Nickel-Catalyzed Azide-Alkyne Cycloaddition to Access 1,5-Disubstituted 1,2,3-Triazoles in Air and Water

Abstract

Transition-metal-catalyzed or metal-free azide-alkyne cycloadditions are versatile and indispensable synthetic methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Although the copper-catalyzed cycloaddition to access 1,4-disubstituted products has been successfully applied to biomolecular reaction systems, the azide-alkyne cycloaddition to access the complementary 1,5-regioisomers under aqueous and ambient conditions remains a formidable challenge due to limited substrate scope or moisture-/air-sensitive catalysts. Herein, we report a general synthetic method to access 1,5-disubstituted 1,2,3-triazoles using a Cp2Ni/Xantphos catalytic system. The reaction proceeds both in water and organic solvents at room temperature. This protocol is operationally simple and scalable with a broad substrate scope including both aliphatic and aromatic substrates. Moreover, triazoles attached with carbohydrates or amino acids are readily prepared via this nickel-catalyzed azide-alkyne cycloaddition.