The Claisen Reaction

The Claisen reaction is the second general reaction of enolates with other carbonyl compounds. In the Claisen reaction, two molecules of an ester react with each other in the presence of an alkoxide base to form a P-keto ester. For example, treatment of ethyl acetate with NaOEt forms ethyl acetoacetate after protonation with aqueous acid. 

Unlike the aldol reaction, which is base-catalyzed, a full equivalent of base is needed to deprotonate the P-keto ester formed in Step [3] of the Claisen reaction. 

The mechanism for the Claisen reaction (Mechanism 24.4) resembles the mechanism of an aldol reaction in that it involves nucleophilic addition of an enolate to an electrophilic carbonyl group. Because esters have a leaving group on the carbonyl carbon, however, loss of a leaving group occurs to form the product of substitution, not addition. 

In Step [1], the base removes a proton from the a carbon to form a resonance-stabilized enolate. 

Steps [2]-[3] Nucleophilic addition and loss of the leaving group 

In Step [2], the nucleophilic enolate attacks the electrophilic carbonyl carbon of another molecule of ester, forming a new carbon-carbon bond. This joins the a carbon of one ester to the carbonyl carbon of a second ester. 

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This Condensation should not be confused with the Claisen Reaction, which is the condensation of an aldehyde with (i) another aldehyde, or (ii) a ketone, under the influence of sodium hydroxide, and with the elimination of water. For details, see Diben zal-acetone. p, 231. 

Other reactions similar to the aldol addition include the Claisen and Perkin reactions. The Claisen reaction, carried out by combining an aromatic aldehyde and an ester in the presence of metallic sodium, is useful for obtaining a,P-unsaturated esters. 

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. 

Problem 23.12 As shown in Figure 23.5, the Claisen reaction is reversible. That is, a /3-keto ester can be cleaved by base into two fragments. Using curved arrows to indicate electron flow, show the mechanism by which this cleavage occurs. 

The Claisen reaction is a carbonyl condensation that occurs between two ester molecules and gives a /3-keto ester product. Mixed Claisen condensations... 

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. 

The scope of the reaction has been successfully extended to a,p-ethylenic aldehydes,5 esters,6 and amides7 as well as to a,p-acetylenic ketones8 (see Table IV). With esters, the reaction must be performed in the presence of chlorotrimethylsilane (MeaSiCI) to avoid the Claisen reaction by trapping the intermediate enolate. In most cases the organomanganese procedure is simple and more efficient than the organocopper procedure. 

The Claisen reaction (sometimes Claisen condensation) is formally the base-catalysed reaction between two molecules of ester to give a P-ketoester. Thus, from two molecules of ethyl acetate the product is ethyl acetoacetate. 

The Claisen reaction may be visualized as initial formation of an enolate anion from one molecule of ester, followed by nucleophilic attack of this species on to the carbonyl group of a second molecule. The addition anion then loses ethoxide as leaving group, with reformation of the carbonyl group. 

However, the reaction is not quite that simple, and to understand and utilize the Claisen reaction we have to consider pAT values again. Loss of ethoxide from the addition anion is not really favourable, since ethoxide is not a particularly good leaving group. This is because ethoxide is a strong base, the conjugate base of a weak acid (see Section 6.1.4). So far then, the reaction will be reversible. What makes it actually proceed further is the fact that ethoxide is a strong base, and able to ionize acids. The ethyl acetoacetate prodnct is a 1,3-dicarbonyl componnd and has relatively acidic protons on the methylene between the two carbonyls (see Section 10.1). With... 

The driving force for the Claisen reaction is formation of the enolate anion of the f3-ketoester product. If... 

This means that a reverse Claisen reaction can occur if a P-ketoester is treated with base. This is most likely to occur if we attempt to hydrolyse the P-ketoester to give a P-ketoacid using aqueous base. Note that the alcoholic base used for the Claisen reaction does not affect the ester group. 

