Ester crossed Claisen reaction

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... 

To be synthetically useful, a mixed Claisen reaction (crossed Claisen reaction) needs one ester with no a-hydrogens, so that it cannot become... 

For die same reason it is generally not feasible to cany out a crossed-Claisen reaction between die enolate of one ester and a second ester which has a protons. This is due to the fact diat if nucleophilic addition to die carbonyl group is not fast, proton exchange can occur, giving a mixture of etiolates and thus a mixture... 

When one ester has no a hydrogens, a crossed Claisen reaction often leads to one product. Common esters with no a H atoms include ethyl formate (HC02Et) and ethyl benzoate (CjH5C02Et). For example, the reaction of ethyl benzoate (as the electrophile) with ethyl acetate (which forms the enolate) in the presence of base forms predominately one p-keto ester. 

The reaction of a ketone and an ester in the presence of base also forms the product of a crossed Claisen reaction. The enolate is always formed from the ketone component, and the reaction works best when the ester has no a hydrogens. The product of this crossed Claisen reaction is a P-dicarbonyl compound, but not a p-keto ester. 

Crossed Claisen reaction (Section 24.6) A Claisen reaction in which the two reacting esters are different. 

Crossed Claisen reactions can be used to give high yields of a desired product from two different esters if one ester has no a-hydrogens (cannot form an enolate anion) and is used in excess. 

In a crossed Claisen reaction between an ester and a ketone, the enolate is formed from the ketone, and the product is a P-dicarbonyl compound. 

A P-dicarbonyl compound like avobenzone is prepared by a crossed Claisen reaction between a ketone and an ester. 

Crossed Claisen reactions can be achieved when one component cannot be enolized— confusingly, this name is used whether the nucleophilic component is an ester or a ketone (Figure 17.35). The product of the reaction in the second example was used in a morphine synthesis and is isolated in the enol form shown. 

A crossed Claisen is die reaction of an ester enolate with an aldehyde or ketone to produce a /3-hydroxy ester. This works well because aldehydes and ketones are more reactive electrophiles than esters thus the ester enolate reacts faster with die aldehyde or ketone than it condenses with itself, avoiding product mixtures. Moreover, die aldehyde or ketone should not have a hydrogens so that proton transfer to die more basic ester enolate is avoided. This would lead to the formation of an aldehyde or ketone enolate in the mixture, and an aldol reaction would be a major competing reaction. 

However, if one of the ester partners has enolizable a-hydrogens and the other does not (e.g., aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful. If ketones or nitriles are used as the donor in this condensation reaction, a P-diketone or a p-ketonitrile is obtained, respectively. 

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. 

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... 

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. 

We shall now give a few examples of crossed Claisen ester condensations between ordinary esters and the compounds we have just discussed. First, a reaction between a simple linear ester and diethyl oxalate performed under equilibrating conditions with ethoxide as the base. 

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... 

When carboxylic esters containing an a hydrogen are treated with a strong base, such as sodium ethoxide, a condensation occurs to give a p-keto ester via an ester enolate anion. ° This reaction is called the Claisen condensation. When it is carried out with a mixture of two different esters, each of which possesses an a hydrogen (this reaction is called a mixed Claisen or a crossed Claisen condensation), a mixture of all four products is generally obtained and the reaction is seldom useful synthetically. However, if only one of the esters has an... 

Crossed Claisen-like reactions can also occur between esters and ketones. The ester generally acts as the electrophile, as ketones are more acidic than esters (i.e. the ketone enolate, which acts the nucleophile, is more easily formed than an ester enolate). For an ester enolate, the lone... 

A potentially valuable example of a crossed Claisen condensation was described by Tanabe and Mu-kaiyama in 1986. It arose from their earlier work on titanium(IV) ditriflate [dichlorobis(trifluorometh-anesulfonato)titanium(IV)] and triethylamine as a catalytic promoter of the simple Claisen reaction. The reaction was run in the presence of benzaldehyde, added to observe the aldol reaction, but the propionate anion added to the carbonyl group of another ester molecule in preference (equation 11). The same result was observed in a Dieckmann reaction dimethyl adipate, TiCh (OTf) (1.5 equiv.) and triethylamine... 

The reaction described for ethyl butanoate is a self-condensation, but as with the aldol condensation, Claisen condensation of two different esters can result in a mixture of products under thermodynamic control conditions. The reaction of two different esters is called the crossed-Claisen (or a mixed Claisen) condensation. A generalized reaction involving RC02Et and RlC02Et can lead to at least four different condensation... 

There are several variations of the Claisen condensation. The intramolecular variation is called the Dieckmann condensation. A crossed Claisen condensation is possible between two different esters, but this reaction can lead to multiple products. Claisen condensations can operate in the forward direction or in the reverse direction, and these two processes lead to the construction and deconstruction of fatty acids. 

It is possible to achieve crossed Claisen condensations (just like we can achieve crossed aldol condensations), but we would have the same concerns as before. We would have to worry about potential side reactions. A crossed Claisen condensation will be more efficient when one of the esters has no alpha protons. You wiU see that some of the problems below are the products of crossed Claisen condensations. Keep an eye out for them. 

A crossed Claisen condensation is a condensation reaction between two different esters. Like a crossed aldol addition, a crossed Claisen condensation is a useful reaction only if it is carried out under conditions that foster the formation of primarily one product. Otherwise, the reaction will form a mixture of products that are difficult to separate. 

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