Acylation of Ester Enolates

What is the effect of the stoichiometric amount of strong base that allows the Claisen condensation to proceed to completion The /3-ketoester C, which occurs in the equilibrium, is an active-methylene compound and rather C,H-acidic. Therefore, its reaction with the alkoxide to form the ester-substituted enolate D occurs with considerable driving force. This driving force is strong enough to render the deprotonation step C — D essentially irreversible. Consequently, the overall condensation also becomes irreversible. In this way, all the substrate is eventually converted into enolate D. The neutral /3-ketoester can be isolated after addition of one equivalent of aqueous acid during workup. 

The use of an ester without acidic a-H atoms ensu res that this ester can act only as the electrophile in a crossed Claisen condensation. Moreover, this nonenolizable ester must be at least 

Accordingly, crossed Claisen condensations occur without any problems if the acylating agent is a better electrophile than the other, nondeprotonated ester. This is the case, for example, if the acylating agent is an oxalic ester (with an electronically activated carboxyl carbon) or a formic ester (the least sterically hindered carboxyl carbon). 

Crossed Claisen condensations can be chemoselective even when the nonenolizable ester is not a better electrophile than the enolizable ester. This can be accomplished by a suitable choice of reaction conditions. The nonenolizable ester is mixed with the base and the enoliz-able ester is added slowly to that mixture. The enolate of the enolizable ester then reacts mostly with the nonenolizable ester for statistical reasons it reacts much less with the noneno-lized form of the enolizable ester, which is present only in rather small concentration. Carbonic acid esters and benzoic acid esters are nonenolizable esters of the kind just described. 

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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. 

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). 

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. 

Acylation of ester enolates with acid halides, anhydrides, and imidazolides... 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

The third procedure illustrated by this preparation involves the reaotion of ketones with trifluoromethanesulfonic anhydride in a solvent such as pentane, methylene chloride, or carbon tetrachloride and in the presence of a base such as pyridine, lutidine, or anhydrous sodium carbonate.7-11,15 This procedure, which presumably involves either acid-catalyzed or base-catalyzed enolization of the ketone followed by acylation of the enol with the acid anhydride, has also been used to prepare other vinyl sulfonate esters such as tosylates12 or methanesulfonates.13... 

Fig. 13.60. Crossed ester condensation via acylation of a quantitatively prepared ester enolate. Three equivalents of ester enolate must be employed because the acylating ester contains a free OH group with an acidic H atom one for the deprotonation of the OH group of the substrate, one for the substitution of the MeO group, and one for the transformation of the C,H-acidic substitution product into an enolate.

The protocol described also can be used for the acylation of ketone enolates with carbonic acid derivatives (Figure 13.62). Especially good acylating agents are cyanocarbonic acid methyl ester (Mander s reagent, Figure 13.62, top) and dialkyl pyrocarbonates (bottom). Usually it is not possible to use dimethyl carbonate for the acylation of ketone enolates because dimethyl carbonate is a weaker electrophile than cyanocarbonic acid methyl ester or diethyl pyrocarbonates. 

Fig. 13.62. Acylation of ketone enolates with carbonic acid derivatives. Especially good acylation reagents are cyanocarbonic acid methyl ester (top) and dialkyl pyrocarbonates (bottom).

Silyl enolates react with acyl cation equivalents to give the C- and/or O-acylated products (Equation (90)).333 Fluoride-catalyzed reaction using acyl fluorides is valuable for O-acylation of silyl enolates derived from aldehydes and ketones.334 CuCl also promotes the 0-acylation with acyl chlorides.335 The CuCl-promoted reaction of ester silyl enolates results in exclusive (7-acylation. Combined use of BiCfl and Znl2 (or Nal) effects catalytic (7-acylation of ketone silyl enolates with acyl chlorides. 

Diketones are also formed by acylation of the enol esters of ketones with anhydrides in the presence of boron trifluoride. ... 

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. 

SYNTHESIS OF p-KETO ESTERS BY C-ACYLATION OF PREFORMED ENOLATES WITH METHYL CYANOFORMATE PREPARATION OF METHYL (1a,4ap,8aa)-2-OXODECAHYDRO-1-NAPHTHOATE... 

TRIFLUORO-2-BUTYNOATE. C-Acylation of an enolate using methyl cyanoformate provides a convenient source of the a-carbometh-oxyoctalone, METHYL (la,4Ap,8Aa)-2-OXO-DECAHYDRO-l-NAPH-THOATE and represents a good example of generating jS-keto esters under mild conditions. The nitrone functionality is featured in a procedure which makes it in a single step from secondary amines and 6-METHYL-2,3,4,5-TETRAHYDROPYRIDINE N-OXIDE is the example described. Finally, the synthesis of phospholes l-PHENYL-2,3,4,5-TETRAMETHYLPHOS-PHOLE is described as an example of the versatility of zirconocene chemistry. 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

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