Lewis base-catalyzed intermolecular triazene alkyne cycloaddition for late-stage functionalization and scaffold diversification

3-Trifluoromethylpyrazole and its derivatives are of major interest to both the agrochemical and pharmaceutical industry for their diverse biological activities. Reported routes for the synthesis of 3-trifluoromethylpyrazoles are hindered by poor regioselectivity and limited scope of application. Here we report a directed Lewis base catalyzed intermolecular triazene-alkyne cycloaddition. It is featured that the combination of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2,2,2-trifluorodiazoethane produces reactive triazene intermediates, which readily participate in cycloaddition reactions with terminal/internal alkynes, thus assembling densely substituted 3-trifluoromethylpyrazole scaffolds with environmental friendliness and operational simplicity. Synthetic utility of the protocol is highlighted by late-stage functionalization and scaffolds diversification. The practical value is also emphasized in potential platelet aggregation inhibitor synthesis. Trifluoromethyl diazomethane is a versatile reagent with a variety of applications. Here its 1,3-dipolar cycloaddition across internal and terminal alkynes is shown to provide an efficient route to trifluoromethyl-substituted pyrazoles, including derivatives of marketed drugs, natural products, and bioactive heterocycles.