General procedure for the synthesis of 4-bromo-2-fluoro-5-methylaniline using 2-fluoro-5-methylaniline as starting material: 2-fluoro-5-methylaniline (6.75 g, 54 mmol) and calcium carbonate (10 g, 100 mmol) were suspended in a solvent mixture of dichloromethane (1 L) and methanol (400 mL). A solution of benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in dichloromethane (180 mL) and methanol (70 mL) was slowly added dropwise with stirring. After the dropwise addition was completed, the reaction mixture was stirred at room temperature overnight and the color of the solution was observed to change to light orange to tan. After completion of the reaction, the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrated residue was diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic phases were combined and purified by fast column chromatography (eluent ratio: n-hexane/ether 2:1 tapering to pure ether) to afford the target product 4-bromo-2-fluoro-5-methylaniline (9 g, yield 69.5%) as a white solid. The product was characterized by 1H-NMR (DMSO-d6): δ 7.23 (d, J = 10.8 Hz, 1H), 6.74 (d, J = 10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H).
