Dual Incorporation of Trifluoromethyl and Cyano Groups into Pyrazole Pharmcophores via Silver-Catalyzed Cycloaddition Reaction of Trifluorodiazoethane

Abstract

The dual incorporation of two important functional groups—trifluoromethyl and cyano moieties into one heterocyclic core in a single-step reaction represents an appealing but largely unaddressed synthetic challenge. Here we demonstrate that a silver-catalyzed [3 + 2] cycloaddition reaction of dicyanoalkenes with trifluorodiazoethane (CF3CHN2) could render a facile construction of a unique category of pyrazoles that are simultaneously adorned by trifluoromethyl and cyano groups. Changing the location pattern of the cyano group in starting dicyanoalkene material allows regiodivergent access to two series of previously elusive trifluoromethyl cyanopyrazoles with an exquisite level of regiocontrol. Thus, this method could be applied in the preparation of cyano-analogues of CF3-containing drugs (Celecoxib) and agrochemicals (Penthiopyrad and Fluazolate). Notably, several cyano-analogues of Celecoxib demonstrate enhanced inhibitory activity towards cyclooxygenase-2 (COX-2), thereby laying a good foundation for developing new lead-based anti-inflammatory agents.