Carbon Dioxide → 1-(3-Fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one

Participants

Reaction Conditions

Reaction Steps

3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole (326 mg, 0.99 mmol) was charged to an oven-dried 100 mL 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, rubber septum and a magnetic stirring bar. Anhydrous THF (35 mL) was added, and the solution was cooled to -78° C. under a dry nitrogen blanket. To this solution, n-butyllithium (1.6 N in hexane; 0.74 mL) was added, via syringe over approximately 3 minutes, keeping the reaction temperature <-75° C. The deep red suspension was stirred at -78° C. for 1 hour. Simultaneously, anhydrous tetrahydrofuran (80 mL) was cooled to -78° C. in an oven-dried 250 mL round-bottom flask. This solvent was saturated with carbon dioxide gas. The red reaction solution was quenched into the carbon dioxide-saturated THF. The yellow reaction was warmed to room temperature over 2 hours, then diluted with water (50 mL) and ether (80 mL). The solution was extracted with aqueous sodium hydroxide (5%, 2×50 mL), and the combined aqueous solution was acidified to pH <2 with aqueous hydrochloric acid (conc.). The acidic solution was extracted with dichloromethane (2×50 mL). The combined organic solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to a crude solid. The solid was dissolved in methanol (20 mL) in a 100 mL round-bottom flask equipped with a magnetic stirring bar and a nitrogen gas inlet. Oxone® (2.13 g, 3.47 mmol) and water (3 mL) were added, the suspension was stirred at room temperature for 2 hours, warmed to reflux and held for an additional 2 hours. Upon cooling to room temperature, water (35 mL) and aqueous hydrochloric acid (6 N, 1 mL) were added. The resulting suspension was cooled to 0° C., held for 30 minutes, filtered and washed with cold water to yield, upon drying, [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid as white crystals (173 mg, 43%): mp 89° C. Mass spectrum: MH+=406. Anal. Calc'd. for C19H16NO6FS: C, 56.29; H, 3.98; N, 3.46; S, 7.91. Found: C, 56.22; H, 4.00; N, 3.44; S, 7.85.

Provenance & Evidence