Quadruple Functionalized Pyrazole Pharmacophores by One‐pot Regioselective [3+2] Cycloaddition of Fluorinated Nitrile Imines and Dicyanoalkenes

Abstract Here we present a quadruple functionalization approach for the modular construction of fully substituted N 1 ‐aryl 3‐di/trifluoro‐methyl‐4/5‐cyanopyrazole pharmacophores from readily available hydrazonyl chlorides and dicyanoalkenes. The realization of this [3+2] cycloaddition reaction hinges upon the employment of N ‐aryl di/trifluoromethyl nitrile imines as the 1,3‐dipoles to bypass external synthetic steps and dicyanoalkenes as the dipolarophiles to tune the regioselectivity. This one‐pot strategy offers access to a divergent library of cyano analogues of prevalent 3‐di/trifluoromethyl pyrazole pharmacophores, among which several compounds have shown potent inhibitory activity towards cyclooxygenase 2 (COX‐2) compared with marketed drug Celecoxib.