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Review
. 2018 Aug 28;47(17):6603-6743.
doi: 10.1039/c8cs00201k.

A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry

Carlo Sambiagio  1 , David Schönbauer, Remi Blieck, Toan Dao-Huy, Gerit Pototschnig, Patricia Schaaf, Thomas Wiesinger, Muhammad Farooq Zia, Joanna Wencel-Delord, Tatiana Besset, Bert U W Maes, Michael Schnürch
Affiliations
Review

A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry

Carlo Sambiagio et al. Chem Soc Rev. .

Abstract

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.

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Figures

Fig. 1
Fig. 1. Examples of classical reactivity versus DG approach.
Fig. 2
Fig. 2. Murai's ketone-directed alkylation.
Scheme 1
Scheme 1. Ketone-directed arylations.
Scheme 2
Scheme 2. Ketone-directed alkylations.
Scheme 3
Scheme 3. Ketone-directed alkylation on carbo- and heterocycles.
Scheme 4
Scheme 4. Ketone-directed olefinations on various substrates.
Scheme 5
Scheme 5. Ketone-directed alkynylation, acylation and C–N bond formation.
Scheme 6
Scheme 6. Aldehyde-directed C–H functionalisation.
Scheme 7
Scheme 7. Arylation with carboxylic acids as DG.
Scheme 8
Scheme 8. Annulation reactions.
Scheme 9
Scheme 9. Arylation with carboxylic acids as traceless DG.
Scheme 10
Scheme 10. Alkylation and allylation reactions directed by carboxylic acids.
Scheme 11
Scheme 11. Alkenylations directed by carboxylic acids to access lactones.
Scheme 12
Scheme 12. Alkenylation directed by carboxylic acids and subsequent annulation to alkylated lactones.
Scheme 13
Scheme 13. Alkenylation directed by carboxylic acids.
Scheme 14
Scheme 14. Alkynylation directed by carboxylic acids.
Scheme 15
Scheme 15. Aminocarbonylation directed by carboxylic acids.
Scheme 16
Scheme 16. C–Heteroatom bond formation directed by carboxylic acids.
Scheme 17
Scheme 17. Functionalisation of C(sp3)–H bonds directed by carboxylic acids.
Scheme 18
Scheme 18. Mn-Catalysed lactonization directed by esters.
Scheme 19
Scheme 19. Ester-directed oxidative alkenylation reactions.
Scheme 20
Scheme 20. Ester-directed alkenylation and consecutive annulation.
Scheme 21
Scheme 21. Ligand-assisted ortho and para borylation.
Scheme 22
Scheme 22. Amide-directed arylation reactions.
Scheme 23
Scheme 23. Tandem amide-directed arylation-oxidative coupling.
Scheme 24
Scheme 24. Amide-directed alkylation and allylation reactions.
Scheme 25
Scheme 25. Amide-directed enamide and aldehyde alkylation.
Scheme 26
Scheme 26. Amide-directed alkylation/allylation–cyclisation sequences.
Scheme 27
Scheme 27. Amide-directed alkenylation reactions.
Scheme 28
Scheme 28. Amide-directed alkenylation with acrylates.
Scheme 29
Scheme 29. Amide-directed alkenylation of non-aromatic C(sp2) centres.
Scheme 30
Scheme 30. Amide-directed aldehyde olefination.
Scheme 31
Scheme 31. Amide-directed alkenylation–cyclisation sequences.
Scheme 32
Scheme 32. Miscellaneous amide-directed reactions.
Scheme 33
Scheme 33. Amide-directed halogenation reactions.
Scheme 34
Scheme 34. Amide-directed C–O bond forming reactions.
Scheme 35
Scheme 35. Amide-directed C–N bond forming reactions.
Scheme 36
Scheme 36. Amide-directed C(sp3)–H functionalisations.
Scheme 37
Scheme 37. Arylation reactions directed by N-alkoxy and N-aryloxyamides.
Scheme 38
Scheme 38. N-Alkoxyamide-directed alkylation/allylation reactions.
Scheme 39
Scheme 39. N-Alkoxy- and N-hydroxyamide-directed alkenylation reactions.
Scheme 40
Scheme 40. Alkenylation–cyclisation sequences directed by N-alkoxyamide/ureas.
Scheme 41
Scheme 41. Various transformations directed by N-alkoxy- and N-aryloxy- and Weinreb amide.
Scheme 42
Scheme 42. Carbamate-directed transformations.
Scheme 43
Scheme 43. Urea-directed alkylation reactions.
Scheme 44
Scheme 44. Urea-directed arylation and olefination.
Scheme 45
Scheme 45. Urea-directed alkenylation–cyclisation sequences.
Scheme 46
Scheme 46. Ligand-assisted meta borylation.
