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.
Highlights
Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals
Owing to the readily accessible feedstocks, simple manipulation, and privileged product formation, the Mannich reaction is well suited for diversity-oriented synthesis (DOS) applicable in drug discovery, and its utility is demonstrated in alkaloid synthesis and the development of the antiulcer drug Ranitidine[4,5,6,7,8,9,10,11]
We report on the discovery of a multicomponent double Mannich reaction for both C(sp2)−H and unactivated benzylic C(sp3)−H bonds (Fig. 1c)
Summary
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. As a highly relevant synthetic strategy, the double Mannich reaction based on enolizable C−H bonds provides straightforward access to cyclic alkylamines. We report on the discovery of a multicomponent double Mannich reaction for both C(sp2)−H and unactivated benzylic C(sp3)−H bonds (Fig. 1c).
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