization of Tryptophan-Containing Peptides

Scheme 24. Electrochemical Oxidative Macrocyclization for the Synthesis of DZ-2384

Scheme 25. Proposed Mechanism for Electrochemical Benzylic C(sp³)–H Functionalization

Scheme 26. Electrochemical Late-Stage Oxidation of Various Methylarenes

Scheme 27. NHPI Mediated Late-Stage Benzylic Oxidation of Methylarenes

Scheme 28. eLSF by Benzylic C–H Amination

Scheme 29. DDQ-Mediated Late-Stage Benzylic C–H Azolation

Scheme 30. Electrochemical Late-Stage Benzylic C–H Azolation

Scheme 31. Electrochemical Late-Stage Benzylic C–H Isothiocyanation

Scheme 32. Electrochemical Late-Stage Benzylic C–H Fluorination

Scheme 33. Electrochemical Late-Stage Benzylic C–H Bonds Oxidation to Form Ketones

Scheme 34. Electrochemical Late-Stage Allylic C(sp³)–H Oxidation

Scheme 35. Electrochemical Late-Stage Allylic C(sp³)–H Amination

Scheme 36. Electrochemical Dehydrogenative Cross-Coupling of Ketones with Xanthenes (66)

Scheme 37. Electrochemically Driven Late-Stage Desaturation of Carbonyl Compounds

Scheme 38. eLSF by α-C(sp³)–H Functionalization of Carbonyls

Scheme 39. Electrochemical Late-Stage α-C(sp³)–H Alkenylation of Carbonyls

Scheme 40. Electrochemical Late-Stage α-Methylation of Amines

Scheme 41. Electrochemically Driven Desaturative β-C(sp³)–H Functionalization of Amines

Scheme 42. Electrochemical Late-Stage α-C(sp³)–H Acyloxylation of Sulfides

Scheme 43. Electrochemical Late-Stage Oxidation of Unactivated C(sp³)–H Bonds

Scheme 44. Electrochemical Late-Stage C(sp³)–H Azidation

Scheme 45. Electrochemical Palladium-Catalyzed Aminocarbonylation of Terminal Alkynes

Scheme 46. Electrochemical Palladium-Catalyzed Oxidative Sonogashira–Hagihara Carbonylation of Arylhydrazines and Alkynes

Scheme 47. Electrochemical Gold-Catalyzed Oxidative C(sp)–C(sp²) Coupling

Scheme 48. Electro-oxidative Chlorotrifluoromethylation of Olefins

Scheme 49. Electrochemical Cobalt-Catalyzed Late-Stage Hydroetherification of Olefins

Scheme 50. Electrochemical Palladium-Catalyzed Late-Stage Hydrofluorination of Olefins

Scheme 51. Electro-oxidative Late-Stage Annulation of Biologically Relevant Olefins

Scheme 52. Electroreductive Cobalt-Catalyzed Late-Stage Functionalization of Olefins and Alkynes

Scheme 53. Late-Stage Difunctionalization of Steroid Derivatives

Scheme 54. Electrochemical Selenium-Catalyzed Late-Stage Hydroazolation of Olefins

Scheme 55. Electrochemical Late-Stage [4 + 2] Annulation of Olefins with Hydroxamic Acid

Scheme 56. Late-Stage Electrochemical Labelling of Biologically Relevant Olefins

Scheme 57. Electroreductive Late-Stage Hydrogenation of Olefins with D₂O

Scheme 58. Electroreductive Late-Stage Defluorinative Alkylation of Trifluoromethylated Styrenes

Scheme 59. Electroreductive Late-Stage Functionalization of Olefins with Deuterochloroform

Scheme 60. Electrochemical Synthesis of Ynones

Scheme 61. Nickel-Catalyzed Electrochemical Amination of Aryl Halides

Scheme 62. Nickel-Catalyzed Electrochemical Amination with Weak N-Centered Nucleophiles

