Claisen condensation and

It was unfortunate that we did not detect any product derived from a diketone in the reaction of w-dimethoxybenzene with tetrafluoroben-zyne. We therefore carried out a reaction of tetrafluorobenzyne with 1,3,5-trimethoxybenzene. The di-enol ether (80) could not be isolated, and after the removal of unreacted 1,3,5-trimethoxybenzene we isolated the phenolic acid (81) in good yield. This compound is undoubtedly formed by the hydrolysis of (80) followed by a retro-Claisen condensation, and aromatisation as shown below. 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

In this reaction, the CH2C12/DMF solvent (9 1) suppresses the undesirable Claisen condensation and increases the yield of 2,2-difluoro-3-hydroxyesters. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which do not undergo the Reformatsky reaction. 

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). 

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

Ace advanced topics — take a closer look at nitrogen compounds, organometallic compounds, the Claisen Condensation and its variations, and biomolecules, such as carbohydrates, lipids, and proteins... 

Lithium amide is used in synthesis of histamine and analgesic drugs. The compound also is used in many organic synthetic reactions including alkylation of ketones and nitriles, Claisen condensation, and in synthesis of antioxidants and acetylenic compounds. 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

These heterocyclic compounds undergo many reactions which are similar to those of the acetone enolate. Thus, Claisen condensation and o-sulfonylation are exemplified by Scheme 57. 

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). 

The conversion of the substituted 1,3-dicarbonyl compound into homophthalic acid is remarkably facile loss of the acetyl group by a retro-Claisen condensation and hydrolysis of the ester group are complete in a few minutes in aqueous sodium hydroxide. The overall synthesis of homophthalic acids from o-bromobenzoic acids occurs in high yield and provides an attractive route. 

F Biological Claisen Condensations and Aldol Additions. Fatty Acid Metabolism... 

The base-induced transfer of the ester acyl group in an o-acylated phenol ester, which leads to a 1,3-diketone. This reaction is related to the Claisen Condensation, and proceeds through the formation of an enolate, followed by intramolecular acyl transfer. 

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. 

Acylations of ester enolates with different esters are called crossed Claisen condensations and are carried out—just like normal Claisen condensations-in the presence of a stoichiometric amount of alkoxide, Na, or NaH. Crossed Claisen condensations can in principle lead to four products. In order that only a single product is formed in a crossed Claisen condensation, the esters employed need to be suitably differentiated one of the esters must be prone to enolate formation, while the other must possess a high propensity to form a tetrahedral intermediate (see example in Figure 13.59). 

Predict the products of Claisen and crossed Claisen condensations, and propose mechanisms. Show how a Claisen condensation constructs the carbon skeleton of a target molecule. 

Unsaturated side-chains are present in the cinnamic acids, some of which occur naturally in the trans form 12. Syntheses of the acids and their esters by the Claisen condensation and the Perkin and Knoevenagel reactions are discussed in Chapter 6. 

The tricyclic pyronolactone, forskolin (29), a polycyclic isoprenoid, has been synthesised by several different approaches (ref.25) from (-ionone, an intermediate actually more easily obtainable from citral and propanone by Claisen condensation and cyclisation rather than from natural sources. 

Cl disappears rapidly in side reactions (Claisen condensation) and the polymerization is prematurely stopped. However, as long as the monomer remains in the reaction medium, the polymerization can be continued by simply adding new amounts of chain initiation. This is a great challenge while using RC for process monitoring since in this way the process becomes a controlled one. 

T. Nakata et al. developed a simple and efficient synthetic approach to prepare (+)-methyl-7-benzoylpederate, a key intermediate toward the synthesis of mycalamides. The key steps were the Evans asymmetric aldol reaction, stereoselective Claisen condensation and the Takai-Nozaki olefination. The diastereoselective Claisen condensation took place between a 5-lactone and the lithium enolate of a glycolate ester. 

Leijonmarck, H. K. E. Studies on the intramolecular Claisen condensation and related reactions. Chem. Commun. 1992, 33 pp. 

III. Claisen condensations, in which -keto carbonyl compounds are formed by the loss of a negative ion from an incipient hemiketal (Claisen condensations, and Dieckmann ring closures). 

In future the aqueous biphasic processes will grow in importance because of the great advantages of this homogeneously catalyzed variant. Dimerizations, telomerizations, hydrocyanations, hydrosilylations, aldolizations, Claisen condensations, and a wide variety of C-C coupling reactions will be objectives above and beyond the currently used syntheses. Only the future will tell what importance asymmetric/enantiomeric conversions, especially hydroformyla-tions, will have here, although initial experience is encouraging. 

The Dieckmann, Thorpe and Thorpe-Ziegler reactions all involve intramolecular cyclization of a stabilized anion to form a cyclic ketone. The Dieckmann reaction is the intramolecular equivalent of the Claisen condensation and yields cyclic 2-alkoxycarbonyl ketones as primary products, whereas the primary products of the Thorpe reaction are 2-cyanoenamines (Scheme 13). Sub quent hydrolysis affords cyclic ketones but the primary products, particularly those from the Dieckmann reaction, have a useful synthetic role (see Section 3.6.3.S.1). 

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