Copper-catalyzed remote C(sp3)–H azidation and oxidative trifluoromethylation of benzohydrazides

Xu Bao, Qian Wang and Jieping Zhu ()
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Xu Bao: Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304
Qian Wang: Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304
Jieping Zhu: Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304

Nature Communications, 2019, vol. 10, issue 1, 1-7

Abstract: Abstract The Hofmann-Löffler-Freytag (HLF) reaction is a prototypical example of radical-based remote functionalization of unactivated C(sp3)–H bond. While 1,5-hydrogen atom transfer (1,5-HAT) of the amidyl radical is thermodynamically favorable and is well-established, the method for the subsequent functionalization of the translocated carbon radical is still limited. We report herein two catalytic remote C(sp3)–H functionalization protocols. Cu(MeCN)4PF6-catalyzed reaction of 2-alkyl benzohydrazides 3 with TMSN3 in the presence of MeCO2OtBu affords the γ-azido amides 4, while CuCl-catalyzed reaction of 3 with Togni’s reagent provides 2-(β-trifluoromethylvinyl)benzamides 5 via an oxidative δ-trifluoromethylation of the alkyl group. Mechanistic studies suggest that the γ-azidation of benzohydrazides 3 goes through 1,5-HAT followed by a Cu-mediated azido transfer cascade, while the oxidative δ-trifluoromethylation of 3 proceeds via, after 1,5-HAT process, a radical-polar crossover mechanism.

Date: 2019
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DOI: 10.1038/s41467-019-08741-w

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