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.

 

MissingLinkText

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.

 

MissingLinkText

Review

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

 

MissingLinkText

 

MissingLinkText