Methyl ethyl ketone malonic acid

The general approach can be enlarged and conditions for condensation made milder by the use of further-activated esters, thus condensation with methyl nitroacetate produces 3-nitro-coumarins, condensations with Wittig ylides " allow orffto-hydroxyaryl ketones to be used ° and the use of diethyl malonate (or malonic acid ) (a 3-ester can be removed by hydrolysis and decarboxylation ), malononitrile, ethyl trifluo-roacetoacetate, or substituted acetonitriles in a Knoevenagel condensation, produces coumarins with a 3-ester, 3-trifluoroacetyl, " 3-cyano, or 3-alkyl or -aryl substituent. Condensation with IV-acetylglycine generates 3-acetylamino-coumarins. ... 

Compounds which dissolve in concentrated sulphuric acid may be further subdivided into those which are soluble in syrupy phosphoric acid (A) and those which are insoluble in this solvent (B) in general, dissolution takes place without the production of appreciable heat or colour. Those in class A include alcohols, esters, aldehydes, methyl ketones and cyclic ketones provided that they contain less than nine carbon atoms. The solubility limit is somewhat lower than this for ethers thus re-propyl ether dissolves in 85 per cent, phosphoric acid but re-butyl ether and anisole do not. Ethyl benzoate and ethyl malonate are insoluble. 

Alcohols, esters (but not ethyl benzoate, ethyl malonate or ethyl oxalate), aldehydes, methyl ketones and cyclic ketones containing less than nine carbon atoms as well as ethers containing less than seven carbon atoms are soluble in 85 p>er cent, phosphoric acid. 

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. 

Use of Ci-bromoethyl methyl ketone as alkylating agent for malonic ester gives a 74% yield of ethyl a-carbethoxy-y0-methyllevulinate. The second a-hydrogen atom may be replaced by a methyl group in 76% yield. The keto acids, /3-methyllevulinic acid (40%) and a,/8-dimethyllevulinic acid (83%), are then obtained by decarboxylation of the dibasic acids at 140° and 120°, respectively. ... 

Variations of the malonic ester and acetoacetic ester sequenees lead to many useful synthetic opportunities. In the examples quoted, the base-solvent pair used was ethanol-sodium ethoxide, where the alkoxide is the conjugate base of tbe solvent. If NaOEt-EtOH were used with a methyl ester, transesterification would give a mixture of methyl and ethyl esters as products. For both malonic ester and acetoacetic ester removal of the most acidic proton (a to both carbonyls) also gives the more thermodynamically stable enolate. Either NaOEt-EtOH or LDA-THF will generate the desired enolate. The malonic ester synthesis is most useful for the synthesis of highly substituted monoacids, and tbe acetoacetic ester synthesis is used to prepare substituted methyl ketones. 

A. N. Dey (174) has described an independent synthesis of the alkaloids. Michael condensation of ethyl 7-ethoxy- or 7-phenoxy-crotonate (LI, R = OEt, R = Et or Ph) with ethyl malonate or cyan-acetate, followed by ethylation and hydrolysis, furnished a mixture of the two racemic forms of the glutaric acid, LII, which were separated by virtue of their different ease of anhydride formation. On treatment with hydrobromic acid, they gave rise to dl-homopilopic acid and dl-homo-isopilopic acid (LIII, R = OH), respectively. Corresponding methyl ketones (LIII, R = Me) were obtained by a similar synthesis from... 

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