Regiochemical Control of Pyrazoles by Solvent and [beta]-Enamino Diketone Structure: Regioselective Synthesis of 4,5-Disubstituted N-Phenylpyrazoles

A simple method for the regiocontrolled synthesis of the 4,5-disubstituted N-phenylpyrazole regioisomers 2 and 3 from [beta]-enamino diketones and phenylhydrazine is described. Pyrazole 2 was prepared regioselectively by carrying out the reaction in a protic solvent, whereas pyrazole 3 was obtained as the main product by using an aprotic solvent. Steric factors regarding the [beta]-enamino diketones also influenced the regiochemistry of 2 and 3. The influence of solvent on the reaction outcome can be rationalized by using Fukui indices. The structures of 2 and 3 were unambiguously elucidated by 1H and 13CNMR spectroscopy, two-dimensional HMBC experiments, high resolution mass spectrometry, and X-ray crystallographic analysis.