Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

Abstract

The generation of alkyl radical from C(sp³)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp³)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.

Hydrogen atom abstraction from C(sp³)−H substrates for the generation of alkyl radical represents an underexplored strategy in alkylation reactions. Here the authors describe the synergistic utilization of photoredox and hydrogen atom transfer catalysis to accomplish a general and practical functionalization of unactived C(sp³)−H centers.