Acetoacetic acid synthesis

Use a malonic ester synthesis if the product you want is an a-substituted carboxylic acid derivative. Use an acetoacetic acid synthesis if the product you want is an a-substituted methyl ketone. 

In which of the following reactions is an enol, rather than an enolate, the reacting species (a) acetoacetic acid synthesis (b) malonic ester synthesis (c) LDA alkylation (d) Hell-Volhard-Zelinsldi reaction... 

Acetoacetic acid synthesis Synthesis of a. ,. -disubstitutcd methyl ketone by alkylation of a j3-dicarbonyl cotnpound. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

The thermal decarboxylation of p keto acids is the last step in a ketone synthesis known as the acetoacetic ester synthesis The acetoacetic ester synthesis is discussed in Section 21 6... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

In the six-membered series the alkaloids of Punica gr ana turn, isopelletier-ine and methylisopelletierine, have been obtained by treatment of enamines with acetoacetic acid. Isopelletierine (194, R = H) was prepared also by Schopf et al. from d -piperideine (309-311). The reversibility of aldol dimerization (124,131) of enamines has been established by the synthesis of methylisopelletierine (194, R = Me) from dimethyltetrahydroanabasine, accomplished by Lukes and Kovaf (101) (Scheme 19). 

Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons. 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Step 2 of Figure 29.11 Decarboxylation The TPP addition product, which contains an iminium ion j8 to a carboxylate anion, undergoes decarboxylation in much the same way that a jB-keto acid decarboxylates in the acetoacetic ester synthesis (Section 22.7). The C=N+ bond of the pyruvate addition product acts... 

Step 3 of Figure 29.12 Oxidation and Decarboxylation (2K,3S)-lsocitrate, a secondary alcohol, is oxidized by NAD+ in step 3 to give the ketone oxalosuccinate, which loses C02 to givea-ketoglutarate. Catalyzed by isocitrate dehydrogenase, the decarboxylation is a typical reaction of a /3-keto acid, just like that in the acetoacetic ester synthesis (Section 22.7). The enzyme requires a divalent cation as cofactor, presumably to polarize the ketone carbonyl group. 

It is obvious that many carboxylic acids of the formulas RCH2COOH and RR CHCOOH can be synthesized by this method (for some other ways of preparing such acids, see 10-106, 10-108, and 10-109). Another important example is the acetoacetic ester synthesis, in which Z is COOEt and Z is COCH3. In this case the product can be decarboxylated with acid or dilute base (12-38) to give a ketone or cleaved with concentrated base (12-41) to give a carboxylic ester and a salt of acetic acid ... 

Acetic anhydride trifluoroborane, 4 144t Acetoacetic acid arylides, 9 408 Acetoacetoxyethyl methacrylate, 16 242 Acetoacetyl, role in cholesterol synthesis, 5 142... 

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) ... 

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. 

During anaerobic glycolysis in the muscles and erythrocytes, glucose is converted into lactate, releasing protons in the process (see p. 338). The synthesis of the ketone bodies acetoacetic acid and 3-hydroxybutyric acid in the liver (see p. 312) also releases protons. Normally, the amounts formed are small and of little influence on the proton balance. If acids are formed in large amounts, however (e. g., during starvation or in diabetes mellitus see p. 160), they strain the buffer systems and can lead to a reduction in pH (metabolic acidoses lactacidosis or ketoacidosis). 

In several subsequent publications, this promising multicomponent synthetic approach was used for the synthesis of certain types of biologically active heterocyclic compounds. For instance. Boros and co-authors [35] reported application of the three-component heterocyclization between bicyclic aminoazole 2, acetoacetic acid derivatives 3, and aldehyde 4 to obtain compound 5 being aza-analog of known [36] agonist of the calcetonine receptor (Scheme 4). 

Malonic esters have two ester groups, each of which may react as in the acetoacetic ester synthesis due to their similar structure (see the preceding section). The malonic ester synthesis provides a method for preparing a substituted acetic acid. Figure 15-14 shows the structure of one type of malonic ester. Figure 15-15 outlines the basic malonic ester synthesis. May repeat in that figure refers to the reaction with a second molecule of RX (or R X). 

Nicardipine Nicardipine, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methyl-phenylmethyl)-amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different )3-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocycUzation reaction is accomplished by reacting, the methyl ester of 8-aminocrotonic acid with the 2-methyl-2-benzyl-aminoethyl ester of acetoacetic acid [24-27]. 

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. 

PREPARATION OF tert-BUTYL ACETOTHIOACETATE AND USE IN THE SYNTHESIS OF 3-ACETYL-4-HYDROXY-5.5-DIMETHYLFURAN-2(5H)-ONE (Acetoacetic acid, 1-thio-, S-tert-butyl ester)... 

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