Desulfurizative Fluorination of N–CF3 Thioformamides for the Efficient Synthesis of N(CF3)(CF2H) Amines with Enhanced Stability

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‐CF₃ 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 2,000‐fold increase in stability. We present the first general synthetic strategy for accessing N(CF₃)(CF₂H) amines. The method relies on an operationally simple desulfurization–fluorination strategy of N‐CF₃ thioformamides and is characterized by broad functional group tolerance.