Ethyl acetoacetate hydrolysis

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... 

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. 

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 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). 

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, IJ5 acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). ... 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

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. 

C2]-Squalene, 80, has been produced71 in the reaction sequence shown in equation 31 which involves alkylation of 3-13C-ethyl acetoacetate with geranyl bromide, followed by hydrolysis, decarboxylation and treatment with triethyl phosphonoacetate and then reduction of the ester 82 with LiAlHr, bromination with CBr4/PPh3 and coupling the farnesyl bromide with Cul/Li-pyrrolidine. Epoxidation of 80 has been effected by... 

In ethyl acetoacetate the methylene group is united to —CO.CH3 and —COOR. Free acetoacetic acid is even much less stable than malonic acid and, on merely warming in solution, decomposes in fundamentally similar fashion, into acetbne and carbon dioxide. Since all synthetic derivatives of ethyl acetoacetate behave in the same way, so that the acetoacetic acids, obtained by hydrolysis of their esters with aqueous mineral acids, decompose spontaneously with loss of carbon dioxide when heated, numerous derivatives of acetone are made available by this synthesis, by what is called Icetonic hydrolysis, e.g. 

Concentrated alkali hydroxide decomposes the acetoacetic acid produced by hydrolysis of the ester in a different manner. The cleavage does not take place between the carboxyl group and the rest of the molecule, but between the latter and the —CO.CH3-group, so that two molecules of acetic acid are produced. This acidic hydrolysis introduces a new variation into the synthesis as a whole. The practical importance of this acid hydrolysis may be illustrated by the same example, the condensation product of ethyl acetoacetate with ethyl chloroacetate. 

Examples of this approach to the synthesis of ketones and carboxylic acids are presented in Scheme 1.6. In these procedures, an ester group is removed by hydrolysis and decarboxylation after the alkylation step. The malonate and acetoacetate carbanions are the synthetic equivalents of the simpler carbanions lacking the ester substituents. In the preparation of 2-heptanone (entries 1, Schemes 1.5 and 1.6), for example, ethyl acetoacetate functions as the synthetic equivalent of acetone. It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.29 In this case, the hydrolysis step is unnecessary, and decarboxylation can be done directly on the alkylation product. 

Active methylene anions also displace the 5-halogen substituent for example, the 5-chloro derivative (152) (X = Cl) reacts with the sodium salt of ethyl acetoacetate to give (90) (R = Et) which is readily hydrolyzed and decarboxylated (Scheme 22) <82M793>. The 5-chloro substituent in (152) (X = Cl) is also readily displaced by the lithium enolate of 3-(methoxycarbonyl)quinuclidine (153) to give (154) which on hydrolysis with sodium hydroxide and then decarboxylation with hydrochloric... 

Methylcoumarins bearing hydroxy and other electron-donating groups can be synthesized from the corresponding phenols by reaction with ethyl acetoacetate in the presence of sulfuric acid. Hydrolysis of the ester group in the product then allows the lactone ring of the coumarin to form (Scheme 5.6). 

To complete the section on the synthesis of 4,4 -bipyridines, we summarize the methods reported for the preparation of some substituted 4,4 -bi-pyridines and 4,4 -bipyridinones. These methods are closely analogous to syntheses already discussed for some of the isomeric bipyridines. Thus the Hantzsch reaction using pyridine-4-aldehyde, ethyl acetoacetate, and ammonia gives 3,5-di(ethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4,4 -bipyridine, which after oxidation, followed by hydrolysis and decarboxylation, afforded 2,6-dimethyl-4,4 -bipyridine. Several related condensations have been reported. Similarly, pyridine-4-aldehyde and excess acetophenone gave l,5-diphenyl-3-(4-pyridyl)pentane-l,5-dione, which with ammonium acetate afforded 2,6-diphenyl-4,4 -bipyridine. Alternatively, 1-phenyl-3-(4-pyridyl)prop-2-enone, A-phenacylpyridinium bromide, and ammonium acetate gave the same diphenyl-4,4 -bipyridine, and extensions of this synthesis have been discribed. Condensation of pyridine-4-aldehyde with malononitrile in the presence of an alcohol and alkaline catalyst produced compounds such as whereas condensations of... 

The products of the addition of one molecule of a nucleophile to a 2-pyrone sometimes were trapped. Thus the reaction of 307a with PhCH2MgBr was reported to give hemiacetal 319 after hydrolysis of the reaction mixture.311 Similarly, a nucleophilic reagent obtained from ethyl acetoacetate by the successive action of sodium hydride in THF and BuLi in hexane reacts with 320 to afford hemiacetal 321 in 20% yield.317... 

The reaction of ethyl acetoacetate with malonyl dichlorides has been used to synthesize a range of substituted 4-hydroxypyran-2-ones (58CB2849). Yields and purity of the products were best using benzene as solvent either without a catalyst or using magnesium acetate in this role. Hydrolysis of the C-5 ester function and subsequent decarboxylation are both feasible. 

Reaction LXVH. (a) Ketonic Hydrolysis of Alkyl Derivatives of Ethyl Acetoacetate. (A., 138, 211.)—This reaction illustrates one of many synthetical uses of acetoacetic ester. When that ester or its mono- or dialkyl derivatives is boiled with dilute aqueous or alcoholic alkalis or baryta water, or sulphuric acid, ketonic hydrolysis occurs, and acetone or its mono- or di-substituted derivatives is formed—... 

Reaction LXVII. (b) Acid Hydrolysis of Alkyl Derivatives of Ethyl Acetoacetate. (B., 19, 227.)—When acetoacetic ester or its mono- or di-alkyl derivatives are refluxed with concentrated aqueous or alcoholic potash, acid hydrolysis occurs and 2 mols. of acetic acid, or 1 mol. of that acid, and 1 mol. of a mono- or di-substituted derivative are obtained. 

This alkaline wash removes traces of ethyl acetoacetate which might form by hydrolysis of unreacted starting material during the preceding acid wash. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Curcumin was synthesized starting from car-bomethoxy feruloyl chloride which, on condensation with ethyl acetoacetate, gave the ester (Lampe, 1910). The ester on hydrolysis and loss of carbomethoxy feruloyl chloride gave the diferuloyl compound. The hydrolysis of this compound released the carboxymethyl and acetyl groups and gave curcumin identical to the natural curcumin (Mayer, 1943). 

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