Diethylmalonate

Barbituric acid and 2-thiobarbituric acid are readily prepared by the condensation of diethylmalonate with urea and thiourea respectively, in the presence of sodium ethoxide. The use of substituted derivatives of urea and thiourea and of diethyl malonate will clearly lead to a wide range of barbituric and thiobarbituric acids having substituents in the i, 3, or 5 positions. 

Diethylbarbituric acid. In a dry 250 ml. distilling flask, fitted with a thermometer reaching to within 3-4 cm. of the bottom and a condenser, place 51 g. of clean sodium and add 110 g. (140 ml.) of super-dr ethyl alcohol (Section 11,47,5). When all the sodium has reacted, introduce 20 g. of ethyl diethylmalonate and 7 0 g. of dry imea (dried at 60 for 4 hours). Heat the flask in an oil bath and slowly distil off the ethyl alcohol. As soon as the temperature of the liquid reaches 110-115°, adjust the flame beneath the bath so that the contents of the flask are maintained at this temperature for at least 4 hours. Allow the flask to cool somewhat, add 100 ml. of water and warm until the solid (veronal-sodium) dissolves. Pour the solution into a beaker, and add a further 100 ml. of water but containing 7 0 ml. of concentrated siilplmric acid this will hberate the veronal from the sodium derivative. The veronal usually crystallises out if it does not, add a few more drops of dilute sulphuric acid until the solution is acid to Congo red. Heat the contents of the beaker, with stirring and the addition of more water if necessary, until all the veronal dissolves at the boiling point. Allow the hot solution to cool, filter off the crystals of veronal and diy in the air. The yield is 12 g., m.p. 190°. 

Ethylmalonic Acid.—Like acetoacetic ester (see p. 83), diethylmalonate contains the gioup CO.CHj.CO. By the action of sodium or sodium alroholate, the hydrogen atoms of the methylene group are successively replaceable by sodium. The sodium atoms are in turn replaceable by alkyl or acyl groups. Thus, in the present preparation, ethyl malonic ester is obtained by the action of ethyl iodide on the monosodium compound. If this substance be treated with a second molecule of sodium alcoholate and a second molecule of alkyl iodide, a second radical would be in roduced, and a compound formed of the general formula... 

In 1885, Just reported the reaction of sodium diethylmalonate with Af-phenylbenzimino chloride to provide 11. Thermal cyclization provided 12. This work was virtually untouched for several decades, but laid the groundwork for further development. 

Alkaline hydrolysis of 6-methoxy- 4-methoxycarbonyl-2-methyl-tbiopyrimidine leaves unaffected only the methylthio group which can then be hydrolyzed in acid. 9-Alkylthioacridines are hydrolyzed by acid less readily than the corresponding alkoxy compounds and more readily than alkylamino derivatives. Peculiarly, a better yield of the amine results from 4-thioxo than from 4-methylthio-quinazoline on heating with primary amines. Displacement in 2-methylthio-quinolinium and 3-methylthiopyridazinium compounds (137) proceeds readily with the carbanion of diethylmalonate or the zwitterion of 2-methylbenzothiazolinium derivatives. 

Trichloro-s-triazine also reacts readily with carbon or phosphorus nucleophiles. Diethylmalonate anion forms a mono-derivative under mild conditions and the tri-substitution product (327) under vigorous conditions with excess nucleophile. Nucleophilic attack by the 7r-electrons of ketene diethylacetal to give 254 and of dimethylaniline to give 253 has been mentioned earlier. Two... 

