Keywords: Heterocycles / Bromopyrazoles / Carboxylation / Hydrogen/metal exchange / Halogen/metal exchange / Organolithium intermediatesModern 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 Efficacy and versatility make organometallic methods particularly suitable for the functionalization of olefinic, aromatic and heterocyclic core structures. [1Ϫ2] The metalation of pyrazole, N-alkylpyrazoles and N-phenylpyrazole at the 5-position has been repeatedly reported. [3Ϫ10] The trapping products qualify as valuable intermediates for the synthesis of pharmaceuticals and agrochemicals. To probe further the intriguing steric and electronic properties of the CF 3 group, [11Ϫ12] we have turned our attention to trifluoromethyl-substituted pyrazoles. Previously, 5-methyl-1-phenyl-3-(trifluoromethyl)pyrazole, 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole and 1-phenyl-3,4-bis(trifluoromethyl)pyrazole have been treated with butyllithium, and metalation at the 4-position of the azole ring has been achieved to the extent of 0%, 11% and 95%, respectively. [13] Under similar conditions, 3-chloro-1-methyl-5-(trifluoromethyl)pyrazole was found to undergo 4-lithiation and subsequent carboxylation in 75% yield. [14] Although (trifluoromethyl)pyrazoles are readily accessible by condensation [15Ϫ27] or [3 ϩ 2] cycloaddition [28] reactions, only one out of eight model substrates studied, 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole, [29] could be prepared according to a literature procedure. The isolation of 1-methyl-5-(trifluoromethyl)pyrazole (1) in 76% yield has also been reported. However, these results were not reproducible. In reality, 4-ethoxy-1,1,1-trifluoro-3-butene-2-one [a] 2913 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). and methylhydrazine afforded a 3:7 mixture (up to 98%) of pyrazole 1 and the regioisomeric 1-methyl-3-(trifluoromethyl)pyrazole (2). A convenient separation of the two components could be accomplished after short reaction times when 4,5-dihydro-...
