Synthesis of 3′-C-substituted thymidine derivatives by free-radical techniques: scope and limitations

The scope and limitations of radical-mediated 3′-C-substitution of pyrimidine nucleosides was evaluated with 5′-O-(tert-butyldimethylsilyl)thymidine or its tert-butyldiphenylsilyl analogue having thionoester or thionoamide groups at O-3′, including (methylthio)thiocarbonyl, (phenoxy)thiocarbonyl, (pentafluorophenoxy)thiocarbonyl, and (1-imidazolyl)thiocarbonyl. Their reaction with acrylonitrile, methyl acrylate, and allyltributyltin under radical-generating conditions affords corresponding 3′-C-alkylated products, together with the product of simple deoxygenation at C-3′. The conditions for optimizing the yield of 3′-C-substituted product are presented.