Sodium ethoxide acetoacetic ester synthesis

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

This method of preparation can be applied generally to the esters of the phenyl-olefinic acids. Although metallic sodium is used, yet as in the acetoacetic ester synthesis (see Reaction XLVI.) a trace of alcohol must always be present to form sodium ethoxide. This is usually the case. If necessary, sodium ethoxide itself can be employed. The use of some other condensing agents will be clear from the following preparation. 

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 ... 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

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. 

Acetoacetic ester, because it is a j8-dicarbonyl compound, can easily be converted to an enolate using sodium ethoxide. We can then alkylate the resulting enolate (called sodio-acetoacetic ester) with an alkyl halide. This process is called an acetoacetic ester synthesis. 

Two procedures called the acetoacetic ester synthesis and the malonic ester synthesis take advantage of the properties of p-dicarbonyl compounds and are standard methods for making carbon-carbon bonds. Both begin with alkylation of the enolate. Ethyl esters are normally used, with sodium ethoxide as the base. 

The properties of diethyl malonate that make the malonic ester synthesis a useful procedure are the same as those responsible for the synthetic value of ethyl acetoacetate The hydrogens at C 2 of diethyl malonate are relatively acidic and one is readily removed on treatment with sodium ethoxide... 

Our synthesis started with ethyl 5-methyl-4-isoxazole carboxylate (50), prepared from ethyl acetoacetate and DMF dimethyl acetal (Scheme 5.4).14 Ester 50 was reduced with LiAlH4 and the resulting alcohol was oxidized to afford aldehyde 51. Enone 52 was obtained from aldehyde 51 using conditions developed by McCurry and Singh.15 The next step was the aromatization of the cyclohexane ring of 52 to produce the aromatic "A" ring of the monomer. Treatment of enone 52 with iodine in the presence of sodium ethoxide produced phenol 53.16... 

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. °... 

Depending on the respective reaction partner, acetic acid esters can react either as C-H acidic compounds or as acylating agents. Both are illustrated by the self-condensation of ethyl [ 1 acetate in the presence of 0.5 equivalent of sodium ethoxide or triphenymethyl sodium to give ethyl [1,3- C2]acetoacetate (Claisen condensation). In the first case, however, because of the relatively low radiochemical yields (40-45%) obtained by this procedure, it is of minor importance for the preparation of labeled ethyl acetoacetate. The deprotonation of alkyl acetates with LiHMDS followed by acylation with unlabeled or labeled acyl halides to labeled give /3-keto esters is discussed in Section 6.4. Claisen condensation of alkyl [ CJacetates with esters lacking a-hydrogens (i.e. ethyl formate, diethyl oxalate, aromatic/heteroaromatic carboxylic acid esters) proceed unidirectionally and are valuable pathways in the synthesis of ethyl [ C]formyl acetate (521. diethyl [ C]-oxaloacetate (53) and ethyl 3-oxo-3-pyrid-3-yl[2- C]acetate (54). The last example... 

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