Taming Distonic Radical Cations for Precise gamma-C–H Functionalization of Alkylamines

Alkylamines are crucial structural motifs found in 43% of pharmaceuticals, where they interact with biological targets such as receptors and enzymes. Consequently, C–H functionalization of alkylamines serves as a powerful strategy for accelerating drug development. Especially, remote C–H functionalization enables selective modification of the periphery of the active nitrogen site, improving bioactivity and pharmacokinetics properties. While remote functionalization of primary and secondary alkylamines is well-established, analogous transformations of tertiary amines remain highly challenging, despite their prevalence in 60% of alkylamine-containing pharmaceuticals. This study unveils the new reactivity of α-ammonio radicals, a class of distonic radical cations, to achieve g-selective functionalization of tertiary amines. Our approach leverages halomethylammonium salts as precursors to α-ammonio radicals, facilitating precise radical transfer to the g-position. The resulting g-radicals enable a diverse range of gamma-selective functionalizations, including thioetherification, amination, alkylation, (hetero)arylation, and alkenylation. This method offers a broad substrate scope and facilitates late-stage functionalization of complex pharmaceutical molecules, highlighting its potential for drug development. Furthermore, this research expands the synthetic utility of distonic radical cations, broadening the methodological landscape for selective radical transformations and inspiring future advancements in radical chemistry.