γ-Selective C–H functionalization of tertiary alkylamines using α-ammonio radical

Alkylamines are crucial structural motifs found in 43% of active pharmaceutical ingredients, where they interact with biological targets such as receptors and enzymes. Consequently, the C–H functionalization of alkylamines is a powerful strategy for accelerating drug development. Remote C–H functionalization enables the selective modification of the periphery of the active nitrogen site and improves bioactivity and pharmacokinetics. Unlike that of primary and secondary alkylamines, the remote functionalization of tertiary amines is highly 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 of γ-selective 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 utility of distonic radical cations, broadening the methodological landscape for selective radical transformations and inspiring future advancements in radical chemistry.