Acetoacetic ester synthesis substituted methyl ketones

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

The acetoacetic ester synthesis produces a methyl ketone with an alkyl group(s) substituted on the a-carbon, whereas the malonic ester synthesis produces a... 

As in the malonic ester synthesis, you should identify the structural fragments of the target compound. The acetoacetic ester synthesis converts an alkyl halide to a methyl ketone ("substituted acetone"). The methyl ketone component comes from acetoacetic ester the other component comes from a halide. 

Use a malonic ester synthesis if the product you want is an a-substituted carboxylic acid derivative. Use an acetoacetic acid synthesis if the product you want is an a-substituted methyl ketone. 

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. 

Alkylation catalyst. In a detailed study of alkylation of acetoacetic esters, Renfrew and Renfrew found potassium t-butoxide in general to be the best base, particularly for alkylation of a-substituted esters. In the Sarett synthesis of cortisone, potassium /-butoxide served well as base for effecting two successive alkylations of the 14-ketone (1). Methylation (CH3I, t-BuOK) gave a single stereoisomer, regarded as... 

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