Regioselectivity in lithiation of 1-methylpyrazole: experimental, density functional theory and multinuclear NMR study

Reaction of 1-methylpyrazole with n-BuLi in THF followed by reaction with monodeuteromethanol (CH3OD) under kinetically controlled conditions leads to functionalisation at the methyl group, whereas reaction under thermodynamically controlled conditions leads to functionalisation at the pyrazole 5-position. The observed regioselectivity can be correctly predicted, at least qualitatively, using density functional B3LYP/6-31+G(d, p) calculations only when solvation effects (IEFPCM) are taken into account. The H-1, Li-6 HOESY and NOESY NMR spectra of the thermodynamic product 5-lithio-1-methylpyrazole (5-Li) in [D-8] THF are consistent with an oligomeric structure.