Butyl Imidates: Highly Stable and Isolable Synthetic Intermediates

Abstract

Imidates are versatile synthetic intermediates that contain ambiphilic reactivity, making them valuable pharmaceutically relevant synthons. Despite their extensive utility, imidates are typically generated in situ rather than isolated due to their inherent instability. This report details a systematic study that led to the discovery of an isolable imidate hydrogen chloride (HCl) salt that exhibits high tolerance to hydrolysis, thereby improving process control and facilitating downstream transformations. Optimization of reaction conditions and anti-solvent selection resulted in a general and scalable approach to access the imidate HCl salt in high yield. A multikilogram campaign of the butyl imidate demonstrated key improvements over the ethyl congener, addressing key practical challenges such as solubility, hydrolysis, and impurity formation. The scope was extended to a series of phenyl- and benzyl-substituted n-butyl imidates.