Ketones crossed Claisen reactions

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. 

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. 

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) ... 

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... 

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. 

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. 

Claisen-Schmidt reaction The cross condensation reaction of an aromatic aldehyde with a simple aliphatic aldehyde or ketone with 10% KOH to yield the dehydrated product, i.e. an a,P-unsaturated arenone. 

The Claisen-Schmidt Reaction. When aromatic aldehydes are treated with aliphatic ketones in the presence of base, three reactions might be expected a Cannizzaro reaction of the aromatic aldehyde an aldol-type reaction of the ketone or a crossed aldol reaction between the ketone and the aromatic aldehyde. In either of the last two possibilities dehydration might also occur. Undoubtedly all these reactions will take place in strong base, but by employing about 10 per cent aqueous sodium hydroxide, good yields are often obtained of j3-unsaturated carbonyl conipounds derived from a crossed aldol reaction between the aldehyde and the ketone. This reaction, generally called a Claisen-Schmidt reaction, can be illustrated by the synthesis of benzalacetophenone.16... 

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... 

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

In the real world of practical organic synthesis, one rarely needs to do a simple aldol condensation between two identical aldehydes or two identical ketones. Far more common is the necessity to do a crossed aldol between two different aldehydes, two different ketones, or an aldehyde and a ketone. As noted earlier, there are difficulties in doing crossed aldol reactions. Suppose, for example, that we want to condense 2-pentanone with benzaldehyde. Benzaldehyde has no a hydrogen, so no enolate can be formed from it. Some version of the Claisen-Schmidt reaction (p. 984) seems feasible. But 2-pentanone can form two enolates, and the first problem to solve is the specific formation of one or the other enolate (Fig. 19.127). 

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. 

If there are two carbonyl compounds present, then a cross condensation might occur, but usually it is of little synthetic value as there are four possible products. However, if one of the carbonyl compounds lacks an a-hydrogen, then the reaction might prove useful, because this compound cannot form the enol intermediate. An example is the Claisen-Schmidt condensation involving an aromatic aldehyde, e.g. benzaldehyde, with a simple aldehyde or ketone,... 

The crossed aldol examples shown in Table 19.1 involve aldehydes as both reactants. A ketone can be used as one reactant, however, because ketones do not self-condense appreciably due to steric hindrance in the aldol adchtion stage. The following are examples of crossed aldol condensations where one reactant is a ketone. Reactions such as these are sometimes called Claisen—Schmidt condensations. Schmidt discovered and Claisen developed this type of aldol reaction in the late 1800s. 

The cross-aldol addition of a ketone to an aldehyde (Claisen-Schmidt reaction) is profitably carried out by using the silyl enol ether of the ketone in an organic solvent in the presence of TiCh (Mukaiyama reaction) [2], but this protocol is not suitable for acid-sensitive substrates. High pressure may be employed in place of the catalyst, but longer reaction times are required [4]. 

We developed powerfiil Ti- or Zr-Claisen condensation between esters and direct crossed Ti-aldol addition between ketones and ketones or aldehydes. These reactions were successfully applied to the short and practical method for synthesizing some natural macrocyclic musks (civetone and muscone), mints (mintlactone and menthofuran), and a jasmine perfume. 

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