Photoredox cobalt-catalyzed late-stage N-methyl-selective C–H vinylation of unactivated trialkylamines with alkynes

Abstract Late-stage functionalization of trialkylamine-containing drugs provides a direct way to access new chemical space, but selective modification of unactivated trialkylamines remains challenging because they contain multiple competing α-amino C–H bonds. Here we show a photoredox/cobalt dual-catalytic strategy for N-methyl-selective α-C–H vinylation of unactivated tertiary alkylamines with internal alkynes. This redox-neutral method provides trisubstituted allylic amines without directing groups or external oxidants, with broad substrate scope and high regioselectivity, stereoselectivity and site-selectivity under mild conditions. The reaction accommodates diverse amines and alkynes, including electronically unbiased dialkyl alkynes, and enables gram-scale synthesis, preparation of the fungicide fenpropidin and late-stage functionalization of structurally complex pharmaceuticals. Some drug analogues show enhanced apparent human histamine H1 receptor binding affinity. Mechanistic experiments and computational studies support a reasonable reaction pathway involving α-amino carbon radical generation via photoredox catalysis, followed by aminomethyl-cobalt I -mediated alkyne migratory insertion and protonolysis. This work provides a practical strategy for selective trialkylamines editing and late-stage diversification.