Site-Selective Functionalization of Unactivated C(sp3)–H Bonds via Synergistic Merger of Photoredox and HAT Catalysis

Abstract Hydrogen atom abstraction from C(sp3)−H substrates for the generation of alkyl radical represents a desirable yet underexplored strategy in alkylation reaction since involving noble metal catalysts, stoichiometric oxidants, and limited scope are common drawbacks. Here we describe the synergistic utilization of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers, which features broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centred radicals, generated from free N−H bond via photoredox catalyzed single-electron oxidation followed by deprotonation 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-centred radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol was further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.