Difluoro(methoxy)methyl is a Neglected Group for Medicinal Chemistry – Revival via CF2OMe Containing Amines

Here we present four key advancements toward the efficient synthesis and application of gem-difluoromethoxyamines from thionoesters. A robust and scalable method was developed for thionoester preparation, employing an imidate-based strategy. Fluorodesulfuration using DAST was systematically evaluated, identifying structural factors influencing reactivity and enabling access to novel CF2OMe-functionalized amines. Stability assessments of hydrolytic resistance compared N-protected derivatives with their hydrochloride counterparts. Additionally, transesterification of thionoesters with primary alcohols expanded the synthetic utility of these intermediates, offering a versatile route to fluorinated building blocks for medicinal chemistry applications.