Ketones from acetoacetic ester synthesis

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. 

Related and equally important reactions are the acetoacetic ester synthesis and the eyanoaeetie ester synthesis Here too the initial substituted product can be hydrolyzed and decarboxylated, to yield a ketone 11 (i.e. a substituted acetone) from acetoacetic ester 10, and a substituted acetonitrile 14 from eyanoaeetie ester 13 respectively. Furthermore a substituted acetoacetic ester can be cleaved into a substituted acetic ester 12 and acetate by treatment with strong alkali ... 

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 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]). 

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. 

Note that the dehydration of citrate takes place specifically away from the carbon atoms of the acetyl group that added to oxaloacetate in step 1. steps 3-4 Oxidative decarboxylations. Isocitrate, a secondary alcohol, is oxidized by NAD in step 3 to give a ketone, which loses C02 to give -ketoglutarate. Catalyzed by the enzyme isocitrate dehydrogenase, the decarboxylation is a typical reaction of a 0-keto acid, just like that in the acetoacetic ester synthesis (Section 22.8). 

It will be seen from the examples given that by means of the acetoacetic ester synthesis ketones of the structure CH3.CO.CH2R and CH3.CO.CHRR may be prepared. R and R indicate radicals. Acid hydrolysis yields acids of the structure RCH2.-COOH and RR CH.COOH. 

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... 

Wislicenus introduced the use of molecular silver in the synthesis of adipic acid from iodopropionic acid, synthesised hydantoin from cyanic acid and glycocoll, glutaric acid (with L. Limpach), and methyl j8-butyl ketone from methylethylacetoacetic ester. He prepared cyclic ketones of dibasic acids by heating the calcium salts, and discovered vinyl ether and vinylacetic acid. The earlier history of acetoacetic ester has been dealt with (see p. 528) two theories of its structure were proposed that of Frankland and Duppa (1865), who represented it as CH3 CO CH2-COOC2H5, and that of Geuther, who discovered the compound (1863), and represented it at first by a type formula (C = 12, O=8) ... 

The Johnson group also examined a synthesis that relied on the Julia olefin synthesis for construction of the central trisubstituted olefin. In this plan, 1 was to be prepared from an a-haloketone of type 39 via diastereoselective addition of a methyl group to the ketone, followed by a Williamson ether synthesis. Ketone 39 was to be prepared from 40 using an acetoacetic ester synthesis. Compound 40 was to be prepared from 41 using the Julia olefin synthesis. A make-or-break aspect of this plan was the stereochemical course of the Julia synthesis. Of course it was anticipated that the proper stereochemistry would result as will be seen shortly. 

This ketone can be made from ethyl acetoacetate via an acetoacetic ester synthesis, as shown in the following scheme ... 

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 Carroll rearrangement, a variation on the ester Claisen rearrangement, is a useful method for the preparation of y, 8-unsaturated ketones from allyl acetoacetates, and has been adapted to provide a method for the synthesis of a number of specific arylacetones. Thus, treatment of the p-quinol 1 with diketene and a catalytic amount of DMAP at room temperature gave a 72% yield of the arylacetone 2 together with 5% of the benzofuran 3. 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

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