Acetoacetates reacting with alkyl halides

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. 

Acetoacetic ester synthesis is the preparation of substituted acetones, and it s an important method for creating a variety of products. It begins with the reaction of acetoacetic ester (a dicarbonyl) or a similar compound with a strong base to produce a carbanion, which then reacts with alkyl halide, RX. The structure of acetoacetic ester is in Figure 15-10. Figure 15-11 illustrates an example of an acetoacetic ester synthesis and two possible outcomes. Figure 15-12 shows the preparation of 2-heptanone with a 65 percent yield via the acetoacetic ester synthesis. Figure 15-13 presents the preparation of 2-benzylcyclohexanone with a 77 percent yield. 

By the malonic ester and acetoacetic ester we make a-substituted acids and a-substituted ketones. But why not do the job directly 1 Why not convert simple acids (or esters) and ketones into their carbanions, and allow these to react with alkyl halides There are a number of obstacles (a) self-condensation—aldol condensation, for example, of ketones (b) polyalkylation and (c) for unsym-metrical ketones, alkylation at both a-carbons, or at the wrong one. Consider self-condensation. A carbanion can be generated from, say, a simple ketone but competing with attack on an alkyl halide is attack at the carbonyl carbon of another ketone molecule. What is needed is a base-solvent combination that can convert the ketone rapidly and essentially completely into the carbanion before appreciable self-condensation can occur. Steps toward solving this problem have been taken, and there are available methods—so far, of limited applicability— for the direct alkylation of acids and ketones. 

These, in turn, react with alkyl halides and yield substitution-products of acetoacetic ester which contain two alkyl radicals —... 

In this reaction sequence, ethyl acetoacetate is alkylated twice, each time with a different alkyl group. Then, hydrolysis followed by decarboxylation produces a derivative of acetone in which two alkyl groups are positioned at the a position. Why is it necessary to use an acetoacetic ester synthesis instead of simply treating the enolate of acetone with an alkyl halide Wouldn t that be a more direct method for preparing substituted acetones There are two answers to this question (1) Direct alkylation ofenolates is often difficult to achieve in good yields and (2) enolates are not only strong nucleophiles, but they are also strong bases, and as a result, enolates can react with alkyl halides to produce elimination products. 

Treatment of 1,3-dicarbonyl eompounds with two equivalents of strong base ean give a dianion that will react selectively with alkyl halides. For example, ethyl acetoacetate reacts first with NaH to form an enolate, and then with n-BuLi to form a dianion. This then adds t-PrI. 

Glycopyranosyl halides react with ethyl acetoacetate and pentan-2,4-dione under soliddiquid phase-transfer catalytic conditions, using potassium phosphate as the base, providing the C-alkylated derivatives (40-60%) ]94],... 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Acetoacetic ester is converted by sodiunL thexide into the sodioacetoacetic ester, which is then allowed to react with aa alkyl halide to form an alkylaceto-acetic ester (an ethyl alkylacetoacetate), CH3COCHRCOOC2H5 if desired, the alkylation can be repeated to yield a dialkylacetoacetic ester, CH3COCRR COO-C2H5. All alkylations are conducted in absolute alcohol. 

The first step is the deprotonation of acetoacetic ester at the C2 position with one equivalent of base. The resulting enolate is nucleophilic and reacts with the electrophilic alkyl halide in an Sn2 reaction to afford the C2 substituted acetoacetic ester, which can be isolated. The ester is hydrolyzed by treatment with aqueous acid to the corresponding p-keto acid, which is thermally unstable and undergoes decarboxylation via a six-membered transition... 

Acyl chlorides, as well as alkyl halides, react with the sodium derivative of acetoacetic ester as a consequence, ketones and acids which contain acyl radicals can be prepared by means of this synthesis. 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

Similar reactions are also possible with ethyl acetoacetate. The electrophiles that work well are primary and secondary alkyl halides and sulfonates. Tertiary halides do not react well— elimination is the main reaction. Acyl halides and unhindered epoxides also react well. An important aspect of these processes is that carboxylic acids with a carbonyl group at the p-position are readily decarboxylated (Figure 17.38). We will see in later chapters that we are using the ester as an activating group so that we can make the enolate more easily, but we can eliminate it later. Some examples of the use of this process in synthesis are given in Figure 17.39. 

Depending on the respective reaction partner, acetic acid esters can react either as C-H acidic compounds or as acylating agents. Both are illustrated by the self-condensation of ethyl [ 1 acetate in the presence of 0.5 equivalent of sodium ethoxide or triphenymethyl sodium to give ethyl [1,3- C2]acetoacetate (Claisen condensation). In the first case, however, because of the relatively low radiochemical yields (40-45%) obtained by this procedure, it is of minor importance for the preparation of labeled ethyl acetoacetate. The deprotonation of alkyl acetates with LiHMDS followed by acylation with unlabeled or labeled acyl halides to labeled give /3-keto esters is discussed in Section 6.4. Claisen condensation of alkyl [ CJacetates with esters lacking a-hydrogens (i.e. ethyl formate, diethyl oxalate, aromatic/heteroaromatic carboxylic acid esters) proceed unidirectionally and are valuable pathways in the synthesis of ethyl [ C]formyl acetate (521. diethyl [ C]-oxaloacetate (53) and ethyl 3-oxo-3-pyrid-3-yl[2- C]acetate (54). The last example... 

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