Synthesis of 1-tert-Butyl-4-chloropiperidine:  Generation of an N-tert-Butyl Group by the Reaction of a Dimethyliminium Salt with Methylmagnesium Chloride

• Published in: Journal of organic chemistry Vol. 70; no. 5; pp. 1930 - 1933
• Main Authors: Amato, Joseph S, Chung, John Y. L, Cvetovich, Raymond J, Gong, Xiaoyi, McLaughlin, Mark, Reamer, Robert A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.03.2005; Amer Chemical Soc
• Subjects: Butanes - chemical synthesis; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hydrolysis; Indicators and Reagents - chemistry; Magnesium Chloride - chemistry; Organic chemistry; Oxidation-Reduction; Physical Sciences; Piperidines - chemical synthesis; Preparations and properties; Salts - chemistry; Science & Technology; REAGENT; AMINES; Grignard reagent; Chlorination; Thionyl chlorides; Nitrogen heterocycle; Iminium compounds; Chlorine Organic compounds; Piperidine derivatives; Chemical synthesis
• DOI: 10.1021/jo048047g
• ISSN: 0022-3263

Two efficient routes to 1-tert-butyl-4-chloropiperidine are described. In the first route, the key thionyl chloride mediated chlorination reaction features the use of tetrabutylammonium chloride as an additive that effectively suppresses the formation of an elimination-derived side product. In the second route, a novel alternative synthesis of 1-tert-butyl-4-chloropiperidine was developed in which the tertiary butyl group on the nitrogen is efficiently generated through the addition of methylmagnesium chloride to a dimethyliminium salt in 71% overall yield.