Methanol → Methyl 2-(4-bromophenyl)acetate

Participants

Reaction Steps

A solution of (4-bromo-phenyl)-acetic acid (6.77 g, 31.48 mmol) in methanol (32 mL) was treated with a catalytic amount of concentrated sulfuric acid (3 drops). The reaction mixture was then heated to reflux for 24 h. At this time, the reaction was concentrated in vacuo. The residue was treated with an aqueous solution of sodium bicarbonate (100 mL). This solution was extracted with ethyl acetate (3×100 mL). The organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo to afford (4-bromo-phenyl)-acetic acid methyl ester (6.75 g, 94%) as a yellow oil. The product was used without further purification. A solution of freshly prepared lithium diisopropylamide (50.5 mL of 0.3 M, 15.15 mmol) cooled to −78° C. was treated with (4-bromo-phenyl)-acetic acid methyl ester (3.36 g, 14.67 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (37 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (3.24 g, 15.45 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.24 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 20 h. The reaction mixture was then quenched by the slow addition of a saturated ammonium chloride solution (40 mL). The reaction mixture was then poured into water (100 mL) and the product was extracted into ethyl acetate (3×75 mL). The organics were washed with a saturated aqueous sodium chloride solution (3×100 mL) and a saturated aqueous solution of lithium chloride (3×100 mL), dried over sodium sulfate and magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (3.86 g, 84.6%) as a clear oil: EI-HRMS m/e calcd for C15H19BrO2 (M+) 310.0568 found 310.0564.

Provenance & Evidence