Abstract
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.
Highlights
3-Trifluoromethylpyrazole and its derivatives are of major interest to both the agrochemical and pharmaceutical industry for their diverse biological activities
This has been challenging because the effective documented processes always rely on the use of stoichiometric catalyst or prefunctionalized starting materials and the explored methods are confined to a narrow range of substrates and limited scope of general applications
In support of an on-going drug discovery strategy, novel Late-stage functionalization (LSF) with high efficiency, selectivity, and operational simplicity is highly desirable. 3-Trifluoromethylpyrazoles, as COXs inhibition pharmacophore[8,9,10,48], their derivatives have been screened as clinical drug candidates and commercial pharmaceuticals
Summary
3-Trifluoromethylpyrazole and its derivatives are of major interest to both the agrochemical and pharmaceutical industry for their diverse biological activities. 3-Trifluoromethylpyrazoles, well-known examples of pyrazole derivatives, are key privileged scaffolds widely existed in many important biologically active molecules, agrochemicals, and pharmaceuticals (Fig. 1a)[3,4,5,6,7,8,9,10,11]. Conventional approaches for the construction of 3-trifluoromethylpyrazoles involve by the condensation of hydrazines with fluoroalkyl 1, 3-dicarbonyl compounds (Fig. 1b)[12,13,14,15] These methods are limited by the need for prefunctionalized starting materials and by poor regioselectivities. Considerable efforts have been expended on the construction of 3-trifluoromethylpyrazoles[25,30] This has been challenging because the effective documented processes always rely on the use of stoichiometric catalyst or prefunctionalized starting materials and the explored methods are confined to a narrow range of substrates and limited scope of general applications. >70 Examples, yield up to 98% Broad substrates scope Simple & mild reaction conditions Functional gropus and scaff olds diversity Pharmaceutical application
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