Sodium ethoxide, reaction with malonate esters

Methyl, propyl, butyl, etc., malonic esters are also obtained in a similar manner. It is to be observed that aryl halides do not undergo this reaction. The di-alkyl esters are obtained from the mono-alkyl esters in the same way as the latter are obtained from malonic ester. But although di-alkyl compounds are not formed directly in any quantity, yet it frequently happens that a little is obtained in the preparation of the mono-alkyl compound from 1 mol. of sodium ethoxide and 1 mol. of alkyl halide, owing to the mono-derivative reacting with more sodium and alkyl halide. This may be prevented when necessary by using only half the calculated quantity of sodium and alkyl halide. By this means the yield of benzoyl malonic ester for example is raised from 55% to 85% in its preparation from sodium, benzoyl chloride and malonic ester. (B., 44, 1507.)... 

Quinoxaline-2-carboxaldehyde has been converted into the 2-carboxylic acid by oxidation with potassium permanganate in acetone and reduced to the 2-hydroxymethyl compound by treatment with formalin and potassium hydroxide. It also undergoes other typical reactions of aromatic aldehydes such as benzoin formation on reaction with potassium cyanide - and condensation reactions with malonic acid and its diethyl ester and Schiff base formation. Acid-catalyzed reaction of quinoxaline-2-carboxaldehyde with ethylene glycol gives the cyclic acetal the diethylacetal has been prepared by reaction of 2-dibromomethylquinoxaline with sodium ethoxide. " An indirect preparation of the oxime 11 is achieved by treatment of 2-nitromethyl-quinoxaline (10) with diazomethane followed by thermolysis of the resulting nitronic ester. 

Malonic ester, like acetoacetic ester (Section 111,151), when treated with an equivalent of sodium ethoxide, forms a mono-sodium derivative, which is of great value in synthetical work. The simplest formulation of the reaction is to r rd it as an attack of the basic ethoxide ion on a hydrogen atom in the CH, group the hydrogen atoms in the CHj group are activated by the presence of the two adjacent carbethoxyl groups ... 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

Less basic malonic ester anions may be employed for the twofold alkylation of dibromides. Cyclic 1,1-dicarboxylic esters are formed, if the reaction is executed in an appropriate manner. In the synthesis of cyclobutane diester A the undesired open-chain tetraester B was always a side product (J.A. Cason, 1949), the malonic ester and its monoalkylation product were always only partially ionized. Alkylation was therefore slow and intermolecular reactions of mono-alkyl intermediates with excess malonic ester prevailed. If the malonic ester was dissolved in ethanol containing sodium ethoxide, and 1,3-dibromopropane as well as more sodium ethoxide were added slowly to the solution, 63% of A and only 7% of B were isolated. The latter operations kept the malonic ester and its monoalkylated product in the ionic form, and the dibromide concentration low, so that the intramolecular reaction was favored against intermolecular reactions. The continuous addition of base during the reaction kept the ethoxide concentration low, which helped to prevent decomposition of the bromide by this nucleophile. 

When treated with one equivalent of sodium ethoxide, diethyl malonate is converted into the mono-sodio derivative, as a result of removal by base of one of the a-methylene protons to yield a mesomeric anion (12). This nucleophilic anion undergoes an S 2 reaction with an alkyl halide to give a C-substituted malonic ester. A second, different, alkyl group can be similarly introduced on to the a-carbon atom, or alternatively two identical alkyl groups may be introduced in a one-step operation by using appropriate proportions of reactants. 

The resulting tetraethyl ester on hydrolysis and decarboxylation yields propane-1, 2,3-tricarboxylic acid.155 In this example the malonate anion is generated by using one molar proportion of sodium ethoxide this is Michael s original method. However, these conditions sometimes lead to competing side reactions and the formation of abnormal reaction products. Better yields of the required product are often obtained with small amounts of sodium ethoxide (the so-called catalytic method) or in the presence of a secondary amine (e.g. diethyl-amine, see below). 

In both the acetoacetic ester synthesis and the malonic ester synthesis, it is possible to add two different alkyl groups to the a-carbon in sequential steps. First the enolate ion is generated by reaction with sodium ethoxide and alkylated. Then the enolate ion of the alkylated product is generated by reaction with a second equivalent of sodium ethoxide, and that anion is alkylated with another alkyl halide. An example is provided by the following equation ... 

Diethyl propanedioate, commonly called diethyl malonate or malonic ester, is more acidic than monocarbonyl compounds pK =13) because its a hydrogens are flanked by two carbonyl groups. Thus, malonic ester is easih converted into its enolate ion by reaction with sodium ethoxide in ethanol. The enolate ion, in turn, is a good nucleophile that reacts rapidh with an alkyl halide to give an a-substituted malonic ester. Note in the following examples that the abbreviation "Et" is used for an ethyl group, CH2CH3. 

The highest yielding Michael reactions are those that take place when a particularly stable enolate ion, such as that derived from a /3-keto ester or malonic ester, adds to an unhindered a,/S-unsaturated ketone. For example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide catalyst to yield the conjugate addition product. 

Diethyl benzoylmalonate has been prepared by treatment of the copper derivative of ethyl benzoylacetate with ethyl chlorocarbonate.9 It has also been obtained by the action of benzoyl chloride on a mixture of malonic ester and sodium ethoxide 1benzoyl chloride and the ethoxymagnesium derivative.14 The present method has been described in a previous communication and is of interest as an illustration of the use of mixed carbonic anhydrides as acylating agents.8... 

The reaction of a silicon substituted malonic ester with urea in the presence of sodium ethoxide affords the 3-oxa-8,10-diaza-2,4-disilaspiro[5.5]undecan-9-one (58) <81MI 627-04>. 

The reaction of 2-amino-3-nitrosopyridines with compounds containing an activated methylene group permits unambiguous synthesis of various derivatives of pyrido[2,3-b]pyrazine. For example, the pyridine 58 reacts in the presence of sodium ethoxide with a variety of arylacetonitriles and cyanoacetic acid derivatives to provide various 2-substituted 3-amino compounds (59). " " Diethyl malonate reacts similarly to give the 2-carboxylic acid 60, its ester being presumably hydrolyzed in the alkaline reaction conditions. Ethyl acetoacetate yields the 2-acetyl-3-oxo compound 61, and acetylacetone ° provides the 2-acetyl-3-methyl compound 62. The latter condensation proceeds poorly in ethanolic sodium ethoxide, but heating the nitroso compound with acetylacetone under reflux in pyridine gives a 59% yield of the product 62. °... 

The ease of reaction depends both on the CH acidity of the addend and on the polarizability of the ethylenic double bond of the acceptor. Thus, in general, only such compounds function as addend in which a methylene or methine group is activated by two neighboring carbonyl or nitrile groups, as, for example, in malonic esters, malonodinitrile, cyanoacetic esters, 1,3-dioxo compounds and 3-oxo carboxylic esters, and their monoalkyl substitution products. The ethylenic double bond of the acceptor is polarized by conjugation with a polar multiple bond, so that the olefinic component is usually an unsaturated ketone, an, / -unsaturated ester, or an, / -unsaturated nitrile. The addition is catalysed by bases such as potassium hydroxide solution, sodium ethoxide, and amines. 

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