Synthesis
General procedure for the synthesis of 2-bromo-4-trifluoromethoxyaniline from 4-(trifluoromethoxy)aniline: N-bromosuccinimide (3.62 g, 20.34 mmol) was slowly added to a solution of 4-(trifluoromethoxy)aniline (3.00 g, 16.9 mmol) in acetonitrile (30 mL) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred continuously for 4 hours. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure to give the crude product. The crude product was purified by column chromatography using 10% ethyl acetate/hexane as eluent to give 2-bromo-4-trifluoromethoxyaniline as a brown oil (3.6 g, 83% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 4.11 (broad single peak, 2H), 6.73 (double peak, 1H), 6.99 (double-double-heavy peak, 1H), and 7.31 (double-heavy peak, 1H).The LC-MS analysis showed that the [M-H]- peak was located at m/z 253.1.
References
[1] Patent: WO2015/100232, 2015, A2. Location in patent: Page/Page column 102
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 1, p. 113 - 128
[3] Patent: EP1183229, 2005, B1. Location in patent: Page/Page column 143-144
[4] Organic Letters, 2011, vol. 13, # 20, p. 5636 - 5639
[5] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
