Catalytic copper(I) alkyne-azide cycloaddition (CuAAC) utilizing arylazothioformamide ligand complexes

Abstract

Azothioformamide (ATF) ligands have been shown to rapidly coordinate with copper(I) salts through a 1,3-diazothiocarbonyl moiety to form stable copper(I) complexes. In this work, a dimeric complex derived from p-methoxyphenyl azothioformamide (p-MeOATF) ligands and copper(I) iodide was employed as a catalyst for an aqueous three component copper(I) alkyne-azide cycloaddition (CuAAC) reaction. Reaction optimization identified that using 2 mol% of the [(p-MeOATF)CuI]₂ complex and 1.2 equiv. each of the alkyl halide and sodium azide in 1:1 water/methanol as solvent for 24 h gave high yields of 1,2,3-triazole products with 11 examples ranging in yields of 60–93 %. As ATFs are known to oxidatively remove metals from materials, the removal of copper during the formal synthesis of the pharmaceutical rufinamide was tested as to offer a promising approach to limiting copper content in CuAAC reaction products.