Ethyl 2-methylmalonate

Three hundred and forty-five grams (1.7 moles) of ethyl ethoxalylpropionate, b.p., ii4-ii6°/io mm. (p. 54), is placed in a round-bottomed flask, of suitable size carrying a reflux condenser, and a thermometer is suspended from the top of the condenser into the liquid. The ethyl ethoxalylpropionate is then heated until a Aigorous evolution of carbon monoxide begins (130-150 ). The temperature of the liquid is gradually raised as the gas evolution diminishes, and finally the liquid is refluxed until no more gas comes off. The ethyl methylmalonate is then distilled. It boils at ig4-iq6 /745 mm., and the yield is 288 g. (97 per cent of the theoretical amount). 

A small amount of hydrogen chloride is evolved in the initial stages of the reaction. 

According to Prins the heptachloropropane can be isolated easily by pouring the reaction mixture into water and removing the unreacted materials by steam distillation. The process is stopped when the product begins to distil, and on cooling the residue is obtained as a colorless solid of the correct melting point. 

The method is essentially that discovered by Boeseken and Prins - and studied further by Prinsd Pentachloroethane can be used in place of tetrachlorethylene, as it is converted into the unsaturated compound in the presence of aluminum chloride. irwiyw.-Heptachloropropane has been obtained also by the action of phosphorus pentachloride on pentachloroacetone, and by treating dichloroacetyl chloride with aluminum chloride.  

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No appreciable decomposition of the ethoxalyl ester into ethyl methylmalonate takes place when the distillation is carried out at 10 mm. To prevent overheating, the use of an oil bath and a heated column is recommended. 

Ethyl methyl ketone, 10, 23 17, 74 Ethyl methyl ketoxime, 11, 59 Ethyl methylmalonate, 17, 56 Ethyl i-methylthiol-3-phthaIimidopro-pane-3,3-dicatboxylate, 14, 58 Ethyl nitrite, 10, 22, 25... 

The three possible products may be illustrated by the condensation of benzalacetophenone and ethyl methylmalonate.26... 

In the reaction between benzalacetophenone and ethyl methylmalonate, this particular product has not been isolated. It is, however, illustrative of the structure which would be expected of a rearrangement product. See footnote 25a. 

Scheme 65 shows the stereospecific ring expansion [127] of 128 on treatment with the enolate anion of ethyl methylmalonate, furnishing a mixture of the equilibrating five-membered-ring compounds 131 and 132 (=D in Scheme 63). 

Fig. 9. Stereospecific ring extension of the cyclopropane derivative 1 on reaction with the eno-late anion of ethyl methylmalonate furnishing a mixture of the enantiomerically pure five-mem-bered ring compounds 4 and 5.

GFP hopo ICBP IP3 Ln3+ mal memal MLCK nota oxine par pdta pmea py quin-2 green fluorescent protein hydroxypyridinon(at)e intestinal calcium-binding protein inositol 1,4,5-triphosphate a lanthanide(III) cation malonate methylmalonate myosin light chain kinase 1,4,7-triazacyclononane-l,4,7-triacetate 8- hydroxyquinoline pyridine-2-azo-4 -dimethylaniline propylene-1,2-diaminetetraacetate 9- [2-(phosphonomethoxy)ethyl] adenine pjrridine pjrridyl 8-amino-2- [(2-amino-5-methylphenoxy )methyl] -6-methoxyquinoline-ATJV -tetraacetate 2- [ [2-[his(carboxymethyl)amino]-5-methyl-phenoxy] methyl] -6-methoxy-8- [bis(carboxymethyl) amino] quinoline]... 

The biosyntheses of the sap beetle pheromones has been carefully investigated by Bartelt and his co-workers [47,48]. The typical methyl-branching of the compounds originates from propanoate (or methylmalonate) units that form the principal structures (see Fig. 2). Replacement of propanoate by butyrate during chain elongation yields ethyl-branching. In about half of the compounds (125-128,133-136,138-140, and 144) the structures suggest acetate to act as a starter while in 133 and 147 the starter should be butyrate. The chains... 

The most detailed results were obtained with ethyl acrylate, which gave varying amounts of the linear product (diethyl succinate) and the branched product (diethyl methylmalonate) depending on the temperature and the gas used (carbon monoxide or nitrogen). The following scheme accounts for their observations ... 

