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Stage #1: at 120℃; for 4 h; Stage #2: With water; sodium hydroxide In ethanol; ethyl acetate; nitrobenzene at 20℃;
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0g, 12.6mmol), glycerol (4.64g, 50.0mmol), and ferrous sulfate (0.56 g, 2.0mmol) was added cone, sulfuric acid (2.2mL) dropwise. The reaction mixture was heated at 120 0C for 4hr. After cooled to RT, the reaction was diluted with ethyl acetate (15OmL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo- 8-(trifluoromethyl)quinoline (1.2g, 48percent).
Reference：
[1] Patent: WO2010/91310, 2010, A1, . Location in patent: Page/Page column 101
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5521 - 5527
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0g, 12.6mmol), glycerol (4.64g, 50.0mmol), and ferrous sulfate (0.56 g, 2.0mmol) was added cone, sulfuric acid (2.2mL) dropwise. The reaction mixture was heated at 120 0C for 4hr. After cooled to RT, the reaction was diluted with ethyl acetate (15OmL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo- 8-(trifluoromethyl)quinoline (1.2g, 48%).
Preparation 12 4-Bromo-2-iodo-1-trifluoromethyl-benzene To a stirred solution of 5-bromo-2-(trifluoromethyl) aniline (300 mg, 1.255 mM) in dry THF (10 mL) was added BF3-etherate (707 mg, 5.02 mM) and tert-butyl nitrite (452 mg, 4.39 mM) at -78 C. Reaction mixture was stirred for 10 min, warmed to room temperature and maintained for 30 min. The reaction mixture was diluted with diethyl ether (30 mL). The solid was filtered off and dried under vacuum. This diazonium salt was added to a mixture of KI (289 mg, 1.746 mM) and iodine (203 mg, 0.876 mM) in acetone taken in an another flask at 0 C. and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water (20 mL) and the product was extracted with diethyl ether (2*20 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as a liquid (230 mg, 68%). 1H NMR (400 MHz, CDCl3) delta 8.19 (s, 1H), 7.59 (d, 1H), 7.50 (d, 1H).
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