Condensation ethyl malonate

Now that fumaric and maleic acid are available commercially, the most convenient method of preparing the above ester consists in condensing ethyl malonate with ethyl fumarate1 or ethyl maleate.2 It has also been prepared by condensing malonic ester with ethyl chlorosuccinate 3 and with ethyl ethoxysucci-nate.4... 

Assemble a 250 ml. three-necked flask, fitted with a stirrer, a reflux condenser and a dropping-funnel, as in Fig. 22(A) and (j), p. 43, or Fig. 23(c), p. 46 (or a two-necked flask, with the funnel fitted by a grooved cork (p. 255) to the top of the condenser). Place 40 ml. of ethanol in the flask, and then add 2-3 g. of sodium cut into small pieces. When all the sodium has dissolved, heat the stirred solution on the water-bath, and run in from the funnel 17 g. (17 ml.) of ethyl malonate and then (more slowly) io-2 g. (12 ml.) of mesityl oxide, the reaction-mixture meanwhile forming a thick slurry. Boil the stirred mixture under reflux for i hour, and then add a solution of 10 g. of sodium hydroxide in 50 ml. of water, and continue boiling the pale honey-coloured solution for ij hours more. 

Dissolve 13 g. of sodium in 30 ml. of absolute ethanol in a 250 ml. flask carrying a reflux condenser, then add 10 g. (9 5 ml.) of redistilled ethyl malonate, and place the flask on a boiling water-bath. Without delay, add a solution of 5 3 g. of thiourea in a minimum of boiling absolute ethanol (about 100 ml.). The sodium salt of thiobarbituric acid rapidly begins to separate. Fit the water-condenser with a calcium chloride guard-tube (Fig. 61, p. 105), and boil the mixture on the water-bath for 1 hour. Cool the mixture, filter off the sodium salt at the pump and wash it with a small quantity of cold acetone. Dissolve the salt in warm water and liberate the acid by the addition of 30 ml. of concentrated hydrochloric acid diluted with 30 ml. of water. Cool the mixture, filter off the thiobarbituric acid, and recrystallise it from hot water. Colourless crystals, m.p. 245 with decomposition (immersed at 230°). Yield, 3 5 -4 0 g. 

Pelargonic acid (n-Nonoic acid), CH3(CH2),COOH. Equip a 1-litre, three-necked flask with a reflux condenser, a mercury-sealed stirrer, a dropping funnel and a thermometer. Place 23 g. of sodium, cut in small pieces, in the flask, and add 500 ml. of anhydrous n-butyl alcohol (1) in two or three portions follow the experimental details given in Section 111,152 for the preparation of a solution of sodium ethoxide. When the sodium has reacted completely, allow the solution to cool to 70-80° and add 160 g. (152 ml.) of redistilled ethyl malonate rapidly and with stirring. Heat the solution to 80-90°, and place 182 5 g. (160 ml.) of n-heptyl bromide (compare experimental details in Section 111,37) in the dropping funnel. Add the bromide slowly at first until precipitation of sodium bromide commences, and subsequently at such a rate that the n-butyl alcohol refluxes gently. Reflux the mixture until it is neutral to moist litmus (about 1 hour). 

Trimethylene dibromide (1 mol) condenses with ethyl malonate (1 mol) in the presence of sodium ethoxide (2 mols) to form ethyl cydobutane-1 1-dksrboxylate (I). Upon hydrolysis of the latter with alcoholic potassium hydroxide, followed by acidification cyciobutane-1 1-dicarboxylic acid (II) is obtained. 

Equip a 3 litre three-necked flask with a thermometer, a mercury-sealed mechanical stirrer and a double-surface reflux condenser. It is important that all the apparatus be thoroughly dry. Place 212 g. of trimethylene dibromide (Section 111,35) and 160 g. of ethyl malonate (Section 111,153) (dried over anhydrous calcium sulphate) in the flask. By means of a separatory funnel, supported in a retort ring and fitted into the top of the condenser with a grooved cork, add with stirring a solution of 46 g. of sodium in 800 ml. of super dry ethyl alcohol (Section 11,47,5) (I) at such a rate that the temperature of the reaction mixture is maintained at 60-65° (50-60 minutes). When the addition is complete, allow the mixture to stand until the temperature falls to 50-55°, and then heat on a water bath until a few drops of the liquid when added to water are no longer alkaline to phenolphthalein (about 2 hours). Add sufficient water to dissolve the precipitate of sodium bromide, and remove the alcohol by distillation from a water bath. Arrange the flask for steam distillation (Fig. this merely involves... 

