Claisen anionic

Unless the p keto ester can form a stable anion by deprotonation as m step 4 of Figure 21 1 the Claisen condensation product is present m only trace amounts at equi librium Ethyl 2 methylpropanoate for example does not give any of its condensation product under the customary conditions of the Claisen condensation... 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

CLAISEN - IRELAND Rearrangment Rearrangement ol allyl phenyl ethers to o (or p-)allylphenols or of allyl vinyl ethers to y.S-unsaturated aldehydes or ketones (Claisen) Rearrangement ol allyl esters as enolale anions to y.S-unsaturated acids (Ireland)... 

The final step in the /3-oxidation cycle is the cleavage of the /3-ketoacyI-CoA. This reaction, catalyzed by thiolase (also known as j8-ketothiolase), involves the attack of a cysteine thiolate from the enzyme on the /3-carbonyI carbon, followed by cleavage to give the etiolate of acetyl-CoA and an enzyme-thioester intermediate (Figure 24.17). Subsequent attack by the thiol group of a second CoA and departure of the cysteine thiolate yields a new (shorter) acyl-CoA. If the reaction in Figure 24.17 is read in reverse, it is easy to see that it is a Claisen condensation—an attack of the etiolate anion of acetyl-CoA on a thioester. Despite the formation of a second thioester, this reaction has a very favorable A).q, and it drives the three previous reactions of /3-oxidation. 

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. 

Isomerization of vinylaziridines is widely used in organic synthesis. Six types of isomerization of vinylaziridines are shown in Scheme 2.40. Outlined in this section are i) azepine formation by aza-[3,3]-Claisen rearrangement of 1,2-divinyl- or 2,3-divinylaziridines 153 (Section 2.4.1), ii) pyrroline formation from 155 (Section 2.4.2), Hi) aza-[2,3]-Wittig rearrangement of anionic species 157 (Section 2.4.3),... 

As an extension of the reaction of sulphinates with organometallic compounds, the Claisen-type condensation between ketone enolate anions 101 and arenesulphinates may be considered. It was found161,162 that this reaction provides an interesting synthetic approach to a-ketosulphoxides 102 (equation 54 Table 9). 

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. 

C4-insertions by means of a sigmatropic rearrangement process have been described using either a thermal Cope reaction, anionic Claisen amide enolate and zwitterionic aza-Claisen rearrangements. 

Crossed Claisen reactions with two different esters, each of which has a-H atoms, are seldom useful synthetically as there are, of course, four possible products. Crossed Claisen reactions are, however, often useful when one of the two esters has no a-H atoms, e.g. HCOzEt, ArC02Et, (C02Et)2, etc., as this can act only as a carbanion acceptor. Such species are in fact good acceptors, and the side reaction of the self-condensation of the other, e.g. RCH2C02Et, ester is not normally a problem. Intramolecular Claisen reactions, where both C02Et groups are part of the same molecule [e.g. (123)], are referred to as Dieckmann cyclisations. These work best, under simple conditions, for the formation of the anions of 5-, 6- or 7-membered cyclic / -ketoesters... 

The third mechanism starts with addition of the AT-allylamine 103 to the cumulated acceptor system of an allene carbonester 108 (Acc=CHC02Me) to form an intermediate iV-allyl ammonium amide enolate 109 (allene carbonester Claisen rearrangement). The anion stabilizing group is exclusively placed... 

Further information concerning the stereochemical properties of the rearrangement were evaluated by submitting rigid cyclohexane derivatives 254/255 to the reaction conditions. In 1975, House described the allylation of a cyclohexyl cyanide 248 [53]. The initial deprotonation with LDA led to a ketene imine anion 249, which was then treated with allyl bromide. Two potential paths rationalized the outcome an AT-allylation generated the intermediate ketene imines 250/251, which underwent aza-Claisen rearrangement to deliver the nitriles 252/253 alternatively, the direct C-allylation of249 produced the nitriles. 

Thermal rearrangement of (3-ketoesters followed by decarboxylation to yield Y-unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 131). 

The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the category of [3,3J-sigmatropic rearrangements. Since it is a concerted process, the arrow pushing here is only illustrative. Cf. Claisen rearrangement. 

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... 

To participate in this sort of reaction, the carboxylic acid derivative acting as nucleophile must have a-hydrogens in order to generate an enolate anion. In practice, esters are most commonly employed in Claisen-type reactions. 

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. 

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