Ester enolates reaction with compounds

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1R2C02R3) with (Rs)-2-(p-tolylsulftnyI (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The 0-metallated /Miydroxyalkanoates formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /i-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Mixed condensations in which the nucleophilic enolate is derived from an ester have also been developed. Very strong bases have usually been used for enolate formation. For example, the lithium enolate of ethyl acetate is generated using lithium bis(trimethylsilyl)amide as the base. Condensation with carbonyl compounds proceeds readily (entry 13, Scheme 2.1) without apparent complications from proton-transfer reactions between the ester enolate and carbonyl compound. The dilithium salts of carboxylic acids can also add to carbonyl compounds (entry 14, Scheme 2.1). 

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. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

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. 

Active methylene compounds may be sulfinylated by reaction of their enolate anions with sulfinate ester . This reaction has been investigated much in recent years and the compounds resulting from it have been of considerable use in asymmetric synthesis (see the chapter by Posner). Examples of the sulfinylation are given in the following paragraphs. 

By reaction of a base with compound 251, attack of the ester enolate at the adjacent nitrile occurs, to give the amino-substituted thienoindolizine 252 <1987CL2043> (Equation 34). 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

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