Switchable reactivity: the site-selective functionalization of trifluoromethyl-substituted pyrazoles

Modern organometallic methods enable the regioflexible conversion of simple heterocyclic starting materials into families of isomers and congeners. Depending on the choice of the reagent, 1-methyl-5-(trifluoromethyl)pyrazole undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached Me group. Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole and 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole are selectively attacked by lithium diisopropylamide at the heterocyclic 4-position and by butyllithium concomitantly at the 4-position and the ortho position of the Ph ring. In contrast, metalation of 1-methyl-3-(trifluoromethyl)pyrazole occurs only at the 5-position, whatever the organometallic or metal amide base. Further sites become accessible to functionalization if bromine is introduced into the heterocyclic or arom. ring. This has been demonstrated with 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole, 4-bromo-1-methyl-3-(trifluoromethyl)pyrazole, 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole and 1-(2-bromophenyl)-5-(trifluoromethyl)pyrazole. [on SciFinder (R)]