Synthesis of Bitriazolyl Nucleosides via Huisgen [2+3] Cycloaddition

Significance

Reported is the synthesis of bitri­azolyl nucleosides using Cu(I)-catalyzed Huisgen [2+3] cycloaddition between 3-azidotriazolyl nucleosides (1a) and various alkynes. The reaction is tolerant to various alkyne substitution patterns, including aliphatic, aromatic, and electron-withdrawing groups. In the absence of the ribosyl moiety at N1 of the triazolyl ring, compound 1a fails to react. Regioselective formation of 1,2,4-triazoles suggests a stepwise addition, involving the copper(I) acetylide and azide. The highest yields were obtained when the reaction was carried out at 80 °C, although reasonable yields were obtained at room temperature. In contrast, the 5-azidotriazolyl nucleoside (1b) did not yield the expected product; instead, the azide was reduced to the corresponding 5-aminotriazole nucleoside. This difference in reactivity was rationalized by electronic effects: The electron deficiency of 1b favors the reduction. The hypothesis was supported by theoretical calculations and testing the reduction step with some simple electron-deficient and electron-rich aromatic azides.