Claisen condensation, side reaction

Ester enolates are less reactive than aldehyde enolates but rapid and quantitative deprotonation is still necessary because of the possibility of Claisen condensation side reactions. 

In Chapter 28 you will meet the reaction of an ester with its own enolate the Claisen condensation. This reaction can be an irritating side-reaction in the chemistry of lithium ester enolates when alkylation is desired, and again it can be avoided only if the ester is converted entirely to its enolate under conditions where the Claisen condensation is slow. A good way of stopping this happening is to add the ester to the solution of LDA (and not the LDA to the ester) so that there is never excess ester for the enolate to react with. 

The basic nature of N-heterocyclic carbenes, stabilized by the presence of two adjacent N atoms, has been emphasized by several authors [38], Therefore, the yield and the selectivity of any organic synthesis (driven by the reactivity of a substrate vs. appropriate bases and carried out in imidazohum salts as solvents) can be affected by side reactions related to the acidity of C2-H unit in 1,3-dialkylimidazo-lium cation and to the basicity and nucleophilicity of the resulting N-heterocychc carbene. On this subject, noticeable work (related to the Baylis-Hillman, Knoevenagel and Claisen condensation, Homer reaction, etc.) carried out in RTlLs has been reported and discussed [37]. 

More recent work in this series demonstrated that a carbonyl group can be interposed between the side-chaincarrying aromatic ring and the ethylene function with full retention of activity. Claisen condensation of benzoate with 2-tetralone affords the e-diketone Reaction of... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Crossed Claisen reactions with two different esters, each of which has a-H atoms, are seldom useful synthetically as there are, of course, four possible products. Crossed Claisen reactions are, however, often useful when one of the two esters has no a-H atoms, e.g. HCOzEt, ArC02Et, (C02Et)2, etc., as this can act only as a carbanion acceptor. Such species are in fact good acceptors, and the side reaction of the self-condensation of the other, e.g. RCH2C02Et, ester is not normally a problem. Intramolecular Claisen reactions, where both C02Et groups are part of the same molecule [e.g. (123)], are referred to as Dieckmann cyclisations. These work best, under simple conditions, for the formation of the anions of 5-, 6- or 7-membered cyclic / -ketoesters... 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

Claisen condensations 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, v. 

Unsaturated side-chains are present in the cinnamic acids, some of which occur naturally in the trans form 12. Syntheses of the acids and their esters by the Claisen condensation and the Perkin and Knoevenagel reactions are discussed in Chapter 6. 

When p-keto esters are treated with concentrated base, cleavage occurs, but is on the keto side of the CR2 group (arrow) in contrast to the acid cleavage mentioned on page 838. The products are a carboxylic ester and the salt of an acid. However, the utility of the reaction is somewhat hmited by the fact that decarboxylation is a side reaction, even under basic conditions. p-Diketones behave similarly to give a ketone and the salt of a carboxylic acid. With both p-keto esters and p-chketones, OEt can be used instead of OH, in which case the ethyl esters of the corresponding acids are obtained instead of the salts. In the case of p-keto esters, this is the reverse of Claisen condensation (16-85). The similar cleavage of cychc a-cyano... 

The pattern of side reactions in the polymerization of a-substituted lactams is slightly different. The keto timide structures (XV) formed in the Claisen type condensation have no acidic a-hydrogen so that the concentration of lactam anions cannot decrease so dramatically as with the acidic keto amides (X)—(XIV). Consequently, the position of the condensation equilibrium is shifted in favour of the initial components. Also the main products formed from af,a -disubstituted keto amides [136], scheme (52), are different from those of the monosubstituted keto amides, scheme (45). 

Cl disappears rapidly in side reactions (Claisen condensation) and the polymerization is prematurely stopped. However, as long as the monomer remains in the reaction medium, the polymerization can be continued by simply adding new amounts of chain initiation. This is a great challenge while using RC for process monitoring since in this way the process becomes a controlled one. 

Undesirable side-reactions, such as Dieckmann ring closure and Claisen condensation reactions, often compete with the acyloin condensation. 

The overall reaction has been a deprotonation to produce the nucleophile for an addition-elimination reaction that is followed by a deprotonation to yield a resonance stabilized anion (Fig. 10.12). The reaction path is shown vertically on the left, and the side routes are shown to the right. This reaction is known as the Claisen condensation. 

The Reformatsky -Claisen variant is complicated by various side reactions, e.g., the condensation of the zinc enolate derived from acetic esters to yield 1,3-dicarbonyl compounds, known byproducts in the classical Reformatsky reaction. This side reaction is depressed by a-alkyl substitution of the ester. 

The terminal C-atoms of the enol systems 16 and 17 can be attacked by electrophiles, which is useful for carrying out C-C-forming reactions (aldol condensation, Claisen condensation, etc.), and exemplifies side-chain-reactivity in heterocyclic systems (see also p 281). The symmetrical conjugated stabilization of the 4-methylene pyran system (17) favours electrophilic attack on the 4-alkyl substituent. For example, the 2,4,6-trimethylpyrylium salt 18 undergoes a regioselective aldol condensation with benzaldehyde yielding only the 4-styryl derivative 19 ... 

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