Solid-Phase Synthesis of 2,4-diaminopyrimidines via Lewis acid-mediated aromatic nucleophilic substitution

Primary amines were immobilized on (4-formyl-3,5-dimethoxyphenoxy)methylpolystyrene resin via reductive amination. Attachment of two different 4-chloro-2-methylthiopyrimidines, followed by sulfide oxidation, led to their corresponding sulfone intermediates. Aromatic nucleophilic substitution with various anilines or heteroaromatic amines in the presence of trimethyl aluminum afforded the desired 2,4-diaminopyrimidines after acidic cleavage from the resin. The synthetic methodology described herein was validated with the synthesis of a small 162-member library.