Synthesis of 1,2,3-triazolo-nucleosides via the post-triazole N-alkylation

2-Substituted-2H-1,2,3-triazolo-nucleosides with 3-phosphonopropyl, 2-hydroxyethyl, 2-cyanoethyl, carbamoylmethyl, or 1-deoxy-2,5-anhydro-D-mannitol-1-yl on the triazole N-2 nitrogen atom were obtained via the DBU-promoted N-alkylation of 3-(pivaloyloxymethyl)-1-[(NH-1,2,3-triazol-4-yl)methyl] thymine with diethyl 3-bromopropylphoshonate, 2-bromoethanol, acrylonitrile, methyl bromoacetate, or 3,4,6-tris(O-benzoyl)-2,5-anhydro-D-mannitol 1-tosylate. The N-2/N-1 regioselectivity of the alkylation varied from 57/43 (methyl bromoacetate) to 97/3 (diethyl 3-bromopropylphoshonate). The 1-substituted-1H-1,2,3-triazoles, when formed in the appreciated amount in the alkylation reaction, were converted into the corresponding 1-substituted-1H-1,2,3-triazolo-nucleosides. The substitution pattern of 2-substituted-2H-1,2,3-triazolo-nucleosides was confirmed by H-1-N-15 HMBC NMR spectra; the triazole nitrogen atoms were identified through their correlations with the triazole exo-cyclic protons. (C) 2011 Elsevier Ltd. All rights reserved.