Synthesis of Diverse <i>N</i>‑Trifluoromethyl\nPyrazoles by Trapping of Transiently-Generated Trifluoromethylhydrazine

A one-pot synthesis of functionalized <i>N</i>-trifluoromethyl\npyrazoles from readily available di-Boc trifluoromethylhydrazine and\ndialdehydes, diketones, carbonylnitriles, and ketoesters/amides/acids\nis described. <sup>19</sup>F NMR studies were used to characterize\nthe stability of trifluoromethylhydrazine HCl salt in solution and\nin solid form and identified a short solution-state half-life of ∼6\nh. Optimization of cyclization conditions identified DCM, combined\nwith a strong acid, as a key to suppress the undesired des-CF<sub>3</sub> side products, which formed as a result of the instability\nof trifluoromethylhydrazine and related intermediates. Despite the\nshort-lived nature of these transient intermediates, their reactivity\ncould be utilized to directly deliver a diverse array of pharmaceutically\nrelevant <i>N</i>-trifluoromethyl pyrazoles in synthetically\nuseful yields.