Polyfluoroalkylated antipyrines in Pd-catalyzed transformations

Abstract

In the direct C–H arylation with arylhalogenides in the presence of Pd(OAc)₂, trifluoromethyl-containing antipyrine reacts very slowly and incompletely owing to the low nucleophilicity of its C4 center. However, it was effective in modifying polyfluoroalkyl-substituted 4-bromo- and 4-iodo antipyrines by the Suzuki and Sonogashira reactions. It was established that using Pd₂(dba)₃ as catalyst and XPhos as phosphine ligand was the optimal catalytic system for the synthesis of 4-aryl- and 4-phenylethynyl-3-polyfluoroalkyl-antipyrines. Moreover, iodo-derivatives as the initial reagents were found to be more advantageous compared to bromo-containing analogs. It was found that 4-phenylethynyl-5-CF₃-antipyrine has a moderate activity against the influenza virus A/Puerto Rico/8/34 (H1N1) and 4-iodo-5-CF₃-antipyrine reveals a weak activity against the vaccine virus (strain Copenhagen) and bovine diarrhea virus (strain VC-1).