Magnesium methyl carbonate carboxylation with

Carboxylation of resorcinols. The acidity of the aromatic hydrogens in resorcinols prompted Israeli chemists4 to investigate the possibility of carboxylation with magnesium methyl carbonate. The reaction was successful. Thus resorcinol gave /3-resorcylic acid (45%) and 2,4-dihydroxyisophthalic acid (15%), together with starting material (43%). 

The carboxylation of nitroalkanes with magnesium methyl carbonate followed by esterification gives a-nitro esters in 40-58% yield.14 Magnesium methyl carbonate is prepared by the saturation of a magnesium methoxide suspension in DMF with C02. More elegantly, sodium salt of nitroalkanes can he carboxylated by means of 1 -ethoxycarbonylbenzotriazole to give a-nitro esters in 55-80% yield (Eq. 5.7).15 Nitroacetic acids and its esters can serve as useful... 

Ketones of the form RCOCH3 and RCOCH2R can be carboxylated indirectly by treatment with magnesium methyl carbonate 52.613 Because formation of the chelate 53 provides the driving force of the reaction, carboxylation cannot be achieved at a disubstituted a position. The reaction has also been performed on CH3N02 and compounds of the form RCH2N02614 and on certain lactones.61s Direct carboxylation has been reported in a number of instances. Ketones have been carboxylated in the a position to give (3-keto acids.616 The base here was lithium 4-methyl-2,6-di-f-butylphenoxide. 

It is of interest to synthetic chemists and biochemists that the reverse of the reaction shown above, namely, a carboxylation, can be carried out by the treatment of nitromethane with magnesium methyl carbonate, (CHaOMgOCChCHs and CO2), in dimethylformamide. A magnesium chelate of the nitroacetate dianion is formed which, when hydrolyzed under acid conditions, gives nitroacetic acid. The success of this carboxylation of a nitroparaffin depends on the formation of the magnesium chelate, which was identified spectrophotometrically (37, 84, 194) ... 

Sodium phenolate, CjHsONa. Magnesium methyl carbonate (which see) has been shown to be an effective agent for carboxylating active methylene groups. Italian investigators have found that sodium (or potassium) phenolate in combination with carbon dioxide carboxylates cyclohexanone in dimethylformamide to give... 

In the Nenitzescu synthesis of 5-hydroxyindoles, an A-aryl substituted amino-propenoic ester may be used, albeit with a low yield of product [2343]. Better yields may be obtained by reacting the quinone at ambient temperature with an enaminonitrile [3246]. The methylthio group may be removed by heating with Raney nickel. Magnesium methyl carbonate is sometimes used to carboxylate a methyl ketone but when it is warmed with the methyl ketone (35.3), it causes cyclization of the keto side-chain [2747]. A dioxopyrimidine aldehyde (35.4) is cyclized in moderate yield by heating with carbonate in DMF [2668]. 

Carboxylation of activated CH groups with MMMC (methoxy magnesium methyl carbonate) 1 (Szarvasy) and addition of the resulting activated groups to C=N bonds (Schopf) (see 1st edition). 

A number of methods describing improved syntheses of a-methylene-butyrolactones have been published. Magnesium methyl carbonate has been found to carboxylate butyrolactones (though not six-membered lactones) in high yield treatment of the acid (41) with aqueous formaldehyde and diethylamine, followed by separate treatment of the crude product with sodium acetate in acetic acid, gives the desired a-methylenebutyrolactone (42). An independently developed, complementary route involves thermal fragmentation of the salt (43), iodide ion functioning as a nucleophile for... 

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 sulfate, and distilled. Fractional distillation then removes residual traces of hydroxy compounds. This method does not apply to esters of inorganic acids (e.g. dimethyl sulfate) 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. 

Mechoulam R, Ben-Zvi Z, Carboxylation of resorcinols with methyl magnesium carbonate. Synthesis of cannabinoid acids, Chem Commun 343—344, 1969. 

A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-l,4-benzoxazine-8-carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3-oxo-2H-l,4-benzoxazine-8-carboxamide. 

Reaction of l-methyl-3-chloro-2-phospholene-l-oxide (9) was particularly difficult even with Kl-activated magnesium . Reaction of 9 with KI-activated magnesium in refluxing THF for 6 1/2 hours gave approximately 40% of the corresponding carboxylic acid after treatment with carbon dioxide and then acid. 

---