The generation of zinc enolates (Reformatsky reagents) by the reaction of metallic zinc with alpha-halo esters is a well-known process with considerable synthetic utility.  Recently, we encountered challenges in reproducibly generating a Reformatsky reagent on large scale. The development of a robust and scalable procedure for the zinc insertion into methyl 1-bromocyclopropanecarboxylate will be presented.  The impact of several additives on the activation of zinc and subsequent generation of the Reformatsky reagent will be discussed.   Key to the development of this process was the extensive use of in situ IR spectroscopy as a non-destructive Process Analytical Technology (PAT).  The use of in situ IR spectroscopy enabled real-time monitoring of reaction intermediates and other key components of the process.

Process development in the manufacture of a Reformatsky reagent from methyl 1-bromocyclopropanecarboxylate

ACS Spring 2022

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