A renewed interest in the chemistry of carbon-centered radicals has led to the discovery of mild methods for accessing these open shell intermediates. In particular, photoredox catalysis has emerged as a powerful platform for the generation of reactive radical species under mild, functional group tolerant conditions. Herein, we report the development of new mechanisms to access methyl radicals using photoredox catalysis. Trimethyl orthoformate, a common laboratory solvent, was used as a source of methyl radical via b-scission of its tertiary radical species. In a Ni/photoredox paradigm, a chloride-containing electrophile can serve as both the reaction coupling partner and a source of chlorine radical for mediating hydrogen atom transfer (HAT) with trimethyl orthoformate to produce methyl radical. Subsequent methyl radical rebound to nickel and reductive elimination produces valuable C(sp²)–C(sp³) methylated products from (hetero)aryl chlorides. Additionally, we have found that methyl radical can mediate a rare C(sp³)–C(sp³) HAT event. N-Acetoxyphthalimide serves as an inexpensive, bench-stable methyl radical source in an oxidative quenching cycle. Upon methyl radical generation, C(sp³)–H bonds are transformed 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. Mechanistic studies indicate that HAT is mediated by methyl radical, a previously underexplored nucleophilic HAT agent in photoredox catalysis. Importantly, this reaction platform can successfully functionalize a variety of C(sp³)–H bonds with nucleophiles—including fluoride, chloride, water, alcohols, thiols, an electron-rich arene, and an azide—to generate a diverse array of biologically-relevant scaffolds.

Isabelle Leibler

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