Diethyl malonate, condensation

Diethyl malonate, condensation with acetone, 50, 39 Diethyl 5-methylcoprost-3-en-yl phosphate, 52, 109 Diethyl phosphorochloridate,... 

The interaction of l-(p-arsonophenyl)biguanide and ethyl acetoacetate failed to give the expected 2-(p-arsonophenylguanidino)-4-hydroxy-6-methylpyrimidine under a variety of conditions (408), as did the corresponding reaction with diethyl malonate. Condensation did occur, however, with acetylacetone (see Section VII J5) (see also ref. 590). 

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. 

Ethyl propane-1 1 3 3-tetracarboxylate. Cool a mixture of 320 g. (302 ml.) of redistilled diethyl malonate and 80 g. of 40 per cent, formaldehyde solution ( formalin ) contained in a 1-htre round-bottomed flask to 5° by immersion in ice, and add 5 g. (7 ml.) of diethylamine. Keep the mixture at room temperature for 15 hours and then heat under a reflux condenser on a boiling water bath for 6 hours. Separate the aqueous layer, dry the organic layer with anhydrous magnesium sulphate, and distil under reduced pressure. Collect the ethyl 1 1 3 3-tetracarboxylate at 200-215°/20 mm. The yield is 250 g. 

CH2=CHCH(NH2)CH2CH2C00H (18), obtained through condensation of diethyl malonate with l,4-dichloro-2-butene [764-41-0] (43), or the antiulcer Rebamipide [90098-04-7] (19), whose synthesis involves the use of 2-(acetylamino)malonate (44), are examples of new pharmaceuticals recently launched. 

The canthinone ring system was also obtained by condensation of jS-carboline-1-carbonyl chloride (412a) with diethyl malonate, followed... 

Functionalized 5-alkoxymethyl- and 5-phenoxymethyl-2(5//)-furanones 44-46 were obtained starting from 3-alkoxy- and 3-phenoxy-2-hydroxy ketones 40 (98T1801). Condensation of the hydroxy ketones 40 with a slight excess of diethyl malonate 41 (Z = COOMe R = Me), ethyl cyanoacetate 42 (Z = CN R = Me),... 

Incorporation of a carbonyl group into the alkyl side chain also proved compatible with biologic activity. The key intermediate (76) is obtainable by Michael addition of the anion from diethyl malonate to methylvinyl ketone followed by ketalization with ethylene glycol. Condensation of 76 with hydrazobenzene leads to the pyrazolodione hydrolysis of the ketal group affords ketasone (78). ... 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

The Knoevenagel reaction is a carbonyl condensation reaction of an ester with an aldehyde or ketone to yield an a,j8-unsaturated product. Show the mechanism of the Knoevenagel reaction of diethyl malonate with benzaldchyde. 

Fluorenylamine, 40,5 Formaldehyde, reaction with diethyl malonate to form diethyl bis-(hydroxymethyl)malonate, 40,27 Formamide, condensation with 4,4-dimethoxy-2-butanone to give 4-methylpyrimidine, 43, 77 Formic acid, and hydrogen peroxide, with indcne, 41, 53... 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

Attempted condensations with diethyl malonate and with ethyl cyano-... 

Knoevenagel condensation of diethyl malonate or related compounds with a,fi-unsaturated aldehydes and ketones results in diene esters (equation 40)78. This condensation reaction has been used to extend the polyene chain length of vitamin A related compounds (equations 4179 and 4280). 

Diethyl Ethylmalonate.—Sodium (4-6 g.) is dissolved, in a small flask fitted with an efficient reflux condenser, in 75 c.c. of absolute alcohol and to the cooled solution 33 g. of diethyl malonate are added (precipitation of diethyl sodio-malonate). To the mixture thus obtained, ethyl bromide (25 g.) or ethyl iodide (35 g.) is added in small portions with shaking and the flask is then heated on the water bath until, after one to two hours, the contents are no longer alkaline. The alcohol is removed by distillation in a vacuum from the water... 

Ethyl diazoacetate condenses with diethyl malonate to yield a derivative of 4-hydroxypyrazole (Bertho and Niissel, Annalen, 1927, 457, 278) ... 

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