[Synthesis]
General procedure for the synthesis of 2-amino-3-bromo-5-methylpyrazine and 2-amino-6-bromo-5-methylpyrazine from 2-amino-5-methylpyrazine: over 15 min, HBr/CH3CO2H solution (360 g (260 mL), 1.50 mol, 33% HBr in CH3CO2H solution) in anhydrous CHCl3 (300 mL) was was slowly added to a solution of CHCl3 (1 L) containing 5-methylpyrazin-2-amine (42 g, 0.38 mmol). The reaction flask was wrapped in aluminum foil to protect it from light and heated at 50 °C for 30 min. Subsequently, a CHCl3 (500 mL) solution of Br2 (68 g, 0.42 mmol) was added dropwise over a period of 3 h, during which time the internal temperature of the reaction was ensured not to exceed 55 °C. The reaction was continued stirring at 55 °C for 18 h before evaporating the solvent under reduced pressure. The crude product was diluted with water (200 mL) and the pH was adjusted to 9 by the addition of solid Na2CO3. The suspension was vacuum filtered and the filtrate was extracted with EtOAc (1L x 5). The organic phases were combined, concentrated under reduced pressure and purified by fast silica gel chromatography with the eluent petroleum ether/EtOAc (5:1→1:1) to afford 6-bromo-5-methylpyrazin-2-amine (36 g, 50%) as a light orange solid with melting point of 154-157 °C. IR (KBr): 3315, 3188, 1744, 1638, 1575, 1482, 1375, 1308, 1051 cm-1; 1H NMR (400MHz, CDCl3): δ=7.84 (s, 1H), 4.55 (br s, 2H), 2.52 (s, 3H); 13C NMR (100MHz, CDCl3): δ=152.2, 141.8, 138.4, 129.2, 22.2; HRMS-ESI: C5H7BrN3 (M+H)+ Calculated values: 187.9823 and 189.9803; Measured values: 187.9816 and 189.9796. 3-bromo-5-methylpyrazin-2-amine analytical samples were also isolated for spectroscopic analysis, melting point 56-57°C. 1H NMR (400MHz, CDCl3): δ=7.80 (s, 1C). 7.80 (s, 1H), 4.95 (br s, 2H), 2.38 (s, 3H); 13C NMR (100MHz, CDCl3): δ=150.6, 142.8, 139.9, 125.2, 19.7; HRMS-ESI: C5H7BrN3 (M+H)+ Calculated values: 187.9823 and 189.9803; measured values: 187.9817 and 189.9796. |