Synthesis of 3-Fluoropyrazoles from 2-Trifluoromethyl-1-alkenes

Key words

3-fluoropyrazoles - hydrazines - trifluoromethylstyrenes

Significance

Reported is a three-step protocol for the de novo synthesis of substituted 3-fluoropyrazoles through annulation of 2-trifluoromethyl-1-alkenes with monosubstituted hydrazines. The first step in this unconventional approach is an S_N2′ addition of an N-deprotonated hydrazine to the trifluoromethyl-substituted alkene to give a 3,3-difluoro allylic hydrazide, which is subsequently tosylated (1→2). While N-alkylation proceeds in a highly regioselective manner when aryl- and Boc-substituted hydrazines are employed, methyl­hydrazine affords a 55:45 mixture of N-regioisomers (66% combined yield, not shown above). Treatment of 2 with NaH in DMF affords the substituted 3-fluoropyrazole 3; control experiments established the need to employ tosylhydrazides in this reaction. 4-Unsubstituted 3-fluoropyrazoles 5 were accessible from the corresponding 2-silyl allylic hydrazide 4.

Comment

Pyrazoles are among the most metabolically stable unsaturated five-membered heterocycles (see Review below) and are frequently incorporated into drug candidates. A successful example is the COX-2 inhibitor celebrex^®. The present method provides efficient access to synthetically challenging substituted 3-fluoropyrazoles through a non-obvious and generally high-yielding annulation sequence that utilizes readily accessible starting materials. On the down side, no mention was made of attempts to achieve the synthesis of C5-substituted pyrazoles; alkyl substitution at C4 was also not explored. Control ­experiments suggest that base-mediated ring ­closure (2→3) proceeds through neither direct nucleophilic vinylic substitution (S_NV) nor an intermediate nitrene. Instead, an unusual pathway is suggested that features an azomethine imine intermediate.

Review

D. K. Dalvie et al. Chem. Res. Toxicol. 2002, 15, 269–299.