General procedure for the synthesis of 2-bromo-5-fluoroacetophenone from 1-(2-bromo-5-fluorophenyl)ethanol:
1. Preparation of 1-(2-bromo-5-fluorophenyl)ethanone
Trichloroisocyanuric acid (59.5 g, 0.256 mol, 1.05 eq.) was added to a solution of 1-(2-bromo-5-fluorophenyl)ethanol (53.4 g, 0.2438 mol) in dichloromethane (500 mL) at 0-20 °C. To the resulting suspension was added TEMPO (2,2,6,6-tetramethylpiperidine 1-yloxy; 188 mg, 1.20 mmol, 0.5 mol%). The reaction mixture was stirred at ice bath temperature until the oxidation was complete (HPLC monitoring, about 4.5 hours). The reaction mixture was diluted with methyl tert-butyl ether (MTBE, ca. 1300 mL), sequentially with 1N NaOH (2 × 250 mL), 1N HCl containing potassium iodide (for the removal of TEMPO; 8 g of KI in 1000 mL of 1N HCl; 2 × 250 mL), 1N NaHCO3 containing sodium thiosulfate (for the removal of I2; 15 g Na2S2O3 in 1000 mL of 1N NaHCO3), 1N HCl containing potassium iodide (1 × 200 mL), 1N NaHCO3 containing sodium thiosulfate (2 × 200 mL), and brine (150 mL) washed. After drying (anhydrous MgSO4), the solvent was removed under reduced pressure to give 1-(2-bromo-5-fluorophenyl)ethanone as a light amber liquid (52.96 g, about 97% yield) with 98% purity by HPLC, which can be used in the next reaction without further purification.
1H-NMR (300MHz, CDCl3) δ 7.59 (dd, J=8.7,4.9Hz, 1H), 7.19 (dd, J=8.5,3.0Hz, 1H), 7.04 (ddd, J=9.1,7.8,3.0Hz, 1H), 2.64 (s, 3H).
