Ketones reaction with ester enolates

Ester enolates, much more sensitive and capricious than ketone and amide enolates, seemed to be unsuitable for palladium-catalyzed allylic alkylations. Thus, Hegedus and coworkers [24] reported on low yields and predominant side reactions in the allylation of the lithium enolate of methyl cyclohexanecarboxylate. It seems that so far the only reliable and efficient version of a Tsuji-Trost reaction with ester enolates is based on the chelated zinc enolates 41 derived from N-protected glycinates 40 - a procedure that was developed by Kazmaier s group. 

Darzens glycidic ester condensation generally involves the condensation of an aldehyde or ketone 2 with the enolate of an a-halo ester 1 which leads to an a,P-epoxy ester (a glycidic ester) (3). Thus the reaction adds two carbons to the electrophile however, the reaction has been primarily developed as a one-carbon homologation method. That is, subsequent to the condensation, the ester is saponified and decarboxylation ensues to give the corresponding aldehyde or ketone 5.2... 

A one-pot reaction between a tryptophan ester, benzotriazole, and 2,5-dimethoxytetrahydrofuran in acetic acid gives the diastereomeric benzotriazolyl tetracycles, 349, in good yield. Substitution of the benzotriazole by reaction with silyl enol ethers and boron trifluoride etherate gives the corresponding ketones 350 and 351, and reaction with allylsilanes gives the corresponding alkenes 352 and 353. If the boron trifluoride etherate is added to the mixture before the silane, elimination of benzotriazole from 349 is also observed (Scheme 83) <1999T3489>. 

The method is useful for preparation of 1-alkenes labeled with deuterium at C, or C2. a-Alkyl-afi-unsaturated esters 2 a-Silyl esters can be obtained in >80% yield by reaction of lithium ester enolates with this silane (10, 91 11, 247). Aldehydes and ketones react with the enolates of these a-silyl esters to give adducts that undergo a Peterson elimination to form a-alkyl-a,(3-unsaturated esters in which the (Z)-isomer predominates. 

An improved version of the Carroll reaction, the ester enolate Carroll rearrangement, was reported in 1984 by Wilson and Ptice. Dianions of allylic acetoacetates, generated by treatment with 2 equiv. of LDA at -78 °C in THF, were rearranged at room temperature or 65 C to yield >keto acids in 40-80% yield (equation 12). In the course of a synthesis of the sesquiterpene isocomene, Snider and Beal used this method for the rearrangement of acetoacetate (73), prepared in 83% yield from reaction of cyclopen-tene (72) with diketene and a catalytic amount of DMAP (Scheme 11). The ( )-isomer of ketone (74) is obtained stereospecifically, since there is a severe steric interaction between the methyl groups in the Carroll rearrangement transition state leading to the (Z)-isomer. 

Attempts to extend the organometallic addition reaction to A -trialkylsilylimines derived from enoliz-able ketones have been frustrated by difficulties encountered in the preparation of these silylimines (due to competitive enolization), in addition to the existence of a tautomeric equilibrium between desired silylimines and the corresponding enamines. As a result, addition products (formed in low yield) are accompanied by significant amounts of starting materials (presumably generated via enamine hydrolysis).However, silylimines derived from enolizable aldehydes reportedly can be generated and trapped in situ with ester enolates to form 3-lactams (18-60% yield). 

The utility of oxaziridines in asymmetric a-hydroxylation also extends to reactions with achiral enolates. This has been made possible by the discovery that certain chiral A -sulfonyl oxaziridines can react with enolates to afford a-hydroxy carbon compounds in excellent yield and enantioselectivity. An application of a highly selective sulfonyloxaziridine derived from camphor to the synthesis of daunomycin is shown in Scheme 8.23. Attack of the oxaziridine presumably occurs such that the enolate ester avoids nonbonded interactions with the exo methoxy group on the bicyclic ring system (cf. Schemes 8.23c and d). This is a very useful reaction of wide scope, and can be carried out on both stabilized enolates derived from keto esters (shown) and simple ketone enolates [99]. 

Reaction with silyl enol ethers. Derivatives from ketones and esters behave to- ards arenediazonium salts according to their relative nucleophilicities. a-Arylation, 9 ketones by a free radical pathway and nonradical a-amination of esters are. bserved. 

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. 

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. 

In the following sections, we focus on condensation reactions at the a-carbon atom of esters. Reactions of these derivatives form carbon—carbon bonds and are useful in synthesis. Alkylation reactions using alkyl halides and reactions at carbonyl carbon atoms both occur with ester enolates. However, the reactions of enolates of acid derivatives differ somewhat from the reactions of enolates of aldehydes and ketones. For one thing, the a-hydrogen atoms of esters (pA 25) are less acidic than those of aldehydes and ketones (pif 20). Two resonance forms are written for aldehydes and ketones. The dipolar resonance form of a ketone has a positive charge on an electron-deficient carbonyl carbon atom. The contribution of this resonance form (2) to the resonance hybrid increases the acidity of the a-hydrogen atom as the result of inductive electron withdrawal. 

The zinc enolate can potentially react with an electrophilic carbonyl carbon atom or at the oxygen atom of the enolate. However, we recall that similar reactions of enolates of aldehydes and ketones occur at carbon, thus retaining the very stable carbonyl group. The same considerations are important for the reactions of ester enolates, which also react at the carbonyl carbon. 

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give p diketones on reaction with ketone enolates... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

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. 

An alkylation reaction is used to introduce a methyl or primary alkyl group onto the a position of a ketone, ester, or nitrile by S 2 reaction of an enolate ion with an alkyl halide. Thus, we need to look at the target molecule and identify any methyl or primary alkyl groups attached to an a carbon. In the present instance, the target has an a methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane. 

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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