Claisen condensation/aldol addition

In principle, the synthesis of a consonant molecule or a bifunctional relationship within a more complex polyfunctional molecule, does not offer too many difficulties. In fact, all the classical synthetic methods of carbon-carbon bond formation that utilise reactions which are essentially reversible, lead to consonant relationships. For instance, the book by H.O. House "Modem Synthetic Reactions" [22], after dealing, for almost 500 pages, with functional group manipulations, devotes the last 350 pages to carbon-carbon bond formation, all of which lead to consonant relationships. These methods can, actually, be reduced to the following four classical condensations (and their variants) Claisen condensation, aldol condensation, Mannich condensation and Michael addition (Table 2.5). 

In contrast with Claisen-Schmidt condensation, aldol addition typically affords diastereoisomers of the mono-adduct, which may be dehydrated in a separate step to give ( )-2-benzylidenecyclohexanone. 

For instance, the CH3 group of 2- or 4-picoline can be alkylated (59), carboxylated (60), and acylated (62) by a CLAiSEN-like condensation aldol addition (61), multiple aldol addition (65), and aldol condensation (63, 64) are also possible. When several alkyl groups are present, deprotonation takes place at the most acidic pyridyl C-H bond. For instance, the synthesis of 3,4-diethylpyridine 67 is effected by selective deprotonation of the 4-methyl group in 3-ethyl-4-methylpyridine 66 followed by alkylation. 

Preformed enolate anions using LDA can be used to carry out a wide variety of crossed enolate reactions, including aldol reactions, Claisen condensations, Michael additions, alkylations, and acylations. 

Notice the use of Claisen condensation, conjugate addition, and aldol dehydration reactions to construct the six-membered ring (annulation chemistry). We will return to possible reasons for choice of this strategy for construction of the B-ring at a later date. Note that the same fundamental strategy is used for construction of the A-ring. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The reactions described in this chapter include some of the most useful synthetic methods for carbon-carbon bond formation the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related olefination methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. 

Classical organic reactions that have been carried out in water include, among others, the Diels-Alder reaction, the Claisen rearrangement, aldol condensations, Michael additions, and nucleophilic substitutions. In the Diels-Alder reaction, for example, water has been found to increase the reaction rate and to enhance the endoselectivity 120). Two reviews summarize the results for organic reactions in water 121). 

The Claisen condensation resembles both the aldol addition (Section... 

Claisen condensations can be carried out between two different esters but, because there are four possible products, mixtures often result. Less difficulty is encountered if one of the esters has no a hydrogen and reacts readily with a carbanion according to Equations 18-11 and 18-12. The reaction then has considerable resemblance to the mixed aldol additions discussed in Section 17-3C. Among the useful esters without a hydrogens, and with the requisite electrophilic reactivity, are those of benzenecarboxyiic, methanoic, ethanedioic, and carbonic acids. Several practical examples of mixed Claisen condensations are shown in Equations 18-14 through 18-16 (all of the products exist to the extent of 10% or so as the enol forms) ... 

An important variation on the Claisen condensation is to use a ketone as the anionic reagent. This often works well because ketones usually are more acidic than simple esters and the base-induced self-condensation of ketones (aldol addition) is thermodynamically unfavorable (Section 17-3C). A typical example is the condensation of cyclohexanone with diethyl ethanedioate (diethyl oxalate) ... 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

F Biological Claisen Condensations and Aldol Additions. Fatty Acid Metabolism... 

Three molecules of acetyl-coenzyme A are used to form mevalonic acid. Two molecules combine initially in a Claisen condensation to give acetoacetyl-CoA, and a third is incorporated via a stereospecific aldol addition giving the branched-chain ester P-hydroxy-P-methylglutaryl-CoA (HMG-CoA) (Figure 5.4). This third acetyl-CoA molecule appears to be bound to the enzyme via a thiol group, and this linkage is subsequently hydrolysed to form the free acid group of HMG-CoA. In the acetate... 

The mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldehvde or ketone and the Claisen condensation of... 

Like the aldol condensation and related reactions, the Claisen condensation involves nucleophilic attack by a carbanion on an electron-deficient carbonyl carbon. In the aldol condensation nucleophilic attack leads to addition the typical reaction of aldehydes and ketones in the Claisen condensation, nucleophilic attack leads to substitution, the typical reaction of acyl compounds (Sec. 20.4). 

Yoshida, Y., Hayashi, R., Sumibara, H., Tanabe, Y. TiCl4/Bu3N/(catalytic TMSOTf) efficient agent for direct aldol addition and Claisen condensation. Tetrahedron Lett. 1997, 38, 8727-8730. 

The usual reactions involved in carbocyclic cyclization of the aforementioned open-chain intermediates are aldol and Claisen condensations as well as Michael additions. Some examples of the Wadsworth-Emmons reactions have been also published. 

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