Claisen condensation, crossed

The application to a mixture of two different esters, each with a-hydrogens, is seldom of preparative value, since a mixture of the four possible condensation products will be obtained. If however only one of the starting esters contains a-hydrogens, the crossed Claisen condensation often proceeds in moderate to good yields. 

In the course of the first total synthesis of (+)-halichlorine <1999TL6513, 1999AGE3542>, the spiroquinolizidine unit 460 was constructed by a two-carbon chain extension in compound 458 through a crossed Claisen condensation, leading to 459, and an intramolecular Mannich reaction of this compound with formaldehyde (Scheme 109). 

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

A crossed Claisen condensation employs two different esters. If the esters are A and B, the possible products are AA, AB, BA, and BB. To minimize the complicated mixture of products, one of the reactants must have no a-hydrogen atoms. If this is ester B, then the products would be AA and AB. If the concentration of A is very low, then only a small quantity of AA can form. Figure 15-6 illustrates an example of a crossed Claisen condensation, where the product is of the AB form. 

Crossed Claisen Condensation A Claisen condensation utilizing a mixture of two different esters. 

If, however, it is necessary to generate a crossed product by the reaction of an enolate derived from one carbonyl compound with a second carbonyl compound as the electrophile, tilings can go bad rapidly. Because both carbonyl groups must be present in solution at the same time and each can form etiolates to some extent, there can be four possible products from the various combinations of etiolates and carbonyl compounds. This problem was illustrated for the crossed-Claisen condensation above. The number of products can be minimized if one carbonyl component lacks a protons and cannot form an enolate and is also a more reactive electrophile than the second carbonyl component. If these conditions are met, then crossed condensations can be carried out successfully using alkoxide bases. Many of the named reactions were developed so that product mixtures could be avoided. 

In both these last two examples, a very strong base is used in the form of LDA such that the enolate ion is formed quantitatively (from ethyl acetate and acetone respectively). This avoids the possibility of self-Claisen condensation and limits the reaction to the crossed Claisen condensation. 

Figure 13.50 outlines how esters in general (not shown) and especially lactones (shown) can be prepared for a one-step aldol condensation with an aldehyde they are exposed to a mixed ( crossed ) Claisen condensation with formic acid methyl ester (cf. Figure 13.59, first line). Like all Claisen condensations (Section 13.5.1), this also first leads to the formation of the enolate of the acylated ester. Unlike other Claisen condensations, this enolate is isolated. 

Acylations of ester enolates with different esters are called crossed Claisen condensations and are carried out—just like normal Claisen condensations-in the presence of a stoichiometric amount of alkoxide, Na, or NaH. Crossed Claisen condensations can in principle lead to four products. In order that only a single product is formed in a crossed Claisen condensation, the esters employed need to be suitably differentiated one of the esters must be prone to enolate formation, while the other must possess a high propensity to form a tetrahedral intermediate (see example in Figure 13.59). 

The use of an ester without acidic a-H atoms ensu res that this ester can act only as the electrophile in a crossed Claisen condensation. Moreover, this nonenolizable ester must be at least... 

Accordingly, crossed Claisen condensations occur without any problems if the acylating agent is a better electrophile than the other, nondeprotonated ester. This is the case, for example, if the acylating agent is an oxalic ester (with an electronically activated carboxyl carbon) or a formic ester (the least sterically hindered carboxyl carbon). 

Crossed Claisen condensations can be chemoselective even when the nonenolizable ester is not a better electrophile than the enolizable ester. This can be accomplished by a suitable choice of reaction conditions. The nonenolizable ester is mixed with the base and the enoliz-able ester is added slowly to that mixture. The enolate of the enolizable ester then reacts mostly with the nonenolizable ester for statistical reasons it reacts much less with the noneno-lized form of the enolizable ester, which is present only in rather small concentration. Carbonic acid esters and benzoic acid esters are nonenolizable esters of the kind just described. 

Fig. 13.59. Crossed Claisen condensation. Although the tautomers of the acylation products shown are not the major tautomer except for the third case from the top, they are presented because they show best the molecules from which these products were derived.

The use of an ester without acidic a-H-atoms ensures that this ester can act only as the electrophile in a crossed Claisen condensation. Moreover, this nonenolizable ester should be no less electrophilic than the other ester. This is because the larger fraction of the latter is present in its nondeprotonated form that is, it represents a possible electrophile, too, capable of forming a tetrahedral intermediate when attacked by an enolate. 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

A crossed Claisen condensation is carried out by first adding the ester without a hydrogens to a solution of the alkoxide base. The ester with a hydrogens is slowly added to this solution, where it forms an enolate and condenses. The condensation of ethyl acetate with ethyl benzoate is an example of a crossed Claisen condensation. 

Propose a mechanism for the crossed Claisen condensation between ethyl acetate and ethyl benzoate. 

Predict the products from crossed Claisen condensation of the following pairs of esters. Indicate which combinations are poor choices for crossed Claisen condensations. 

Show how a crossed Claisen condensation might be used to prepare... 

Show how crossed Claisen condensations could be used to prepare the following 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. 

Predict the major products of the following crossed Claisen condensations. O... 

Predict the products of Claisen and crossed Claisen condensations, and propose mechanisms. Show how a Claisen condensation constructs the carbon skeleton of a target molecule. 

Only one enolate can be formed and this attacks either of the two aromatic ester groups to give a 1,3-diketone by a crossed Claisen condensation. 

Many observations, however, have provided strong evidence that site-site interactions are quite facile. Carboxylic acids bound to polystyrenes of varying degrees of cross-links have been observed to undergo anhydride formation even at low levels of functionalization 140,14I). The observation that cross-Claisen condensation products result from polymers on which two esters are attached also supports the view that intersite reactions can occur in polymer matrices142). Barany and Merrifield U) analysed a number of situations under which intersite reactions occured and found that they usually occur when... 

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