Acylation, ketones with esters

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 ... 

Acid Amides can be produced by acylating ammonia with esters, acid anhydrides, or the acids themselves (above 100 °C) an important product is formamide from methyl formate. Alternatively acid amides can be synthesized by reacting acid halides with ammonia. Catalytic hydrogenation converts the acid amides to primary amines. Ammonia and aldehydes or ketones are the basis for different stable products. With formaldehyde hexamethylenetetramine (urotropine) is obtained with acetaldehyde, ammono acetaldehyde with benzaldehyde, hydrobenzamide with ethylene and propylene oxides, aqueous ammonia reacts to form ethanol- or propanolamine. 

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. 

The acylation of enolates derived from ketones with esters is an important tool for enhancing reactivity and selectivity in synthetic modification of ketones. Some representative examples are given in Scheme 2.7. The most common example of this is the formylation of ketone enolates by formate esters ... 

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

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

The reaction of enamino ketones with isocyanates and isothiocyanates has not been studied extensively. The enamino ketone (162) has been shown to react with phenyl isothiocyanate to give 163, the product of C acylation 114). Enamino ester derivatives of acetoacetic ester react similarly with isothiocyanates, also giving the C-acylated products 115). 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

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