Ketones crossed Claisen condensation

Crossed Claisen condensations between ketones and esters are also possible. Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation. The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution and thereby acylates the ketone. 

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. 

Steps 1 and 2 bring about a crossed Claisen condensation in (a) and a Dieckmann condensation in (b) to form a /3-ketoester. Steps 3 and 4 bring about hydrolysis of the /3-ketoester to give a j3-ketoacid, and Step 5 brings about decarboxylation to give a ketone ... 

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

In addition to crossed aldol additions and crossed Claisen condensations, a ketone can undergo a crossed condensation with an ester. If both the ketone and the ester have a-hydrogens, then LDA is used to form the needed enolate ion and the other carbonyl compound is added slowly to the enolate ion to minimize the chance of its forming an enolate ion and reacting with another molecule of its parent ester. 

AldolRea.ctlons, In the same way, hydroxybenzaldehydes react readily with aldehydes and ketones to form a,P-unsaturated carbonyl compounds in the Claisen-Schmidt or crossed-aldol condensation (60). 

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... 

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. 

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. 

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. 

Claisen-Schmidt condensation (Section 19.7) A crossed aldol condensation of an aldehyde without (X hydrogens with a ketone that does have at least one (X hydrogen. 

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. 

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,... 

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. 

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). 

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