Acylation of esters

Scheme 2.15. Acylation of Ester Enolates with Acyl Halides, Anhydrides, and Imidazolides... 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

These reactions accomplish the same overall synthetic transformation as the acylation of ester enolates, but use desulfurization rather than decarboxylation to remove the anion-stabilizing group. Dimethyl sulfone can be subjected to similar reaction sequences.232... 

Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2-5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. /V-Mcthoxy-iV-methylamidcs are also useful for acylation of ester enolates. 

Acyl imidazolides have also been used for acylation of ester enolates and nitromethane anion, as illustrated by entries 9 and 10 in Scheme 2.14. 

Other substituents of the glucosaminyl-disaccharide, such as D-glucosamine (in Rhodospirillum tenue, position C), 3. The type (normal, branched) and chain length of fatty acids, and 4. The facultative 3-0-acylation of ester-linked 3-hydroxy fatty acids (position D). Variation of these parameters creates a larger number of related, but not identical, chemical structures, i.js. li pid A structures. (For a more detailed discussion of these structures compare (8,31). 

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). 

B. R. Davis, P. J. Garratt, Acylation of Esters, Ketones and Nitriles, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 2, 795, Pergamon Press, Oxford, 1991. 

Under different reaction conditions, esters still other than the ones shown in Figure 10.53 can be employed for the acylation of ester enolates. In such a case, one completely deprotonates two equivalents of an ester with LDA or a comparable amide base and then adds one equivalent of the ester that serves as the acylating agent. The acylation product is a /3-ketoester, and thus a stronger C,H acid than the conjugate acid of the ester enolate employed. Therefore, the initially formed /3-ketoester reacts immediately in an acid/base reaction with the second equivalent of the ester enolate The /3-ketoester protonates this ester enolate and thereby consumes it completely. 

The strong base is necessary in the cyclization because no stable enolate can be formed ftorr. product. In other acylations of esters by esters the product has at least one hydrogen atom or carbon atom between the two carbonyl groups and forms a stable enolate under the reaj conditions. There are several examples in the chapter and the answer to Problem 3 makes a sp. point of this. The strong base is needed to convert one of the esters completely into its enofi i The stereochemical point is that one of the esters becomes an enolate and so lose stereochemistry but the other must be pointing inwards for cycUzation to occur. This can happer reversible formation of the enolate anion. 

The Dieckmann condensation is an intramolecular variant of the Claisen condensation where a diester is converted to a 3-ketoester. Typically, an alkoxide is used as the base to form the enolate which attacks the remaining ester to form the carbocycle. Five- and six-membered rings are formed readily with this method. Reviews (a) Davis, B. R. Garrett, P. J. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 1. Eds. Pergamon Press Oxford, 1991 Vol. 2, Chapter 3.6 Acylation of Esters, Ketones, and Nitriles, pp. 806-829. (b) Schaefer, J. P Bloomfield, J. J. Org. React. 1967,15, 1-203. 

The reactions have been comprehensively reviewed in Organic Reactions-, the acylation of esters in Volume 1 (1942), the acylation of ketones in Volume 8 (1954) and the Dieckmann and Thorpe-Ziegler reactions in Volume 15 (1967). More recent reviews are provided by House and in a book on carbon-carbon bond-forming reactions. Specific examples of many of these reactions are given in Organic-Syntheses . 

Acylation of Esters, Ketones and Nitriles 3.63 THE ACYLATION OF ESTERS... 

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