Scheme 47
Scheme 47. Cyano-directed ortho functionalisation.
Fig. 3
Fig. 3. General strategy for designing meta-directing moieties.
Scheme 48
Scheme 48. Cyano-directed meta-alkenylation.
Scheme 49
Scheme 49. Cyano-directed meta-functionalisation.
Scheme 50
Scheme 50. Cyano-directed para-(and meta-)alkenylation.
Scheme 51
Scheme 51. Imine-directed arylation reactions.
Scheme 52
Scheme 52. Imine-directed alkylation/allylation reactions.
Scheme 53
Scheme 53. Imine-directed alkenylation and alkenylation–cyclisation reactions.
Scheme 54
Scheme 54. Imine-directed functionalisation–cyclisation sequences.
Scheme 55
Scheme 55. In situ formed imine DGs and subsequent cyclisation.
Scheme 56
Scheme 56. O-Methyl oxime-directed arylation reactions.
Scheme 57
Scheme 57. O-Methyl oxime-directed alkylation reactions.
Scheme 58
Scheme 58. Alkenylation reactions and alkenylation–cyclisation sequences directed by oximes and derivatives.
Scheme 59
Scheme 59. O-Methyl oxime-directed acylation and acylation/cyclisation reactions.
Scheme 60
Scheme 60. C–O bond forming reactions directed by oxime derivatives.
Scheme 61
Scheme 61. C–N and C–Se bond forming reactions directed by O-methyl oximes.
Scheme 62
Scheme 62. Hydrazine·HCl- and hydrazine-directed transformations.
Scheme 63
Scheme 63. Miscellaneous transformations directed by hydrazine/hydrazide/hydrazone derivatives.
Scheme 64
Scheme 64. Hydrazone and dibenzylidenehydrazine-directed transformations.
Scheme 65
Scheme 65. Pd-Catalysed arylation of C(sp2) centres with 8-aminoquinoline-derived amides as DG.
Scheme 66
Scheme 66. Arylation of 8-aminoquinoline-derived amides as DG.
Scheme 67
Scheme 67. Alkylation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 68
Scheme 68. Allylation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 69
Scheme 69. Alkenylation, alkynylation and annulation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 70
Scheme 70. Reactions with isocyanide and nitromethane using 8-aminoquinoline-derived amides as DG.
Scheme 71
Scheme 71. Carbonylation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 72
Scheme 72. Trifluoromethylation and halogenation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 73
Scheme 73. Amination and nitration of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 74
Scheme 74. Hydroxylation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 75
Scheme 75. Thiolation and trifluoromethylthiolation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 76
Scheme 76. Selenylation and silylation of C(sp2) centres using 8-aminoquinoline-derived amides as DG.
Scheme 77
Scheme 77. Arylation of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 78
Scheme 78. Diastereoselective or enantioselective arylation of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 79
Scheme 79. Arylation of C(sp3) centres of saturated heterocycles with 8-aminoquinoline-derived amides as DG.
Scheme 80
Scheme 80. Alkylation, cyanomethylation and alkoxycarbonylation of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 81
Scheme 81. Alkenylation and carbonylation of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 82
Scheme 82. Halogenation and C–O bond formation on C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 83
Scheme 83. Amination of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 84
Scheme 84. Sulfenylation, sulfonylation, trifluoromethylthiolation and silylation of C(sp3) centres with 8-aminoquinoline-derived amides as DG.
Scheme 85
Scheme 85. Functionalisation of C(sp2) centres using amides derived from 5-chloro-8-aminoquinoline (Q′NH2) and from 5-methoxy-8-amino-quinoline (MQNH2) as DGs.
Scheme 86
Scheme 86. Functionalisation of C(sp3) centres using amides derived from 5-chloro-8-aminoquinoline (Q′NH2) and from 5-methoxy-8-amino-quinoline (MQNH2) as DGs.
Scheme 87
Scheme 87. Functionalisation of C(sp2) centres using sulfonamides featuring 8-aminoquinoline and amides derived from phenylenediamine as DGs.
