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.

The 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 as PowerPoint slide