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.
Highlights
The Hofmann-Löffler-Freytag (HLF) reaction is a prototypical example of radical-based remote functionalization of unactivated C(sp3)–H bond
We focused on the use of stable and readily available TMSN3 as an azide source and the benzohydrazides 341,42 as precursors of amidyl radicals
In line with our working hypothesis and knowing that peroxide is compatible with the Cu-catalyzed carboazidation process[50,51], the reaction of 3a (R2 = Me, R = R1 = H) with TMSN3 was investigated in the presence of copper salts and peroxides
Summary
The Hofmann-Löffler-Freytag (HLF) reaction is a prototypical example of radical-based remote functionalization of unactivated C(sp3)–H bond. Complementary to this work, significant efforts have been made recently in identifying tailored precursors for the generation of the N-centered radicals[19,20,21,22,23,24,25] The development of these available and stable amidyl radical precursors in conjunction with the recent advent of metal and visible-light photoredox catalysts allowed the execution of the HLF reaction under much milder conditions, providing opportunities to expand the repertoire of the remote C(sp3)–H functionalization process. The process is initiated by the polarity-matched abstraction of the Hantzsch ester’s C-4 hydrogen by the electrophilic thiophenol radical to afford, after fragmentation, the amidyl radical and pyridine The addition of the former to the double bond followed by hydrogen transfer from thiophenol to the resulting radical adduct afforded the product 2 with concurrent regeneration of the thiophenol radical to propagate the chain. Conversion of ethyl to trifluoromethylvinyl group is, to the best of our knowledge, unknown
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