Acylation of Ketones with Esters

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

Aluminum hydride reduction of sodium enolates of hydroxymethylene ketones gives hydroxymethyl ketones. 

A sequence for directing an alkylation to a monosubstituted site has been developed the sequence involves a dianion intermediate  

On the other hand, if an unsymmetrical ketone is to be alkylated at the site where acylation would be favored, the hydroxymethylene derivative can be directly subjected to alkylation. Condensation with ethyl carbonate or diethyl oxalate before alkylation can also serve the purpose of increasing reactivity at the a position of a ketone. The resulting jS-keto esters are readily alkylated by the procedures described in the previous chapter. 

Related synthetic intermediates are the jS-keto sulfoxides, which are prepared by acylation of dimethyl sulfoxide anion with esters  

SAMPLE SOLUTION (a) Diethyl carbonate cannot form an enolate, but ethyl phenylacetate can. Nucleophilic acyl substitution on diethyl carbonate by the enolate of ethyl phenylacetate yields a diester. 

The reaction proceeds in good yield (86%), and the product is a useful one in further synthetic transformations of the type to be described in Section 21.7. 

In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to 3-keto esters by reaction with diethyl carbonate. 

Esters of nonenolizable monocarboxylic acids snch as ethyl benzoate give 3-diketones on reaction with ketone enolates  

Intramolecular acylation of ketones yields cyclic (3-diketones when the ring that is formed is hve- or six-membered. 

Sodium hydride was used as the base in this example. It is often used instead of sodium ethoxide in these reactions. 

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The acylation of ketones with esters an example of the Clalsen 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 ... 

J. A. Conroy, J. T. Adams and Ch. R. Hauser The Acylation of Ketones with Esters to Form -Diketones by the Sodium Amide Methode. J. Amer. chem. Soc. 67, 1510 (1945). 

Acylation of ketones with esters requires the presence of a strong base under anhydrous conditions. Ketones where only one unique mesomeric carbanion is formed (e.g. symmetrical ketones or alkyl aryl ketones) yield a single regio-isomer. The reaction is illustrated by the formation of benzoylacetone from acetophenone and ethyl acetate (Expt 5.103), and may be outlined mechanistically as follows ... 

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). 

Aldehyde, Ketone, and Ester Enolates 867 Enolate Regiochemistry 872 The Aldol Condensation 873 Mixed Aldol Condensations 878 Chalcones From the Mulberry Tree to Cancer Chemotherapy 880 The Claisen Condensation 882 Intramolecular Claisen Condensation The Dieckmann Cyclization 884 Mixed Claisen Condensations 885 Acylation of Ketones with Esters 886 Alkylation of Enolates 887 The Acetoacetic Ester Synthesis 889 The Malonic Ester Synthesis 891 Alkylation of Chiral Enolates 893 Enolization and Enol Content 895 a Halogenation of Aldehydes and Ketones 900... 

The starting material in this reaction is the P-keto ester product formed by the Dieckmann cyclization seen in part (a) of Problem 20.14. The P-keto esters formed by Claisen condensations (Sections 20.5 and 20.7) and the acylation of ketones with esters (Section 20.8) can also be employed as reactants in analogous alkylation-saponification-decarboxylation sequences. 

U THE CLAISEN CONDENSATION Dieckmann Condensation Mixed Claisen Condensations Acylation of Ketones with Esters... 

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