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

Bao Li^†, Fenglei Xie^†, Rui Zhang^†, Yaoyi Wang^†, Vijaya B. Gondi^‡, and Christopher R. H. Hale^‡*

^†WuXi AppTec Research Chemistry Services, 168 NanHai Road, 10th Avenue, TEDA, Tianjin, 300457, China

^‡ Karuna Therapeutics – A Bristol Myers Squibb Company, Chemical Development, 99 High Street, Floor 26, Boston, Massachusetts 02110, United States

*Email: khale@karunatx.com

ABSTRACT

A one-pot synthesis of functionalized N-trifluoromethyl pyrazoles from readily available di-Boc trifluoromethylhydrazine and dialdehydes, diketones, carbonylnitriles, and keto-esters/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 hours. Optimization of cyclization conditions identified DCM, combined with a strong acid, as 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.

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