Alkylation of phenolic aldehydes in a melt-phase reaction by trimethyl phosphate

by Cesium

Useful aldehydes can be prepared by alkylating corresponding phenolic aldehydes by a variety of agents (alkyl halides, alkyl sulphites or sulphates). However, the alkylating agents, e.g. dimethyl sulfate or methyl chloride, are themselves acutely toxic and require special handling procedures. In US Pat 4,453,004 a process for the preparation of an alkylated phenolic ether comprising reacting a phenolic compound at a temperature of at least the melting point of the phenol and in the absence of a solvent with trimethyl phosphate as an alkylating agent (with low toxicity and handling hazard) is described.

Examples of phenolic compounds that can be alkylated are such monohydric phenols as phenol and o, m and p-cresol; phenolic aldehydes such as protocatechualdehyde, vanillin, syringaldehyde, p-hydroxybenzaldehyde, 5-formylvanillin and salicylaldehyde; phenolic ketones such as p-hydroxyacetophenone, acetovanillone, acetosyringone, acetamidophenol and guaiacol; and phenolic acids such as vanillic acid, syringic acid and p-hydroxybenzoic acid. The alkylating agent may be essentially any compound which is a source of a one to four carbon atom alkyl group. It may be either a gas or a liquid. In general, the alkylating agents may be alkyl sulfonates such as methyl and ethyl p-toluenesulfonate and methyl and ethyl benzenesulfonate; trialkyl phosphates such as trimethyl and triethyl phosphate; and dialkyl sulfites such as dimethyl and diethyl sulfite. (Other alkylating agents which may be used are alkyl sulfates such as dimethyl sulfate, diisopropyl sulfate and diethyl sulfate; alkyl halides such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide and similar propyl and butyl halides).


In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 85° C. The mixture was a clear to amber melt of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125° C. The mixture was maintained at about 80° C. for one hour and then cooled to 40° C. The mixture was poured into 20 ml water and extracted two times with 20 ml of methylene chloride. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4g (99%) of veratraldehyde as a pale oil.


In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and 15.0 g (0.11 mol) of potassium carbonate were heated to 105°C under nitrogen and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The mixture was maintained at about 80° C. for 3 hours then cooled to 45° C. and quenched with 50 ml of H2 O. The tan solid which precipitated was collected, washed with 3×50 ml of water and dried to give 15 g (92%) of 3,4,5-trimethoxybenzaldehyde.

From US Pat 4065504 (melt-phase reaction with dimethyl sulfate):


A mixture of 100g of syringealdehyde (0.55 mol), 85.0g of sodium carbonate (0.80 mol) and 106.0g of dimethyl sulfate (0.84 mol) was placed in a round-bottomed flask equipped with a reflux condenser, a stirrer and a dropping funnel. The syringealdehyde was of about 99% purity and was obtained, by distillation, from a crude mixture of vanillin and syringealdehyde produced by alkaline oxidation of waste Kraft liquor. The dimethyl sulfate was of commercial quality (B.P. 75°-77°/15 mm) and the sodium carbonate was of reagent grade in some experiments and of commercial grade in others. The flask was kept in a silicone oil bath on a hot plate. The mixture as prepared at room temperature was a thick paste which could be kneaded but could not be mixed by the stirrer driven by an electric motor. When the temperature of the mixture reached 75° C the mixture became fluid and was easily stirred by the blades of the stirrer. The temperature was further raised to about 85° C and maintained at this temperature with stirring for a total of about 2 hours. After the initial 35 minutes of this period the reaction mixture began to thicken due to the consumption of dimethyl sulfate and, in order to maintain it fluid, water in 5 gram portions was added from time to time through the funnel while the stirring continued. In total about 60g of water were added to the mixture during the reaction period. At the end of two hours, the heating was discontinued and about 500 ml of hot water was added to the mixture. The mixture was acidified with concentrated hydrochloric acid and was then extracted three times with about 250 ml of benzene (toluene,...) and the combined extract was washed with water. The benzene was removed by distillation and the solid product was dried in a vacuum oven and weighed. The yield was 106.9 g of 3,4,5-methoxybenzaldehyde, representing a yield of 99.3% of the theoretical. Analysis by gas-liquid chromatography (g.l.c.) showed a purity of 99.85% with syringealdehyde as the only detectable impurity.


50. of syringealdehyde (0.275 mol) 40g of sodium carbonate (0.38 mol) and 53.4g of dimethyl sulfate (0.42 mol) were placed in a round-bottom flask and heated substantially as in Example 1. When the temperature reached 75° C the reaction mixture became fluid but after 30 minutes at a temperature between 80° and 87° it began to thicken again. 30 ml. of water was then added dropwise while the temperature was maintained for 1.2 hours. On completion of the reaction 250 ml of hot water was added to the mixture. Then the mixture was cooled, the solidified organic material separated by filtration, washed with water and vacuum dried. The yield of 3,4,5-trimethoxybenzaldehyde was 99.6% with about 0.4% syringealdehyde remaining.


On mixing 50 g of vanillin (0.329 mol), 48.0 g of sodium carbonate (0.453 mol), and 60.2 ml of diethyl sulfate (0.460 mol) a fluid mixture was obtained almost immediately. The mixture was maintained at 80° for 3.5 hr. Water (25 ml) was added in small portions over the last 2.0 hr. Work-up as in the previous examples yielded 58.06 gm. (98.1%) of 4-ethoxy-3-methoxybenzaldehyde which contained 2.4% vanillin.


20.g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80° C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1% p-hydroxybenzaldehyde.

Bandil: 2,5-dimethoxytoluene by Trimethylphosphate alkylation of 2-Methylhydroquinone

30.5 g (0.3 moles) of 2-Methylhydroquinone was placed in a 250 mL RBF. This was placed in a water bath at room temperature. 110 mL 20% NaOH was added while stirring. The whole lot dissolved in a matter of seconds, and the mixture turned black/brown within seconds. After a minute 70 mL's of trimethylphosphate was added. The temperature remained constant during the next five minutes. A reflux condensor was attached and the waterbath was slowly heated to a gentle boil over the course of 30 min's. When the waterbath was boiling, the mixture refluxed slightly. This was continued for another hour.

After a hour, the mixture was removed from the waterbath and allowed to cool to almost room temperature. Next, the reaction mixture was added to a seperating funnel, containing 200 mL's of cold water. This was extracted three times with 3x75 mL's of DCM. The first extraction separated fine, but the following two caused heavy emulsion. A bit of NaCl was added, but it did not help a whole lot. Some carefull swirling got rid of the worst emulsion.

The DCM phase was very blackish looking, but two water washes took care of the worst color. The remaning DCM was deeply red in color. The DCM was placed in a large RBF and heated on an oil bath. The DCM was distilled off and the remaining viscous oil was distilled under vacuum. This yeilded a beautiful red-amber colored liquid, which boiled at 130-140°C. The total yeild was 31 grams (90% molar) of 2,5-dimethoxytoluene.