Generation of Alkyl Radicals: From the Tyranny of Tin to the Photon Democracy

Abstract

Alkyl radicals are key intermediates in organic synthesis. Their classic generation from alkyl halides has a severe drawback due to the employment of toxic tin hydrides to the point that "flight from the tyranny of tin" in radical processes was considered for a long time an unavoidable issue. This review summarizes the main alternative approaches for the generation of unstabilized alkyl radicals, using photons as traceless promoters. The recent development in photochemical and photocatalyzed processes enabled the discovery of a plethora of new alkyl radical precursors, opening the world of radical chemistry to a broader community, thus allowing a new era of photon democracy.

Figure 1

(A) Thermal generation of radicals from alkyl halides in the Giese reaction. (B) LD₅₀ values for selected organotin compounds. (C) Thermal generation of radicals from alcohols via xanthates (I). (D) Thermal and photochemical generation of radicals from carboxylic acids via Barton esters (II).

Figure 2

Different approaches for the photogeneration of alkyl radicals (A) by photochemical means through the introduction of a photoauxiliary group (B) via fragmentation of a radical cation (oxidative pathway) or anion (reductive pathway) formed by photoredox catalysis (C) via a halogen atom transfer reaction (XAT) with a photogenerated radical (D) through the photocatalyzed cleavage of a C–H bond via direct (d-HAT) or indirect (i-HAT) hydrogen atom transfer (E) by the remote-controlled C–H activation via a photogenerated heteroatom based radical (F) by a ring-opening via a photogenerated heteroatom (nitrogen) based radical.

Figure 3

On the left, substrates used to promote the photochemical formation of alkyl radicals divided according to the C–Y bond cleaved. The oxidation potentials (E^ox, in orange) or the reduction potentials (E^red, in green) of the precursors as well as the BDE values of the bond that is broken (highlighted in gray) by direct photocleavage are reported. On the right, a selection of common photoredox catalysts with their main redox features are collected.

Scheme 1. Different Strategies for the Decarboxylative Adamantylation of Electron-Poor Alkenes

Scheme 2. Decarboxylative-Decarbonylation of an α-Keto Acid

Scheme 3. Enantioselective Preparation of Cheloviolene A

Scheme 4. Visible and Solar Light Photocatalyzed Functionalization of Michael Acceptors with Alkyl Trifluoroborate Salts

Scheme 5. Activation of Boronic Acids with a Lewis Base

Scheme 6. Desulfurative Strategy for the Conjugate Addition of Alkyl Radicals onto Michael Acceptors

Scheme 7. Alkyl-DHPs as Radical Precursors in Combination with Iminium Catalysis

Scheme 8. Synthesis of (−)-Solidagolactone via N-(Acyloxy)phthalimides

Scheme 9. Generation of Alkyl Radicals from N-Phthalimidoyl Oxalates

Scheme 10. Giese-Type Reaction of Iodides in the Presence of BH₃CN^–

Scheme 11. Synthesis of Vorinostat via XAT Strategy

Scheme 12. TBADT-Photocatalyzed Hydroalkylation of Acrylonitrile

Scheme 13. TBADT-Driven Functionalization of Tertiary Carbons

Scheme 14. Functionalization of a Vinylpyridine with a Cycloalkane

Scheme 15. Indirect HAT Mediated by a Cl^• Radical

Scheme 16. Intramolecular 1,5-HAT Forming Tertiary Alkyl Radicals

Scheme 17. 1,5-HAT Promoted by an Iminyl Radical

Scheme 18. Oxyalkylation via Alkyl Diacyl Peroxides

Scheme 19. Multicomponent Oxyalkylation of Styrenes

Scheme 20. Photocatalyzed Oxyalkylation of Styrenes Based on the Kornblum Oxidation

Scheme 21. Oxyalkylation by Using N-(Acyloxy)phthalimide Derivatives as Radicals Source

