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Rapid Synthesis of α-Chiral Piperidines via a Highly Diastereoselective Continuous Flow Protocol

Chao Shan, Jinping Xu, Liming Cao, Chaoming Liang, Ruihua Cheng, Xiantong Yao, Maolin Sun* and Jinxing Ye*

*School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China, Email: maolinsungdut.edu.cn, jinxingyegdut.edu.cn

C. Shan, J. Xu, L. Cao, C. Liang, R. Cheng, X. Yao, M. Sun, J. Ye, Org. Lett., 2022, 24, 3205-3240.

DOI: 10.1021/acs.orglett.2c00975


Abstract

A practical continuous flow reaction of readily accessible N-(tert-butylsulfinyl)-bromoimine with Grignard reagents provides various enantioenriched α-substituted piperidines in good yields and high diastereoselectivities within minutes. The reaction can be scaled-up smoothly and an efficient synthesis of a drug precursor further showcases its utility.

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Details

The document details a study on the rapid synthesis of α-chiral piperidines using a highly diastereoselective continuous flow protocol. The method employs N-(tert-butylsulfinyl)-bromoimine and Grignard reagents to produce various functionalized piperidines with high yields (typically >80%) and excellent diastereoselectivity (>90:10 dr) within minutes. This continuous flow process offers significant advantages over traditional batch processes, including improved yields, selectivities, and scalability under mild conditions. The study highlights the importance of α-chiral piperidines in organic and medicinal chemistry, as they are key structural motifs in natural products and medicinal compounds. The optimized conditions for the flow synthesis involve precise control of temperature, residence time, and reagent concentrations. The method's utility is further demonstrated by the efficient synthesis of drug precursors and the successful scale-up of the process. The continuous flow protocol provides a practical and scalable approach to synthesizing enantioenriched α-substituted piperidines, which can be readily converted into chiral medicinal agents. The study underscores the potential of flow chemistry to address long-standing challenges in organic synthesis and pharmaceutical manufacturing.


Key Words

piperidines, flow chemistry


ID: J54-Y2022