Synthesis of 1H-1,2,3-triazoles—Rufinamide analogs by 1,3-dipolar cycloaddition and eletrocyclization reactions of trifluoroacetyl enolethers under thermal solventless conditions

•Trifluoroacetyl enolethers react with 2,6-difluorbenzyl azide to give 1H-triazoles.•1,2,3-Triazoles are obtained from 1,3-dipolar cycloaddition and electrocyclization.•Two mechanisms are proposed and discussed according to the FMO theory.•The nJC–F values from the 13C NMR data are used for the regioisomer assignments.•Structures are solved by 1H and 13C NMR, X-ray and DFT calculations data.

This paper describes an efficient method for synthesis of rufinamide analogs from the 1,3-dipolar cycloaddition and/or electrocyclization reactions under conventional thermal conditions of 4-alkyl(aryl/heteroaryl)-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with 2,6-difluorobenzyl azide, where 4-alkyl = H, Me; 4-aryl = Ph, 4-NO2C6H4, 4-OCH3C6H4, 4-FC6H4, 4,4′-BiPh; and 4-heteroaryl = 2-thienyl; for the efficient preparation of a series of ten new trifluoroacetyl(trifluoromethyl) substituted 1H-1,2,3-triazoles. Yields in the range of 30–71% were obtained when the reactions were performed at high temperatures (130–150 °C) under solvent-free conditions. The pure regioisomers or mixtures of triazoles could be isolate with dependency of the 4-substituent of the enones 1. Finally, two mechanisms are proposed and the results are discussed in accordance with the X-ray diffraction results and FMO theory, which describes the possible HOMO/LUMO interactions via DFT calculations for both precursors.

Graphical abstractThe synthesis of new trifluoroacetyl(trifluoromethyl) substituted 1H-1,2,3-triazoles (30–71% yield) from the 1,3-dipolar cycloaddition and/or electrocyclization reactions under thermal solventless conditions at 130–150 °C of 4-alkyl(aryl/heteroaryl)-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,6-difluorbenzyl azide, is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide