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 N¹ -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.

Keywords: COX-2 inhibitors; cycloaddition; di/trifluoromethyl group; pharmacophores; pyrazoles.