A Regioselective Cycloaddition Route to Pyrazoles

Significance

A regioselective synthesis of substituted pyrazoles by the reaction of N-monosubstituted hydrazones with nitroolefins is described. The reaction proceeds by a stereoselective [3+2] cycloaddition to a pyrazolidine intermediate which, upon exposure to air, undergoes aromatization to the pyrazole. Evidence for this mechanism has been obtained by a React-NMR study. The reaction occurs under mild conditions and tolerates both alkyl and aryl groups in the hydrazone component. The scope and limitations of the reaction have not been sufficiently explored. Pyrazole motifs are important core structures in numerous biologically active compounds, e.g. commercial drugs such as Celebrex (T. D. Penning et al. J. Med. Chem. 1997, 40, 1347-1365) and Viagra (N. K. Terrett, A. S. Bell, D. Brown, P. Ellis Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) (see also review below).