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 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.
Balle
Thomas
T
Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark. tb@dfuni.dk
Begtrup
Mikael
M
Jaroszewski
Jerzy W
JW
Liljefors
Tommy
T
Norrby
Per-Ola
PO
D007700:Kinetics; D008094:Lithium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013816:Thermodynamics
D011720:Pyrazoles; D008094:Lithium