Step 1. Anisaldehyde from anethole via oxidative cleavage.
20 g anise oil was suspended in a mixture of 150 mL water and 30 mL conc. sulfuric acid; addition of 55 g sodium bichromate at such a rate that the temperature did not exceed 40 °C. The reaction mixture was extracted with 4 x 125 mL toluene and the solvent evaporated. The residual oil was vacuum distilled to yield 9.1 g anisaldehyde.
Step 2. O-formyl-4-methoxyphenol.
6 mL anisaldehyde was dissolved in 75 mL dichloromethane (DCM). A mixture of 12g hydrogen peroxide 60% aq.soln and 10 mL conc. formic acid was added over 30 min. The reaction mixture was gently refluxed for 21 h.
Step 3. 4-methoxyphenol.
Evaporating the solvent from reaction Step 2 and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent) yielded 4.1 g 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.
Step 4. Reimer-Tiemann formylation of 4-methoxyphenol to 2-hydroxy-5-methoxybenzaldehyde.
124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.
Step 5. Methylation of 2-hydroxy-5-methoxybenzaldehyde.
The yellow oil from Step 4 was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxy-benzaldehyde. The mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde.
20 g anise oil was suspended in a mixture of 150 mL water and 30 mL conc. sulfuric acid; addition of 55 g sodium bichromate at such a rate that the temperature did not exceed 40 °C. The reaction mixture was extracted with 4 x 125 mL toluene and the solvent evaporated. The residual oil was vacuum distilled to yield 9.1 g anisaldehyde.
Step 2. O-formyl-4-methoxyphenol.
6 mL anisaldehyde was dissolved in 75 mL dichloromethane (DCM). A mixture of 12g hydrogen peroxide 60% aq.soln and 10 mL conc. formic acid was added over 30 min. The reaction mixture was gently refluxed for 21 h.
Step 3. 4-methoxyphenol.
Evaporating the solvent from reaction Step 2 and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent) yielded 4.1 g 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.
Step 4. Reimer-Tiemann formylation of 4-methoxyphenol to 2-hydroxy-5-methoxybenzaldehyde.
124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear, yellow oil that did not solidify upon standing at room temperature.
Step 5. Methylation of 2-hydroxy-5-methoxybenzaldehyde.
The yellow oil from Step 4 was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxy-benzaldehyde. The mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde.
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