Methylation of vanillin

CgHjoO,. A compound of largely historical interest for its role in establishing the structure of many natural products. Methylation of vanillin gives veratraldehyde which may be oxidized to veratric acid. Veratric acid was identified as a degradation product of the alkaloid papaverine. 

Veratraldehyde can be prepared by methylation of vanillin. It is used in oriental and warm-woody fragrances, as well as in flavor compositions for vanilla notes. It is an intermediate in, for example, the synthesis of pharmaceuticals. 

Veratric Aldehyde (13,102) By methylation of vanillin with methyl p-toluene-sulfonate. Kanbvska, Arch. Phaim. 271, 462 (1933). 

In detergent perfumes, the stabiUty of vanillin is not always certain. It depends on the association made with other raw materials, eg, with patchouli, frankincense, cloves, most of the animal notes, and such chemicals as amyl saUcylate, methyl ionones, heflotropin, gamma undecalactone, linalool, methyl anthrarulate, benzyl acetate, phenyl ethyl alcohol, cedar wood derivatives, oak mosses, coumarin, benzoin. Pern balsam, and cistus derivatives. In some cases, these mixtures can cause discoloration effects. 

The use of high concentrations of vanillin in soap perfumery can cause discoloring effects over time, dark or black spots appear on the soap and foaming power is reduced. In some cases, however, the use of Rhodiarome ethylvanillin is possible, because ethylvanillin [121 -32-4] does not cause the same discoloration problems and, being at least three times more powerful than vanillin, can be used alone. Some surprising cases show that with oak or tree mosses and large amounts of methyl ionones, the soap perfume may look fine and have a low discoloration, and yet over time vanillin crystals can appear on the soap itself. 

Pyrogallol monomethyl ether has been prepared by the methylation of pyrogallol with dimethyl sulfate or methyl iodide by the decarboxylation of 2,3-dihj droxy-4-methoxy-benzoic acid and by the methylation of pyrogallol carbonate with diazomethane and subsequent hydrolysis. The method described is taken from the improved procedure of Baker and Savage for the preparation of pyrogallol monomethyl ether from o-vanillin by oxidation with hydrogen peroxide. 

Creosol (also called 2-methoxy-jb-cresol, 4-methylguaiacol, and 3-methoxy-4-hydroxytoluene) has been obtained by the fractionation of beach creosote tar,4 by the reduction of vanillin by electrolytic methods,6 6 by hydrogen and palladium on charcoal or barium sulfate,7 8 with hydrazine,9 and by amalgamated zinc and hydrochloric acid.3 10 11 It has also been prepared by methyl-ation of 4-methylcatechol with methyl iodide 12 13 or with methyl sulfate 14 and is reported to be formed by the distillation of the calcium salt of 3-methoxy-4-hydroxyphenylacetic acid.16... 

Uses Manufacture of vanillin, Michler s ketone, methyl violet, and other dyes solvent reagent for methyl alcohol, hydrogen peroxide, methyl furfural, nitrate, and formaldehyde chemical intermediate stabilizer reagent. 

Vanillylamine [(4-hydroxy-3-methoxy-phenyl)methylamine] is the substrate of choice for the formation of vanillin with the help of amine oxidase. It can be obtained by cleavage of capsaicin (N-[(4-hydroxy-3-methoxy-phenyl)methyl]-8-methyl-6-nonenamide) isolated from pepper and capsicum [83]. As natural vanillin extracted from beans of Vanilla planifolia is rare and extremely expensive, this pathway for the production of natural vanillin is regarded to have a great potential. The vanillin obtained by the process can be labelled as natural if the cleavage of capsaicin is performed enzymatically. 

The ratio of vanillin to vanillic acid and the yields of these two products, expressed as percentages of wood lignin, are the most significant data available to judge the severity of an alkaline nitrobenzene oxidation of a coniferous wood. The yields of vanillin and vanillic acid reported in Tables IV and V as methyl ether and methyl ether ester are only approximately 8 and 50%, respectively, of amounts that might be expected based on previous work. The ratio of vanillin to vanillic acid has been found to be 8 1 whereas in the reaction reported here it is 1 2. Furthermore, Leopold 32) reported vanillin vanillic acid oxalic acid as 6 1 2 whereas... 

In studies on the oxidation of lignin that had alternately been methylated at the p-hy-droxyl and benzylic hydroxyl groups, Leopold (1952) concluded that methylation caused the low yield of vanillin obtained in the oxidation. As mentioned in Section 6.6.3, the replacement of the OH group by OMe seriously impedes C-C bond cleavage in the water reaction medium. 

