Claisen condensation examples

Claisen condensation example (source is deprotonated sink), details in Section 10.7.2 ... 

This preparation was discovered independently by Geuther (1863) and by Frankland and Duppa (1865). The reaction was subsequently investigated in detail and so w idely extended by Claisen that it has become solely a specific example of the more general process known as the Claisen Condensation. Claisen showed that an ester under the influence of sodium ethoxide would not only condense with itself (as in the preparation of ethyl acetoacetate), but also with (i) another ester, (ii) a ketone, if of formula RCHgCOR, (iii) a nitrile, if of formula RCH CN, in each case with the elimination of alcohol. Examples of these modifications are ... 

Many other examples of the Claisen Condensation will be found in textbooks of theoretical organic chemistry. 

The preparation of benzoylacctone Is another example of the acylation of a ketone (acetophenone) by ethyl acetate to a p diketone (Claisen condensation compare preceding Section) ... 

The Claisen condensation of an aliphatic ester and a thiazolic ester gives after acidic hydrolysis a thiazolylketone (56). For example, the Claisen condensation of ethyl 4-methyl-5-thiazolecarboxylate with ethyl acetate followed by acid hydrolysis gives methyl 4-methyl-5-thiazolyl ketone in 16% yield. 

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 following equation shows an example of a mixed Claisen condensation m which a benzoate ester is used as the nonenohzable component... 

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 ... 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

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. 

Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a jS-diketone. The reaction works best when the ester component has no a hydrogens and thus can t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. 

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. 

A crossed Claisen condensation employs two different esters. If the esters are A and B, the possible products are AA, AB, BA, and BB. To minimize the complicated mixture of products, one of the reactants must have no a-hydrogen atoms. If this is ester B, then the products would be AA and AB. If the concentration of A is very low, then only a small quantity of AA can form. Figure 15-6 illustrates an example of a crossed Claisen condensation, where the product is of the AB form. 

Very strong bases can be used in other reactions that are similar to the Claisen condensation. In these reactions, carbanions are formed instead of enolates. Figures 15-7, 15-8, and 15-9 show examples of various reactions employing three different strong bases sodium ethoxide, sodium amide, and sodium triphenylmethanide. Sodium hydride, NaH, is a strong base that would also work. Any of these very strong bases could be used in each of the specific reactions. 

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... 

As seen in many of the above examples, acetic anhydride and zinc chloride each make effective condensation catalysts for the free bases, presumably by efficient coordination with the ring nitrogen. The quaternary salts condense readily in the presence of piperidine. Potassium hydroxide, methoxide or piperidinium acetate are suitable for condensations with 2- and 4-methylpyridine AAoxides. For example, the Claisen condensation is effective with these Af-oxides using ethoxide catalyst (Scheme 45) but the reaction fails with the parent picolines unless activated by nitro substitution (69JHC775). 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

Esters are rarely used as electrophiles in Reformatsky reactions. An example was reported by Atkins and coworkers the quinohne ester 89 failed to react with butanoic acid esters in classical Claisen condensation conditions, but was found to smoothly react with f-butyl ester 90 in the presence of zinc in good yield (equation 54)138. 

The acylation of ketones with esters an example of the Claisen condensation is generally effected with a basic reagent, such as sodium ethoxide, sodium, sodamide or sodium hy dride. Thus acetone and ethyl acetate condense in the presence of sodium ethoxide to yield acetylacetone ... 

Both bacteria and plants have separate enzymes that catalyze the individual steps in the biosynthetic sequence (Fig. 17-12). The fatty acyl group grows while attached to the small acyl carrier protein (ACP).54 58 Control of the process is provided, in part, by the existence of isoenzyme forms. For example, in E. coli there are three different P-oxoacyl-ACP synthases. They carry out the transfer of any acyl primer from ACP to the enzyme, decarboxylate malonyl-ACP, and carry out the Claisen condensation (steps b, e, and/in Eq. 17-12)58a e One of the isoenzymes is specialized for the initial elongation of acetyl-ACP and also provides feedback regulation.58c The other two function specifically in synthesis of unsaturated fatty acids. 

A wide variety of reactants and reaction conditions can be used to prepare chromones via a Claisen condensation and the review by Ellis contains a comprehensive list of examples <77HC(31)496). 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

On treatment with alkoxide bases, esters undergo self-condensation to give a (3-keto ester and an alcohol. Ethyl acetate, for example, undergoes a Claisen condensation on treatment with sodium ethoxide to give a (3-keto ester known by its common name ethyl ace-toacetate (also called acetoacetic ester) ... 

Claisen condensations can be carried out between two different esters but, because there are four possible products, mixtures often result. Less difficulty is encountered if one of the esters has no a hydrogen and reacts readily with a carbanion according to Equations 18-11 and 18-12. The reaction then has considerable resemblance to the mixed aldol additions discussed in Section 17-3C. Among the useful esters without a hydrogens, and with the requisite electrophilic reactivity, are those of benzenecarboxyiic, methanoic, ethanedioic, and carbonic acids. Several practical examples of mixed Claisen condensations are shown in Equations 18-14 through 18-16 (all of the products exist to the extent of 10% or so as the enol forms) ... 

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) ... 

In one of the few examples not involving enolate ions, the substitution of Br in o-bromo-benzaldehyde or -acetophenone by "SCHaCChEt ion followed by Claisen condensation of the resulting sulfides, (46) and (47), under the reaction conditions ultimately gave substituted benzo[ft]thiophenes (48) and (49) in... 

A number of other transformations of the CHDTX->CDTXY type have been tabulated 149) most of them involve retention of configuration, with the notable exception of Claisen condensations (vide supra) which all go with inversion. A recent example 160) is the hydroxylation of CH3(CH2)6CHDT to CH3(CH2)6CDTOH by Pseudomonas oleovorans this reaction proceeds with retention of configuration. 

Diketones are synthesized by Claisen condensation of appropriate acetyl methyl ketone and ethyl perfluoroalkyl carboxylate. For example, 4,4/-bis(l",l,/,l//,2//,2",3//,3//-heptafluoro-4//,6//-hexanedion-6"-yl)-chlorosulfo-o-terphenyl (BHHCT) was synthesized from o-terphenyl by three step reactions (scheme 3 (Yuan et al., 1998a, 1998b)). The o-ter-phenyl are acetylated by acetyl chloride with anhydrous aluminum chloride as a Lewis acid and 4,4 -diacetyl-e>-terphcnyl is obtained. Then, the 4,4/-diacetyl-o-terphenyl is reacted with perfluoropropionic acid ethyl ester with sodium methoxide as a base. Finally, 4,4,-bis(l", 1",l//,2,2,3,/,3"-heptafluoro-4//,6"-hexanedion-6//-yl)-o-terphenyl is chloro-sulfonylatcd by chlorosulfonic acid to form BHHCT. 

For another elegant example of an acyclic Claisen condensation being applied in an enantiospecific synthesis of prostaglandin F2a, see G. Stork, T. Takahashi, I. Kawamoto and T. Suzuki, 1978, J. Amer. Chem. Soc., 100, 8272. 

In both these last two examples, a very strong base is used in the form of LDA such that the enolate ion is formed quantitatively (from ethyl acetate and acetone respectively). This avoids the possibility of self-Claisen condensation and limits the reaction to the crossed Claisen condensation. 

---