Claisen self-condensation

Intramolecular cyclization of benzothiazole derivative 698 by a Claisen self-condensation afforded 699 (81JHC1273) (Scheme 120). 

Alkyl a,a-dichloroalkanoates. Alkyl dichloracetates can be metallated in THF—HMPT at -78° with this base. The resulting anion (1) is alkylated by primary alkyl bromides at -40° in high yield. Yields are lower with secondary alkyl bromides owing to decomposition of (1). Note that only fair yields are obtained with methyl a-lithiodichloroacetate because of concomitant Claisen self-condensation. 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

On treatment with alkoxide bases, esters undergo self-condensation to give a p-keto ester and an alcohol. Ethyl acetate, for exanple, undergoes a Claisen condensation on treatment with sodium ethoxide to give a p-keto ester known by its common nane ethyl ace-toacetate (also called acetoacetic ester) ... 

An important group of acylation reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation.216 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl acetate. All of the steps in the mechanism are reversible, and a full equivalent of base is needed to bring the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present and is converted to its conjugate base in the final step. The (3-ketoester product is obtained after neutralization. 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

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... 

An important group of these reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation. 118 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl... 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

An important variation on the Claisen condensation is to use a ketone as the anionic reagent. This often works well because ketones usually are more acidic than simple esters and the base-induced self-condensation of ketones (aldol addition) is thermodynamically unfavorable (Section 17-3C). A typical example is the condensation of cyclohexanone with diethyl ethanedioate (diethyl oxalate) ... 

Synthesis of substituted acetic acids via acetoacetic ester Acetoacetic ester, an ester formed by the self-condensation of ethyl acetate via a Claisen condensation, has the following structure ... 

With stereocontrol mastered, the preparation of 32 was optimized. The efficiency of the Claisen rearrangement strongly depended upon the conditions employed. For example, the amount of base needed to be strictly controlled in that at least two equivalents of base were required. With a single equivalent of base, only self-condensation was observed and further, excess base did not improve the yield. Perhaps the by-products formed early during enolization react further with remaining... 

The Claisen ester condensation and other self-condensations... 

The self-condensation of ethyl acetate, with which we opened this chapter, is the most famous example of the Claisen ester condensation and it works in good yield under convenient conditions. The product (ethyl acetoacetate) is commercially available—and cheap too—so you are unlikely to want to do this particular example. 

If cyclopentanone and base are mixed first, aldol self-condensation of cyclopentanone can occur before ethyl formate is added. If both carbonyl components are mixed together before adding base, the more favorable mixed Claisen condensation occurs with less competition from the aldol self-condensation reaction. 

This is the only Claisen monocondensation product (aldol self-condensation of cyclohexanone also occurs). 

In the presence of a strong base, the a carbon of a carboxylic ester or other acid derivative can condense with the carbonyl carbon of an aldehyde or ketone to give a p-hydroxy ester, ° amide, and so on., which may or may not be dehydrated to the a,p-unsaturated derivative. This reaction is sometimes called the Claisen reaction an rmfortunate usage since that name is more firmly connected to 16-85. Early reactions used hydroxide or an alkoxide base in water or alcohol solvents, where self-condensation was the major process. Under such conditions, the aldehyde or ketone was usually chosen for its lack of an a-proton. Much better control of the reaction was achieved when amide bases in aprotic solvents, such as ether or THE, were used. The reaction of tert-butyl acetate and in hexane... 

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. ° ... 

Direct disconnection of compound C suggests a crossed Claisen ester condensation but, if we —.ove one methyl group first, a great simplification results as we can use a self-condensation. 

X -.".e third case, cyclopentanone has self-condensed and ignored the enone to which it was to add in a conjugate fashion and continue with a Robinson annelation (p. 761). The liiis - - again is to use a specific enolate such as an enamine though the simplest here is a keto-ester can be easily prepared by intramolecular Claisen ester condensation (p. 727). 

Like a crossed aldol condensation (Sec. 21.8), a crossed Claisen condensation is generally feasible only when one of the reactants has no a-hydrogens and thus is incapable of undergoing self-condensation. For example ... 

A feature distinguishing Reformatsky enolates from base-generated enolates is that zinc enolates add to highly hindered as well as to easily enolizable ketones, such as cyclopentanones, thus avoiding formation of condensation products. Moreover, there is no danger of a Claisen-type self-condensation since zinc-enolates do not react with esters but react readily with aldehydes and ketones to furnish aldol-type products. 

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