Synthesis of Diverse N-Trifluoromethyl Pyrazoles by Trapping of Transiently-Generated Trifluoromethylhydrazine

A one-pot synthesis of functionalized N-trifluoromethyl pyrazoles from readily available di-Boc trifluoromethylhydrazine and dialdehydes, diketones, carbonylnitriles, and ketoesters/amides/acids is described. ¹⁹F NMR studies were used to characterize the stability of trifluoromethylhydrazine HCl salt in solution and in solid form and identified a short solution-state half-life of ∼6 h. Optimization of cyclization conditions identified DCM, combined with a strong acid, as a key to suppress the undesired des-CF₃ side products, which formed as a result of the instability of trifluoromethylhydrazine and related intermediates. Despite the short-lived nature of these transient intermediates, their reactivity could be utilized to directly deliver a diverse array of pharmaceutically relevant N-trifluoromethyl pyrazoles in synthetically useful yields.