Trisubstituted pyrimidine derivatives from tetrafluoropyrimidine

The use of tetrafluoropyrimidine as a scaffold for the synthesis of 2,4,6-trisubstituted pyrimidine derivatives by three sequential nucleophilic aromatic substitution processes is assessed. Reactions of tetrafluoropyrimidine with various amine nucleophiles followed by a series of nitrogen and oxygen centred nucleophilic species gave a range of 4,6-disubstituted-2,5-difluoropyrimidine systems regioselectively and in good yield. Displacement of a further fluorine atom from representative difluoropyrimidine derivatives proceeded to give trisubstituted pyrimidine derivatives although mixtures of products could be obtained depending upon the substrate.