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

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 2000-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.