Methanol → Methyl 3-methyl-4-(methylthio)benzoate

Participants

Reaction Conditions

Reaction Steps

Thionyl chloride (5.8 g, 3.5 mL, 48.7 mmol) was added dropwise to a solution of 4-fluoro-3-methyl-benzoic acid (5.0 g, 32.4 mmol) in methanol (40 mL). The reaction mixture was stirred at 35° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resulting methyl 4-fluoro-3-methylbenzoate was used in the next step without further purification. ESI-MS m/z calc. 167.1. found 168.2 (M+1)+; Retention time: 1.57 minutes (3 min run). The crude ester was dissolved in DMF (20 mL) and powdered sodium thiomethoxide (2.3 g, 32.4 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and at 80° C. for 1 hour. The reaction mixture was concentrated in vacuo, the residue was partitioned between 1M HCl solution and ethyl acetate. The layers were separated and the organic was washed with 1M hydrochloric acid solution. The ethyl acetate layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 3-methyl-4-(methylthio)benzoate. ESI-MS m/z calc. 182.2. found 183.1 (M+1)+; Retention time: 1.48 minutes (3 min run). Methyl 3-methyl-4-(methylthio)benzoate (32.4 mmol) was heated in a mixture of acetic acid (80 mL) and hydrogen peroxide (40 mL of 30% w/w,) at 80° C. for 30 minutes. The reaction mixture was cooled, concentrated in vacuo and then partitioned between water and ethyl acetate. The layers were separated and the organic was washed sequentially with water (1×20 mL), sat. NaHCO3 (1×20 mL) and brine (1×20 mL), then dried over MgSO4 and concentrated in vacuo. The residue was triturated with ethyl ether to give methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g) as a white solid. The mother liquor was concentrated in vacuo then triturated with hexanes (3×) to give a second crop (1.2 g) (combined yield 95%). ESI-MS m/z calc. 228.3. found 229.5 (M+1)+; Retention time: 1.04 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.20-8.09 (m, 1H), 8.04-8.00 (m, 2H), 3.96 (s, 3H), 3.10 (s, 3H), 2.77 (s, 3H).

Provenance & Evidence