General strategies for C(sp3)–H functionalization are critical to the advancement of modern methods for molecular diversification. In recent years, photoredox catalysis has provided critical avenues to C(sp3)–H functionalization, allowing selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, photocatalytic functionalization of carbon-centered radicals is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating interest in developing mild, general C(sp3)–H functionalization strategies with nucleophiles in a photocatalytic setting. Here we describe a photocatalytic strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or strong oxidant. The resulting carbocation can be functionalized by halides, water, alcohols, thiols, an electron-rich arene, and an azide, affecting a diverse array of bond formations. Reaction development is demonstrated in the context of nucleophilic fluorination, which is gratifyingly applicable to the late-stage diversification of several bioactive molecules. Mechanistic studies indicate that HAT is mediated by methyl radical, a HAT agent previously unexplored and with differing polarity to many of those used in photoredox catalysis. Accordingly, in the fluorination of ibuprofen ethyl ester, this methodology delivers new site-selectivity for late-stage C(sp3)–H functionalization.

Nucleophilic C(sp3)–H functionalization using methyl radical as a hydrogen atom abstractor

ACS Spring 2022

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