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Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol
Author(s) -
Li Hui,
Sheeran Jillian W.,
Clausen Andrew M.,
Fang YuanQing,
Bio Matthew M.,
Bader Scott
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201704882
Subject(s) - allene , transmetalation , reagent , yield (engineering) , flow chemistry , chemistry , process (computing) , scalability , alcohol , continuous flow , flow (mathematics) , dissolution , combinatorial chemistry , process engineering , organic chemistry , computer science , biochemical engineering , materials science , catalysis , engineering , mathematics , metallurgy , geometry , database , operating system
The development of a flow chemistry process for asymmetric propargylation using allene gas as a reagent is reported. The connected continuous process of allene dissolution, lithiation, Li‐Zn transmetallation, and asymmetric propargylation provides homopropargyl β‐amino alcohol 1 with high regio‐ and diastereoselectivity in high yield. This flow process enables practical use of an unstable allenyllithium intermediate. The process uses the commercially available and recyclable (1 S ,2 R )‐ N ‐pyrrolidinyl norephedrine as a ligand to promote the highly diastereoselective (32:1) propargylation. Judicious selection of mixers based on the chemistry requirement and real‐time monitoring of the process using process analytical technology (PAT) enabled stable and scalable flow chemistry runs.