Enolate anions, esters, reaction with aldehydes

Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or acid derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Metallation of the arylsulfinyl-N-methoxyacetimidate (49), which may be prepared in two steps from commercially available V-hydroxyacetimidate, followed by reaction with aldehydes provides adducts that after sequential desulfurization and hydrolysis may be converted into -hydroxy esters with 280% enantiomeric excess (Scheme 20). Thus, under kinetic conditions the reaction of the anion derived from (49) with aldehydes gives mixtures of the syn and anti products, (50) and (51) respectively, in nearly equal amounts. Under thermodynamic conditions, however, the more stable anti adducts (51) dominate, and after desulfurization and hydrolysis the P-hydroxy esters (53) are obtained in 75-94% enantiomeric excess. When the zinc enolate derived from (49) is condensed with aldehydes, the anti adducts (51) are again the major products and the p-hydroxy esters (53) can be isolated in 76-86% enantiomeric excess. On the other hand, the reaction of the zirconium enolate of (49), which is obtained by the addition of Cp2ZrCl2 to the corresponding lithium enolate, with aldehydes followed by desulfurization gives p-hy-... 

When primary or secondary amides are treated with a base, there is a complicating reaction that was not possible with esters, ketones, or aldehydes. The N—H moiety is acidic enough to react with the bases used for deprotonation. Treatment of 56 with base gave the A-lithio derivative, but the a-lithio derivative (57) can be generated by addition of two equivalents of base. Enolate anion formation is straightforward with tertiary amides, such as dimethylisobutyramide (56, R = Me) and the resultant enolate anion (58) reacted with butanal to give amido-alcohol 59 in 68% yield O (see sec. 9.4.B). 

A variation of this condensation involves reaction with aldehydes, and it is called the Perkin reaction. Condensation of an aldehyde (having no enolizable protons) with the enolate of an acid anhydride leads to an acetoxy ester such as 182.10 Internal acyl substitution by the alkoxide forms the 0-acetyl ester and liberates the carboxylate anion (183). Subsequent reaction with more acetic anhydride generates a new mixed... 

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form P-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes. 

Triphenylmethide (19) is formed by the reaction of triphenylmethane (PhaCH) with sodium metal, as seen in Section 22.1. It is an unusual but effective base in this reaction because it is a relatively non-nucleophilic base (see Section 22.3). To explain the reaction with 60 and formation of product 61, a mechanism requires that the base first remove the acidic a-proton on C2 from the ester to form enolate anion 62. As with enolate anions derived from ketones and aldehydes, there are two resonance forms, and the carbanion form (62A) is the more nucleophilic. Therefore, resonance contribution 62A will lead to the... 

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form p-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes 56,57,84,99,100,102,108,110,114,115. Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product 52, 53, 54, 55, 59, 68, 69,98,99,101,125. 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

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. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

Besides ordinary esters (containing an a hydrogen), the reaction can also be carried out with lactones and, as in 16-38, with the y position of a,p-unsaturated esters (vinylogy). There are also cases, where the enolate anion of an amide was condensed with an aldehyde. ... 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

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... 

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations ... 

The stability of the phosphonium-stabilized enolates also means that, although they react well with aldehydes, their reactions with ketones are often poor, and it is better in these cases to use phos-phonate-stabilized enolates. Being anionic, rather than neutral, these are more reactive. If an ester enolate equivalent is being used, the best base is the alkoxide ion belonging to the ester with a ketone enolate equivalent, use sodium hydride or an alkoxide. 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

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