Sodium Hydroxide → 4-Methoxy-3-methylphenol

Participants

Reaction Steps

4-Methoxy-3-methylphenol was prepared according to the procedures described in Higgins et al., “An Assessment of the Reaction Energetics for Cytochrome P450-Mediated Reactions,” Arch. Biochem. Biophys. (2001); 385: 220-30. Specifically, phosphorus oxychloride (5.1 ml, 0.057 mol) was added dropwise to a solution of o-methylanisole (5.33 ml, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 hours, cooled, and then added to 100 ml of water. To the solution, 10% NaOH was added and the solution was extracted with 4×100 ml of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate, and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The purified oil (1.78 g, 28%) was dissolved in dichloromethane (100 ml) and then 3.03 g (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 hours, cooled, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressured. The dark oil that remained was dissolved in 7 ml of methanol and 5.5 ml of 10% aqueous potassium hydroxide solution was added. The solution was stirred for ˜2 hours, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give 4-methoxy-3-methyl-phenol as long white needles.

Provenance & Evidence