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 (1) undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached methyl group. Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole (5) and 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole (8) 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 phenyl ring. In contrast, metalation of 1-methyl-3-(trifluoromethyl)pyrazole (2) 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 aromatic ring. This has been demonstrated with 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (3), 4-bromo-1-methyl-3-(trifluoromethyl)pyrazole (4), 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole (7) and 1-(2-bromophenyl)-5-(trifluoromethyl)pyrazole (6). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)