Enolate anions, esters, reaction with

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. 

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. 

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... 

Another important reaction of esters is the Claisen condensation. In this reaction, an enolate anion is formed from the reaction between an ester and a strong base, e.g. sodium ethoxide (NaOEt in EtOH). The enolate anion reacts with another molecule of ester to produce (3-ketoester (see Section 5.5.5). 

B.vi. Tbe Darzens Glycidic Ester Condensation. When an a-halo ester is treated with base and the resulting enolate anion condensed with a carbonyl derivative, the product is an alkoxide. This nucleophilic species can displace the halogen intramolecularly to produce an epoxide, which forms the basis of a classical reaction known as the Darzens glycidic ester condensation. 13S Reaction of ethyl a-chloroacetate and sodium ethoxide, in the presence of benzaldehyde. generated the usual alkoxide (221). Intramolecular displacement... 

As we saw in section 9.4.B,C, the reaction of an ester such as 623 with LDA, under kinetic control conditions, and subsequent reaction of the enolate anion (624) with chlorotrimethylsilane gives the silyl enol... 

With anions such as ester enolate anions, reaction occurs within minutes at -78 °C and the intermediate cyclohexadienyl complex can be observed spectroscopically [103]. The intermediates are exceedingly air sensitive and are generally quenched directly, without purification. In one case, from the addition of 2-lithio-l,3-dithiane, the adduct has been crystallized and fully characterized by X-ray diffraction analysis [103]. Oxidation with excess iodine (at least 2.5 mol-... 

The key step in a basealdol reaction is nucleophilic addition of the enolate anion from one carbonyl-containing molecule to the carbonyl group of another carbonyl-containing molecule to form a tetrahedral carbonyl addition intermediate. This mechanism is illustrated by the aldol reaction between two molecules of acetaldehyde. Notice that OH is a true catalyst An OH is used in Step 1, but another OH is generated in Step 3. Notice also the parallel between Step 2 of the aldol reaction and the reaction of Grignard reagents with aldehydes and ketones (Section 12.5) and the first step of their reaction with esters (Section 14.7). Each type of reaction involves the addition of a carbon nucleophile to the carbonyl carbon of another molecule. 

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. 

Just as an ester enolate anion reacts with an aldehyde or ketone via acyl addition, it is also reasonable that the enolate anion of an aldehyde or a ketone may react with an ester via acyl substitution. In the former reaction, the ester enolate is the nucleophile in the latter reaction, a ketone or aldehyde enolate is the nucleophile. When cyclohexanone (80) is treated with LDA (THF, -78°C) and then with methyl propanoate, the initial product is 81. Loss of OMe completes the acyl substitution sequence to give diketone 82. There is nothing special or unusual about these two variations. Virtually any ketone or aldehyde enolate reacts with an ester to form 1,3-diketones such as 82. 

The esters derived from dicarboxylic acids in Chapter 20 (Section 20.9) behave more or less like all other esters in enolate anion reactions. Dimethyl succinimide (87 dimethyl 1,4-butanedioate), for example, has a pK relatively close to that of ethyl butanoate (about 25) and it reacts similarly. Treatment of 87 with NaOMe will give 88 and this enolate anion reacts with aldehyde, ketones, or another ester. If 88 is treated with benzaldehyde in a second chemical step, the final product is 89, analogous to the conversion of 74 and 21 to 79 in Section 22.7.2. 

Aqueous acid workup of 92 gives the alcohol, 93. With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating because the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. Although it is possible to isolate 83, it is more usually difficult. The enolate anion of malonate esters also reacts with ketones and may be condensed with other esters in acyl substitution reactions. When 90 is treated with NaOEt in ethanol and then with ethyl butanoate, the final product after mild hydrolysis is a keto-diester, 95. 

A p-keto ester can be hydrolyzed to a P-keto acid, and heating leads to decarboxylation. Malonic acid derivatives, as well as P-ketone acids decarboxylate upon heating 63,109, 111, 135. Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds 65, 67, 70, 84, 108, 116, 127,... 

Compound 58 clearly offers more possibilities for disconnection. Disconnections are available at or near the carbon atom bearing the OH group, but also at or near both carbonyl carbons. The larger number of functional groups leads to more choices. Does the chemistry of the alcohol, the aldehyde, or the ketone offer the best choice for a disconnection The chemistry of alcohols is associated with oxidation and reduction (Chapter 17, Section 17.2 Chapter 19, Sections 19.2,19.3.4,19.4.1), formation and reactions of alkoxides as nucleophiles (Chapter 11, Section 11.3.2) and as bases (Chapter 12, Section 12.1), and formation of esters (Chapter 20, Section 20.5). Alcohols are converted to alkyl halides (Chapter 11, Section 11.7). Aldehydes and ketones are formed by the oxidation of alcohols (Chapter 17, Section 17.2), are reduced to alcohols (Chapter 19, Sections 19.2, 19.3.4, 19.4.1), undergo acyl addition (Chapter 18, Sections 18.1-18.7), and participate in enolate anion reactions (Chapter 22, Sections 22.2, 22.4, 22.6). Based on these reactions, several disconnections are shown, but several more are possible. 

Enolate anions react with aldehydes, ketones, and esters in carbonyl addition reactions. 

Claisen Condensation (Section 19.3A) The product of a Claisen condensation is a j8-ketoester. Condensation occurs by nucleophilic acyl substitution in which the attacking nucleophile is the enolate anion of an ester. The Claisen condensation mechanism involves reaction of one ester molecule with base to form an enolate anion, which reacts as a nucleophile with another molecule of ester to give a tetrahedral carbonyl addition intermediate, in which the RO" group is lost to give a /3-ketoester, which is deprotonated at the a position by the RO". 

A typical reaction that uses an amino acid derivative involves initial conversion to an enolate anion. This nucleophilic species is then reacted with an alkyl halide or a carbonyl derivative. An example that produces a new amino acid is the reaction of the ethyl ester of n-benzyl glycine with lithium diisopropylamide to give the enolate. Subsequent reaction with the mixed anhydride shown below proceeded with displacement of acetate to give /.22J.13 Acid hydrolysis generated a P-keto amino acid, which decarboxylated under the reaction conditions to give 4-oxo-5-aminopen-tanoic acid 1.156, also known as 5-aminolevulinic acid). 

The reactions discussed in section 4.1 obviously describe enolate anion reactions. The reactions in this section involve malonate derivatives that react with bases such as sodium hydride or lithium dialkylamides to generate the malonate anion, a highly stabilized enolate. This section also includes reactions of enolate anions derived from mono-esters and other acid derivatives. 

Ketone or ester enolate anions react with selenium metal, followed by methyl iodide, to give the corresponding a-methylselenenyl derivatives in high yield. This relatively cheap procedure is useful for moderate- or large-scale reactions. 

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

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 reactive species is the corresponding enolate-anion 4 of malonic ester 1. The anion can be obtained by deprotonation with a base it is stabilized by resonance. The alkylation step with an alkyl halide 2 proceeds by a Sn2 reaction ... 

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. 

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. 

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