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Synthesis of 3-methyl-2,5-dimethoxybenzaldehyde

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This is a very interesting benzaldehyde, which can be used in the preparation of a DOM/STP isomer.


To 138g 2-methyl-4-methoxyphenol in 800 ml water 81g 37% formalin was added. To this suspension with cooling under a blanket of nitrogen, 28g CaO was added gradually. The operation was performed in a jar and after the lid was closed tightly all the material went into solution upon shaking. After standing overnight in an ice box, wart-like crystals had separated on the walls of the reaction vessel. Upon shaking, the whole contents of the jar became solid due to formation of the calcium salt of the reaction product. The reaction mixture was diluted with water, acidified with acetic acid and the precipitated oily phenol extracted with ether. The ether extract was washed with NaHCO3 to remove excess acetic acid, washed with water, and dried over Na2SO4. Evaporation afforded 137.5 g. of crude 2-methyl-4-methoxy-6-hydroxymethylphenol. Distillation of the crude product under vacuum resulted in extensive decomposition. The distillate, bp 136-140C/1mmHg., solidified (mp 56-57C). On crystallization from isohexanes, it melted at 58-59C and was found to be 2-methyl-4-methoxy-6-hydroxymethylphenol.


137.5g of the crude 2-methyl-4-methoxy-6-hydroxymethylphenol prepared above was dissolved in 200 ml. of acetone. After addition of 115g anhydrous K2CO3 and 125g methyl iodide, the solution came to reflux due to an exothermic reaction. After the initial reaction ceased, the mixture was refluxed with stirring for 18 hours. It was poured into a large volume of water and the precipitated oil extracted with ether. The ether extract was washed with 2 N NaOH to remove unreacted phenols and after repeated washing with water, dried over Na2SO4. Rectification in vacuo afforded:

  1. 5.8g, 65-85C/0.6 mmHg, nD24 1.5215.
  2. 14.2g, 85-109C/0.6 mmHg, nD24 1.5232.
  3. 78.5g, 109-114C/0.6 mmHg, nD24 1.5327.
  4. 19.7g, 114-116C/0.6 mmHg, nD24 1.5344.

The first two fractions are mainly 2,5-dimethoxytoluene. Fractions 3-4 consist mainly of 3-methyl-2,5-dimethoxybenzyl alcohol, yield was 98.2g. From the NaOH extract, 7.1 g. of phenolic material was recovered.

3-methyl-2,5-dimethoxybenzylalcohol (Mannich route)

To a mixture of 20g 2-methyl-4-methoxyphenol and 29g 25% dimethylamine, 13g 37% formaldehyde was added dropwise with stirring and the temperature was kept below 20C. After stirring for two hours, the reaction mixture was extracted with benzene, dried over Na2SO4 and the benzene was evaporated. The resulting crude 2-methyl-4-methoxy-6-dimethylaminomethyl phenol was refluxed for 3h with 50g acetic anhydride. After dilution with water, it was extracted with benzene, washed with water, sodium carbonate and finally with water and the solvent evaporated. The residue is 2-acetoxy-3-methyl-5-methoxybenzyl acetate. The diacetate was heated in NaOH with dimethyl sulfate for 90 minutes, acidified with HCl, extracted with ether and the ether evaporated. The residue was distilled in vacuo and 3.1g of 3-methyl-2,5-dimethoxybenzyl alcohol was obtained, bp 113-118C/1 mmHg.


Careful oxidation of 3-methyl-2,5-dimethoxybenzylalcohol gave the aldehyde with mp 40-41C, after recryst. from pet ether white needles was obtained, mp 42C.


[1] US Patent 3,236,898