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.

A General Strategy for C(sp3)–H Functionalization with Nucleophiles Using Methyl Radical as a Hydrogen Atom Abstractor

“…Electron-rich functionality, traditionally vulnerable to electrophilic reagents or stoichiometric oxidants, was well tolerated (11 and 12). 48,49 In general, electron-rich ethylbenzenes displayed higher reactivity (11-13 and 15) than more electron-deficient analogues (19)(20)(21)(22). This trend is consistent with electron donating substituents conferring higher carbocation stability than electron withdrawing analogues.…”

“…16,17 Whereas nucleophilic reagents represent an abundant and practical reagent class, few strategies have been reported for radical-based C(sp 3 )-H functionalization with nucleophiles. 4,7,[18][19][20] This deficit likely reflects the challenge of productively engaging a nucleophilic carbon-centered radical with a nucleophilic functionalizing reagent. Recent contributions have centered on the use of a transition-metal catalyst to mediate radical capture and bond formation, rendering the nucleophile an electrophilic ligand in the presence of a stoichiometric oxidant.…”

Functionalization of remote C(sp3)-H bonds enabled by copper-catalyzed coupling of O-acyloximes with terminal alkynes

“…While dual photocatalyst/Cu catalytic system has emerged as a powerful tool for cross-coupling reactions 47 , the catalytic cycle depicted in Fig. 1e using copper as the only catalyst remained uncommon [48][49][50][51] . We report herein the successful realization of this endeavor by developing synthesis of γand δ-alkynyl nitriles 4 and γ-alkynyl ketones 5 from simple oxime esters 1 or 2 and terminal alkynes 3 (Fig.…”

Advances in C(sp3)–H Bond Functionalization via Radical Processes

“…using TMSN 3 and Togni's reagent, respectively (Scheme 25). 32 Studer and co-workers reported, in 2018, a remote site selective functionalization of an unactivated aliphatic C-H bond in an amide (Scheme 26). 33 The N-allylsulfonyl moiety was employed as a N-radical precursor.…”