Abstract
We report a copper-catalyzed cycloaddition of hydrogen azide (hydrazoic acid, HN3) with terminal alkynes to form 4-substituted-1H-1,2,3-triazoles in a sustainable manner. Hydrazoic acid was formed in situ 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 in situ 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.
Highlights
Copper-catalyzed azide−alkyne cycloaddition (CuAAC), the prototypical example of “click” chemistry, has become one of the most widely used reactions and has been extended to various fields of science.[1]
Our goal was to avoid the direct handling of hydrazoic acid and, we wanted to form it in situ from accessible sodium azide
The reactions proceed with in situ formed hydrazoic acid that is present in solutions in low (
Summary
Copper-catalyzed azide−alkyne cycloaddition (CuAAC), the prototypical example of “click” chemistry, has become one of the most widely used reactions and has been extended to various fields of science.[1] As for the substrate scope, the reaction was extended to all types of starting alkyne reagents and almost all types of organic azide reagents (Figure 1a), and the resulting 1,2,3-triazoles are found in a variety of applications.[2] the CuAAC reaction of hydrogen azide (HN3, hydrazoic acid), leading to 4-substituted-1H-1,2,3triazoles, has not yet been realized. The 4substituted-1H-1,2,3-triazoles moiety is a part of a β-lactam cephalosporin antibiotic cefatrizine (BL-S640),3e noncanonical amino acid azahistidine,3f,g which can be incorporated into proteins in vivo.3h 4-Substituted-1H-1,2,3-triazoles have been shown to be useful in coordination chemistry,[4] e.g., the bis(1,2,3-triazol-4-yl)pyridine motif was demonstrated as a versatile tridentate ligand for supramolecular and coordination chemistry4a and as a ligand for ruthenium in dye-sensitized solar cells.4b NH-triazole is a convenient scaffold for further modifications, e.g., N2-selective modifications into 2,4disubstituted triazoles,[5] halogenation at the C-5 position of the triazole,[6] N1-oxidative C−N bond coupling with quinoxalinone[7] and pyrroles,[8] gold-catalyzed N1-selective alkenylation,[9] and for the preparation of 1,2,3-triazolide ionic liquids.[10]
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