Phenetole → (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone

Participants

Reaction Steps

N,N-Dimethylforamide (9 mL) was added to a suspension of 5-bromo-2-chlorobenzoic acid (1500 g, 6.41 mol) and oxalyl chloride (975 g, 7.69 mol) in a 5 L 4-necked flask containing dichloromethane (2.8 L) at room temperature. Once the vigorous evolution of gas ceased, the reaction was stirred for 10 h at room temperature. The reaction mixture was concentrated under vacuum to give a yellow residue. The residue was dissolved in dichloromethane (1.2 L) in a 5 L 4-necked flask equipped with an internal thermometer and a water condenser. The stirred mixture was cooled to −3° C. and phenetole (799 g, 6.54 mol) was added. Aluminum (III) chloride (973 g, 6.54 mol) was added to the above solution via a solid addition funnel over 1 h while maintaining the internal temperature below 4° C. After the addition was complete, the reaction mixture was stirred for 2 h at 5˜10° C. The reaction was poured into ice (10 kg). The mixture was further stirred at 4° C. for 1 h, diluted with water (3 L), transferred to a 50 L extraction funnel and extracted with dichloromethane (10 L×2). The combined organic layers were washed with 1 N HCl (7.5 L×2), water (10 L), 1N sodium hydroxide (7.5 L×2), brine (10 L×2), dried over sodium sulfate (1000 g), and concentrated. The residue was recrystallized in absolute ethanol (3.5 L) to give the title compound as a white solid (1.450 kg, yield 67%, HPLC purity>99%). 1H NMR (CDCl3, 400 MHz): δ 7.77 (d, J=9 Hz, 2H), 7.49-7.53 (m, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Provenance & Evidence