Synthesis of 1-tert-butyl-4-chloropiperidine: generation of an N-tert-butyl group by the reaction of a dimethyliminium salt with methylmagnesium chloride.
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.
Amato
Joseph S
JS
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
Chung
John Y L
JY
Cvetovich
Raymond J
RJ
Gong
Xiaoyi
X
McLaughlin
Mark
M
Reamer
Robert A
RA
D002073:Butanes / Q000138:chemical synthesis*; D006868:Hydrolysis; D007202:Indicators and Reagents / Q000737:chemistry; D015636:Magnesium Chloride / Q000737:chemistry*; D010084:Oxidation-Reduction; D010880:Piperidines / Q000138:chemical synthesis*; D012492:Salts / Q000737:chemistry*
C499766:1-tert-butyl-4-chloropiperidine; D002073:Butanes; D007202:Indicators and Reagents; D010880:Piperidines; D012492:Salts; D015636:Magnesium Chloride