Ethyl acetoacetates

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

This Reaction should be carefully distinguished from the Claisen Conden-tation, which is the condensation of an ester, under the influence of sodium ethoxide, with (i) another ester, (ii) a ketone, or (iii) a nitrile, with the elimination of alcohol. For details of this condensation, see Ethyl Acetoacetate, p. 264. 

Ethyl acetoacetate is a tautomeric substance which at room temperature exists as an equilibrium mixture of the keto and enol forms, the latter form being present to the extent of about 7%. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

The ethyl acetoacetate obtained as above is sufficiently pure for most purposes it should, however, be refractionated under reduced pressure if a sample of specially high purity is required. 

Ethyl acetoacetate is a colourless liquid, d, i 03, slightly soluble in water, but almost insoluble in brine. It has a faint but pleasant odour. It is widely used in chemical syntheses. 

Note. To obtain satisfactory results with tests (2) and (3), pure redistilled ethyl acetoacetate should be used. 

Synthetic use of Ethyl Acetoacetate, In view of the great importance of the ester in synthetic work, the following practical points concerning its use should be borne in mind. 

Mono and Di-iubstitution Derivatives. The enolic sodium derivative of ethyl acetoacetate (E) is prepared by mixing ethanolic solutions of the ester and of sodium ethoxide. It should not be prepared by the direct action of metallic sodium on the ester, as the reaction is slow and the nascent hydrogen evolved reduces some of the ester to ethyl p4iydroxy- butyrate, CH3CH(OH)CHjCOOEt. 

Hydrolysis. Ethyl acetoacetate when treated w ith cold dilute sodium hydroxide solution gives the sodium salt of acetoacetic acid. This acid is unstable, and readily breaks down into acetone and carbon dioxide it is of considerable... 

In brief, suitable hydrolysis of ethyl acetoacetate derivatives will give mono-or di-alkyl substituted acetones or acetic acids. Tri-substituted acetones or acetic acids cannot be obtained moreover, the di-substituted acetones must... 

For other examples of the synthetic application of ethyl acetoacetate, see below and pp. 293 295. 

The preparation of methyl-phenyl-pyrazolone illustrates one of the synthetic uses of ethyl acetoacetate, as distinct from those involving the hydrolysis of substitution derivatives. 

If ethyl acetoacetate is warmed with an equivalent quantity of phenyl hydrazine, the corresponding phenylhydrazone (A) is readily formed. On... 

Mix 6 2 ml. (6 4 g.) of pure ethyl acetoacetate and 5 ml. of pure phenylhydrazine in an evaporating-basin of about 75 ml. capacity, add 0 5 ml. of acetic acid and then heat the mixture on a briskly boiling water-bath (preferably in a fume-cupboard) for I hour, occasionally stirring the mixture with a short glass rod. Then allow the heavy yellow syrup to cool somewhat, add 30-40 ml. of ether, and stir the mixture vigorously the syrup may now dissolve and the solution shortly afterwards deposit the crystalline pyrazolone, or at lower temperatures the syrup may solidify directly. Note. If the laboratory has been inoculated by previous preparations, the syrup may solidify whilst still on the water-bath in this case the solid product when cold must be chipped out of the basin, and ground in a mortar with the ether.) Now filter the product at the pump, and wash the solid material thoroughly with ether. Recrystallise the product from a small quantity of a mixture of equal volumes of water and ethanol. The methyl-phenyl-pyrazolone is obtained... 

Ethyl malonate, like ethyl acetoacetate, exists as a tautomeric mixture of keto and enol forms, although in the case of ethyl malonate... 

Precisely similar results are obtained with ethyl acetoacetate, except that in tests 2 a) and 2 b) the deep red coloration is produced without a preliminary violet coloration. 

Substitution Derivatives of Ethyl Malonate, Ethyl malonate resembles ethyl acetoacetate in that it gives rise to mono- and di-substituted derivatives in precisely similar circumstances. Thus when ethanolic solutions of ethyl malonate and of sodium ethoxide are mixed, the sodium derivative (A) of the enol form is produced in solution. On boiling this solution with an alkyl halide, e.g, methyl iodide, the methyl derivative (B) of the keto form is obtained. When this is treated again in ethanolic solution with sodium ethoxide, the... 

