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Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds.
- Source :
- Nature Communications; 1/21/2022, Vol. 13 Issue 1, p1-8, 8p
- Publication Year :
- 2022
-
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(sp<superscript>2</superscript>)−H and activated C(sp<superscript>3</superscript>)−H bonds while the unactivated C(sp<superscript>3</superscript>)−H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp<superscript>2</superscript>)−H and unactivated benzylic C(sp<superscript>3</superscript>)−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(sp<superscript>3</superscript>)−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(sp<superscript>3</superscript>)−H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery. The Mannich reaction is a three-component reaction for preparing alkylamines, but the nucleophilic components rely on C(sp<superscript>2</superscript>)−H and activated C(sp<superscript>3</superscript>)−H bonds. Here, the authors report an unprecedented multicomponent double Mannich alkylamination for both C(sp<superscript>2</superscript>)−H and unactivated benzylic C(sp<superscript>3</superscript>)−H bonds. [ABSTRACT FROM AUTHOR]
- Subjects :
- MANNICH reaction
DENSITY functional theory
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 13
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 154815016
- Full Text :
- https://doi.org/10.1038/s41467-022-28088-z