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

Abstract

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 ¹H,⁶Li HOESY and NOESY NMR spectra of the thermodynamic product 5-lithio-1-methylpyrazole (5-Li) in [D₈]THF are consistent with an oligomeric structure.