Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds

Zhencheng Lai, Rongkai Wu, Jiaming Li, Xing Chen, Linwei Zeng, Xi Wang, Jingjing Guo, Zujin Zhao, Hironao Sajiki and Sunliang Cui ()
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Zhencheng Lai: Zhejiang University
Rongkai Wu: Zhejiang University
Jiaming Li: Zhejiang University
Xing Chen: Tianjin University
Linwei Zeng: Zhejiang University
Xi Wang: Beijing Jiaotong University
Jingjing Guo: South China University of Technology
Zujin Zhao: South China University of Technology
Hironao Sajiki: Gifu-Pharmaceutical University
Sunliang Cui: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: Abstract Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)−H and activated C(sp3)−H bonds while the unactivated C(sp3)−H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)−H and unactivated benzylic C(sp3)−H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)−H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C–H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)−H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.

Date: 2022
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DOI: 10.1038/s41467-022-28088-z

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