Alkylation, acetoacetic ester ketone

This general procedure is effective for the preparation of many types of phenylhydrazones. For example, a substituted diazo compound can be employed.2 Alkylated acetoacetic esters 8 and ethyl benzoylacetate 4 may be used. For the higher homologs, the a-formyl derivatives of ketones may be used in place of ethyl acetoacetate.6 6 Ethyl pyridylacetates may also be substituted for ethyl acetoacetate.7 The products in these cases are the phenylhydrazones of 2-acylpyridines. 

Fig. 13.26. Acetoacetic ester synthesis of methyl ketones I preparation of an alkylated acetoacetic ester.

Ester-substituted ketone enolates are stabilized, and these enolates can be alkylated (acetoacetic ester synthesis). Alkylation is, however, also possible for enolates that are not stabilized. In the case of the stabilized enolates, the alkylated ketones are formed in two or three steps, while the nonstabilized enolates afford the alkylated ketones in one step. However, the preparation of nonstabilized ketone enolates requires more aggressive reagents than the ones employed in the acetoacetic ester synthesis. 

Acetoacetic ester synthesis (Section 21 6) A synthetic method for the preparation of ketones in which alkylation of the enolate of ethyl acetoacetate... 

This reaction sequence is called the acetoacetic ester synthesis. It is a standard procedure for the preparation of ketones from alkyl halides, as the conversion of 1-bromobutane to 2-heptanone illustrates. 

Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons. 

Strategy The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide. 

What alkyl halides would you use to prepare the following ketones by an acetoacetic ester synthesis ... 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Acetoacetic ester synthesis (Section 22.7) The synthesis of a methyl ketone by alkylation of an alkyl halide, followed by hydrolysis and decarboxylation. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

The esters of nitrous acid are characterised by their high velocities of formation and hydrolysis. They are almost instantaneously decomposed by mineral acids and in the method of preparation given this has been taken into account. The slightest excess of hydrochloric acid must be avoided. Advantage is taken of this property of the alkyl nitrites in all cases where it is desired to liberate nitrous acid in organic solvents (in which metallic nitrites are insoluble). Examples addition of N203 to olefines, preparation of solid diazonium salts (p. 286), production of isonitroso-derivatives from ketones by the action of HN02. This synthesis is often also carried out in the manner of the acetoacetic ester synthesis, with ketone, alkyl nitrite, and sodium ethylate the sodium salt of the isonitrosoketone is formed (cf. in this connexion p. 259) ... 

As will be seen in the following section the most widespread use of the alkylation of lactones is that of y-lactones. Clearly the need for a-substitution of y-lactones was present before the advent of Creger s non-nucleophilic base. The most versatile method was the reaction of a-substitutcd malonic or acetoacetic esters with epoxyethane or 2-chloroethanol, followed by hydrolysis and decarboxylation or ketonic cleavage5. Another common approach was the condensation of butyrolactones (y-lactones) with aldehydes and subsequent hydrogenation5,s. It should be mentioned at this point that these older methods still have their merits, especially for large scale production. 

Problem 17.48 Use acetoacetic ester (aae) and any needed alkyl halide or dihalide to prepare (a) CH3C0CH2CH,C0CH, (b) cyclobutyl methyl ketone, (c) CHjCOCHjCHjCHjCOCH, and (d) 1,3-diacetyl-cyclopentane. ... 

Reaction LXVH. (a) Ketonic Hydrolysis of Alkyl Derivatives of Ethyl Acetoacetate. (A., 138, 211.)—This reaction illustrates one of many synthetical uses of acetoacetic ester. When that ester or its mono- or dialkyl derivatives is boiled with dilute aqueous or alcoholic alkalis or baryta water, or sulphuric acid, ketonic hydrolysis occurs, and acetone or its mono- or di-substituted derivatives is formed—... 

Fig. 13.29. Synthesis of complicated ketones in analogy to the acetoacetic ester synthesis II generation of a cyclic ketone. In the first step, the /3-ketoester is alkylated at its activated position. In the second step, the /3-ketoester is treated with Li I . SN2 reaction of the iodide at the methyl group generates the /3-ketocar-boxylate ion as the leaving group. The /3-ketocarboxylate decarboxylates immediately under the reaction conditions (temperature above 100 °C) and yields the enolate of a ketone.

Alkylation of the enolate anion derived from ethyl acetoacetate followed by removal of the ester group is known as the acetoacetic ester synthesis and is an excellent method for the preparation of methyl ketones. The product of an acetoacetic ester synthesis is the same as the product that would be produced by the addition of the same... 

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Decide which synthesis to use. The acetoacetic ester synthesis is used to prepare methyl ketones, and the malonic ester synthesis is used to prepare carboxylic acids. Both syntheses provide a method to add alkyl groups to the a-carbon. Therefore, next identify the group or groups that must be added to the a-carbon. Remember that the a-carbon is the nucleophile, so the groups to be attached must be the electrophile in the Sn2 reaction they must have a leaving group bonded to the carbon to which the new bond is to be formed. 

The acetoacetic ester synthesis produces a methyl ketone with an alkyl group(s) substituted on the a-carbon, whereas the malonic ester synthesis produces a... 

The butylated /3-ketoester C of Figure 10.23 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context the /3-ketoester C is converted into the corresponding /3-ketocarboxylic add via add-catalyzed hydrolysis (Figure 10.24 for the mechanism, see Figure 6.19). This /3-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /3-ketocarboxylic add de-carboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone in general and to phenyl methyl ketone in the specific example shown. In general, alkyl methyl ketones are obtained by such acetoacetic ester syntheses. 

The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones specifically, substituted derivatives of acetone. In the acetoacetic ester synthesis, substituents are added to the enolate ion of ethyl acetoacetate (acetoacetic ester), followed by hydrolysis and decarboxylation to produce an alkylated derivative of acetone. 

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