Hydrochloric Acid → Methyl 4-bromo-3-(trifluoromethoxy)benzoate

Participants

Reaction Steps

To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (2.00 g, 9.10 mmol) in MeOH (25.0 mL), was slowly added HCl (1.0 mL, 1.0 M in ether) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. Benzene (20 mL) was added, and the reaction was heated at reflux with a Dean-Stark trap to remove the half volume of the solvent. The rest of the solvent was then evaporated to give the product. MS (ESI) m/e=235.9 [M+1]+, Calc'd for C8H6F3NO3, 235.1. The crude product was used in the next step without further purification. To an ice-cooled suspension of methyl 4-amino-3-(trifluoromethoxy)benzoate hydrogen chloride salt (8.60 g, 31.70 mmol) in 17.1 mL of water and concentrated HBr (48%, 17.1 mL), was slowly added a prepared 2.5 M solution of sodium nitrite (2.20 g in 12.7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Meanwhile, a solution of CuSO4 (6.68 g) in 35 mL of water was heated and sodium bromide (6.52 g) was added. The solution became a green color, and a solution of Na2SO3 (2.80 g) in water (10 mL) was then added to it. The solution was cooled at 0° C. and washed with water (25×3 mL). The water was then decanted off. Concentrated HBr (16.7 mL) was added, and the solution became a purple color. The solution of CuBr was slowly added to the diazonium salt (prepared above) at 0° C. After addition, the ice-bath was removed, and an oil-bath was placed under the reaction vessel. The reaction mixture was then heated to 60° C. for 15 minutes, at 80° C. for 15 minutes, and then at 100° C. for 20 minutes. The reaction mixture was next cooled to room temperature and made basic with Na2CO3 to a pH 8. The aqueous solution was extracted with EtOAc (100×2 mL). The organic layer was washed with brine (25 mL) and dried with MgSO4. The solvent was removed to give the crude product 28.2. 1H NMR (CDCl3) δ 3.96 (s, 3H), 7.75 (d, J=8.4 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.98 (s, 1H).

Provenance & Evidence