Claisen condensations are acylations that always involve esters as the electrophilic partner, but enolates of other carbonyl compounds—ketones, for example—may work equally well as the enol partner. In a reaction with a carbonate, only the ketone can enolize and the reactive carbonate ester is more electrophilic than another molecule of the ketone. A good example is this reaction of cyclooctanone. It does not matter which side of the carbonyl group enolizes— they are both the same.

Unsymmetrical ketones often give a single product, even without the use of a specifi c enol equivalent, as reaction usually occurs on the less substituted side. This is another consequence of the final enolization being the irreversible step. In this example, both possible products may form, but only one of them can form a stable enolate. Under the equilibrating conditions of the reaction, only the enolate is stable, and all the material ends up as the isomer shown.

Unsymmetrical ketones work well even when one side is a methyl group and the other a primary alkyl chain. This example gives an impressive yield and shows that, as expected, a remote alkene does not affect the reaction.

Even when both enolates can form, the less substituted dicarbonyl enolate is preferred because it constrains fewer groups to lie in the hindered plane of the tetrasubstituted enolate double bond.

Diethyl oxalate also gives well-controlled condensations with ketones and we shall take the synthesis of a new drug as an example. One way to try to prevent heart disease is to reduce the amount of ‘bad’ lipoproteins in the blood. The drug Acifran does this, and a key step in its synthesis is the base-catalysed reaction between diethyl oxalate and a methyl ketone.

Notice that the hydroxyl group on the ketone does not interfere with the reaction. No doubt the first molecule of base removes the OH proton and the second molecule forms the enolate (the only possible enolate in either molecule). Fast condensation with highly electrophilic diethyl oxalate follows. The drug itself results from simple acid treatment of this product.

The other two unenolizable esters undergo cross-condensations with ketones. Unlike formaldehyde, formate esters are well behaved—no special method is necessary to correspond with the Mannich reaction in aldol chemistry. Here is what happens with cyclohexanone.

The product aldehyde is not at risk from nucleophilic attack, as it appears to be, because it immediately enolizes in base. On work-up, the product is formed as a stable enol with an intramolecular hydrogen bond.

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مواضيع ذات صلة

Sulfur-stabilized anions

Sulfur is a very versatile element

Symmetry in intramolecular crossed Claisen condensations

Intramolecular crossed Claisen ester condensations

Crossed Claisen ester condensations between two different esters

Directed C-acylation of esters

Reactive esters that cannot enolize

The Claisen ester condensation and other self-condensations

Problems with acylation at carbon

Cross-condensations

The aldol reaction

Nitroalkanes are superb nucleophiles for conjugate addition