Scheme 88
Scheme 88. Transition metal catalysed functionalisation of C(sp2) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.
Scheme 89
Scheme 89. Alkynylation of C(sp2) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.
Scheme 90
Scheme 90. C(sp2)–heteroatom bond formation using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.
Scheme 91
Scheme 91. Pd-Catalysed functionalisation of C(sp3) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.
Scheme 92
Scheme 92. Functionalisation of C(sp3) centres using the amides derived from 2-(2-pyridyl)ethylamine (PE) and 2-(aminomethyl)pyridine (PM) as DGs.
Scheme 93
Scheme 93. Picolinamide-directed arylation and alkylation of C(sp2) centres.
Scheme 94
Scheme 94. Picolinamide-directed alkenylation and alkynylation of C(sp2) centres.
Scheme 95
Scheme 95. Picolinamide-directed functionalisation of C(sp2) centres.
Scheme 96
Scheme 96. Picolinamide-directed alkenylation, arylation, carbonylation and esterification of C(sp3) centres.
Scheme 97
Scheme 97. Alkylation, allylation, alkenylation and alkynylation of C(sp2) centres using triazolyldimethyl amide as DG.
Scheme 98
Scheme 98. Alkylation and alkynylation of C(sp3) centres using triazolyldimethyl amide as DG.
Scheme 99
Scheme 99. Functionalisation of C(sp2) centres using 2-(2-oxazolinyl)phenyl amide as DG.
Scheme 100
Scheme 100. Functionalisation using amides derived from other heterocyclic amines as bidentate DGs.
Scheme 101
Scheme 101. Arylation using N,S-bidentate DGs.
Scheme 102
Scheme 102. Alkenylation of C-(sp2) centres using 2-pyridine-N-oxide amide as DG.
Scheme 103
Scheme 103. Alkoxylation and amination of C(sp2) centres using 2-pyridine-N-oxide amide as DG.
Scheme 104
Scheme 104. Arylation and amination of unactivated C(sp3)–H bonds using 2-pyridine-N-oxide amide as DG.
Scheme 105
Scheme 105. Functionalisation of C(sp2) centres using oxalyl amide as DG.
Scheme 106
Scheme 106. Silylation and germanylation of C(sp2) centres using oxalyl amide as DG.
Scheme 107
Scheme 107. Functionalisation of C(sp3) centres using oxalyl amide as DG.
Scheme 108
Scheme 108. Acetoxylation of C(sp3) centres using amide derived from 1-aminoanthraquinone as DG.
Scheme 109
Scheme 109. C(sp2)–H arylation using pyridine as DG.
Scheme 110
Scheme 110. Pyridine-directed C(sp2)–H alkylations via addition to double bonds.
Scheme 111
Scheme 111. Pyridine-directed C(sp2)–H alkylations via cross-coupling and carbene insertion.
Scheme 112
Scheme 112. Pyridine-directed alkylation/cyclisation.
Scheme 113
Scheme 113. Pyridine-directed allylations on C(sp2) centres.
Scheme 114
Scheme 114. Pyridine-directed C(sp2)–H olefination.
Scheme 115
Scheme 115. Pyridine-directed olefination/cyclisations via C–N bond formation or rollover pathways.
Scheme 116
Scheme 116. Alkynylation and alkynylation/cyclisation using pyridine-based DGs.
Scheme 117
Scheme 117. Pyridine-directed ortho cyanation of C(sp2)–H bonds.
Scheme 118
Scheme 118. C(sp2)–H acylation using pyridine as DG.
Scheme 119
Scheme 119. Pyridine-directed alkoxy- and aminocarbonylation.
Scheme 120
Scheme 120. C(sp2)–S bond formation with pyridine DGs.
Scheme 121
Scheme 121. Si–N and B–N non-covalent interactions during pyridine-directed functionalisations.
Scheme 122
Scheme 122. Pyridine-directed borylation of C(sp2) centres.
Scheme 123
Scheme 123. Pyridine-directed silylation of C(sp2) centres.
Scheme 124
Scheme 124. Amidation reactions with pyridine DGs.
Scheme 125
Scheme 125. Amination and related reactions with pyridine DGs.
Scheme 126
Scheme 126. Azidation of aranes using pyridine as DG.
Scheme 127
Scheme 127. Pyridine-directed C(sp2)–O bond formation.
Scheme 128
Scheme 128. Pyridine-directed C(sp2)–H halogenation reactions.
Scheme 129
Scheme 129. Arylation of 2-ethylpyridines and 8-methylquinoline derivatives.
Scheme 130
Scheme 130. Alkylation of 8-methylquinoline derivatives.
Scheme 131
