Methyl esters with dimethyl sulphate

Methylphenobarbital can also be prepared by the interaction of ethylphenyl malonie ester and dicyandiamide when it results into the formation of 5-ethyl-5-phenyl-3-cyano barbituric acid, which on methylation with dimethyl sulphate yields 5-ethyl-5-phenyl-3-cyano-1-methyl barbituric acid. This on acid hydrolysis converts the cyano moiety at position 3 into a free COOH group which on decarboxylation finally gives methylphenobarbital. 

Methyl esters potassium salt with dimethyl sulphate... 

Esters. The most common impurities are the corresponding acid and hydroxy compound (i.e. alcohol or phenol), and water. A liquid ester from a carboxylic acid is washed with 2N sodium carbonate or sodium hydroxide to remove acid material, then shaken with calcium chloride to remove ethyl or methyl alcohols (if it is a methyl or ethyl ester). It is dried with potassium carbonate or magnesium sulphate, and distilled. Fractional distillation then removes residual traces of hydroxy compounds. This method does not apply to esters of inorganic acids (e.g. dimethyl sulphate) which are more readily hydrolysed in aqueous solution when heat is generated in the neutralisation of the excess acid. In such cases, several fractional distillations, preferably under vacuum, are usually sufficient. 

Typical synthetic procedures include the reaction of alkyl halides with the silver salts of carboxylic acids, the reaction of carboxylate anions in alkali with an excess of a dialkyl sulphate, (especially dimethyl sulphate), and heating tertiary184 or quaternary ammonium salts of carboxylic acids. These routes are particularly valuable for the preparation of esters of seriously sterically hindered acids. For example, Fuson et al.iK made the methyl ester of 2,4,6-triethylbenzoic acid by heating the tetramethyl ammonium salt to 200-250°C, viz. 

These esters are insoluble in water though they are decomposed on contact with water to split off the alkyl group, especially dimethyl sulphate. This same scission also takes place in presence of other substances containing the hydroxyl group. It is for this reason that dimethyl sulphate is widely employed both in the laboratory and in industry as a methylating agent. 

It may be prepared by the eondensation of N-methyl urea, obtained from urea and dimethyl sulphate, and ethylphenyl malonie ester with the elimination of two moleeules of ethanol. 

Methyl, ethyl, benzyl, benzhydryl, p-nitrobenzyl, p-methoxy-benzyl, 4-picolyl, j3j -trichloroethyl, j3-methylthioethyl, /J-p-toluenesulphonylethyl, and -p-nitrophenylthioethyl esters may be prepared directly from the acid and alcohol. TTie most usual method [4, 5] consists of heating the acid and an excess of the alcohol with an acid catalyst (e.g., Fischer-Speier, hydrochloric or sulphuric acid). The extent of reaction is improved if the water formed is removed by azeotropic distillation with an inert solvent (benzene, carbon tetrachloride, or chloroform). Considerable variation is possible in the natvire of the acid catalyst thus phosphoric acid [6], aryl sulphonic acids [7, 8, 9], alkyl sulphates [10], and acidic ion-exchange resins [11] may be employed. Removal of the water by azeotropic distillation during the formation of methyl esters is difficult and Brown and Lovette [12] introduced the novel reagent acetone dimethyl acetal (7) for the direct formation of methyl esters. In the presence of a trace of methanol and an acid catalyst the reagent acts as a scavenger of water formed by esterification and liberates further methanol for reaction. 

Methylating agents for phenolic groups are a) diazomethane (the reaction time varies from minutes to 24 hours), b) dimethyl sulphate (DMS) - potassium carbonate in acetone or dimethylformamide (DMF) and c) methyl iodide - potassium carbonate in acetone. For demethylation of a methyl ether group ortho to a methyl ester group boron tribromide is used, while demethylation of a methyl ether para to a methyl ester group is carried out with boron trichloride (see Scheme 8). 

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