Copper-Catalyzed Azide–Alkyne Cycloaddition of Hydrazoic Acid Formed <i>In Situ</i> from Sodium Azide Affords 4-Monosubstituted-1,2,3-Triazoles

Abstract

We report a copper-catalyzed cycloaddition of hydrogen azide (hydrazoic acid, HN₃) with terminal alkynes to form 4-substituted-1<i>H</i>-1,2,3-triazoles in a sustainable manner. Hydrazoic acid was formed <i>in situ</i> from sodium azide under acidic conditions to react with terminal alkynes in a copper-catalyzed reaction. Using polydentate N-donor chelating ligands and mild organic acids, the reactions were realized to proceed at room temperature under aerobic conditions in a methanol-water mixture and with 5 mol % catalyst loadings to afford 4-substituted-1,2,3-triazoles in high yields. This method is amenable on a wide range of alkyne substrates, including unprotected peptides, showing diverse functional group tolerance. It is applicable for late-stage functionalization synthetic strategies, as demonstrated in the synthesis of the triazole analogue of losartan. The preparation of orthogonally protected azahistidine from Fmoc-l-propargylglycine was realized on a gram scale. The hazardous nature of hydrazoic acid has been diminished as it forms <i>in situ</i> in <6% concentrations at which it is safe to handle. Reactions of distilled solutions of hydrazoic acid indicated its role as a reactive species in the copper-catalyzed reaction.