Synthesis
General procedure for the synthesis of 2,6-dimethyl-4-methoxybenzoic acid from carbon dioxide and 4-bromo-3,5-dimethylanisole: 4-bromo-3,5-dimethylanisole (3.38 g, 15.79 mmol) was dissolved directly in 100 mL of anhydrous tetrahydrofuran (THF) without further purification. The reaction mixture was cooled to -78 °C under argon protection, followed by slow dropwise addition of n-butyllithium (1.6 M hexane solution, 9.9 mL, 15.8 mmol) over 15 min. After the dropwise addition was completed, the reaction mixture continued to be stirred at -78 °C for 15 min. Subsequently, a small amount of dry ice was added to the reaction system and stirring was continued at -78 °C for 20 minutes. The cooling bath was removed and the reaction mixture was allowed to gradually warm up to room temperature while stirring was continued until the release of carbon dioxide gas ceased. The reaction mixture was poured into 100 mL of ice water and acidified with 6N hydrochloric acid. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (EtOAc). All organic phases were combined, washed sequentially with saturated saline and deionized water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2,6-Dimethyl-4-methoxybenzoic acid was finally obtained as a white solid (2.7 g, 95% yield). Mass spectrometry analysis showed that the (M+H)+ peak was located at m/z 181.
