Claisen condensation between ketones and esters

Crossed Claisen condensations between ketones and esters are also possible. Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation. The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution and thereby acylates the ketone. 

This condensation works best if the ester has no a hydrogens, so that it cannot form an enolate. Because of the difference in acidities, however, the reaction is sometimes successful between ketones and esters even when both have a hydrogens. The following examples show some crossed Claisen condensations between ketones and esters. Notice the variety of difunctional and trifunctional compounds that can be produced by appropriate choices of esters. 

A Claisen condensation between two different esters or between a ketone and an ester, (p. 1074)... 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a jS-diketone. The reaction works best when the ester component has no a hydrogens and thus can t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. 

The aldol condensation involves the reaction between a car-banion from an aldehyde or ketone and a second carbonyl component and leads to a P-hydroxy ketone. The Claisen condensation between two molecules of an ester leads to a P-keto ester. 

Formation of the 5,6-bond is also involved in the Claisen condensation between diethyl oxalate and an a,/3-unsaturated ester at its 7 position, to generate an intermediate in which ring closure via the ketone enol produces a 2-pyrone. ... 

We developed powerfiil Ti- or Zr-Claisen condensation between esters and direct crossed Ti-aldol addition between ketones and ketones or aldehydes. These reactions were successfully applied to the short and practical method for synthesizing some natural macrocyclic musks (civetone and muscone), mints (mintlactone and menthofuran), and a jasmine perfume. 

Cyclohexanedione (margin) can be prepared by an intramolecular mixed Claisen condensation between the ketone carbonyl and ester functions of a single molecule. What is the structure of this... 

In Summary Claisen condensations are endothermic and therefore would not take place without a stoichiometric amount of base strong enough to deprotonate the resulting 3-ketoester. Mixed Claisen condensations between two esters are nonselective, unless they are intramolecular (Dieckmann condensation) or one of the components is devoid of a-hydrogens. Ketones also participate in selective mixed Claisen reactions because they are more acidic than esters. 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination... 

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.)... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

Unfortunately neither reaction will work The black route requires a controlled condensation between two different enolizable esters—a recipe for a mixture of products. The simple alkylation route above removes the need for control. The green route requires a condensation between an unsymmetrical ketone and diethyl carbonate. This condensation will work all right, but not to give this product. As you saw on p. 730, Claisen condensations prefer to give the less substituted dicarbonyl compound, and condensation would occur at the methyl group of the ketone on the right to give the other unsymmetrical keto-ester. 

The mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldehvde or ketone and the Claisen condensation of... 

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