Scheme 131. Olefination and alkynylation of 8-methylquinolines.
Scheme 132
Scheme 132. Acylation of 8-methylquinolines and 2-ethylpyridines.
Scheme 133
Scheme 133. Directed amidation on 8-methylquinoline and 2-ethylpyridine derivatives.
Scheme 134
Scheme 134. Directed amination and nitration on 8-methylquinoline and 2-ethylpyridine derivatives.
Scheme 135
Scheme 135. C–O bond formation on 8-methylquinolines.
Scheme 136
Scheme 136. C(sp3)–H borylation and silylation.
Scheme 137
Scheme 137. Common strategies for pyrimidine DG cleavage or migration.
Scheme 138
Scheme 138. Pyrimidine-directed arylation of indoles.
Scheme 139
Scheme 139. Pyrimidine-directed alkylation of indoles.
Scheme 140
Scheme 140. Pyrimidine-directed allylation of indoles.
Scheme 141
Scheme 141. Pyrimidine-directed olefinations.
Scheme 142
Scheme 142. Pyrimidine-directed alkynylations.
Scheme 143
Scheme 143. Pyrimidine-directed cyanation, acylation and aminocarbonylation of indoles.
Scheme 144
Scheme 144. Phosphoramidation and amination on indoles and indolines.
Scheme 145
Scheme 145. Directed C–S bond formation on indoles and indolines.
Scheme 146
Scheme 146. Protocols for the cleavage/modification of N-, O-, S-, and Si-linked pyridine DGs.
Scheme 147
Scheme 147. C(sp2)–H and C(sp3)–H functionalisation with NH-linked pyridine and pyrimidine DGs.
Scheme 148
Scheme 148. Functionalisation with O-linked pyridine and pyrimidine DGs.
Scheme 149
Scheme 149. Functionalisation with Si-linked pyridine and pyrimidine DGs.
Scheme 150
Scheme 150. Functionalisation with S-linked pyridine DGs.
Scheme 151
Scheme 151. C8-Functionalisation of quinoline-N-oxides.
Scheme 152
Scheme 152. Examples of cleavage/modification of pyrazole DGs.
Scheme 153
Scheme 153. Pyrazole-directed C(sp2)–H functionalisation.
Scheme 154
Scheme 154. Pyrazole-directed C(sp3)–H functionalisation.
Scheme 155
Scheme 155. 1,2,3-Triazoles as DGs.
Scheme 156
Scheme 156. Purine-directed C–H functionalisations.
Scheme 157
Scheme 157. C–H functionalisation directed by 7-azaindole moieties.
Scheme 158
Scheme 158. Oxadiazoles and benzisoxazoles as DGs.
Scheme 159
Scheme 159. Ring-opening/cyclisation involving oxazoline DGs.
Scheme 160
Scheme 160. Oxazolines and benzoxazoles as DGs.
Scheme 161
Scheme 161. Benzothiazoles as DGs.
Scheme 162
Scheme 162. C(sp2)–H functionalisation using thioether-based DGs.
Scheme 163
Scheme 163. Rare examples of dithiane DGs.
Scheme 164
Scheme 164. Disulfide-directed C–H hydroxylation.
Scheme 165
Scheme 165. Sulfoxide-directed C–H functionalisation.
Scheme 166
Scheme 166. Sulfone-directed C–H functionalisation.
Scheme 167
Scheme 167. Direct functionalisation using sulfonamides as DG.
Scheme 168
Scheme 168. (Free-NH)-sulfoximine-directed C–H functionalisation.
Scheme 169
Scheme 169. (N-Benzoyl)sulfoximine and related DGs.
Scheme 170
Scheme 170. Thioamide, thioketones, alkoxythiocarbonyls and thiocarbamates as DG.
Scheme 171
Scheme 171. Phosphine oxide- and sulfide-directed transformations.
Scheme 172
Scheme 172. Other P-based DGs in C–H functionalisation.
Scheme 173
Scheme 173. Silanes as DGs (intramolecular silylation).
Scheme 174
Scheme 174. In situ formed silyl ethers as DGs (C(sp2)–H intramolecular silylation).
Scheme 175
Scheme 175. In situ formed silyl ethers as DGs (C(sp3)–H intramolecular silylation).
Scheme 176
Scheme 176. Silane-directed borylation reactions.
Scheme 177
Scheme 177. Silanols and siloxanes as DGs.
Scheme 178
Scheme 178. Hydroxy- and methoxy-directed transformations.
Scheme 179
Scheme 179. Aromatic amines as DGs.
Scheme 180
Scheme 180. Functionalisation of C-sp3 centres directed by aliphatic amines.
Scheme 181
Scheme 181. Amine-directed remote functionalisations.
Scheme 182
Scheme 182. Nitrone-based DGs.
None
Carlo Sambiagio
None
David Schönbauer
None
Joanna Wencel-Delord
None
Tatiana Besset
None
Bert U. W. Maes
None
Michael Schnürch
See this image and copyright information in PMC

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