Scheme 22. Synthesis of Alkylated Ketones from Mercaptothiazolinium Salts

Scheme 23. Carbofluorination of (a) Styrenes and (b) Dehidroalanine Derivatives

Scheme 24. Enantioselective Cyanoalkylation of Styrenes

Scheme 25. Allylation through Alkyl Radicals Generated (a) via HAT and (b) from Si bis-Catecholates

Scheme 26. Hantzsch Ester Mediated Photocleavage of N-Alkoxyphthalimides

Scheme 27. Photocatalyzed Allylation by Using Katritzky Salts

Scheme 28. Remote Allylation via Amidyl Radicals

Scheme 29. Synthesis of gem-Difluoroalkenes from Alkyl Trifluoroborates

Scheme 30. Dual-Catalytic Allylation of Vinyl Epoxides

Scheme 31. Synthesis of a Precursor of Tirofiban by a Metallaphotoredox Strategy

Scheme 32. Different Strategies in the Alkylation of N-Aryl Tetrahydroisoquinolines

Scheme 33. Addition of an Alkyl Radical to Chiral Sulfinimines

Scheme 34. Gold Catalyzed Activation of Bromoalkanes

Scheme 35. Alkenylations Mediated by Benziodoxole

Scheme 36. Different Strategies Toward Decarboxylative Alkenylations

Scheme 37. Heck-Like Alkenylation of an Alkyl Iodide

Scheme 38. Cobaloxime-Mediated Decarboxylative Coupling of Carboxylic Acids with Styrenes

Scheme 39. Alkenylation via Alkenyl Iodides

Scheme 40. Alkenylation of an Alkyl Iodide with Alkenyl Sulfones

Scheme 41. Photocatalyzed Synthesis of Ynones

Scheme 42. Synthesis of Enones via Photocatalyzed C–N Bond Activation

Scheme 43. Photocatalyzed Synthesis of Unsymmetrical Ketones

Scheme 44. Dual Catalytic Acylation of Alkyl Trifluoroborates

Scheme 45. Dual Catalytic Acylation of Cycloalkanes

Scheme 46. Alkylation of Fasudil

Scheme 47. Minisci Reaction by Using Alkyl Boronic Acids

Scheme 48. Photocatalyzed Butylation of Lepidine

Scheme 49. Decarboxylative Minisci Alkylation

Scheme 50. Aliphatic Alcohols as Radical Precursors in Minisci Reaction

Scheme 51. Alkylation of Quinine

Scheme 52. Cyclopentenylation of 2-Chloroquinoxaline

Scheme 53. Functionalization of 6-Chloroimidazo[1,2-b]pyridazine

Scheme 54. PFBI–OH Mediated Minisci Reaction

Scheme 55. Remote C(sp³)–H Heteroarylation of Alcohols

Scheme 56. Minisci Alkylation of Pyridine Oxides

Scheme 57. Decarboxylative Alkylation of Heterocycles

Scheme 58. Dual TBADT-Ni Catalysis for the Synthesis of Pyridyl-Functionalized Bicycles

Scheme 59. Dual Catalytic Cross-Coupling of Aryl Bromides with Alkyl Sulfinates

Scheme 60. Coupling of Alkyl Oxalates with Aryl Bromides

Scheme 61. Consecutive Functionalization of Bromo-Iodo Arenes with bis-Catecholato Silicates

Scheme 62. Ir/Ni Complex Mediated Coupling Between Alkyl and Aryl Bromides

Scheme 63. Photocatalyzed Smiles Rearrangement

Scheme 64. Photoredox/Nickel Dual Catalytic Coupling of β-Trifluoroboratoketones with Aryl Bromides

