3-Trifluoromethyl (CF3) and 3-difluoproemthyl (CF2H) pyrazoles have emerged as an important type of privileged structural motifs that have been frequently found in a vast number of pharmaceuticals and agrochemicals. In this study, we demonstrate that a silver-catalyzed [3 + 2] cycloaddition reaction of dicyanoalkenes with trifluorodiazoethane (CF3CHN2) could render the facile construction of a unique category of pyrazoles that are simultaneously adorned by trifluoromethyl and cyano groups. Changing the location pattern of cyano group in starting dicyanoalkenes allows regiodivergent access to two series of previously elusive trifluoromethyl cyanopyrazoles with exquisite level of regiocontrol. This method could be applied in the preparation of cyano-analogues of CF3-containing drugs (Celecoxib) and agrochemicals (Penthiopyrad and Fluazolate). Noteworthy is that several cyano-analogues of Celecoxib demonstrate enhanced inhibitory activity towards cyclooxygenase-2 (COX-2), thus laying a good foundation for developing new lead compounds of anti-inflammatory agents. Furthermore, we develop a straightforward approach for the regioselective construction of N-aryl 3-difluoromethyl and 3-trifluoromethyl pyrazole-carbonitriles from readily available hydrazonyl chlorides and dicyano-alkenes under mild and simple conditions. The realization of this cycloaddition reaction hinges upon the employment of N-substituted nitrile imines as the 1,3-dipoles to reduce synthetic steps and two cyano groups-equipped alkenes as the dipolarophiles to increase reactivity and direct regioselectivity. This strategy offers efficient access to a divergent library of cyano analogues of 3-fluoroalkyl pyrazole pharmacophores, among which several compounds have demonstrated potent inhibitory activity towards cyclooxygenase 2 compared with drug Celecoxib.

Privileged pharmacophore-oriented divergent synthesis of fluoroalkyl pyrazoles

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ACS Fall 2022

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