Ethyl malonate, addition

While the sodium ethoxide solution is cooling, prepare a solution of 7 7 g. of finely powdered iodine in 60 ml. of ether. When this solution is ready, add 9 ml. (9 6 g.) of ethyl malonate to the ethanolic sodium ethoxide solution, mix w ell and then allow to stand for 30-60 seconds not longer) then cautiously add the ethereal solution of the iodine, mixing thoroughly during the addition in order to avoid local overheating by the heat of the reaction. (If, after the ethyl malonate has been added to the sodium ethoxide, a considerable delay occurs before the iodine is added, the yield of the final product is markedly decreased.)... 

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

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. 

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... 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Quinone monoacetals such as 2-methoxyben2oquinonemonoacetal [64701-03-7] (66) show regiospeciftc addition of active methylene compounds (66), yielding 83% (67) and 63% (68) on reactions with ethyl malonate. 

This work was repeated by several groups7 11 in the reaction of sodium dimethyl-malonate with methyl sorbate, Farmer and Metha9 observed small amounts of the 1,4-adduct besides the 1,6-addition product. Difficulties in conducting the transformations and analyzing the products are evident from reports on malonate additions to ethyl muconate12-14 depending on the reaction conditions, the expected 1,4-adduct (equation 4) or isomerization products formed by double bond displacement were isolated. Nucleophilic 1,4- and 1,6-addition reactions to 2,4-pentadienenitrile were also reported15-17. 

Diethyl phenyl ethyl malonate. 1 mole of benzyl cyanide is added dropwise to a solution of 1 mole of ethyl carbonate in 2 liters of anhydrous ethanol containing 5 g of clean sodium metal. This mixture is refluxed (preferably on a steam bath) for 5 hours. It is then cooled and to it is added a cooled mixture of 40 g of sulfuric acid in 100 ml of anhydrous ethanol. This alcoholic solution is refluxed for 5 hours, cooled, neutralized with sodium ethylate (use external indicator). The mixture is evaporated to half bulk, filtered from the sodium sulphate and to it is added 1 mole of clean metallic sodium. Reflux while adding 1 mole of ethyl bromide dropwise. Heat for another 2 hours after the addition is completed. Remove the alcohol by distillation and dissolve the remaining residue in water. Extract the substance from the water with benzene and after drying, the benzene is recovered and the ester should be purified by distilling in vacuo. 

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]. 

A reaction of bromobenzene with ethyl malonate in the presence of sodamide affords homophthalimide [103], This fascinating reaction involves sequential elimination, addition, intramolecular acylation, fragmentation, and addition. Excellent polarity alternation along the chains of atoms in various intermediates allows so many steps to proceed efficiently. 

Malonate anions react with the ri2-ethylene-Fe(CO)4 complex to afford after demetallation ethyl malonate derivatives. Reaction of nucleophiles with tetracar-bonyliron-activated c/.Jl-unsatu rated carbonyl compounds leads after protonation of the intermediate alkyl-Fe(CO)4 anions to the products of Michael addition. 

An ethanolic solution of sodium ethoxide is prepared by the addition of 11.5 g. (0.5 gram atom) of sodium to 160 ml. of absolute ethanol (p. 142) under a reflux condenser. After cooling to room temperature, 160 g. (1.0 mole) of ethyl malonate is added to the solution, and this is followed by the dropwise addition of 63.2 g. (0.60 mole) of benzyl chloride. The resulting mixture is refluxed for 1 hour, and then most of the ethanol is distilled off. The residue is treated with water, and the organic layer is separated and distilled. There is collected 80 g. of unreacted malonic ester, b.p. 91-96°/12 mm, pressure and 107 g. (85 yield based on malonic ester consiuned) of benzylmalonic ester, b.p. 163-170°/12 mm. 

Depending upon reaction conditions, dibenzalacetone and ethyl malonate can be made to yield any of three products by Michael addition. 

They then examined the Michael addition of the optically active a,/l-unsaturated sulfoxide (1) with di.ethyl malonate with an equimolar amount of sodium ethoxide at 80° under argon. Diethyl 2-(p-tolylsulfinyl)-1-phenylethylmalonate (5) was obtained in... 

The solution is diluted with the same volume of water previously used to dissolve the caustic potash. To this is added carefully and with cooling concentrated hydrochloric acid, until an acid reaction may just be detected. The ethyl malonic acid is precipitated out in the form of its difficultly soluble calcium salt, by the addition of a cold solution of calcium chloride, as concentrated as possible. This is filtered off, well pressed on a porous plate, and the ethyl malonic acid liberated by treating carefully with concentrated hydrochloric acid is obtained pure as in (1). 

The major part of the reactions of a-arylation which have been reported were performed on substrates containing active methylene groups, such as p-diketones, p-ketoesters, P-ketonitriles and malonic acid derivatives. Less activated compounds, such as P-ketosulfides have also been efficiently arylated on the a-carbon. (Table 5.3) The yield of the arylated product can be increased by addition of 1,1-diphenylethylene, acting as a free radical trap. For example, in the reaction of phenylation of ethyl cyclohexanonecarboxylate, addition of 1,1-diphenylethylene reduced the radical chain decomposition in such a way that an 80% yield was obtained instead of 55% in absence of 1,1-diphenylethylene. ... 

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