4-BROMO-2-(TRIFLUOROMETHOXY)PHENOL

Bromine (1.0 M in CHBromine (1.0 M in CHBromine (1.55 ml, 30.3 mmol, 1.1 eq.) in DCM (50 ml) was added dropwise to a solution of 2-trifluoromethoxyphenol (5.0 g, 28.1 mmol, 1.0 eq.) in DCM (70 ml) at -78 Preparation 55 To a solution of 2-(trifluoromethoxy)phenol (5 g, 28.1 mmol) in CH2C12 (50 mL) at -78 °C was added a bromine (1 M in CH2C12; 30.4 mL, 30.4 mmol) drop wise over 20 mm. The reaction was allowed to warm to ambient temperature and stirredfor 48 h. Saturated Na2SO3 (100 mL) solution was added and the reaction mixture was stirred vigorously until disappearance of the orange color was observed. The biphasic mixture was diluted with CH2C12 (50 mL), and the organic layer was separated, washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuum to give phenol B7a (6.2 g, ) as a pale yellow solid. ‘H NMR (400 MHz, CDC13) 6.95 (d, J=8.7 Hz, 1 H), 7.33 (dd, J=8.7, 2.3 Hz, 1 H), 7.38 (d, J=8.8 Hz, 1H).Bromine (1.0 M in CH2Cl2, 45 mmol, 45 mL) was added dropwise to 2-trifluoro- methoxyphenol (7.40 g, 41.5 mmol) in CH2Cl2 (100 mL) at -78 0C. The mixture was allowed to warm to rt and was stirred for 48 hours. Na2SO3 (aq, sat, 100 mL) was added, and the mixture was stirred vigorously until the orange color dissapeared. The mixture was diluted with CH2Cl2 (200 mL) and the organic layer collected, washed with brine, dried (Na2SO4) and concentrated to afford 9.6 g(91%) of the sub-title product.Bromine (1.0 M in CH2Cl2, 45 mL, 45 mmol) was added dropwise over 20 min to a solution of 2-trifiuoromethoxyphenol (7.40 g, 41.5 mmol) in CH2Cl2 (100 mL) at -78 0C. The mixture was allowed to warm to rt and was stirred at rt for 48 h. Na2SO3 (aq, sat, 100 mL) was added and the mixture was stirred vigorously until the orange colour dissapeared. The mixture was diluted with CH2Cl2 (200 mL) and the organic layer was washed with brine, dried (Na2SO4) and concentrated to afford 9.6 g (91%) of the sub-title product.Bromine (1.55 ml, 30.3 mmol, 1.1 eq.) in DCM (50 ml) was added dropwise to a solution of 2-trifluoromethoxyphenol (5.0 g, 28.1 mmol, 1.0 eq.) in DCM (70 ml) at -78 0C. The reaction mixture was heated to ambient temperature and stirred for a further 48 h. Then a Na2S2Os SH2O (70 ml) solution was added and the mixture was stirred until the orange colour had disappeared. The solution was diluted with DCM (100 ml), the organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The purification was carried out by column chromatography (silica gel, eluted with 20% EtOAc-hexane) to afford 4-bromo-2- (trifluoromethoxy)phenol in 74% yield.Preparation 55 4-Bromo-2-trifluoromethoxy-phenol Bromine (449 mg, 2.81 mmol) was added to a solution of 2-(trifluoromethoxy)phenol (500 mg, 2.81 mmol) and sodium acetate (169 mg, 2.81 mmol) in acetic acid (5 mL) and the solution was stirred for 1 hour. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (2*50 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give a colourless oil. The oil was purified by column chromatography on silica gel, eluding with pentane:ethyl acetate, 85:15, to afford the title compound as a white solid in 23% yield. LRMS (APCI+): m/z [M+H]+ 255/257A solution of bromine (3.1 ml, 61.79 mmol) in 200 ml of DCM was added drop- wise to a solution of 2-trifiuoromethoxyphenol (10 g, 56 mmol) in dichloro methane (100 ml) at 0 0C. The mixture was stirred at room temperature for 48 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with DCM twice. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to afford crude 4-bromo-2-trifluoromethoxyphenol which was taken without further purification for next step. 1H-NMR (400 MHz, DMSO-d6) delta 10.468 (s, IH), 7.455 (s, IH), 7.355-7.383 (dd, IH, J=I 1.2 Hz, 2.4 Hz), 6.961-6.983 (d, IH, J=8.8 Hz) ppm.To a solution of 2-(trifluoromethoxy)phenol (5 g, 28.1 mmol) in CH2C12 (50 mL) at -78 C was added a bromine (1 M in CH2C12; 30.4 mL, 30.4 mmol) drop wise over 20 mm. The reaction was allowed to warm to ambient temperature and stirredfor 48 h. Saturated Na2SO3 (100 mL) solution was added and the reaction mixture was stirred vigorously until disappearance of the orange color was observed. The biphasic mixture was diluted with CH2C12 (50 mL), and the organic layer was separated, washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuum to give phenol B7a (6.2 g, ) as a pale yellow solid. 'H NMR (400 MHz, CDC13) 6.95 (d, J=8.7 Hz, 1 H), 7.33 (dd, J=8.7, 2.3 Hz, 1 H), 7.38 (d, J=8.8 Hz, 1H).To a solution of phenol B7a (6.2 g, 24.12 mmol) in CH2C12 (50 mL) at 0 C was added a pyridine (3.90 mL, 48.2 mmol) and followed bytrifluoromethanesulfonic anhydride (6.11 mL, 36.2 mmol) dropwise over 10 mm.The reaction mixture was allowed to warm to ambient temperature and stirred for 12h. Water (50 mL) was added and the reaction mixture stirred for 10 mm. The organic layer was separated and washed with water (2x) and brine, dried (Na2504) and concentrated in vacuo to afford triflate B7b (9 g). 'H NMR (400 MHz, CDC13) 7.30 (d, J=8.9 Hz, 1 H), 7.53 (dd, J=8.9, 2.3 Hz, 1 H), 7.59 (dq, J=2.4, 1.4 Hz, 1 H).Synthesis of 4-bromo-2-iodo-6-(trifluoromethoxy)phenol (237): 4-Bromo-2- (trifluoromethoxy)phenol (3.2 g, 12 mmol) was dissolved in 100 mL of NH4OH. A solution of KI (6.2 g, 37 mmol) and I2 (3.3 g, 13 mmol) in 50 mL of H20 was added to the reaction mixture and stirred at room temperature up to 5 h. The reaction mixture was cooled down to 0 C (ice bath), neutralized with HC1 (cone.) until pH ~ 6-7: extracted with EtOAc (150 mL X 3). The combined organic layers were washed with sat. aq. sodium bisulfite solution, brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 4 g of 4- bromo-2-iodo-6-(trifluoromethoxy)phenol (237) as a yellow solid (85% yield). LCMS: tR = 1.79 min.

Molecular Weight:257.00
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:255.93468
Monoisotopic Mass:255.93468
Topological Polar Surface Area:29.5
Heavy Atom Count:13
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes