Ethyl acetoacetate preparation

This preparation was discovered independently by Geuther (1863) and by Frankland and Duppa (1865). The reaction was subsequently investigated in detail and so w idely extended by Claisen that it has become solely a specific example of the more general process known as the Claisen Condensation. Claisen showed that an ester under the influence of sodium ethoxide would not only condense with itself (as in the preparation of ethyl acetoacetate), but also with (i) another ester, (ii) a ketone, if of formula RCHgCOR, (iii) a nitrile, if of formula RCH CN, in each case with the elimination of alcohol. Examples of these modifications are ... 

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. 

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. 

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... 

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. 

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... 

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. 

Ethyl acetoacetate may be prepared by the action of sodium upon dry ethyl acetate and decomposition of the resulting sodio compound with dilute acetic acid. Most samples of ethyl acetate contain some ethyl alcohol and it is usually assumed that sodium ethoxidc is the condensing agent ... 

This is an alternative experiment to the actual preparation of the ester and will give the student practice in conducting a distillation under diminished pressure. Commercial ethyl acetoacetate generally contains inter alia some ethyl acetate and acetic acid these are removed in the following procedure. 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Ethyl acetoacetate may also be subjected to double alkylation Show how you could prepare 3 methyl 2 butanone by double alkylation of ethyl acetoacetate ... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Show how you could prepare each of the following compounds Use the starting material indicated along with ethyl acetoacetate or diethyl malonate and any necessary inorganic reagents Assume also that the customary organic solvents are freely available... 

Acetoacetic ester synthesis (Section 21 6) A synthetic method for the preparation of ketones in which alkylation of the enolate of ethyl acetoacetate... 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Ethyl acetoacetate has been prepared from ethyl acetate by the action of sodium/ sodium ethylate/ sodamide/ and calcium. ... 

Ethyl acetoacetate (acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are... 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

Ethyl Acetoacetate. -The e. planation of the manner in which this substance is produced has been given in the account of the preparation. The result was anived at, not by the iscila-tion of the intermediate compound formed by the union of ethyl acetate with sodium ethylate, but by analogy with the behaviour of benzoic methyl ester with sodium benzylate, which gave the same additive product as that obtained by combining benzoic benzyl ester with sodium methylate, showing that such combinations could occur,... 

Bohlmann (207) reported the reaction of /I -dehydroquinolizidine with methyl vinyl ketone and with propargyl aldehyde forming a partially saturated derivative of julolidine 135 and julolidine (136), respectively. Compound 135 can be prepared also by mercuric acetate dehydrogenation of ketone 137, which is formed by condensation of 1-bromoethylquinolizi-dine with ethyl acetoacetate (Scheme 11). 

Syntheses of trisubstituted furans are much less common than the disubstituted derivatives only one 2,4-disubstituted 3-furoate has been prepared using the Feist-Benary reaction. Combination of chloroacetone (4) with ethyl acetoacetate (9) provides ethyl 2,4-dimethyl-3-furoate (28) in 54-57% yield. The procedure for this... 

In 1887, Conrad and Limpach described the condensation of ethyl acetoacetate 5 with aniline 1 to provide enamine 6. Subsequent warming of the mixture provided quinoline 7. Limpach reported several years later that the yield of the cyclization step was improved when an inert solvent (e.g., mineral oil) was employed. While the cyclization step was normally quite facile at 240-280 °C, the physical properties and the methods described for the preparation of enamino-esters were inconsistent. 

Hydroxy-2-methyl-4//-pyrido[l,2-n]pyrimidin-4-one was prepared in the reaction of 2-amino-3-benzyloxypyridine and ethyl acetoacetate at 60 °C, then at 100 °C for 3 h in 22% yield (96MIP1). Reaction of 2-amino-3-hydroxypyridine and ethyl 2-methylacetoacetate in a 1 2 mixture of... 

The only known derivative of this class was prepared from ethyl 8-anilinecrotonate, ethyl acetoacetate, and benzaldehyde. In the first instance, a pyrimidine derivative is formed, this is then subjected to partial hydrolysis to form the 3,4-dihydro-l,3-2H-oxazine derivative (42). 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding P-aminocrotonate 32. The aldehyde (34) required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to isradipine (35) [9]. The same aldehyde with ethyl acetoacetate and the P-aminocrotonate from ethyl acetoacetate gives darodipine (36) [10]. In much the same vein, condensation of the ben-zaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords riodipine (38) [11]. 

The 3-o-ch orophenvl-5-methvlisoxa2ole4-carboxylic acid, from which the acid chloride was prepared, was obtained by hydrolysis of the ester product of the reaction between o-chloro-benzohydroxamic chlorideand ethyl acetoacetate in methanolic sodium methoxide. Reaction with thionyl chloride gave the starting material. 

Al Preparation of 7-Hydroxy-4,8-Dimethy/coumarin Chilled ethyl acetoacetate (157 ml, 1.20 mols) followed by 2-methyl-resorcinol (130 g, 1.04 mols) was dissolved in well-stirred concentrated sulfuric acid (600 ml) at such a rate as to keep the temperature below 10°C (ice bath). The stirred solution was allowed to warm gradually and after 3 hours was added to water (ca 8 liters) with mechanical stirring. The product was collected, washed twice with water, and dried at 70° to 80°C until the first sign of darkening. Yield 191.3 g (95.4%). Recrystallization from aqueous ethanol gave 7-hydroxy-4,8-dimethylcoumarin as colorless needles, MP 260.5° to 261°C. In dilute sodium hydroxide, the compound gives a yellow solution which exhibits blue fluorescence. 

The compound known as Ha emmm s ester is prepared by treatment of a mixture of formaldehyde and ethyl acetoacetate with base, followed by acid-catalyzed decarboxylation. 

Pyrimido[5, 4 4,5]pyrazolo[3,2-c][l,2,4]triazine derivatives 1049and 1050 were prepared by treatment of diazo compound 1048, prepared from 1047, with pentane-2,4-dione and ethyl acetoacetate, respectively [92JCS(Pl)239]. 

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