We report a copper-catalyzed
cycloaddition of hydrogen azide (hydrazoic
acid, HN
3
) with terminal alkynes to form 4-substituted-1
H
-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.
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