Taming distonic radical cations for precise γ-C–H functionalization of alkylamines

Alkylamines are crucial structural motifs found in 43% of active pharmaceutical ingredients, where they interact with biological targets. As a consequence, the C–H functionalization of alkylamines is a powerful strategy for accelerating drug development. Remote C–H functionalization enables selective modification of the periphery of the active nitrogen site and can improve bioactivity and pharmacokinetics. Unlike that of primary and secondary alkylamines, the remote functionalization of tertiary amines remains challenging, despite their prevalence in 60% of alkylamine-containing pharmaceuticals. This study exploits the reactivity of α-ammonio radicals, a class of distonic radical cations, to achieve the γ-selective functionalization of tertiary amines. Our approach uses halomethylammonium salts as α-ammonio radical precursors, facilitating precise radical transfer to the γ-position. The resulting γ-radicals enable diverse γ-selective C–H functionalizations, including thioetherification, amination, alkylation, (hetero)arylation and alkenylation. The developed method has a broad substrate scope and enables the late-stage functionalization of complex pharmaceutical molecules, thus holding promise for drug development. Furthermore, our work expands the synthetic use of distonic radical cations, broadening the methodological landscape for selective radical transformations and inspiring future advancements in radical chemistry. γ-Selective C–H functionalization of tertiary alkylamines is achieved using α-ammonio radicals generated from halomethylammonium salts. This strategy enables diverse bond formations, broad substrate scope and late-stage modification of pharmaceuticals, expanding the synthetic utility of distonic radical cations for selective radical transformations in drug discovery.