Variations on the Claisen Condensation

An important variation on the Claisen condensation is to use a ketone as the anionic reagent. This often works well because ketones usually are more acidic than simple esters and the base-induced self-condensation of ketones (aldol addition) is thermodynamically unfavorable (Section 17-3C). A typical example is the condensation of cyclohexanone with diethyl ethanedioate (diethyl oxalate) ... 

A variation on the Claisen condensation is an important biochemical reaction responsible for carbon-carbon bond formation in the biosynthesis of fatty acids. Also, a reverse Claisen condensation occurs in the catabolism of fatty acids. We have seen that the base-catalyzed condensation of two car-boxylate esters occurs because the proton a to the carbonyl group is slightly acidic. The a-hydrogen atom in P-keto esters has a pA of about 10.5. This p/f value is too high for P-keto esters to be of much use in biochemical reactions. At pH 7, the ratio of the conjugate base (the enolate anion) to the keto ester is less than 0.001. 

The condensation of P-keto esters with hydroxylamine can occur in two directions to give either isoxazolin-3-ones [which exist predominately as 3-hydroxyisoxazoles (2)] or isoxazolin-5-ones (3). Early work by Claisen, Hantzch, and others showed that the products from 2-unsubstituted P-keto esters were isoxazolin-5-ones. In the early 1960 s, Katritzky found that 2-substituted analogues give 3-hydroxyisozaoles. Jacquier later showed that both types of products could be produced from both types of keto esters depending on the precise pH variation during the reaction workup. ... 

This is a difficult chapter because condensations take on a wide variety of forms. You should try to understand the reactions and their mechanisms so you can generalize and predict related reactions. Work enough problems to get a feeling for the standard reactions (aldol, Claisen, Michael) and to gain confidence in working out new variations of the standard mechanisms. Make sure you can recognize and propose condensations that form new rings. 

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