Aldehydes reaction with ester enolates

Mechanistically, a-methylenecyclopentenone (2-391) reacts with ester enolate 2-392 in a Michael addition to give the enolate 2-393, which is then trapped with an aldehyde 2-394 generating the alcoholate 2-396. This eventually cyclizes through lactonization to afford 2-397 in good yield. The products 2-397 are obtained as single diastereomer thus, it can be assumed that the aldol reaction proceeds via the six-membered chair-like transition state 2-395. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

The scope was then extrapolated to the two-step three-component aza-Baylis-Hillman setup to obtain (3-amino-a-methylene structures. A two-step approach was chosen to avoid the competition between the aldehyde and the imine for the reaction with the enolate, that would lead to mixtures of Baylis-Hillman and aza-Baylis-Hillman adducts, that is (3-hydroxy and (3-amino esters [87]. 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

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 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. 

Simple aldehyde, ketone, and ester enolates are relatively basic, and their alkylation is limited to methyl and primary alkyl halides secondary and tertiary alkyl halides undergo elimination. Even when alkylation is possible, other factors intervene that can reduce its effectiveness as a synthetic tool. It is not always possible to limit the reaction to monoalkylation, and aldol addition can compete with alkylation. With unsymmetrical ketones, regioselectivity becomes a consideration. We saw in Section 20.2 that a strong, hindered base such as lithium diisopropylamide (LDA) exhibits a preference for abstracting a proton from the less-substituted a carbon of 2-methylcyclohexanone to form the kinetic enolate. Even under these conditions, however, regioisomeric products are formed on alkylation with benzyl bromide. 

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. 

We recall that the conjugate base of an aldehyde must react with the aldehyde, which is present in a significantly greater concentration, to make an aldol condensation possible. A similar condensation reaction, called the Claisen condensatioii, occurs when low concentrations of ester enolates react with esters (Section 22.15). If an ester reacts vdth a very strong base, such as hthium diisopro-pylamide (LDA), high concentrations of the ester enolate form, and no ester would remain for a bimolecular self-condensation reaction. The ester enolate yield is stoichiometric when LDA is used as the base because diisopropylamine is a much weaker acid than an ester. Furthermore, LDA is a sterically hindered nucleophile, so it does not react with the electroplulic carbon atom of the ester. 

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. 

Reductive aldol reaction of a,(5-unsaturated esters and enones with aldehyde mediated by a transition metal hydride complex and a hydride source, such as hydrosilane, is a versatile process to produce p-hydroxy carbonyl compounds (Scheme 15a) [21]. This reaction is thought to be an alternative transformation of Lewis acid-catalyzed Mukaiyama-type aldol reaction with silyl enol ethers or silyl ketene acetals (Scheme 15b). 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

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... 

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. 

On the other hand, syn-carboxylic acids are obtained from a deprotonation of the /5-silyl ester, giving the (E)-enolate, followed by reaction with different aldehydes and subsequent hydrogenolysis. No diastereomers of the aldol product are detected720. 

Aldehydes and ketones RCOR react with oc-methoxyvinyllithium CH2= C(Li)OMe to give hydroxy enol ethers RR C(OH)C(OMe)=CH2, which are easily hydrolyzed to acyloins, RR C(OH)COMe. this reaction, the CH2=C(Li)OMe is a synthon for the unavailable H3C—C=0. The reagent also reacts with esters RCOOR to give RC(OH)(COMe=CH2)2- A synthon for the Ph—C=0 ion is PhC(CN)OSiMe3, which adds to aldehydes and ketones RCOR to give, after hydrolysis, the a-hydroxy ketones, RR C(OH)-COPh. °... 

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