Asymmetric synthesis of (−)-α-conhydrine

Exp. Modification Necessary to Address Variable Yield


In one of my recent projects, I need find a method to convert diethyl malonate-d2 into 3-bromopropanol-d6. Following a literature reported procedure (Eur. J. Org. Chem. 2011, 3339–3346), diethyl malonate-d2 underwent lithium aluminum deuteride (LAD) reduction smoothly to form 1,3-propanol-d6. Then I hope I could use the procedure decribed in this paper to prepare 3-bromopropanol-d6 from 1,3-propanol-d6. Therefore, I reproduced the preparation of 13 starting from 12 (Scheme 2) several times and found the yield of the product is variable (23%-82%). After carefully examing the reaction, I observed the starting material 1,3-propanol could be brought to Dean-Stark water separator by solvent when the reaction mixture was heated too fast. This is responsible for the variable yield. To address this issue, I modified the procedure, in which the reaction mixture was heated under reflux for 28 h without using the Dean-Stark water separator and the yield could be significantly improved to 94% (79% in the paper). This also suggested that using the Dean-Stark to remove water from the reaction system to drive the reaction forward was NOT necessary.         

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