Scheme 63. Ni-Catalyzed Late-Stage Fluoroalkylation of Aryl Iodides

Scheme 64. Electrochemical Nickel-Catalyzed Deoxygenative Thiolation Reactions

Scheme 65. Nickel-Catalyzed Late-Stage Aminomethylation of Aryl Bromides

Scheme 66. Electrochemical Late-Stage Borylation of Alkyl Halides

Scheme 67. Electrochemically Driven Late-Stage C(sp³)–C(sp³) Bond Formation

Scheme 68. Electrochemical Late-Stage Deuteration of Alkyl Halides

Scheme 69. Electrochemical Carboxylation of Aryl Halides

Scheme 70. Decarboxylative Synthesis of Sterically Hindered Ethers

Scheme 71. Electrochemical Decarboxylative Functionalization of Bioactive Carboxylic Acids

Scheme 72. Late-Stage Modification through Electrochemical Nozaki–Hiyama–Kishi Reaction

Scheme 73. Plausible Mechanism for Electrochemical NHK Reaction

Scheme 74. Electrochemical Synthesis of Peptides

Scheme 75. Electrochemical Decarboxylative Functionalization of Peptides

Scheme 76. Electrochemical Decarboxylative Modification of C-Terminal Peptides

Scheme 77. Electrochemical Decarboxylative Aromatization of C-Terminal Hydroxyproline Containing Peptides

Scheme 78. Electroreductive Nickel-Catalyzed Decarboxylative C(sp³)–C(sp³) Bond Formation

Scheme 79. Late-Stage Dehydroxylative Halogenation and Alkoxylation

Scheme 80. Electrochemical Late-Stage Dehydroxylative Azolation

Scheme 81. Electrochemical Transition-Metal Free Reduction of Epoxides

Scheme 82. Electrochemical Transition-Metal Free Carboxylation of Epoxides

Scheme 83. Electrochemical Late-Stage Birch Reduction

Scheme 84. Selective Reduction of Phthalimides under Alternating Current

Scheme 85. eLSF of Silylated Amino Acids

Scheme 86. Electrochemical Synthesis of C-Glycosides

Scheme 87. Electrochemical Construction of Disulfide Linkages in Peptides

Scheme 88. Selective C-5 Functionalization of Proline and Analogues

Scheme 89. Selective C–O/O–H Metathesis under Alternating Current

Scheme 90. Electroauxiliary-Assisted Late-Stage Functionalization of Peptides

Scheme 91. Photoelectrochemical C(sp²)–H Trifluoromethylation via Minisci-Type Reactions

Scheme 92. Photoelectrochemical C–H Alkylation via Minisci Reactions

Scheme 93. Photoelectrochemical Decarboxylative C–H Alkylation

Scheme 94. Photoelectrochemical C–H Alkylation with Alkanes

Scheme 95. Photoelectrochemical C–H Alkylation with Bench-Stable Katritzky Salts

Scheme 96. Photoelectrochemical C–H Silylation of Heteroarenes

Scheme 97. Photoelectrochemical Hydroxylation of Aryl C–H bonds

Scheme 98. Photoelectrochemical Diamination of Vicinal C–H Bond

Scheme 99. Photoelectrochemical Amination of Benzylic C(sp³)–H Bond

Scheme 100. Photoelectrocatalytic Multiple C–H Bonds Oxygenations

Scheme 101. Photoelectrochemical Manganese-Catalyzed C(sp³)–H Azidation

Scheme 102. Photoelectrochemical Asymmetric Cyanation of Benzylic C–H Bonds

Scheme 103. Photoelectrochemical Acetoxyhydroxylation of Aryl Olefins

Scheme 104. Photoelectrocatalytic Nucleophilic Aromatic Substitution Reaction

Scheme 105. Photoelectrochemical C(sp³)–O Cleavages of Phosphinated Alcohols to Carbanions

Scheme 106. Photoelectrochemical Asymmetric Decarboxylative Cyanation