Carbon Dioxide → 2-(3-Methoxy-4-(methoxycarbonyl)phenyl)acetic acid

Participants

Reaction Conditions

Reaction Steps

A dry 2 L 3-neck RBF fitted with an argon inlet, a thermometer, a magnetic stirring bar and a septum was charged with THF (220 mL) and diisopropylamine (54.6 mL, 0.39 mol, 1.2 eq). The resulting mixture was cooled to −50° C. and a solution of 2.5 M n-BuLi (156 mL, 0.39 mol, 1.2 eq) was added slowly via cannula. After 30 min of stirring at −50° C., the solution of LDA generated was cooled to −78° C. and HMPA (67.8 mL, 0.39 mol, 1.2 eq) was added, followed by a solution of methyl 2-methoxy-4-methylbenzoate 10b (57 g, 0.32 mol) in THF (220 mL), while maintaining the temperature at −78° C. The reaction mixture was stirred two more hours at −78° C., and then cannulated into a flask containing 100 g dry ice and THF (200 mL). After 30 min stirring at −78° C., the reaction mixture was allowed to warm up slowly to RT and then poured into water (1.5 L). The organic layer was separated and the aqueous layer was further extracted with ether (3×1 L). The water layer was acidified with a solution of 10% H2SO4 (150 mL) and the reaction product was extracted into CH2Cl2 (3×1.5 L). The combined organic extracts were dried over anhydrous Na2SO4, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (eluent EtOAc: hexane 3:7), followed by recrystallization from CH2Cl2:hexane 1:1 to afford pure methyl 4-carboxymethyl-2-methoxybenzoate 10c (38.8 g, 54.7% yield).

Provenance & Evidence