Acetoacetic ester, alkylation ketones from

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. 

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) ... 

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 ... 

As in the malonic ester synthesis, you should identify the structural fragments of the target compound. The acetoacetic ester synthesis converts an alkyl halide to a methyl ketone ("substituted acetone"). The methyl ketone component comes from acetoacetic ester the other component comes from a halide. 

The over-all yields (R equals w-C,-Q, -C , and -C ) from the esters vary from 55% to 78%. Certain heterocyclic ketones, namely, 8-acetyl-quinoline and /3-acetylpyridine, have been prepared through a mixed ester condensation. (3) If acetoacetic ester is acylated in the form of its sodium enolate and carefully hydrolyzed, a new /3-keto ester is formed. Alkylation of this keto ester followed by hydrolysis gives ketones of the type RCOCH,R. ... 

The acetoacetic ester synthesis and direct enolate alkylation are two different methods that prepare similar ketones. 2-Butanone, for example, can be synthesized from acetone by direct enolate alkylation with CH3I (Method [1]), or by alkylation of ethyl acetoacetate followed by hydrolysis and decarboxylation (Method [2]). 

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. 

When treated with concentrated alkali, acetoacetic ester is converted into two moles of sodium acetate, (a) Outline all steps in a likely mechanism for this reaction. (Hint See Sec. 21.11 and Problem 5.8, p. 170.) (b) Substituted acetoacetic esters also undergo this reaction. Outline the steps in a general synthetic route from acetoacetic ester to carboxylic acids, (c) Outline the steps in the synthesis of 2-hexanone via acetoacetic ester. What acids will be formed as by-products Outline a procedure for purification of the desired ketone. (Remember that the alkylation is carried out in alcohol that NaBr is formed that aqueous base is used for hydrolysis and that ethyl alcohol is a product of the hydrolysis.)... 

The only difference between the acetoacetic ester synthesis and the malonic ester synthesis is the use of acetoacetic ester rather than malonic ester as the starting material. The difference in starting material causes the product of the acetoacetic ester synthesis to be a methyl ketone rather than a carboxylic acid. The carbonyl group of the methyl ketone and the carbon atoms on either side of it come from acetoacetic ester, and the rest of the ketone comes from the alkyl halide used in the second step of the reaction. 

Aldehyde, Ketone, and Ester Enolates 867 Enolate Regiochemistry 872 The Aldol Condensation 873 Mixed Aldol Condensations 878 Chalcones From the Mulberry Tree to Cancer Chemotherapy 880 The Claisen Condensation 882 Intramolecular Claisen Condensation The Dieckmann Cyclization 884 Mixed Claisen Condensations 885 Acylation of Ketones with Esters 886 Alkylation of Enolates 887 The Acetoacetic Ester Synthesis 889 The Malonic Ester Synthesis 891 Alkylation of Chiral Enolates 893 Enolization and Enol Content 895 a Halogenation of Aldehydes and Ketones 900... 

While the preceding provides perfectly good solutions, the problem requires us to employ methodology from the current chapter. Having ruled out acetoacetic ester chemistry, we have an alternative in the use of acyl anion equivalents, for which we saw examples applied to the synthesis of a-hydroxyketones (Section 23-4). Can simple aldehydes and ketones be prepared with these equivalents as well The answer is yes, by simple alkylation with RX, followed by hydrolysis. Thus,... 

Ketones of great structural variety may therefore be prepared by careful selection of the starting /7-keto ester (cf. Section 5.14.3, p. 736) and the alkyl halides. The standard procedure is illustrated for the preparation of hexan-2-one from ethyl acetoacetate (Expt 5.95), and it may be suitably adapted to the preparation of most alkyl (straight-chain and branched-chain) methyl ketones. 

Vinyllithiums of type 663 (R2 = R3 = H) reacted with primary alkyl bromides, carbonyl compounds, carbon dioxide, DMF, silyl chlorides, stannyl chlorides, disulfides and phenylselenyl bromide142,970-979. Scheme 173 shows the synthesis of dihydrojasmone 669 from the corresponding 1,4-diketone. a-(Phenylsulfanyl)vinyllithium 665, prepared from phenyl vinyl thioether, reacted with hexanal and the corresponding adduct 666 was transformed into its acetoacetate. This ester 667 underwent a Carrol reaction to produce the ketone 668, which was transformed into the cyclopentenone 669 by deprotection either... 

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