Mesityl oxide (Section 111,79) (I) condenses with ethyl malonate in the presence of sodium ethoxide to give the sodium derivative of (II) this upon hydrolysis with aqueous potassium hydroxide, followed by acidification, gives the cyclic diketone 5 5-dimethyl-l 3-cycfohexanedione (III), of which the enoUc form is 5 5-dimethyldihydroresorcinol (IV) ... 

Ethyl malonate condenses with urea in the presence of sodium ethoxide to yield barbituric acid (malonylurea) ... 

In a 2 litre round-bottomed flask, fitted with a double surface reflux condenser, place 11-5 g. of clean sodium. Add 250 ml. of absolute alcohol in one portion if the reaction is unduly vigorous, immerse the flask momentarily in ice. When all the sodium has reacted, add 80 g. (76 ml.) of ethyl malonate (Section 111,153), followed by a solution of 30 g. of dry urea in 250 ml. of hot (ca. 70°) absolute alcohol. Shake the mixture well, fit a calcium chloride (or cotton wool) guard tube to the top... 

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 diethylraalonate. Upon allowing the latter to react with the theoretical quantity of urea in the presence of an alcoholic solution of sodium ethoxide, veronal (diethylbarbituric acid or diethylmalonylurea) is produced. 

Muconic acid has been obtained in a variety of ways. The procedures that seem most important from a preparative point of view are by treatment of ethyl o ,5-dibromoadipate with alcoholic potassium hydroxide, by condensation of glyoxal (as the sodium bisulfite addition product) with malonic acid, by heating ethyl l-acetoxy-l,4-dihydromuconate (obtained by condensing ethyl oxalate and ethyl crotonate, acetylating, and reducing),and by oxidation of phenol with peracetic acid. ... 

In a 2-1. round-bottomed flask fitted with a reflux condenser protected by a calcium chloride tube 11.5 g. (0.5 gram atom) of finely cut sodium is dissolved in 250 cc. of absolute alcohol. To this solution is added 80 g. (0.50 mole) of ethyl malonate followed by 30 g. (0.50 mole) of dry urea dissolved in 250 cc. of hot (70°) absolute alcohol. After being well shaken the mixture is refluxed for seven hours on an oil bath heated to 1 io°. A white solid separates rapidly. After the reaction is completed, 500 cc. of hot (50°) water is added and then enough hydrochloric acid (sp. gr. 1.18) to make the solution acidic (about 45 cc.). The resulting dear solution is filtered and cooled in an ice bath overnight. The white product is collected on a Buchner funnel, washed with 50 cc. of cold water, and then dried in an oven at 105-1 io° for three to four hours. The yield of barbituric acid is 46-50 g. (72-78 per cent of the theoretical amount). 

Ethyl Propane-a,a,y,y-tetracarboxylate.—To a mixture of 1600 g. (10 moles, 1510 cc.) of ethyl malonate (Note 1) and 400 g. of 40 per cent formalin (5.3 moles) in a 5-I. round-bottom flask, cooled to 50 by immersion in ice, is added 25 g. (35 cc.) of diethyl-amine. The mixture is then allowed to come to room temperature and remain for fifteen hours, after which the flask is heated under a reflux condenser on a boiling water bath for six hours. The aqueous layer is then separated, and the residue is distilled under reduced pressure (Note 2) from a 3-I. special Claisen flask (Org. Syn. 1,40). The ester distils at i9o-2oo°/i2 mm.(2io-2i5°/2o mm.) The yield (Note 3) is 1000 g. (61 per cent of the theoretical amount). 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The addition of a phenylsulfoxide moiety to the end of the side chain markedly changes the activity of this class of compounds. This product, sulfinpyrazone (97-11), stimulates uric acid excretion, making it a valuable dmg for dealing with the elevated serum uric acid levels associated with gout. The compound is stiU one of the more important uricosuric agents available today. The starting ester (96-9) is available by alkylation of the dianion from ethyl malonate with 2-chloroethylphenyl thioether. Condensation with diphenylhydrazine (97-3) in the presence of a base then affords the pyrrazolodione (97-10). Oxidation of sulfur with a controlled amount of hydrogen peroxide leads to the sulfoxide and thus sulfinpyrazone (97-11) [107]. 

FuranonesS The first step in a simplified synthesis of bislactones involves condensation of an a-halo aldehyde (1) and potassium ethyl malonate (2) in benzene- water in the presence of tetra-n-butylammonium bromide. The furanone 3 is converted to the hislactone 4 by bromination followed by treatment with HBr. The product is a precursor to df-avcnaciolide (5), a fungicide from Aspergillus arenaceous. 

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