Desulfurizative Fluorination of <i>N</i> ‐CF ₃ Thioformamides for the Efficient Synthesis of <i>N</i> (CF ₃ )(CF ₂ H) Amines with Enhanced Stability

Abstract

Abstract With poor metabolic stability being a major cause of failure in drug development, there is a pressing need for strategic molecular modifications to optimize for desired properties and function. N ‐substitution has emerged as a powerful approach, with N ‐CF 3 amines previously demonstrating enhanced lipophilicity and reduced susceptibility to oxidation, albeit inherent instability to hydrolysis. This report discloses the further evolution of this motif—the introduction of an additional N ‐difluoromethyl unit, resulting in an extraordinary 2000‐fold increase in stability. We present the first general synthetic strategy for accessing N (CF 3 )(CF 2 H) amines. The method relies on an operationally simple desulfurization–fluorination strategy of N ‐CF 3 thioformamides and is characterized by broad functional group tolerance.