3,4,5-Trimethoxybenzaldehyde from p-Cresol

Synth. Comm. Vol 32, No 18, pp 2809–2814 (2002)

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A 3-Necked round-bottomed flask equipped with a condenser attached to a calcium chloride drying tower, a mechanical stirrer, a thermometer, and a dropping funnel was charged with a solution of 43.2 g (0.40 mol)of p-cresol in 200 mL of o-dichlorobenzene. The solution was cooled to 10°C and treated during 1 h with a solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-benzene at such a state that the temperature was kept below 40°C. The mixture was stirred, heated at 160°C and simultaneously dropped with another solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-benzene during 3 h. This deep red mixture was sequentially stirred for 30 min. After being cooled to room temperature and 145 mL of water being added, the mixture was heated to 120°C and kept at the temperature for 4 h. After being cooled to 5°C, the mixture was separated into upper organic layer, middle aqueous layer and lower solid layer. The solid product was collected by filtration and washed with water up to neutrality. It was dried in vacuo at 50°C to give 91.4 g (81.6%) of the off-white solid mp 180–182°C (lit. 179–182°C).


About 142.0 g (0.74–0.79 mol) of freshly prepared 28–30 wt% sodium methoxide, 8 mL of DMF, 4 g of cuprous chloride and 56.0 g (0.20 mol) of 3,4-Dibromo-4-hydroxybenzaldehyde were added into a 500 mL magnetically stirred stainless steel autoclave. After the air was replaced with N2, the autoclave was heated to 120°C and kept at the temperature for 3 h. After being cooled to room temperature, the reaction mixture was taken out from the autoclave and transferred into a round-bottomed flask. Solvents were evaporated from the flask in vacuo below 60°C, and the residue was treated with 200 mL of water. The mixture was stirred and heated to 90°C for dissolution, then cooled to 0°C for crystallization. After NaBr dissolved in the stock was removed by filtration, yellow green sodium phenolate 8 was obtained. The filter cake was dissolved in 300 mL of water, added with 1.5 g of active carbon,and then heated to 95°C for 30 min. After hot-filtration for removing the filter residue (catalyst included), the filtrated stock was cooled to 40°C, and was treated by slowly dropping 50.0 g (0.40 mol) of dimethylsulfate and 30 wt% 112 g (0.84 mol) of NaOH aqueous solution during 2 h. The pH value should be carefully controlled within 8.5–9.3. Stirring was continued at 50°C for 30 min and then at 0°C for 30 min, and the product was collected by filtration. It was washed with water up to neutrality and dried in vacuo at 45°C to give 32.4 g (82.6%) of 3,4,5-trimethoxybenzaldehyde as colorless crystals, m.p. 74–75°C (lit. 73–75°C).