ENOLATE CONDENSATION REACTIONS

The condensation reaction of enolate anions and carbonyl derivatives is one of the most useful of all reactions in organic chemistry. The condensation is nothing more than an acyl addition reaction of the nucleo- 

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Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

When a ketone reacts with a suitable base (secs. 9.1, 9.2) an enolate anion is formed by removal of the a-proton. In the case of an unsymmetrical ketone such as 30, a mixture of (Z)-enolate (31) and ( )-enolate (32) usually results (secs. 9.2.E, 9.5.A). This mixture influences the diastereoselectivity and enantioselectivity of enolate condensation reactions (sec. 9.5). Such a mixture of geometrical isomers generates both syn- and antiproducts upon reaction with aldehydes so it is important to control or at least identify the geometry of the enolate. Several solutions to this problem have been developed, including formation of stable and separable enolate isomers and controlling reaction conditions to maximize production of one isomer. 

Other methods for the preparation of 6.99 from leucine involved reduction of the acid moiety with borane and then oxidation to an aldehyde with chromium irioxide and pyridine. Another variation added zinc bromide to the enolate condensation reaction,75 which led to greater selectivity for the anti diastereomer. 

The usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

Metal alkoxides cataly2e the Tishchenko condensation of aldehydes (62), the transesterification of carboxyhc esters, the Meerwein-Poimdorf reaction (63), and other enolization and condensation reactions. 

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. 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

Fluoroalkyl ketones may be used as the electrophilic partners in condensation reactions with other carbonyl compounds The highly electrophilic hexafluo-roacetone has been used in selective hexafluoroisopropyhdenation reactions with enol silyl ethers and dienolsilyl ethers [f] (equation 1)... 

Fluoroalkyl ketone enolates and enol etliers have also been use in condensation reactions with ketones [22] Interestingly, these materials fail to undergo Dar/ens-type side reactions (equation 18)... 

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Although the carbonyl condensation reaction appears different from the three processes already discussed, it s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 5. 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

Carbonyl condensation reactions take place between two carbonyl partners and involve a combination of nucleophilic addition and -substitution steps. One partner is converted into an enolate-ion nucleophile and adds to the... 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

Extension of this aldol reactivity to the preparation of chiral materials via condensation reactions of the chiral enolate species 2 and 3 is discussed in the following sections. 

The oxidation of /(-amino-substituted iron acyl complexes which are prepared via condensation reactions of iron-acyl enolates and imines or iminium ions26,5 -47-54 generates /(-lactams 32,33,61. Brief treatment with bromine in dichloromethane at low temperature is the usual procedure. 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

The intermediate enolate or enol ether from the initial reduction of an enone may be alkylated in situ (Eq. 281).455 / -Substituted cyclopentenones may be asymmetrically reduced and alkylated459 (see section on asymmetric reductions of enones). Enolates may also be trapped with an aldehyde in a reductive aldol condensation of an enone with an aldehyde,455 permitting a regioselective aldol condensation to be carried out as shown in Eq. 282.455 This class of reductive aldol condensation reactions can also occur in a cyclic manner (Eq. 283).460... 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

One of the earliest studies to address the issue of aldehyde dia-stereoface selection in enolate condensation was performed by Matsumoto and coworkers (91). The Reformatsky reaction of methyl 2-bromopropionate and 2-phenylpropanal (98) afforded the four aldol adducts illustrated in eq. [70]. Although the aldol diastereo-... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Crossed aldol condensation reactions may present a problem because multiple products can be formed. For example, a mixture of carbonyl A and carbonyl B can give two different enolates, each of which can then attack either an A or a B molecule. Therefore, four products are possible (Ag, A + B, B + A, and B2). 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

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