Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

Abstract

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 (1S,2R)‐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.

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org Concept stable hetero-substituted organolithiums generated in flow by deprotonation has been reported by Barker andc o-workers. [23] Ad ifferent approach, for the introduction of ad ihalomethylenic unit, was recently reported by Knochel, who developed a continuousf low tactic for homologation of esters using di-chloroacetic acid 13.T he reported strategy, was an unprecedented mild and scalable Claisen reactiont hat used an unstable chloroacetated ianion tamed using flow technology (Scheme 6).…”

“…Chem. Eur.J.2020, 26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org tion of an aldol reactioni nvolving an ester lithium enolate and an aldehydee nding up with adduct 29 (Scheme 14). [41] To comply with recommendations by pharmaceutical regulatory authorities, the process was designedt aking advantages from processa nalytical technology( PAT) that allow for an accurate processd evelopment.…”

“…Fang and Bio reported ac ontinuous flow asymmetricp ropargylation by exploiting an allenyllithium generated by deprotonation of allene gas with n-hexyllithium. [29] The use of ad ynamic mixer allowed to generate the intermediate allenyllithium, avoiding clogging of the flow system. The efficiency of the dynamic mixer was also tested in transmetallation reactions leadingt oa llenylzinc, magnesiuma nd boron (Scheme 10).…”

“…Negishi and decarboxylative Negishic ross-coupling of flow-prepared organozinc reagents.Chem. Eur.J.2020,26,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] www.chemeurj.org2020 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 29…”