Regioselective Two-Component Synthesis of Polysubstituted Pyrazoles

Significance

A simple thermal or acid-catalyzed synthesis of polysubstituted pyrazoles by reaction of various hydrazones with nitroolefins is reported. An extensive screening of conditions showed that alcohols are the best solvents and acids as additives promote the reaction. In DMF and DMSO, for example, no reaction takes place. Choosing the right alcohol and acid proved to be crucial, since otherwise complex mixtures resulted. Lewis acids are not efficient in promoting the reaction. Two sets of reaction conditions were developed (A and B), which complement each other in terms of functional group compatibility. The substrate scope was extensively studied and the yields range from poor (electron-deficient hydrazones) to good (electron-rich hydrazones). A mechanistic pathway was considered involving tautomerization of the hydrazone to an azomethine imine, which undergoes a 1,3-dipolar cycloaddition with the nitroolefin. Subsequent oxidation by air followed by elimination of HNO₂ furnishes the product. To differentiate between a stepwise or concerted cycloaddition mechanism, the stereocontrol during this step was studied, and the lack of it suggests a stepwise mechanism.