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

Jie Xu, Ruihan Li, Yijian Ma, Jie Zhu, Chengshuo Shen () and Heng Jiang ()
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Jie Xu: Shanghai Jiao Tong University
Ruihan Li: Shanghai Jiao Tong University
Yijian Ma: Zhejiang Sci-Tech University
Jie Zhu: Shanghai Jiao Tong University
Chengshuo Shen: Zhejiang Sci-Tech University
Heng Jiang: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51239-3

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