The diethyl 2-[3-bis(methoxycarbonyl)methyl-4-nitrophenyl]-2-methylmalonate obtained above,(4.13 g, 9.71 mmol) was dissolved in acetic acid (40 ml). To the solution were added water (16 ml) and concentrated sulfuric acid (4 ml), and the resulting mixture was heated for 15 hours under reflux. The acetic acid was distilled off under reduced pressure. The residue was concentrated under reduced pressure after addition of toluene. The precipitated crystals were collected by filtration and washed with water to give 2.06 g of the desired compound as a pale brown crystalline product. The filtrate and washing were combined and subjected to extraction using ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 0.32 g of 2-(3-carboxymethyl-4-nitrophenyl)propionic acid as a yellow crystalline product. The total amount was 2.38 g (yield 96.8%). 

Insects utilize propionate and methylmalonate in the biosynthesis of ethyl branched juvenile hormones and methyl branched cuticular hydrocarbons. The sources of propionate and methylmalonate in some insects appear to differ from those in mammals. Succinate is the precursor of propionate and methylmalonate in a termite, whereas valine and probably other amino acids are the sources of propionate and methylmalonate in several other species. An unusual pathway for propionate metabolism has been shown to occur in insects and it may be related to the absence or low levels of vitamin B found in many species. Propionate is converted directly to acetate with carbon 1 of propionate lost as C02> carbon 2 of propionate becoming the methyl carbon of acetate and carbon 3 of propionate becoming the carboxyl carbon of acetate. This pathway suggested the possibility that 2-fluoropropionate might be selectively metabolized in insects to the toxic 2-fluoro-acetate. However, preliminary data indicate that 2-fluoropropionate is not toxic to the housefly or the American cockroach. 

To 250ml ethyl alcohol was added 5-(amidino)methyl-l,3-benzodioxolane (0.23 mol), 50 ml diethyl methylmalonate, 125 ml 25% NaOH in methyl alcohol, and the mixture refluxed 5 hours. The solvent was removed, the residue dissolved in water, acidified with 6 M HCl, and the product isolated by precipitation. 

Also, ethyl 2-methylmalonate 336 on treatment with DCC affords the ketene intermediate... 

Benzyloxy)-2-fluoro-2-methylpropanal (8) is prepared in optically active form from ethyl (5 )-2-fluoro-3-hydroxy-2-methylpropanoate (7). Ester 7 is readily obtained from ethyl (S)-2-fiuoro-2-methylmalonate (6) which can, itself, be prepared by enzymatic hydrolysis. ... 

Chloropyrazine and derivatives have been shown to react with alkali metal derivatives of a phenylacetonitrile or of a phenylacetamide for example, 2-chloropyrazine treated with diphenylacetonitrile in toluene with sodium amide gave 2-(T-cyano-r,r-diphenylmethyl)pyrazine (68, R = H) (1021, 1022). 2-Chloro-5-phenylpyrazine(s) with diethyl methylmalonate and sodium hydride gave 2-(r,l -di(ethoxycarbonyl)ethyl]-5-phenylpyrazine(s) (363-365, 824, 825), and a similar reaction occurred with 2-chloropyrazine (364, 365,1023). 

CH CHs) = (C00H)2 Methylmalonic acid. Iso-succinic acid. CH(C2H5) = (C00H)2 Ethyl malonic acid. 

The reaction of FITS compounds with the sodium salt of 2-methylcyclohexan-l,3-dione led to the 0-perfluoroalkylated and the C-perfluoroalkylated products. The ratio 0-derivatives C-derivatives was strongly dependent upon the reaction temperature, the C-perfluoroalkylated product predominating at lower temperature. Similar results were obtained with ethyl 2-methylacetoacetate. In the case of the sodium salt of diethyl 2-methylmalonate and of 2-nitropropane, only the C-perfluoroalkylated products were isolated. ... 

Interestingly, the Marckwald definition is taken from a paper that was rebutting a criticism [33] of Marckwald s claim to have achieved an asymmetric synthesis by a group-selective decarboxylation of the bmcine salt of 2-ethyl-2-methylmalonic acid [34,35] ... 

Methylcorrinoids are competent for the efficient methylation of alkyl radicals. Thermolysis of 2 -bis(ethoxycarbonyl)propylcobalamin and methylcobalamin at 70 °C led to formation of cob(II)alamin and the organic products 2-ethyl-2-methylmalonic acid diethyl ester and 2,2-dimethylmalonic acid diethyl ester. The former product was generated with quantitative deuterium incorporation from CDsCobjllljalamin. The proposed mechanism involves homolytic substitution on methylcob(III)alamin by the 2 -bis(ethoxycarbonyl)propyl radical, resulting in net methyl-radical abstraction, a process calculated to be highly exothermic (A7/ -201 kJmoK ). The stereochemical course of the reaction should result in net inversion at the methyl carbon, although this has not been demonstrated. The reaction may serve as a precedent for several biosynthetic methylations, such as the antibiotic thienamycin synthesis. ... 

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