Ethyl acetate: Claisen ester condensation with

Acetoacetic ester is prepared by condensing ethyl acetate by means of sodium ethylate. Ethyl acetate containing a trace of ethyl alcohol is boiled with sodium. When the metal has dissolved, the reaction-product is treated with dilute acid, and the oil set free is dried and purified by distillation. The various steps involved in the transformation of ethyl acetate into ethyl acetoacetate, have been the subject of much discussion. The view accepted by most chemists is that given by Claisen. It is as follows When sodium is added to ethyl acetate it first reacts with the small amount of alcohol present to form sodium ethylate and hydrogen. The addition-product of sodium ethylate and ethyl acetate which results, condenses with a second molecule of ethyl acetate —... 

The self-condensation of ethyl acetate, with which we opened this chapter, is the most famous example of the Claisen ester condensation and it works in good yield under convenient conditions. The product (ethyl acetoacetate) is commercially available—and cheap too—so you are unlikely to want to do this particular example. 

In the case of two non-identical substrates, four different products of Claisen ester condensation may be formed. In fact, that is exactly what happens if ethyl acetate and ethyl propionate are employed as components in the Claisen ester condensation under classical conditions (treatment of the mixture of the esters with sodium ethoxide). The synthetic potential of such condensations depends entirely upon how efficiently the casting between the potential nucleophilic and electrophilic partners is achieved. 

This synthesis was carried out by Claisen and the reaction is known as the Caisen condensation. The acetoacetate (8) we used in Chapter 13 is also made this way. This time the starting materials are two molecules of the same compound. The synthesis,known as the Claisen ester condensation, simply involves treating ethyl acetate with base. 

In the late nineteenth century, Ludwig Claisen (Germany 1851-1930) treated an ester with a base the isolated product was a P-keto ester. This product results from the enolate anion of one molecule of the ester condensing with a second molecule via an acyl substitution reaction (Chapter 16, Section 16.8). In a typical experiment, ethyl 2-methyl propionate (60) is treated with a specialized base (sodium triphenylmethide, 19) in diethyl ether and stirred at room temperature for 60 hours. This reaction mixture is then acidified with glacial acetic acid (i.e., 100% acetic acid) the final isolated product is ethyl 2,2,4-tri-methyl-3-oxopentanone (61) in 74% yield. It is clear that when an ester enolate reacts with another ester, the product is a -keto ester and the reaction is now called the Claisen condensation. 

The Claisen condensation of an aliphatic ester and a thiazolic ester gives after acidic hydrolysis a thiazolylketone (56). For example, the Claisen condensation of ethyl 4-methyl-5-thiazolecarboxylate with ethyl acetate followed by acid hydrolysis gives methyl 4-methyl-5-thiazolyl ketone in 16% yield. 

On treatment with alkoxide bases, esters undergo self-condensation to give a p-keto ester and an alcohol. Ethyl acetate, for exanple, undergoes a Claisen condensation on treatment with sodium ethoxide to give a p-keto ester known by its common nane ethyl ace-toacetate (also called acetoacetic ester) ... 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

The acylation of ketones with esters an example of the Claisen condensation is generally effected with a basic reagent, such as sodium ethoxide, sodium, sodamide or sodium hy dride. Thus acetone and ethyl acetate condense in the presence of sodium ethoxide to yield acetylacetone ... 

A crossed Claisen condensation is carried out by first adding the ester without a hydrogens to a solution of the alkoxide base. The ester with a hydrogens is slowly added to this solution, where it forms an enolate and condenses. The condensation of ethyl acetate with ethyl benzoate is an example of a crossed Claisen condensation. 

PROBLEM 21.3 Give the structure of the product obtained when ethyl phenyl-acetate (C6H5CH2CO2CH2CH3) is treated with each of the following esters under conditions of the mixed Claisen condensation ... 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

---