Thionyl Chloride → 2-Methyl-4-(methylthio)benzoic acid

Participants

Reaction Conditions

Reaction Steps

Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of 4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoate was used in the next step without further purification. Methyl 4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodium thiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was then partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-methyl-4-(methylthio)benzoic acid which was carried to the next step without further purification. 2-Methyl-4-(methylthio)benzoic acid was suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, then partitioned between 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (50 mL). The combined organics washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was rinsed with ether (2×10 mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid (0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. Found 215.5 (M+1)+; Retention time: 0.48 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s, 3H), 2.59 (s, 3H).

Provenance & Evidence