Radical-Mediated γ-C(sp3)−H Functionalization of Quaternary Ammonium Salts

Abstract

Quaternary ammonium salts (QAS), despite their prevalence in pharmaceuticals and materials, remain underexplored in directed C−H functionalization due to the absence of lone-pair coordination sites and electronic deactivation of proximal C−H bonds. We report a traceless strategy for remote γ-C−H functionalization of quaternary ammonium salts enabled by in situ generation of highly reactive α-ammonioalkyl radicals. These electron-deficient radicals drive efficient, regioselective intramolecular hydrogen atom abstraction (HAA) from unactivated γ-positions. The protocol exhibits broad substrate scope and regioselectivity. Traceless N-demethylation completes formal remote functionalization of tertiary amines. This work establishes a powerful radical platform for remote C−H diversification of ammonium salts and amines, with potential for late-stage modification of nitrogen-rich pharmacophores.