A Regioselective Azide–Alkyne Cycloaddition to 1,2,3-Triazole-4-carboxaldehydes, Polyheteroaryls, and Synthesis of Rufinamide

Abstract

Herein, we report the azide–alkyne cycloaddition reactions of highly reactive propiolaldehyde without any metal catalyst, base, or any other additives. The propiolaldehyde, generated in situ from propargyl mesylate in DMSO, readily annulated onto organic azides in the absence of metal catalyst, affording 1,2,3-triazole-4-carboxaldehydes with excellent regioselectivity. Furthermore, these triazole aldehydes were engaged in a number of one-pot cascade reactions yielding heterobiaryls and heteroterphenyl hybrids. The synthetic utility of the methodology was demonstrated through the gram-scale synthesis of the antiepileptic drug Rufinamide.