Ketones from acetoacetate ester

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 ... 

In an exactly similar way acetone (B.P. 56°) can be prepared from acetoacetic ester (see p. 148) methyl propyl ketone (B.P. 102°) from monoethyl acetoacetic ester (see p. 140). The higher ketones may be purified by washing with saturated brine until alcohol is removed they are then, after drying over calcium chloride, fractionated. In all these hydrolyses dilute aqueous or alcoholic potash, or dilute sulphuric acid, may be used in place of baryta water. The yields in these preparations are all of the same order—70%. 

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. 

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. 

Outline s)mtheses of each of the following from acetoacetic ester and any other required reagents (a) rerf-Butyl methyl ketone (c) 2,5-Hexanedione (e) 2-Ethyl-1,3-butanediol... 

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) ... 

Dilute sodium hydroxide was used as a condensing ent by J. G. Schmidt and the method was applied by Claisen and collaborators to the s3mthesis (Claisen reaction) of aromatic ketonic esters, e.g. benzylidene acetone and di-benzylidene acetone from benzaldehyde and acetone. An alternative method was the use of an aromatic aldehyde or ketone with acetoacetic ester in presence of hydrogen chloride. Benzoylacetic ester, CgHgCO CHe-COOCoHs, was obtained by condensing benzoic and acetic esters in presence of sodium ethoxide, and j8-diketones by condensing ketones and acid esters, e.g. acetyl-acetone CHaCO-CHaCOCHg."... 

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) ... 

Another reaction in which the cleavage of a carbon-hydrogen bond is important is the bromination of ketones. In the bromination of ethyl acetoacetate and 2-carboethoxycyclopentanone, it was shown that multivalent cations are catalysts. In the latter reaction, cupric, nickelous, lanthanum, zinc, plumbous, manganous, cadmium, magnesium, and calcium ions were effective (45). One can interpret the effect of the metal ion in terms of its catalysis of the proton transfer from the ester to a base, whether the reaction is carried out in dilute hydrochloric acid solution (acid-catalyzed bromination) or in acetate buffer (base-catalyzed bromination). 

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. 

If the reaction between the enol and the electrophile proceeds extremely fast, the enol tautomer of a carbonyl or carboxyl compound might be consumed completely. The generation of enol becomes the rate-determining step. This situation occurs with the enol titration of ace-toacetic ester, (Figure 12.4). In this process, bromine is added to an equilibrium mixture of the ketone form (B) and the enol form (iso-B) of an acetoacetic ester. Bromine functionalizes the enol form via the intermediacy of the carboxonium ion E to form the bromoacetic ester D. The trick of conducting the enol titration is to capture the enol portion of a known amount of acetoacetic ester by adding exactly the equivalent amount of bromine. From the values for... 

The proper amount of bromine can be determined by a series of identical parallel experiments. Iron(III) chloride is added as an indicator to the equilibrium mixtures consisting of the ketone and the enol form of the acetoacetic ester and various amounts of bromine are added. If too much bromine has been added, the reaction mixture turns brown. If too little bromine has been added, the reaction mixture remians yellow, as the added iron(III) chloride reacts with the enol iso-B extremely fast, hut reversibly to form the yellow octahedral complex C. This way the enol tautomer is made visible. Only if the proper amount of bromine has been identified does the reaction mixture turn colorless—only for a few seconds, of course, until by HBr catalysis enough of the enol form (iso-B) has been regenerated from the ketone form (B) of the acetoacetic ester and complexed to give the yellow C. 

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 ... 

Dimethyl-4-carbethoxy-2-cyclohexen-l-one and 3,5-di-methyl-2-cyclohexen-l-one have always been prepared from acetaldehyde and acetoacetic ester through the Knoevenagel condensation.2 The keto ester has previously been obtained by selective saponification and decarboxylation methods which have involved heating the crude condensation product with water at 140° 2 3 or with sodium ethoxide in alcohol.3 The ketone has been obtained from the same condensation product by prolonged refluxing in 20% sulfuric acid.2-4 6... 

The ester group in the product must be derived from ethyl acetoacetate. The carbon from the ester (now part of the C = C double bond) should be derived from the ketone of ethyl acetoacetate. The stmcture of MVK can be seen in the remaining four carbons. 

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. 

Reaction of 272 with acrylic acid, /9-chlorobutyric acid, /9-diketones, or a,/9-unsaturated ketones gave the expected diazepines, while acetoacetic ester and diketene reacted only at the primary amino group.323 Similarly, 273 was obtained from acetylacetone and 2,3-dimethyl - 7- aminoindole.32 4... 

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. 

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