Malonic acid esters,

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

Comprehensive work in this field has been done by Slovak authors (98MI1, 95M1359, 96CCC269, 96CCC371, 97CCC99). They prepared 2-substituted (H, Me, Ph) 4-, 5-, 6-, and 7-nitrobenzoxazoles, which were then reduced to amines (not isolated) and subjected to subsequent nucleophilic substitution with activated enol ethers such as alkoxymethylene derivatives of malonic acid esters and nitrile, 3-oxobutanoic acid esters, pentanedione, or cyanoacetic acid esters to yield aminoethylenes 8. 

Malonic acid ester synthesis is a classic but still one of the most important C—C bond-forming reactions, because it is widely applicable to various types of compounds and the reaction can be performed under mild conditions without special care to remove the trace amount of water and oxygen contained in the solvent. This reaction is especially useful in the synthesis of carboxylic acids. One important class of carboxylic acids is arylpropionates because optically active ones are known to have anti-inflammatory activity and other interesting physiological... 

C-Alkylation of malonic acid esters Malonic acid esters, alkyl halides... 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

Of the four possible optical isomers, the (+)-( I )-cw-isomer possesses the most characteristic jasmin odor. Methyl dihydrojasmonate is prepared by Michael addition of malonic acid esters to 2-pentyl-2-cyclopenten-l-one, followed by hydrolysis and decarboxylation of the resulting (2-pentyl-3-oxocyclopentyl) malonate, and esterification of the (2-pentyl-3-oxocyclopentyl)acetic acid [136]. 

Monoalkylated Malonic Acid Esters. Diethyl [Pg.23]

Acetoacetic esters, acetylacetone, or malonic acid esters react with cartxxli-imides to give amidines. 

Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis <0314851>. While alkyl or aromatic substitutions on the P position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3- disubstituted thiophene. 

In the case of malonic acid and other compounds when the methylene group is linked to two carboxyl groups the sodium compounds are more easily formed than are the sodium compounds of the alkyl radicals themselves. These sodium compounds of malonic acid ester, are especially reactive toward alkyl halides with the result that the alkyl radical is introduced into the malonic acid ester in place of the sodium, i.e.y in place of hydrogen of the methylene group. This is shown by the following reactions. 

By this view the sodium malonic acid ester does not have the same constitution as the malonic acid ester itself. The sodium malonic acid ester containing a double bond now reacts with the alkyl halide and forms first an addition product similar to the one formed with the sodium alcoholate which then decomposes and yields the alkyl substitution product of the ester with the constitution first given. 

Mono- and dialkylations of malonic acid esters generally are performed in an alcoholic solution of a metal alkoxide. Alkylation of a monoalkylated malonic ester requires the presence of another equivalent of alkoxide and the appropriate alkyl halide. The alkylation works well with RCH2X (X=l, Br, OTs), PhCH2X (X=C1, Br) and even with unhindered sec alkyl bromides." Subsequent hydrolysis of the diester under acidic or basic conditions followed by heat-induced decarboxylation yields the a-alkylated carboxylic acid. Thus, dialkyl malonates are the synthetic equivalents (SE) of acetate enolate anions and can be used to obtain mono- or disubstituted carboxylic acids. 

Decarboxylation of mono- or dialkylated malonic acid esters can be effected by heating in the presence of aqueous acids (e.g., 48% aq HBr, reflux). 

Derivation By condensing malonic acid ester with urea. 

MaIonic acids25 and malonic acid esters,26 likewise, form carbanions which can be alkylated. Trianions of malonic acids can be formed by treatment with n-butyllithium in the absence of an amine. 

I. Of 2-[(3-oxopyrazol-4-yl)hydrazono]malonic Acid Esters or Substituted Acetonitriles... 

Resins based on Meldrum s acid chemistry (resin bound cyclic malonic acid ester) have been described for the synthesis of thiophene derivatives (Figure 15.5). Release and heterocycle formation was performed in NaOMe/MeOH at reflux for... 

The pyrimido[2,1 -b][ 1,3]thiazine-diones (369)-(372) can be described only by a series of mesomeric forms. For (370) <77ZN(B)1204> and (369) <74ZN(B)258> the IR spectrum supports the mesoionic enolate/enol forms. Compounds (371) have poor stability, (371 R = H) decomposes above its melting point with the expulsion of C3O2 in water or alcohols it undergoes ring fission to malonic acid/esters (72S312). 

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

The detection of other unusual features, such as malonic acid esters and phosphorodiesters is discussed later. 

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