Perhalogenated pyrimidine scaffolds. Reactions of 5-chloro-2,4,6-trifluoropyrimidine with nitrogen centred nucleophiles

BACKGROUND: Highly functionalised pyrimidine derivatives are of great importance to the life-science industries and there exists a need for efficient synthetic methodology that allows the synthesis of polysubstituted pyrimidine derivatives that are regioselective in all stages to meet the demands of RAS techniques for applications in parallel synthesis. 5-Chloro-2,4,6-trifluoropyrimidine may be used as a scaffold for the synthesis of polyfunctional pyrimidine systems if sequential nucleophilic aromatic substitution processes are regioselective. RESULTS: Use of 5-chloro-2,4,6-trifluoropyrimidine as a core scaffold for the synthesis of functionalised pyrimidine systems is assessed in reactions with a small range of nitrogen centred nucleophiles. Mixtures of products arising from nucleophilic aromatic substitution processes are formed, reflecting the activating effect of ring nitrogen and the steric influences of the chlorine atom. CONCLUSIONS: 5-Chloro-2,4,6-trifluoropyrimidine is not an ideal scaffold for analogue synthesis or for multiple substitution processes because purification must be performed to remove the 2-substituted regioisomer from the mixture before further reactions can be carried out. However, 4-amino derivatives can be isolated in acceptable yields using this methodology.