Disubstituted malonic ester

The monosubstituted malonic ester still possesses an activated hydrogen atom in its CH group it can be converted into a sodio derivative (the anion is likewise mesomeric) and this caused to react with an alkyl halide to give a C-disubstituted malonic ester. The procedure may accordingly be employed for the synthesis of dialkyImalonic and dialkylacetic acids ... 

The synthesis of the disubstituted malonic ester cannot be achieved by successive ethylation and phenylation procedures [cf. Section 5.11.6, p. 680] since for the latter reaction the aryl halide is not sufficiently reactive. The procedure described below (formulated in Expt 8.37) provides a suitable indirect alternative route. This involves a mixed Claisen ester condensation (cf. Section 5.14.3, p. 738) between ethyl phenylacetate and diethyl oxalate, followed by decarbony-lation of the a-keto diester on heating to 175 °C. 

A) produces the disubstituted malonic ester B. Hydrobromic acid hydrolyzes the ester functions of B—which, upon heating, is followed by the usual decarboxylation—as well as the acetamido group. The reaction product is the hydrobromide C of the a-amino acid phenylalanine. 

Answer XIV-g is a disubstituted malonic ester (dictiiyt methylethylmalonate. ... 

This method is illustrated by the preparation of ethyl diethylacetate (67%). A similar modification involves the treatment of the disubstituted malonic ester with metallic sodium or potassium in ether. In this way di-n-propylacetic ester is obtained in 61% yield. ... 

Nitriles are directly converted to esters by heating with an alcohol and sulfuric or hydrochloric acid. When water is absent, the imino ester salt is readily isolated (method 402). Aliphatic,aromatic, and heterocycliccyano compounds react in this manner. Most of the aromatic compounds contain a cyanomethyl group although the cyanide radical may be attached directly to the aromatic nucleus. Monosub-stituted malonic esters free from unsubstituted and disubstituted malonic esters are made from the corresponding a-cyano esters by this method. Malonic ester and disubstituted malonic esters have been similarly prepared. ... 

Decarboxylation of disubstitntej mabmates. In an attempt to effect acyloin-type reduction of disubstituted malonic esters, Ainsworth, Bloomfield, and co-workers obtained instead in high yield ketene alkyl silyl acetals (1) an equivalent amount of... 

Krapcho, A. P., Jahngen, E. G. E., Jr., Lovey, A. J., Short, E. W. Decarbalkoxylations of germinal diesters and P-keto esters in wet dimethyl sulfoxide. Effect of added sodium chloride on the decarbalkoxylation rates of mono- and disubstituted malonate esters. Tetrahedron Lett. 1974,1091-1094. 

As in acetacetic ester, the second hydrogen of the malonic ester can also be replaced by sodium consequently the malonic ester is capable of reacting a second time with organic halides, so that disubstituted malonic esters can also be prepared. 

Disubstituted malonic esters are dealkoxycarbonylated under the modified acyloin condensation condition (Na-McgSiCl). Thus, the intermediary ester enolates are also alkylated at the oxygen with the hard acid. 

The formation of hydrazides from the esters of disubstituted malonic esters becomes increasingly difficult with increase in the size of the substituents. Diethyl ben lmethylmalonate with excess hydrazine in... 

Disubstituted malonic esters are conveniently dealkoxycarbonylated by reduction with sodium in the presence of chlorotrimethylsilane the reactive keten alkyl trimethylsilyl acetals (87) produced are readily hydrolysed. 

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

By performing two successive alkylation steps the malonic ester synthesis can be applied to the synthesis of a a disubstituted derivatives of acetic acid... 

The alkylmalonic ester has a second acidic proton that can be removed by a base. Removing this proton and alkylating the enolate with another alkyl halide gives a dialkylated malonic ester. Hydrolysis and decarboxylation lead to a disubstituted derivative of acetic acid. 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

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. 

Malonic ester synthesis Synthesis of 2,2-disubstituted carboxylic acids from diethyl propanedioate Imitlonic ester). 

Anions of methylene-active compounds (1,3-dione enolates and ester enolates), ketene acetals, and even electron-rich five-membered heterocycles comprise another group of nucleophiles that attack triazine rings, preferably in the form of l,2,3-triazin-2-ium salts. 4,6-Disubstituted-2-methyl-l,2,3-triazinium iodides add malonic ester anion at the C-5 position to form 4,6-disubstituted-2-methyl-5-bis(ethoxy-carbonyl)methyl-2,5-dihydro-l,2,3-triazines in 57-76% yield <1992CPB2283, 1996CHEC-II(6)483>. The following cases have been published more recently. 

Under much milder conditions, oxidative substitutions in BODIPY s with malonic esters, acetophenone, and ethyl phenylacetate proved to take place (Scheme 39). For example, the reaction with tc/t-butyl malonate in the presence of potassium carbonate and oxygen proceeds at the position 3. When a twofold excess of nucleophile was used, 3,5-disubstituted product was obtained [134]. 

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