Trimethoxybenzaldehyde from Vanillin via 5-Iodovanillin

A process has now been discovered from the conversion -d ai omatic compounds to hydroxy aromatic compounds which does not isolate an intermediate haloaromatic compound and which permits 

The first step of the reaction involves iodination of the aromatic compound with the triiodide salt in the presence of water as a solvent. The water should contain from 0.7 to 1.25 molar equivalents of a hydroxide, preferably an alkali metal hydroxide, and from 1-2 molar-equivalents of an alkali metal triiodide (e.g. iodine plus sodium iodide). The aqueous solvent should also contain from 0.1 to 20 mole % of an acid catalyst, which may be a mineral acid such as sulfuric, hydrochloric or phosphoric acid. Reaction is carried out at temperatures ranging from 20°-120° C. If the starting compound contains a nuclear substituent, iodination will occur in the ortho or para position on the nuclear ring. 

The subsequent step of the reaction, hydroxylation, is carried out directly with the reaction mixture from iodination without any interme diate isolation or other processing of the reactants or by-products. Abase, such as an alkali metal hydroxide or a quaternary amine such as tetraalkylammonium hydroxide, is added directly to the reaction mixture to make a final concentration of 0.5 to 6 molar, with 0.1 to 20 mole % copper metal, or cuprous salts such as oxide, chloride or iodide, at temperatures of from 50°-120° C. The preferred conditions art-addition of sodium hydroxide to the iodination reaction mixture to give a concentration of 2-5 molar, then addition of 1-5 mole % copper dust, cuprous oxide or cuprous chloride, then allowing reaction at reflux (100°-120° C.) for about 18 hours. 

A specific description of a preferred practice of the invention with vanillin as the aromatic compound is as follows. Vanillin is dissolved in water with one molar equivalent of sodium hydroxide while the solution is warmed to 50°-100° C. One molar equivalent of iodine and two molar equivalents of sodium iodide are added to water to prepare one molar equivalent of NalS.Nal. This sodium triiodide solution is added to the sodium vanillate solution along with a catalytic amount of sulfuric acid--preferably from 5 to 10 mole %. The mixture is stirred about one hour at a temperature of 50°-100° C., then sodium hydroxide is added to make the solution alkaline (from 1 to 5N). The copper catalyst is then added and the mixture heated at reflux until the iodovanillin is consumed, about 12 hours. The excess hydroxide is then neutralized and the 5-hydroxyvanillin extracted with a water-immiscihle organic solvent. The aqueous phase bearing the sodium iodide is then subjected to oxidizing conditions and the resultant iodine precipitates from solution. The solid element is filtered out, and a sodium triiodide solution prepared by reducing a portion of the iodine to sodium iodide and dissolving the iodine in the iodide to make the sodium triiodide solution. 

Alkylation of the hydroxy aromatic compound to the corresponding alkoxy aromatic compound may be performed in accordance with known alkylation procedures in which the hydroxy aromatic compound is reacted with an alkyl sulfate, alkyl halide or alkyl sulfonate in a suitable solvent, usually water, containing a base such as sodium hydroxide. Such reactions are shown at various places in the literature, as for ex. in Organic Synthesis, Col. Vol. II, page 619, 1943, in which veratraldehyde is prepared from vanillin. The iodide salt may, if desired, be recaptured subsequent to the alkylation reaction. 

---