Enolate anions, ester self-condensation

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

A more generally useful reaction is the self-condensation of simple substituted acetates RCH2C02Et. These work well under the same conditions (EtO- in EtOH), The enolate anion is formed first in low concentration and in equilibrium with the ester. It then carries out a nucleophilic attack on the more abundant unenolized ester molecules. 

Addition of the anion of 2-methyl-l,3-cyclopentadione (348) to protoane-monin (349), easily prepared from levulinic acid in four steps (207), led to adduct 350 in low yield due to ready self-condensation (Scheme 39). Transesterification with acidic methanol set the alcohol free, which cyclized spontaneously to the 1 1 mixture of ketals 351 and 352. To enhance the yield of the ketal 352, ketal 351 was recycled by equilibration in acidic methanol. Under Kharash-Grignard conditions, the isopropenyl group added unselectively in 1,4-mode and the ester enolate 353... 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

If the enolate of a carboxylic ester is formed at room temperature then selfcondensation of the ester results. This reaction is known as the Claisen condensation and gives a p-keto ester product. A variety of bases including EDA, sodium hydride or sodium alkoxides can be used and the reaction may be driven to completion by the deprotonation of the product, to give the anion of the P-keto ester (p.Sra 11). The Claisen condensation reaction works best when the two ester groups are the same, to give the self-condensation product (1.59), or when one of the ester groups is non-enoUzable. The reaction is less useful in cases where two different enolizable esters are used, as a mixture of up to four p-keto ester products is normally obtained. The product P-keto esters are useful in synthesis as they readily undergo alkylation and decarboxylation reactions (see Section 1.1.1). 

Keto-ester 61 results from self-condensation of the ester 60, but the reaction of two different esters under these conditions gives a different result. Condensation between two different esters is called a mixed Claisen condensation and it occurs when the enolate anion of one ester condenses with the second ester. Under thermodynamic conditions, however, the ester is always present along with the ester enolate because it is an equilibrium process. At equilibrium, there are two esters in the medium as well as two different ester enolates, and each enolate anion wiU react with both esters to give a different product. 

Once an ester enolate is generated, it can react with another ester in a Claisen condensation however, it may also react with the carbonyl of an aldehyde or ketone. The ester enolate anion is a nucleophile and it reacts with an aldehyde or ketone via acyl addition. Kinetic control conditions are the most suitable for this reaction in order to minimize Claisen condensation of the ester with itself (self-condensation). If ester 74 (ethyl propanoate, in green in the illustration) is treated first with LDA and then with butanal (21, in violet), for example, the initial acyl addition product is 78. The new carbon-carbon bond is marked in blue and treatment with dilute aqueous acid converts the alkoxide to an alcohol in the final product of this sequence, 79. Compound 79 is a P-hydroxy ester, which is the usual product when an ester enolate reacts with an aldehyde or a ketone. Ester enolate anions react with ketones in the same way that they react with aldehydes. 

In 1887, the Russian chemist Sergei Reformatsky at the University of Kiev discovered that treatment of an a-haloester with zinc metal in the presence of an aldehyde or a ketone followed by hydrolysis in aqueous acid results in formation of a /3-hydroxyester. This reaction is similar to a Grignard reaction in that a key intermediate is an organo-metallic compound, in this case, a zinc salt of an ester enolate anion. Grignard reagents, however, are so reactive that they undergo self-condensation with the ester. 

The most generally used carbonyl compounds for the acylation of enolate ions are esters. Here, nucleophilic addition of the anion to the carbonyl group is followed by loss of alkoxide from the tetrahedral intermediate. A classic example of this type of reaction is the Claisen condensation—the base-catalyzed self-condensation... 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

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