3.3. General Synthesis Procedure for Substituted 2-Aminopyrimidines Ia–c

Intermediates Ia–c were prepared according to the literature [17]. A solution of NaH (0.35 g, 14.6 mmol) in dry THF (12 mL) was cooled to 0 °C under N₂, then a substituted alcohol (15.2 mmol) was added dropwise. The mixture was stirred for 15 min while maintaining the temperature at 0 °C. Next, 2-amino-4,6-dichloropyrimidine (1.0 g, 6.1 mmol) was added to the solution. The reaction was continued at 62 °C for 15 h. Then the mixture was cooled to ambient temperature, and quenched with 1 mL of 1 M hydrochloric acid solution. The mixture was diluted with EtOAc (20 mL), washed twice with a saturated NaHCO₃ solution (20 mL) and brine (20 mL), dried with anhydrous Na₂SO₄ and evaporated in vacuo. Finally, the residue was purified by silica gel column chromatography (EtOAc/petroleum ether) to afford compounds Ia–c.

4,6-Bis(2,2,2-trifluoroethoxy)pyrimidin-2-amine (Ia). Yellow oil, yield = 94%. ¹H-NMR (CDCl₃) δ 5.58 (s, 1H, ArH), 4.96 (s, 2H, NH₂), 4.57 (q, J = 8.6 Hz, 4H, OCH₂CF₃).

4,6-Dimethoxypyrimidin-2-amine (Ib). White solid, mp 87–89 °C, yield = 91%. ¹H-NMR (CDCl₃) δ 5.46 (s, 1H, ArH), 5.09 (s, 2H, NH₂), 3.84 (s, 6H, OCH₃).

4,6-Diethoxypyrimidin-2-amine (Ic). White solid, mp 174–176 °C, yield = 94%. ¹H-NMR (CDCl₃) δ 5.42 (s, 1H, ArH), 4.95 (s, 2H, NH₂), 4.23 (q, J = 7.1 Hz, 4H, OCH₂CH₃), 1.35 (t, J = 7.1 Hz, 6H, OCH₂CH₃).