Azide–Tetrazole Equilibrium of C-6 Azidopurine Nucleosides and Their Ligation Reactions with Alkynes

Facile syntheses of C-6 azidopurine ribonucleosides and 2′-deoxyribonucleosides have been developed. For silyl- and acetyl-protected as well as unprotected nucleosides, access to the azido derivatives could be readily attained via displacement of BtO− from the O6-(benzotriazol-1-yl)inosine nucleosides by azide anion. Use of diphenylphosphoryl azide/DBU as a simple route to the acetyl-protected azido nucleosides was also evaluated, but this proved to be inferior. Since these azido nucleosides can exist in an azide·tetrazole equilibrium, the effect of solvent polarity on this equilibrium was investigated. Subsequently, a detailed analysis of Cu-mediated azide−alkyne (“click”) ligation was undertaken. Biphasic CH2Cl2/H2O medium proved to be best for the ligation reactions, suppressing the undesired azide reduction that was competing. Interestingly, although the tetrazolyl isomer predominates (ca. 80%) in CD2Cl2 and in CD2Cl2/D2O, the Cu-catalyzed click reactions proceed smoothly with the silyl-protected ribo...