Chemoselective Difluoromethylation of Nucleosides

A profiling platform to define the chemoselectivity of the carbene-mediated difluoromethylation of nucleosides is described. First, the optimized reaction conditions for the difluoromethylation of silyl-protected nucleosides are established using TMS-CF₂Br and KOAc to form the difluoromethyl carbene <i>in situ</i>. Second, the scope of these reaction conditions to difluoromethylate uridine- and cytidine-based 2'-deoxyribonucleoside and ribonucleoside analogues is established. When uridine analogues are substrates, O-difluoromethylation at the 4-position is observed, whereas O-difluoromethylation at the 2-position of cytidine analogues predominates. S-Difluoromethylation is preferable over O-difluoromethylation when thionucleosides are used. In all cases, no N-difluoromethylation is observed. Finally, silyl deprotection afforded difluoromethylated free nucleosides, thereby enabling the exploration of their utility for broader applications in medicinal chemistry and chemical biology.