30318-99-1

124-38-9

78071-30-4

At -78 °C, n-butyllithium (n-BuLi, 1.6 M hexane solution, 14.6 mL, 23.3 mmol) was slowly added dropwise to a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in tetrahydrofuran (THF, 35 mL). After the dropwise addition was completed, the reaction mixture was kept stirred at -78 °C for 15 minutes, followed by continued stirring for 30 minutes. Next, carbon dioxide gas (CO2) was passed into the reaction mixture for 10 minutes and stirring was continued at the same temperature for 20 minutes. Upon completion of the reaction, the mixture was slowly warmed to 0 °C and the reaction was quenched with 1 M aqueous sodium hydroxide (NaOH) solution (60 mL), followed by washing with ethyl acetate (EtOAc, 2 x 50 mL). The aqueous phase was acidified to pH about 5 and extracted with dichloromethane (DCM, 2 × 50 mL). The organic layers were combined, washed sequentially with water (100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. Finally, the residue was purified by column chromatography (silica gel as stationary phase, 8% methanol/dichloromethane as eluent) to afford the target product 4-methylthiophene-3-carboxylic acid (1.5 g, 70% yield) as a white solid.