Regioselective Synthesis of Phosphonyl Pyrazoles

Significance

Based on a previous one-pot ­synthesis of triazoles from aldehydes using the Bestmann-Ohira reagent 3 (D. Luvino et al. ­Synlett 2007, 3037), the synthesis of substituted 5-phosphonyl pyrazoles 4 by a three-component (aldehydes, cyanoacetic derivatives, and 3) domino Knoevenagel condensation-formal 1,3-dipolar cycloaddition sequence has been developed. A range of aldehydes 1 and cyanoacid derivatives 2 afforded 4 in good to excellent yields (cyanoacetic derivatives, e.g. phenylbutyronitrile, benzylcyanide, and trimethylsilylacetonitrile give the homologated alkyne). The structure of 4 was confirmed by single crystal X-ray analysis. A mechanism is proposed involving Michael-type addition of B on the Knoevenagel product A resulting in the intermediate C. C undergoes cyclization to the pyrazoline D and thence affords 4 after HCN elimination and ­intramolecular proton transfer.