Reaction of 2-aminopyridine with dimethyl 2-methylmalonate in the presence of some drops of cone. HCl at 150°C for 1 h (96EUP733633), and with diethyl 2-(l-decyl)malonate at 120°C for 5 min (94JCR(S)206) gave 2-hydroxy-3-methyl- and 2-hydroxy-3-(l-decyl)-4//-pyrido[l, 2-n]pyrimidin-4-ones in 2.2% and 7.5% yields, respectively. Reaction of 3-benzyl-2-aminopyridine and diethylmalonate at 190-200 °C for 4 h yielded 9-benzyl-2-hydroxy-4//-pyrido[l, 2-n]pyrimidin-4-one (01MIP9). Cyclocondensation... 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

When the nucleophile is a stabilized carbanion such as the enolate of acetylacetone, 1-benzoylacetophenone, diethylmalonate, or ethyl acetatoacetone, the reaction proceeds similarly. The monosubstituted complex is isolated as long as it contains an acidic hydrogen in the benzylic position. In addition, for the case of diketones CH2(COR)2 (R = Me, Ph, OEt), a deacetylation is observed in an acidic medium [92,93]. These features are the same as described above in the case of the substitution of Cl by stabilized carbanions in monochloroaromatics (the second chlorine being an inert arene substituent [99] Scheme XVII, Eq. (31) and Tables 10 and 11. 

Enzymatic action, of thiazolocyanines, 80 Ethanol, action on thiazolium salts, 32 Ethoxymethylene diethylmalonate, in synthesis of trimethine thiazolocyanines, 55... 

The enantioselective Michael reaction of malonates to nitroolefins catalysed by bifunctional amino-thioureas has recently been reported by Take-moto [161]. Excellent ee (75-93%) were obtained with diethylmalonate after solvent optimisation, toluene being the best solvent both for the activity and for the selectivity. Substituted malonates were then reacted with various nitroolefins under the same conditions. Excellent enantioselectivities were observed (Scheme 45). 

The condensation of 1 mol of ethyl malonate with two mols of ethyl iodide in the presence of two mols of sodium ethoxide gives a good yield of ethyl diethylmalonate. Upon aUowing the latter to react with the theoretic quantity of urea in the presence of an alcoholic solution of sodium ethoxide, veronal (diethylbarbituric acid or diethylmalonylurea) is produced. 

Sulfoximines bearing a chiral sulfur atom have recently emerged as valuable ligands for metal-catalysed asymmetric synthesis.In particular, C2-symmetric bis(sulfoximines), such as those depicted in Scheme 1.51, were applied to the test reaction, achieving enantioselectivities of up to 93% ee. The most selective ligand (R = c-Pent, R = Ph) of the series was also applied to the nucleophilic substitution reaction of l,3-diphenyl-2-propenyl acetate with substituted malonates, such as acetamido-derived diethylmalonate, which provided the corresponding product in 89% yield and 98% ee. 

Another route to the preparation of Cgo derivatives involves the reaction of a halogen derivative of diethylmalonate in the presence of a strong base with fullerenes, which results in a... 

Structure 20 and salts 115 and 116 are formed by condensation of nitric oxide with diethylmalonate. Arulsamy and Bohle warn that this new type of compact ring structure forms dense crystals, and compounds 20, 115, and 116 are potential energetic materials which decompose violently at high temperatures <2002AGE2089>. 

Comparative activity ofTS-1, Ti-MCM-41 and amorphous Ti02-Si02 in transesterification of (a) ethylacetoacetate with benzyl alcohol and allylalcohol and (b) diethylmalonate with allylalcohol... 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

Although most of these early reactions were conducted with allylic acetates, reactions of allylic carbonates, trifluoroacetates, and phosphates also occur. Sodium diethylmalonate also reacts with allylic alcohols in the presence of the iridium-triphenylphosphite catalyst. However, the alcohol itself does not act as a leaving group. Instead, transesterification occurs with one equivalent of malonate nucleophile to form a more labile ester leaving group. 

Other bases found to react with 1,1,1-trinitroethane via formation of 1,1-dinitroethene include trimethylamine, guanidine and diethylmalonate anion (152), the latter forming (153) in 36 % yield. Shechter and Zeldin found no correlation as to why some bases react with 1,1,1-trinitroethane so differently to others but noted that simple alkoxides, aliphatic amines, guanidine, cyanide and malonate anions reacted via the 1,1-dinitroethene pathway. 

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