66.61% |
With tert.-butylnitrite; copper(I) bromide In acetonitrile at 70℃; for 1h; |
5.A Step A. 4-Bromo-2-methoxy-3,5-dimethylpyridine
To a mixture of /-butyl nitrite (0.8 mL, 6.57 mmol) in MeCN (10 mL) was added CuBr (1.4 g, 9.86 mmol). The mixture was stirred at 70 °C for 10 minutes. Then a mixture of 2-methoxy-3,5-dimethylpyridin-4- amine (500 mg, 3.29 mmol) in MeCN (5 mL) was added drop wise to the reaction mixture. After stirring at 70 °C for one hour, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (20 mL) and sat. aq. NaHCO3 (10 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, gradient elution: 0 - 2% ethyl acetate in petroleum ether) to give the title compound (480 mg, 2.19 mmol, 66.61% yield) as a colorless oil. MS (ESI): mass calcd. for C8H10BrNO, 215.0; m/z found, 216.0 [M+H]+. 1H NMR (400MHz, CDCl3) δ = 7.80 (s, 1H), 3.92 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). |
4.3 g |
With tert.-butylnitrite; copper(I) bromide In acetonitrile at 70℃; for 1h; |
28.3 (3) Synthesis of 4-bromo-2-methoxy-3,5-dimethylpyridine
(3) Synthesis of 4-bromo-2-methoxy-3,5-dimethylpyridine A mixture of copper(I) bromide (12.1 g) and t-butyl nitrite (7.07 mL) was stirred in an acetonitrile solvent (80 mL) at 70° C. for 10 minutes. A solution of 2-methoxy-3,5-dimethylpyridin-4-amine (3.9 g) in acetonitrile (40 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at 70° C. for one hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane, 100%, then NH-silica gel pad, n-heptane, 100%) to give the title compound (4.3 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.28-2.29 (m, 3H), 2.29-2.31 (m, 3H), 3.93 (s, 3H), 7.77-7.84 (m, 1H). ESI-MS m/z 216 [M+H]+ |
4.3 g |
With tert.-butylnitrite; copper(I) bromide In acetonitrile at 70℃; for 1h; |
2.9 (9) Synthesis of 4-bromo-2-methoxy-3,5-dimethylpyridine
A mixture of copper(I) bromide (12.1 g) and t-butyl nitrite (7.07 mL) was stirred in an acetonitrile solvent (80 mL) at 70° C. for 10 minutes. A solution of 2-methoxy-3,5-dimethylpyridin-4-amine (3.9 g) in acetonitrile (40 mL) was added dropwise to the reaction mixture at the same temperature, and the mixture was stirred at 70° C. for one hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane, 100%, then NH-silica gel pad, n-heptane, 100%) to give the title compound (4.3 g). (0215) 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.28-2.29 (m, 3H), 2.29-2.31 (m, 3H), 3.93 (s, 3H), 7.77-7.84 (m, 11-1). (0216) ESI-MS m/z 216 [M+H]+ |