Desulfurizative Fluorination of N-CF3 Thioformamides for the Efficient Synthesis of N(CF3)(CF2H) Amines with Enhanced
Gina Wycich1, Jaime Ponce-de-León1, Linhao Liu1
1Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany.
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-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.
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