Organic synthesis acetoacetic-ester

Anions of (3-keto esters are said to be synthetically equivalent to the enolates of ketones. The anion of ethyl acetoacetate is synthetically equivalent to the enolate of acetone, for example. The use of synthetically equivalent groups is a common tactic in synthetic organic chemistry. One of the skills that characterize the most creative practitioners of organic synthesis is an ability to recognize situations in which otherwise difficult transfonnations can be achieved through the use of synthetically equivalent reagents. 

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) ... 

Some of the best-known examples of decarboxylation in organic chemistry include the conversion of 3-ketoacids to ketones in the acetoacetic ester synthesis and the conversion of malonate derivatives to substituted carboxylic... 

Microwave-assisted organic synthesis may also be used for carrying out the multicomponent reactions of ketones and 1,2-diamines [20, 21, 92, 100]. For example, the three-component reaction of o-PDA 1 with acetoacetic acid ethyl ester 83 and a series of aromatic and heteroaromatic aldehydes 84 proceeds under microwave irradiation with very high yields of diazepines 85 (up to 95%) [100]. Reaction of 2 equiv of cyclohexanone 86 with o-PDA 1 was also realized in a microwave field on a basic alumina surface in 4 min [92] (Scheme 4.27). 

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. 

The Af -Mbv amino acid derivatives are used as potassium l or DCHA salts,the latter being less hygroscopic and more stable, crystalline compounds soluble in organic solvents. N-Enamine derivatives have also been used for intermediate protection in the synthesis of esters, whereby best results were obtained with the methyl or ethyl acetoacetate derived enamines.f 1... 

Of the very many alkylation methods that have been developed, we can look at only a few first, two classics of organic synthesis, the malonic ester synthesis and the acetoacetic ester synthesis and then, several newer methods. In doing this we shall be concerned not only with learning a bit more about how to make new molecules from old ones, but also with seeing the variety of ways in which carbanion chemistry is involved. 

The ordinary yeast used by bakers in their bread making is a valuable organism for the enantioselective reduction of unsymmetrical ketones.2 It is particularly efficient at the reduction of P-keto-esters such as ethyl acetoacetate 1. An Organic Synthesis procedure3 reveals that the true reagent is sucrose, which provides just one H atom, that plenty of yeast is required, and that 3-4 days are needed to make 20-30 g product 2 in only 85% ee. 

Two specific j8-dicarbonyl compounds have had broad use in organic synthesis. These are acetoacetic ester (ethyl acetoacetate, ethyl 3-oxobutanoate), which can be used to make substituted acetone derivatives, and diethyl malonate (diethyl 1,3-propanedicarboxylic acid), which can be used to make substituted acetic acid derivatives. We shall consider syntheses involving ethyl acetoacetate and diethyl malonate in the upcoming sections of this chapter. 

The alkyl esters of 3-hydroxybutanoic acid are a particularly useful group of compounds in organic synthesis because they are available in both chiral forms. Ethyl (5)-3-hydroxybutanoate, for example, may be prepared by the reduction of ethyl acetoacetate on the re side of the keto group with fermenting yeast and leads to an enantiomeric purity of about 85% which may be enriched further via a crystalline dinitrobenzoate. Synthesis of the R form was a little more difficult but could be achieved with 83-88% purity by the reduction of the acetoacetate with hydrogen in the presence of Raney nickel which had been treated with tartaric acid. " ... 

The synthesis of cyclobutanecarboxylic acid given in Section 18.7 was first carried out by William Perkin, Jr., in 1883, and it represented one of the first syntheses of an organic compound with a ring smaller than six carbon atoms. (There was a general feeling at the time that such compounds would be too unstable to exist.) Earlier in 1883, Perkin reported what he mistakenly believed to be a cyclobutane derivative obtained from the reaction of acetoacetic ester and 1,3-dibromopropane. The reaction that Perkin had expected to take place was the following ... 

It is not only the esters of organic acids which combine, in the manner of the ethyl acetoacetate synthesis , with the enolates of ketones and of esters an analogous behaviour is shown by the esters of nitrous and nitric, acids. The process which leads to the formation of isonitroso-and atinitro-compounds yields products fundamentally similar to those already described just as with ethyl acetate the group CO.CHs enters, so here, the NO- and N02-groups are involved, and enolise " exactly as does >O=0 ... 

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