[Synthesis]
Under stirring, 2,4-dimethylpyridine (5.39 mL, 46.7 mmol, 1 equiv.) was dissolved in bromide (50 mL) containing 20% free SO3, keeping the reaction temperature at 0 °C. An efficient reflux condenser was installed and the reaction mixture was heated to 165 °C in an oil bath. Bromine (4.30 mL, 83.4 mmol, 0.9 eq.) was added slowly in 0.5 mL portions over a period of 5 hours and stirring was continued at 155-175 °C for 20 hours. After completion of the reaction, the solution was cooled to room temperature, poured onto crushed ice (200 g) and stirred for 1 hour. The resulting orange solution was neutralized by careful addition of solid Na2CO3, diluted with water and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuum. The crude product was purified by automated fast column chromatography (Biotage KP-Sil.TM.SNAP 340g column, 0-15% EtOAc/hexane) and dried under vacuum to give three bromo products: 3,5-dibromo-2,4-dimethylpyridine (8), 5-bromo-2,4-dimethylpyridine (9) and 3-bromo-2,4-dimethylpyridine (10).
3,5-Dibromo-2,4-dimethylpyridine (8) is a white solid (1.48 g, 12%) with a melting point of 28-30 °C; 1H NMR (400 MHz, CDCl3) δ 2.54 (s, 3H, CH3), 2.61 (s, 3H, CH3), 8.41 (s, 1H, pyHortho); 13C NMR (100 MHz, CDCl3) δ 23.8 (CH3), 25.7 (CH3), 120.3 (ArC), 124.4 (ArC), 146.4 (ArC), 148.5 (ArCH), 156.5 (ArC); IR νmax (film)/cm?1 3045, 2998, 2956, 2921, 1558, 1433, 1376, 1349, 1232, 1376, 1349, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232, 1232 1376, 1349, 1232, 1049, 993, 928, 783; HRMS (ESI+) m/z calcd for C7H8Br2N [M+H]+ 263.9018, found 263.9027.
5-Bromo-2,4-dimethylpyridine (9) was a colorless oil (1.89 g, 22%); 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H, CH3), 2.44 (s, 3H, CH3), 7.00 (s, 1H, pyHortho), 8.47 (s, 1H, pyHmeta); 13C NMR ( 100 MHz, CDCl3) δ 22.1 (CH3), 23.6 (CH3), 120.4 (ArC), 125.5 (ArCH), 146.7 (ArC), 150.5 (ArCH), 157.0 (ArC); IR νmax (film)/cm?1 2985, 2957, 2924, 2854, 1592, 1461, 1377 1592, 1461, 1377, 1353, 1289, 1177, 1032; HRMS (ESI+) m/z calcd for C7H9BrN [M+H]+ 185.9913, found 185.9918.
3-Bromo-2,4-dimethylpyridine (10) was a colorless oil (3.04 g, 35%); 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H, CH3), 2.61 (s, 3H, CH3), 6.91 (d, J = 5.0 Hz, 1H, pyHmeta), 8.18 (d, J = 5.0 Hz, 1H, 2995, 2958, 2922, 1585, 1437, 1389, 1123, 1024, 916, 825; HRMS (ESI+) m/z calcd for C7H9BrN [M+H]+ 185.9913, found 185.9917. |