Diethyl ketone malonate

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

In this reaction the enolate of diethyl malonate adds to the p carbon of methyl vinyl ketone... 

Tlie bifunctional sulfenyl chloride 213 was obtained by chlorination of 144 in good yield, although excessive chlorination led to the saturated compound 214 (94CB533). A series of compounds 215-220 were obtained from 213 by reactions with secondary amines ferf-butyl methyl ketone hexane-2,4-dione 2,6-dimethylcyclohexanone diethyl malonate and acetylacetone, respectively. 

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-... 

N, N-Diethylethylenediamine Tiapride Diethyl ketone Molindone Diethyl maleate Malathion Diethyl malonate Bupivacaine Kebuzone... 

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. 

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. 

OS 52[ [OS 53[ [OS 54[ [OS 55[ [R 4b[ [P 38[ In a two-micro-mixing tee chip reactor, substrates with diketone moieties of known different reactivity, such as 2,4-pentanedione, benzoylacetone and diethyl malonate, were processed, each with the same acceptor ethyl propiolate [8]. Also, a reaction with the less alkynic Michael acceptor methyl vinyl ketone was carried out. 

The conversions observed followed the sequence of reactivity known from batch experiments carried out in advance. For example, only 15% conversion was found for the less reactive reagent benzoylacetone in the micro reactor experiment, while 56% was determined when using the more reactive 2,4-pentanedione (batch syntheses 78% and 89%, respectively) [8]. Using the stopped-flow technique (2.5 s with field applied 5.0 s with field turned off) to enhance mixing, the conversions for both syntheses were increased to 34 and 95%, respectively. Using a further improved stopped-flow technique (5.0 s with field applied 10.0 s with field turned off), the conversion could be further enhanced to 100% for the benzoylacetone case. For the other two substrates, diethyl malonate and methyl vinyl ketone, similar trends were observed. 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

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). 

In general terms, a P-ketoester like ethyl acetoacetate and diethyl malonate is a source of substituted can be considered as a pathway to substituted ketones, acids. 

The same zwitterions can give pyrid-2-ones (798) when treated with dimethyl acety-lenedicarboxylate (71AG(E)925). Quaternary pyrimidinium salts are attacked by the anions from diethyl malonate or malononitrile to produce pyrid-2-ones (799) or 2-aminopyridines (800) respectively (74RCT233). Quinazoline Af-oxide (801) reacts with ketones on heating to give quinolines the reaction is assumed to be initiated by attack at C-4, with subsequent... 

The Bayer synthesis of ciprofloxacin (1) patented in 1981 utilized 2,4-dichloro-5-fluorobenzoyl chloride (15) as the starting material. With the aide of magnesium ethoxide, condensation of acid chloride 15 and diethyl malonate assembled ketone 16, which was subsequently decarboxylated using tosylic acid to form ethyl 2,4-dichloro-5-fluorobenzoylacetate (17) in 82% yield in two steps from 15. A Dieckman-like condensation of 17 with ethyl orthoformate was carried out in refluxing acetic anhydride... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonate[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7]. Deformylation and reduction leads to 2-sub-stituted indoles. 

Pyrrole- and indole-carboxylic acid chlorides react with dialkyl- and diaryl-cadmium to yield the ketones and it is noteworthy that the reaction of the anhydride of indole-2,3-dicarboxylic acid with diphenylcadmium produces 3-benzoylindole-2-carboxylic acid and not its isomer (53JCS1889). The ability of l-methylindole-2-carboxylic acid to react with nucleophiles is enhanced by conversion into the mixed anhydride with methanesulfonic acid. The mixed anhydride reacts with carbanions derived from diethyl malonate and from methyl acetate to yield the indolyl (3- keto esters (80TL1957). 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

Michael addition to unsaturated amides. This system (1 equiv. of each) effects Michael addition of ketones, nitro compounds, ethyl cyanoacetate, and diethyl malonate to a,(3-unsaturated amides. Addition to methacrylamides is interesting because the final products are glutarimides or dihydropyridinones. 

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