Claisen condensation ketone enolate reaction with esters

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

Reaction of an ester enolate with an acid chloride will also generate a (3-keto-ester and is a useful alternative to the Claisen condensation. Ketone enolates can also be condensed with acid chlorides. An ester enolate can be trapped with trimethylsilyl chloride, as with aldehydes and ketones. An interesting variation of this... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

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... 

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. 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

A crossed Claisen is die reaction of an ester enolate with an aldehyde or ketone to produce a /3-hydroxy ester. This works well because aldehydes and ketones are more reactive electrophiles than esters thus the ester enolate reacts faster with die aldehyde or ketone than it condenses with itself, avoiding product mixtures. Moreover, die aldehyde or ketone should not have a hydrogens so that proton transfer to die more basic ester enolate is avoided. This would lead to the formation of an aldehyde or ketone enolate in the mixture, and an aldol reaction would be a major competing reaction. 

Claisen condensations always involve esters as the electrophilic partner, but enolates of other carbonyl compounds—ketones, for example—may work equally well as the enol partner. In a reaction with a carbonate, only the ketone can enolize and the reactive carbonate ester is more electrophilic than another molecule of the ketone, A good example is this reaction of cyclooctanone. It does not matter which side of the carbonyl group enolizes—they are both the same, v. 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

When competing Claisen condensation of the ester is a problem, the use of the sterically hindered t-butyl esters is recommended. Unlike with ketone enolates, the 0-alkylation of ester enolates generally is not a problem. Consequently, HMPA may be added to ester enolate alkylations to improve yields. Many S 2 reactions proceed more readily in HMPA than in THF, DME, or DMSO. A solvent for replacing the carcinogenic HMPA in a variety of alkylation reactions is l,3-dimethyl-3,4,5,6-tetrahy-dro-2(lH)pyrimidinone (A,A -dimethylpropyleneurea, DMPU), which also has a strong dipole to facilitate metal counterion coordination. ... 

It will be observed that throughout this discussion of carbanions no mention has been made of the intermediate formation of an enol or of enolization. It now seems extremely probable that in reactions such as aldol formation (p. 176), the Claisen condensation (p. 185), acetoacetic or malonic ester reactions (pp. 182, 201), and the halogenation of ketones (pp. 206, 207) the carbanion is the actual reaction intermediate and that the formation of an enol simply represents an alternative non-essential course of reaction for the carbanion. In the alkylation of malonic ester, for example, a carbanion (XXV and XXVI) may be formed by reaction of the neutral ester with ethoxide ion. 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

In many reactions there is an equilibrium between reactants and products so that only the more stable of the two alkenes is produced. In the Claisen ester condensation of cyclohexanone 8 with ethyl formate, the true product under the conditions of the reaction is the stable enolate 9 and this is reversibly protonated on workup to give the more stable H-bonded enol of the ketoaldehyde Z-10. In the aldol reaction between the same ketone and benzaldehyde, the initial product 7 gives the enolate 6 and dehydration is reversible only the more sterically favourable E isomer of 5 is formed. Note that it is irrelevant that the aldol 7 is a mixture of diastereoisomers all stereochemistry is lost in the formation of the enolate 6. In later parts of this chapter a more specific relationship between 3D and 2D stereochemistry will be established. 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

Carbon-carbon bond formation is a reaction of fundamental importance to the cellular metabolism of all living systems and includes alkylation reactions involving one and five carbon fragments as well as carboxylation reactions. In addition, a very common method of generating carbon-carbon bonds in biology includes the reactions of enolates and their equivalents (such as enamines) with aldehydes, ketones, keto acids, and esters. Reactions in which the enolate derives from an acyl thioester are Claisen condensations, whereas the remainder are classified as aldol reactions. 

There are two important variations of this condensation. In the first, an ester enolate is condensed with a ketone or aldehyde. This has been called the Claisen reaction. An example is taken from the Omura co-... 

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