Successively, 145 g (0.5 mole) of trimethoprime and 83 g (0.5 mole) of vanillin was added to 500 ml of pyridine, and about 130 g of sulfurous anhydride was added in three hours. The temperature of the reaction mixture rose spontaneously between 40° and 50°C from the start of the introduction and was held there until the end of the reaction. It was left for 24 hours at ordinary temperature. Then the reaction mixture was poured into a large volume of ether, the precipitate which appeared was filtered off and washed with ether. The crude product was then dispersed in water and treated with dilute sodium hydroxide to pH 9.30-9.40. A light insoluble substance was filtered off, then the product was reprecipitated by the addition of hydrochloric acid to the alkaline solution to pH 2-3. It was filtered, washed with water, and then with ethanol. After drying, (+/-)-a-[[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]-2-pyrimidinyl]amino]-3-ethoxy-4-hydroxybenzenemethanesulfonic acid, was obtained, melting point 145°C. TLC of the product gave a single spot. 

Eugenol has been used as a feedstock in the production of isoeugenol, which is needed in the manufacture of vanillin. Methylation of eugenol yields methyleugenol, which acts as a sex attractant for a certain type of fly (Dacus dorsalis) [7,8]. 

Fig. 4-1. Examples of classical methods indicating a phenylpropanoid structure of lignin. (A) Permanganate oxidation (methylated spruce lignin) affords veratric acid (3,4-dimethoxybenzoic acid) (1) in a yield of 8% and minor amounts of isohemipinic (4,5-dimethoxyisophtalic acid) (2) and dehydrodiveratric (3) acids. The formation of isohemipinic acid supports the occurrence of condensed structures (e.g., /3-5 or y-5). (B) Nitrobenzene oxidation of softwoods in alkali results in the formation of vanillin (4-hydroxy-3-methoxybenzaldehyde) (4) (about 25% of lignin). Oxidation of hardwoods and grasses results, respectively, in syringaldehyde (3,5-dimethoxy-4-hydroxybenzaldehyde) (5) and p-hydroxybenzaldehyde (6). (C) Hydrogenolysis yields pro-pylcyclohexane derivatives (7). (D) Ethanolysis yields so-called Hibbert ketones (8,9,10, and 11).

Fig. 4.5 Extent of hydrolysis of glycoside of different volatile compounds during MLF with four strains of malolactic bacteria (MLB). Values are calculated as a percentage ratio between the concentration of glycosides in MLF samples and in a non-MLF control. Sum of 1-hexanol, trans- and CM-3-hexenol, trans- and c/i-2-hexenol sum of isoamyl alcohols, heptanol, and 4-hydroxy-4-methyl-2-pentanol sum of benzyl alcohol and 2-phenylethanol sum of vanillin and benzaldehyde sum of 4-vinylphenol and 4-vinylguaiacol sum of Unalool and a-terpineol sum of nerol and geraniol sum of cis- and rrani-linalool oxides (pyranic and furanic) sum of 3,7-dimethyl-l,5-octadien-3,7-diol and the two 2,7-dimethyl-2,7-octadien-l,6-diol isomers (from Ugliano and Moio 2006, reproduced with permission)...

Thoma and Klimek (115) also found that the natural food colorant curcumin as well as Fast Yellow, chrysoine, apocarotinol, and, cochineal Red A photostabi-lized solutions of nifedipine and nitrofurazone. They also found that vanillin and methyl gallate could stabilize solutions of dihydroergotamine. These authors also found that furosemide was stabilized by the addition of vanillin, haloperidol by benzyl alcohol, and vanillin and thiothixene by quinosol and vanillin. 

The choice of liquid phase can affect the course of ozonation. This has been shown with phenylindenes by Miura et al. (1985) and with lignin models by Kratzl et al. (1976), who found that 4-methylveratrole gave a higher yield of dimethyl -methyl-cis,cis-muconate in 45% aqueous acetic acid than in dichloromethane and that the yield of dimethyl oxalate from acetoveratrone was markedly dependent on the solvent. Eriksson and Gierer (1985) found that in methanol the benzene ring of vanillin is cleaved (albeit only very slowly, after acetalization has occurred), but that in nonprotic solvents, such as acetone, the initial reaction is oxidation of the aldehyde function to a carboxyl group. 

Compound DD is insoluble in aqueous NaOH, and readily decolorizes dilute KMn04 and Br2/CCU. Treatment of DD with hot concentrated base gives FF, Cj 1H14O2. Ozonolysis of EE gives a compound that is isomeric with vanillin (p. 792). Ozonolysis of FF gives a compound that is identical with the one obtained from the treatment of vanillin with methyl sulfate. 

Alkylation of vanillin 158 with methyl 4-bromobutyrate and subsequent nitration afforded 159. Addition of the methyl group to the aldehyde was performed with the commercially available AlMes to yield 160 this could be crystallized directly from the crude reaction mixture after the three steps. After hydrolysis, the corresponding acid may be attached to a hydroxy-modified support as an ester. Acylation then results in the desired construct 157. 

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