Site-selective α-C(sp3)–H arylation of dialkylamines via hydrogen atom transfer catalysis-enabled radical aryl migration.

Site-selective C(sp³)–H arylation is an appealing strategy to synthesize complex arene structures but remains a challenge facing synthetic chemists. Here we report the use of photoredox-mediated hydrogen atom transfer (HAT) catalysis to accomplish the site-selective α-C(sp³)–H arylation of dialkylamine-derived ureas through 1,4-radical aryl migration, by which a wide array of benzylamine motifs can be incorporated to the medicinally relevant systems in the late-stage installation steps. In contrast to previous efforts, this C–H arylation protocol exhibits specific site-selectivity, proforming predominantly on sterically more-hindered secondary and tertiary α-amino carbon centers, while the C–H functionalization of sterically less-hindered N-methyl group can be effectively circumvented in most cases. Moreover, a diverse range of multi-substituted piperidine derivatives can be obtained with excellent diastereoselectivity. Mechanistic and computational studies demonstrate that the rate-determining step for methylene C–H arylation is the initial H atom abstraction, whereas the radical ipso cyclization step bears the highest energy barrier for N-methyl functionalization. The relatively lower activation free energies for secondary and tertiary α-amino C–H arylation compared with the functionalization of methylic C–H bond lead to the exceptional site-selectivity. Site-selective C(sp³)–H arylation is an appealing strategy to synthesize complex arene structures but remains a challenge facing synthetic chemists. Here the authors report the use of photoredox-mediated hydrogen atom transfer (HAT) catalysis to accomplish the site-selective α-C(sp³)–H arylation of dialkylamine-derived ureas through 1,4-radical aryl migration. [ABSTRACT FROM AUTHOR]