Scheme 65. Adamantylation of Aryl Bromides

Scheme 66. Functionalization of 7-Azaindole Pharmacophores in Flow

Scheme 67. Coupling of DHP-Cyclohexene with Cyanobromopyridine

Scheme 68. Photocatalyst-Free Activation of DHPs

Scheme 69. Copper^I-Mediated Synthesis of Nitriles

Scheme 70. Cyanation of (a) Trifluoroborates and (b) Carboxylic Acids

Scheme 71. Photocatalyzed Cyano Migration in Cyanohydrines

Scheme 72. Alkynylation of Alkyl Trifluoroborates

Scheme 73. Ir^III-Catalyzed Alkynylation of Carboxylic Acids

Scheme 74. Cascade Double Alkynylation of Functionalized Adipic Acids

Scheme 75. Alkylation of Terminal Alkynes

Scheme 76. Photocatalyzed Borylation of N-Hydroxyphthalimides

Scheme 77. Photocatalyst-Free Borylation

Scheme 78. Borylation of 2-Iodophenyl Thionocarbonates

Scheme 79. Photocatalyzed Amination of Methane

Scheme 80. Cerium-Catalyzed Decarboxylative Amination

Scheme 81. Tandem N-Methylation and N-Sulfonylation of Azobenzenes

Scheme 82. Photocatalyzed Synthesis of (a) Amides and (b) Carbamates

Scheme 83. Azidation of Tertiary Aliphatic C–H Bonds

Scheme 84. Photocatalyzed C–H to C–N₃ Conversion

Scheme 85. Decarboxylative C–N Coupling in Cholic Acid Triacetate

Scheme 86. Radical Relay Chaperone Strategy Driven by the Photodecomposition of PhI(OAc)₂

Scheme 87. Late Stage Functionalization of Skelaxin

Scheme 88. Decarboxylative Oxygenation of Phthalimide Esters

Scheme 89. Decarboxylative C(sp³)-O Cross-Coupling

Scheme 90. Late Stage Regioselective Carbonylation of Artemisinin

Scheme 91. Photoinduced Monochlorination of Cyclohexane

Scheme 92. TBADT-Catalyzed Fluorination of Alkanes

Scheme 93. Regioselective Fluorination of Carboxylates

Scheme 94. DBN-Mediated HAT in C–F Bond Formation

Scheme 95. Ring-Opening Halogenation of Oximes

Scheme 96. Bromomalonate as Brominating Agent

Scheme 97. Gem di-Iodination of a Cholic Acid Derivative

Scheme 98. Difluorothiomethylation of Carboxylic Acids

Scheme 99. Trifluoromethylthiolation of Ambroxide

Scheme 100. Arylthiation of N-Acyloxyphthalimides

Scheme 101. Sulfonylation of (a) Styrenes and (b) Alkynes

Scheme 102. Photocatalyzed Reduction of Alkyl Iodides

Scheme 103. Hydrodecarboxylation of Carboxylic Acids

Scheme 104. Reduction of a Xylofuranose Derivative

Scheme 105. Synthesis of 1,1-Disubstituted Cyclopropanes

Scheme 106. Metal-Photocatalyzed Synthesis of Cyclopentanes from Alkyl Halides

Scheme 107. Photocatalyzed Synthesis of Tetrahydrofurans in Flow

Scheme 108. Photocatalyzed Lactonization of Alkenoic Acids

Scheme 109. Photochemically Induced Synthesis of Pyrrolidines

Scheme 110. Three-Component Synthesis of 2-Oxazolidinones

Scheme 111. Photocatalyzed Preparation of 1,2,3,4-Tetrahydrophenanthrenes

Scheme 112. Intramolecular C–C Bond Formation in Indoles

Scheme 113. Photocatalyzed Synthesis of Functionalized Phenanthridines

Scheme 114. Photoredox Preparation of Pyrrolo[1,2-a]quinoxalines

Scheme 115. Late Stage Functionalization of Ursolic Acid

Figure 4

(A) Upconversion of the reducing power of the intermediates in a photocatalytic/photoinitiated cyclization. (B) Two pathways to employ the photoelectrocatalytic strategy: either promoting a single electron transfer with photocatalysis first and a second one with electrocatalysis or vice versa.