Efficient access to 3′-deoxy-3′-(4-substituted-1,2,3-triazol-1-yl)-thymidine derivatives via ligand-promoted CuAAC

Abstract

Herein we describe an efficient and rapid access to 3′-deoxy-3′-(4-substituted-1,2,3-triazol-1-yl)-thymidine derivatives using 1,3-dipolar cycloaddition reaction catalyzed by copper(I). Innovative conditions allow us to generate target compounds in a one-pot reaction mixing 3′-azido-3′-deoxythymidine, alkyne, copper sulfate pentahydrate, sodium ascorbate and tris(benzyltriazolylmethyl)amine in a water:tert-butanol solvent mixture. Rapid treatment of the reaction and subsequent flash purification chromatography afforded pure compounds in an overall yield of 71 – 100% . All eleven synthesized compounds were identified on the basis of their spectral data analysis ( 1 H, 13 C, 2D NMR and high-resolution mass spectra). • Innovative, rapide and efficient 1,3-dipolar cycloaddition reaction catalyzed by copper(I) was set-up. • THPTA (tris(benzyltriazolylmethyl)amine), a polydentate N -donor ligand was key in the efficiency of the reaction. • AZT-derived 1,2,3-triazole compounds are obtained in 30 min reaction at RT in a water:tert-butanol mixture. • Eleven new 3′-deoxy-3'-(4-substituted-1,2,3-triazol-1-yl)-thymidine derivatives were synthesized efficiently. • Eleven new 3′-deoxy-3'-(4-substituted-1,2,3-triazol-1-yl)-thymidine derivatives were characterized by NMR (1D, 2D) and HRMS.