A photoredox-catalyzed approach for formal hydride abstraction to enable Csp3–H functionalization with nucleophilic partners (F, C, O, N, and Br/Cl)

Abstract

A catalytic Csp3–H functionalization manifold for accessing reactive carbocation intermediates directly from a range of Csp3–H bonds is reported. The catalytic design relies on a strategy driven by visible-light photoredox catalysis that combines two mechanistic steps in one catalytic cycle: hydrogen-atom transfer (HAT) and radical-polar crossover (RPC), representing a net hydride abstraction. We herein demonstrate a mild and robust [HAT + RPC] platform that can efficiently enable a Csp3–H fluorination with nucleophilic fluoride—a classically poor nucleophile. Notably, the [HAT + RPC] protocol was successful in the late-stage fluorination of several commercial drugs. Difluorination of methylene groups is also demonstrated, and represents the first C–H difluorination with nucleophilic fluoride. Importantly, long-term potential of the design was demonstrated with the engagement of other nucleophile classes including halides, alcohols, water, N-heterocycle, carboxylic acids, azide, and arenes, thus showcasing its potential as a unified C–H functionalization method.