Crossed Claisen condensation reaction

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

M "oR), a crossed Claisen condensation reaction will take... 

Claisen condensation reactions that occur between two different partners are called crossed Claisen condensations. Just as we saw with aldol reactions, crossed Claisen condensation reactions also produce a mixture of products and are only efficient if one of the two following criteria are met ... 

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). 

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. 

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. 

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... 

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 same sequence of reactions starting with a crossed Claisen condensation gives an unsymmetrical ketone. 

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. 

The initial Diels-Alder reaction worked well to provide a mixture of endo (127) and exo (not shown) cycloadducts. A crossed Claisen condensation provided 128, and a series of functional group manipulations provided Cope substrate 129. The Cope rearrangement proceeded well to give 123 in excellent yield. Unfortunately a number of problems were encountered thereafter. 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

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... 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

The Claisen-Schmidt reaction (Figure 11-17) produces an a,P-unsaturated aldehyde or ketone, the general structure of which is shown in Figure 11-18. The Claisen-Schmidt reaction is a crossed aldol condensation. 

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