Aldehydes, reaction with enolate anions

One of the most important reactions of aldehydes and ketones is the Aldol condensation. In this reaction, an enolate anion is formed from the reaction between an aldehyde or a ketone and an aqueous base, e.g. NaOH. The enolate anion reacts with another molecule of aldehyde or ketone to give (3-hydroxyaldehyde or (3-hydroxyketone, respectively (see Section 5.3.2). 

Another variation of this classic reaction is called the aldol-transfer reaction, reported by Nevalainen. In the presence of a suitable catalyst, usually an aluminum compound, an aldol product reacts with an aldehyde, gen-erating a ketone and a new aldol. An example is the reaction of benzaldehyde with aldol 143 in the pres-ence of 5% of aluminum catalyst (144). In dichloromethane at ambient temperatures, a 62% yield of aldol 145 was obtained after a reaction time of 43 h. The other product of this reaction was acetone, which was readily removed. This transformation involves a retro-aldol reaction of 143 (see sec. 9.5.A.vi.) and the resul-tant enolate anion reacts with benzaldehyde. This reaction has been done with several aldehydes and 143 is particularly attractive (the aldol condensation product of acetone), because acetone is the second product. 

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. 

All of the examples shown for the aldol condensation in Sections 22.2 and 22.4 involved an intermolecular reaction (the reaction of two different molecules). If a molecule has two carbonyl units as well as at least one acidic a-hydrogen and is treated with base, an intramolecular aldol condensation can take place. A simple example is 1,6-hexanedial (57), which, when treated with lithium diisopropylamide in THF, gives enolate anion 58 (the carbanion is drawn at C2). This enolate anion reacts with the most available electrophilic center, which in this case is the aldehyde carbonyl on the other end of the molecule (labeled C6). 

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. 

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. 

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. 

The most common representatives of alkenyliron complexes are iron-substituted enones and enals. They are prepared from Fp-anions and P-halovinyl ketones and aldehydes (Scheme 4-30), ° and they can be further functionalized via their enolates and reaction with alkyl halides or mesylates. ... 

The anion B is just the enolate anion of a carbonyl compound, actually the same as A. So there is no need to use a Grignard reagent or any other synthetic equivalent in this reaction anion B itself can be the intermediate and we simply treat the aldehyde with mild base ... 

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]... 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

Because enolate anions ffle sources of nucleophilic car bon, one potential use in organic synthesis is their- reaction with alkyl halides to give a-alkyl derivatives of aldehydes and ketones ... 

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. 

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. 

The stereochemical outcome of the addition of lithium enolates of aldehydes and ketones to nitroalkenes is dependent upon the geometry of the nitroalkene and the enolate anion. The synjanti selectivity in the reaction of the lithium enolates of propanal, eyelopentanone and cyclohexanone with ( )- and (Z)-l-nitropropene has been reported1. 

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. 

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. ... 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

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... 

In the aldol reaction, we saw an enolate anion acting as a nucleophile leading to an addition reaction with aldehydes and ketones. 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

The reaction of an amino group with an aldehyde or ketone leads to an imine, which, as we have just seen with aldolase, provides a splendid example of how to bond a carbonyl substrate to an enzyme, and yet maintain its chemical reactivity in terms of enolate anion chemistry. Another type of covalent interaction is quite commonly encountered, and this exploits the thiol group of cysteine. Thiols are more acidic than... 

Aldehyde (B) also has hydrogen a to the carbonyl and can generate an enolate anion the aldol reaction follows as with the first aldehyde to give the product shown. However, dehydration of the P-hydroxyaldehyde is not favoured. 

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