The Claisen Ester Condensation

The mechanism of the Claisen Ester condensation has been suggested along the following lines ... 

Synthesis This cyclisation version of the Claisen ester condensation is sometimes called the Dieckmann Reaction. 

Carboxylic esters 1 that have an a-hydrogen can undergo a condensation reaction upon treatment with a strong base to yield a /3-keto ester 2. This reaction is called the Claisen ester condensation or acetoacetic ester condensation, the corresponding intramolecular reaction is called the Dieckmann condensation ... 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

The typical / -keto ester is ethyl acetoacetate (ethyl 3-oxo-butanoate). A retro-synthetic disconnection on this compound points to one of the most common methods for its synthesis, namely the Claisen ester condensation. 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations ... 

Mechanism of the Claisen ester condensation. Test yourself on the concepts in this figure at OrganicChemistryNow. 

A similar process is described in the Focus On box titled The Reverse Aldol Reaction in Metabolism on page 880. The Claisen ester condensation also has an equilibrium step in which an enolate anion leaves in the reverse of the step (see Figure 20.4). 

R—C—OR1 Esters are useful in the Claisen ester condensation. Most often, R = Me or Et... 

Ester Condensations Active Figure 20.4 Mechanism of the Claisen Ester Condensation (page 882)... 

Planning Syntheses Using Aldol Condensations 1069 22-12 The Claisen Ester Condensation 1070... 

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... 

The Claisen ester condensation (Sections 22-12 through 22-14) (Cyclizations are the Dieckmann condensation.)... 

CHAPTER 22 Base-Catalyzed Aldol Condensation 1061 Base-Catalyzed Dehydration of an Aldol 1064 The Claisen Ester Condensation 1071... 

Introduction the Claisen ester condensation compared to the aldol reaction ... 

We introduced this chapter with an example of the second type of reaction, and we shall continue with a more detailed consideration of the Claisen ester condensation and related reactions. 

The Claisen ester condensation and other self-condensations... 

The self-condensation of ethyl acetate, with which we opened this chapter, is the most famous example of the Claisen ester condensation and it works in good yield under convenient conditions. The product (ethyl acetoacetate) is commercially available—and cheap too—so you are unlikely to want to do this particular example. 

The intramolecular version of the Claisen ester condensation is sometimes known as the Dieckmann reaction, It provides an excellent route to heterocyclic ketones (cyclic ketones with heteroatoms in the ring very important in. . 

Attempts to make this compound by the Claisen ester condensation would require one of the approaches in the diagram below, The dashed curly arrows suggest the general direction of the condensation required and the coloured bonds are those that would be formed if the reaction worked. 

The reactions use thiol esters rather than ordinary esters. The esterifying group is a thiol called coenzyme A, and we shall just represent this molecule as R (you can find its full structure on p. 1386). The first reaction is between a malonate half-thioester and an acetate thioester of coenzyme A Look at the mechanism and you will see how similar it is to the Claisen ester condensation. 

Polyketides of enormous variety are known with all these groups present in the chain at the various stages of reduction. But all are made by Nature s version of the Claisen ester condensation. 

This difference affects each stage of the CLaisen ester condensation in the same way. Thiol esters are more easily converted to enolate anions, they are more easily attacked by nucleophiles, and RS is a better leaving group than RO. In each case the reaction is better (faster or equilibrium further towards product), the Claisen thiol ester condensation... 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

The Claisen ester condensation involves the only possible enolate attacking the only possible electrophilic carbonyl group. The stereochemistry of the ring junction cannot be changed by the reaction, and the two ester groups that started tram must end up trans in the product. 

In the synthesis, the product of the Claisen ester condensation is actually the enolate anion of the keto-aldehyde and this can be combined direcdy without isolation with cyanoacetamide to give tire pyridone in the same flask. 

The Claisen ester condensation gives the right product just by treatment with base The reasons for this are discussed in Chapter 28. We had then planned to react the keto-diester with methyl-hydrazine but there is a doubt about the regioselectivity of this reaction—the ketones are more electrophilic than the ester all right, but which ketone will be attacked by which nitrogen atom ... 

A different cyclization leads to the flavones and anthocyanidins. Reaction of the stable enol from a 1,3-diketone with the thiol ester as electrophile results in acylation at carbon in the manner of the Claisen ester condensation (Chapter 28) with loss of CoASH and the formation of a trihydroxyben-zene ring. 

The first step is the Claisen ester condensation of two molecules of acetyl CoA, one acting as an enol and the other as an electrophilic acylating agent to give acetoacetyl CoA. We saw the same reaction in the biosynthesis of the pyrrolidine alkaloids earlier in this chapter. 

In the case of two non-identical substrates, four different products of Claisen ester condensation may be formed. In fact, that is exactly what happens if ethyl acetate and ethyl propionate are employed as components in the Claisen ester condensation under classical conditions (treatment of the mixture of the esters with sodium ethoxide). The synthetic potential of such condensations depends entirely upon how efficiently the casting between the potential nucleophilic and electrophilic partners is achieved. 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

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