C-O Bond formation on C-5 of 2,4-Diaminopyrimidines

Abstract

This work aims to find a robust oxidation condition that can efficiently convert 2,4-diaminopyrimidines to its C5-hydroxylated derivative. Although Boyland-Sims oxidation of these substrates has been reported, this procedure suffers low yield and poor reproducibility. The conditions for Boyland-Sims oxidation of 2,4-diaminopyrimidines were thus re-optimized. The parameters that could affect the yields of the 5-hydroxy products were investigated using 2,4-diamino-6-ethylpyrimidine as a model compound. The reactions were performed at 0.10 mmol scale of the starting pyrimidine. The yields of the products were monitored by 1H NMR spectroscopy with reference to an internal standard. The reaction was reproduced at larger scale employing the optimized condition. The 5-hydroxylated products were obtained in satisfactory yields (43-58%) from the oxidation of 2,4-diaminopyrimidines without substituent or with an electron-donating alkyl group such as ethyl and isopropyl group at the C-6 position. However, the same conditions gave no oxidation product with electron-deficient 2,4-diaminopyrimidines bearing chloro or trifluoromethyl group at the C-6 position. Oxidation of the electron-deficient 2,4-diaminopyrimidines was further studied using other oxidants. The electron-deficient 6-trifluoromethyl substituted analogue was selected as a model compound, since the trifluoromethyl group facilitates reaction monitoring using 19F NMR technique. The reactions were performed at 0.05 mmol scale of the fluorinated pyrimidine substrate with various oxidants. The expected C5-hydroxylated product was not obtained from the oxidation of 2,4-diamino-6-trifluoromethylpyrimidine under various conditions. However, side products such as the N-oxide and the 5-halogenated products were isolated and fully characterized. Therefore, this work has provided the optimized conditions for Boyland-Sims oxidation of 2,4-diaminopyrimidines and demonstrated that this oxidation is only suitable for electron rich 2,4-diaminopyrimidines. At present, oxidation of electron-deficient substrates still remains challenging, and could not be achieved by any methods.