[Synthesis]
General procedure for the synthesis of 3,5-difluoro-4-bromoaniline from 3,5-difluoroaniline:
1. 3,5-difluoroaniline (10.0 g, 77.5 mmol) was dissolved in DMF (100 mL), then NBS (13.9 g, 78.0 mmol) was added in batches at room temperature. The reaction mixture was stirred overnight at room temperature and then diluted with Et2O and washed with brine. The organic phase was separated, dried over Na2SO4 and concentrated to give an oil. Purification by column chromatography afforded 4-bromo-3,5-difluoroaniline (i) (12.9 g, 80.2%).
2. A mixture of 4-bromo-3,5-difluoroaniline(i) (6.0 g, 28.8 mmol), ferrous sulfate (1.82 g), glycerol (8.6 mL), nitrobenzene (1.79 mL) and concentrated sulfuric acid (5.0 mL) was gently heated. After the first vigorous reaction, the mixture was boiled for 5 hours. Nitrobenzene was removed by vacuum distillation and the aqueous solution was acidified with glacial acetic acid to isolate a dark brown precipitate. Purification by rapid chromatography (silica gel, petroleum ether/ethyl acetate = 12/1) gave 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8%).
3. To a solution of 6-bromo-5,7-difluoroquinoline(ii) (250 g, 1.02 mol) in anhydrous THF (2200 mL) was added dropwise a hexane solution of n-BuLi (2.5 M, 408 mL, 1.02 mol) at -78 °C. The resulting mixture was stirred at -78 °C for another 30 min. Then, anhydrous THF (200 mL) solution of DMF (79 mL, 1.02 mol) was added while the temperature was kept below -70 °C and the mixture was stirred at the same temperature for 30 min. The reaction mixture was slowly warmed to room temperature and diluted with saturated aqueous NH4Cl solution (1000 mL) and water (800 mL). The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give a brown oil. Purification by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (10:1), afforded 5,7-difluoroquinoline-6-carbaldehyde (Intermediate H) as a yellow solid (100 g, 50%).
1H NMR (DMSO, 300 MHz) δ (ppm): 10.38 (s, 1H), 9.10~9.12 (m, 1H), 8.62~8.66 (m, 1H), 7.68~7.78 (m, 2H). |