In Box 10.12 we saw that nature employs a Claisen reaction between two molecules of acetyl-CoA to form acetoacetyl-CoA as the first step in the biosynthesis of mevalonic acid and subsequenfiy cholesterol. This was a direct analogy for the Claisen reaction between two molecules of ethyl acetate. In fact, in nature, the formation of acetoacetyl-CoA by this particular reaction using the enolate anion from acetyl-CoA is pretty rare. 

Therefore, we could consider using the Claisen reaction in fatty acid synthesis. 

The Claisen reaction can now proceed smoothly, but nature introduces another little twist. The carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation. Accordingly, we now see that the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base (see Box 10.17). 

In this case, we formulate the Claisen reaction between two ester molecules as enolate anion formation, nucleophilic attack, then loss of the leaving group. Now reverse it. Use hydroxide as the nucleophile to attack the ketone carbonyl, then expel the enolate anion as the leaving group. All that remains is protonation of the enolate anion, and base hydrolysis of its ester function. 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

Other interesting examples of asymmetric syntheses involving chiral monoterpenoids include the Claisen reaction between (—)-menthyl phenylacetate and benz-aldehyde (optical purity is confirmed by microcalorimetry), a highly enan-tioselective carbenoid cyclopropanation catalysed by (4), ° and the crossed aldol... 

Many continuous processes are used to prepare early pharmaceutical intermediates, but Pfizer recently presented a continuous process to prepare the API itself. A continuous process to prepare the anti-inflammatory drug celecoxib was described (Scheme 11.3) [6]. The batch process for celecoxib consists of two steps (1) a base-mediated Claisen reaction between 4-methylacetophenone and ethyl trifluoroacetate, and (2) an acid-mediated pyrazole condensation between enolate intermediate 8 and hydrazine 9 giving celecoxib (Scheme 11.4) [7]. Continuously flowing the Claisen reaction step 1 into the pyrazole condensation step 2 offers the advantages of directly telescoping continuous processing steps, as described in the introduction to this chapter. 

For example, the Claisen reaction is a reaction of an ester enolate with an ester to produce a /3 ketoester. We learned this reaction earlier. 

A further example of the above reaction type is provided by the condensation between an aromatic aldehyde and an ester (the Claisen reaction, e.g. the synthesis of ethyl cinnamate, Expt 6.137), which requires a more powerfully basic catalyst (e.g. sodium ethoxide) to effect conversion of the ester into the corresponding anion. 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

By analogy with the Cope reaction, can we predict substituent effects on the Claisen reaction ... 

A donor substituent at position 4 or 6 will favor the reaction and an attractor similarly placed will hinder it. Conversely, an attractor (donor) at position 1 stabilizes (destabilizes) the enolate fragment. As atoms 2 and 5 bear no charge, the electronic character of the substituent has little consequence. By analogy with the Cope reaction, we expect that a substituent at these positions also accelerates the Claisen reaction. 

More precisely, the Claisen reaction comprises a replacement of a C=C double bond (energy = 146-151 kcal mol-1, according to Smith M. B., March J., March s Advanced Organic Chemistry, 5th ed., John Wiley Sons, Inc., New York, 2001, p. 24) by a C=0 double bond (173-181 kcal moL1) and of two C-O bonds (85-91 kcal moL1) by two C-C bonds (83-85 kcal mol-1). Therefore, it should be exothermic by 20 kcal mol-1. 

The Claisen reaction can be catalyzed by palladium 328 thus, the [3,3]-sigmatropic rearrangement of a bulky allylsilane derivative 12 proceeds with high selectivity (Scheme 26.11).329-331... 

The Claisen reaction involves the condensation or linking of two ester molecules to form a 3-ketoester (Fig.T). This reaction can be considered as the ester equivalent of the Aldol reaction The reaction involves the formation of an enolate ion from one ester molecule which then undergoes nucleophilic substitution with a second ester molecule (Fig.U, Step 1). 

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