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

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.

Functionalization of carbon radicals formed via 1,5-hydrogen atom transfer of amidyl radicals is an underdeveloped protocol for remote C–H functionalization. Here, the authors report a Cu-catalyzed γ-azidation and oxidative δ-trifluoromethylation of benzohydrazides for the synthesis of more functionalized amides.