It follows therefore that ethyl malonate can be used (just as ethyl aceto- acetate) to prepare any mono or di-substituted acetic acid the limitations are identical, namely the substituents must necessarily be alkyl groups (or aryl-alkyl groups such as CjHjCHj), and tri-substituted acetic acids cannot be prepared. Ethyl malonate undergoes no reaction equivalent to the ketonic hydrolysis of ethyl acetoacetate, and the concentration of the alkali used for the hydrolysis is therefore not important. 

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

Since Grignard reagents can easily be obtained from aryl halides, they are of special value in the s nthesis of many aromatic compounds, particularly as, for reasons already stated (pp. 270, 276), aromatic compounds cannot generally be prepared by means of ethyl acetoacetate and ethyl malonate. 

In the present preparation, ethyl acetoacetate is treated with sufficient nitrous acid to convert half into the a-nitroso (or a-oximino) ester, which is reduced by zinc and acetic acid to the a-amino ester (I). The latter then condenses with... 

Required Ethyl acetoacetate, 20 g. sodium nitrite, 5 4 g. zinc dust, 11 g. glacial acetic acid, 60 ml. 

Fit a three necked 250 ml. flask with a central rubber-sleeved or mercury-sealed stirrer, c/. Fig. 23(c), p. 45, where only two necks are shown, and with a thermometer the bulb of which reaches as near the bottom of the flask as the stirrer allows the third neck will carry at first a dropping-funnel and later a reflux condenser. Place 20 g. (19-5 ml.) of ethyl acetoacetate and 45 ml. of glacial acetic acid in the flask and by ice-water cooling adjust the temperature of the stirred mixture to 5 -7° maintain this temperature whilst adding a solution of 5 4 g. of sodium nitrite in 8 ml. of water slowly from the dropping-funnel during 15 minutes. Continue the stirring for 20-30 minutes, and then... 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Required Ethyl acetoacetate, 32 g. (32 ml.) acetaldehyde-ammonia, lO g. Note. The aldehyde-ammonia should preferably be fresh material the quantity should be increased to 15 g. if an old sample, which has formed brown sticky lumps, is employed.)... 

Gently warm a mixture of 32 g. (32 ml.) of ethyl acetoacetate and 10 g. of aldehyde-ammonia in a 400 ml. beaker by direct heating on a gauze, stirring the mixture carefully with a thermometer. As soon as the reaction starts, remove the heating, and replace it when the reaction slackens, but do not allow the temperature of the mixture to exceed 100-no the reaction is rapidly completed. Add to the mixture about twice its volume of 2A -hydrochloric acid, and stir the mass until the deposit either becomes solid or forms a thick paste, according to the quality of the aldehyde-ammonia employed. Decant the aqueous acid layer, repeat the extraction of the deposit with more acid, and again decant the acid, or filter off the deposit if it is solid. Transfer the deposit to a conical flask and recrystallise it twice from ethanol (or methylated spirit) diluted with an equal volume of water. The i,4-dihydro-collidine-3,5-dicarboxylic diethyl ester (I) is obtained as colourless crystals, m.p. 130-131°. Yield 12 5 g,... 

For the preparation of 4-substituted coumarins, a phenol may be condensed with ethyl acetoacetate under the influence of sulphuric acid. Thus resorcinol (II) readily undergoes this condensation (which is represented diagrammatically above) to give 7-hydroxy-4-methyl-coumarin (III). Note that the coumarins, like all 2 pyrones, are systematically lactones. 

Successful results have been obtained (Renfrew and Chaney, 1946) with ethyl formate methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and iso-amyl acetat ethyleneglycol diacetate ethyl monochloro- and trichloro-acetates methyl, n-propyl, n-octyl and n-dodecyl propionates ethyl butyrate n-butyl and n-amyl valerates ethyl laurate ethyl lactate ethyl acetoacetate diethyl carbonate dimethyl and diethyl oxalates diethyl malonate diethyl adipate di-n-butyl tartrate ethyl phenylacetate methyl and ethyl benzoates methyl and ethyl salicylates diethyl and di-n-butyl phthalates. The method fails for vinyl acetate, ieri.-butyl acetate, n-octadecyl propionate, ethyl and >i-butyl stearate, phenyl, benzyl- and guaicol-acetate, methyl and ethyl cinnamate, diethyl sulphate and ethyl p-aminobenzoate. 

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