J8-ketoacids

Addition of isocyanates and isothiocyanates, followed by hydrolysis, yields amides, thioamides,274-277 or ureides of j8-ketoacids 82 and 83 are examples of typical intermediates in this reaction. 

Ketenes and derived products. Triethylamine dehydrohalogenates an acid chloride having an a-hydrogen atom to give a ketene isolable as the ketene dimer, which can be converted into a j8-ketoacid or a symmetrical ketone (Sauer An example is the preparation of laurone from lauroyl chloride. An ethereal solution of the acid... 

Retro-aldol and retro-Michael reactions occur under acidic conditions. The mechanisms are the microscopic reverse of the aldol and Michael reactions, as you would expect. One of the most widely used acid-catalyzed retro-aldol reactions is the decarboxylation of j8-ketoacids, malonic acids, and the like. Protonation of a carbonyl group gives a carbocation that undergoes fragmentation to lose CO2 and give the product. Decarboxylation does not proceed under basic conditions because the carboxylate anion is much lower in energy than the enolate product. 

The third looked at a wide range of thermal decarboxylations, and showed that NBT could calculate rate constants over a very wide range of reactivity. The one exception was the decarboxylation of glycine, where the calculated rate constant was too slow. It was suggested that this reaction may proceed by a more elaborate mechanism involving a concerted proton transfer to carbon. Unfortunately we do not yet know how to calculate the rate constant for such a process. Decarboxylations of neutral )8-ketoacids consistently proceeded by way of the zwitterions. This contrasts with decarboxylation of carbonic acid that follows a concerted path. The difference was attributed to the energy of the zwitterions relative to the overall kinetic barrier if the zwitterion is relatively unstable (carbonic acid case), the reaction is concerted to avoid it if the zwitterion is not relatively unstable (j8-ketoacid case), then the reaction is stepwise (Figures 5.6 and 5.7 and Table 5.7). 

Decarboxylation on moderate heating is a unique property of 3-oxocarboxylic acids (j8-ketoacids) and is not observed with other classes of ketoacids. 

Account for the observation that the foUowing j8-ketoacid can be heated for extended periods at temperatures above its melting point without noticeable decarboxylation. 

Recall from Section 18.4C that hydrolysis of an ester in aqueous sodium hydroxide (saponification) followed by acidification of the reaction mixture with aqueous HCl converts an ester to a carboxylic acid. Also recall from Section 17.9 that j8-ketoacids and j8-dicarboxylic adds (substituted malonic acids) readily undergo decarboxylation (lose CO2) when heated. Both the Claisen and Dieckmann condensations yield esters of j8-ketoacids. The following equations illustrate the results of a Claisen condensation followed by hydrolysis of the ester, acidification, and decarboxylation. 

Hydrolysis of the alkylated acetoacetic ester in aqueous NaOH followed by acidification with aqueous HCl (Section 18.4Q gives a j8-ketoacid. 

The same sequence of reactions can be used with other j8-ketoacids, not only ethyl... 

The demonstration that acetyl-CoA is a relatively stable thiolester as well as later reports from Lynen s laboratory showing, (a) that thiolester derivatives of saturated, unsaturated and j8-ketoacids could be differentiated from one another by differences in their ultraviolet absorption spectra, and (b) that acyl-CoA analogs (i.e. thiolesters of A-acetylthioethano-lamine and panthetheine) are catalytically active substrates for sheep liver enzymes, provided the much needed tools for more definitive studies on the role of acyl-CoA derivatives in intermediary metabolism. These studies were facilitated also by the eventual development of reliable methods for the isolation of substrate quantities of CoA of relatively high purity.8... 

There are also reactions in which electrophilic radicals react with relatively nucleophilic alkenes. These reactions are perhaps best represented by a group of procedures in which a radical intermediate is formed by oxidation of the enol of a readily enolized compound. This reaction was initially developed for j8-ketoacids. The method has been extended to -diketones, malonic acids, and cyanoacetic acid. ""... 

Decarboxylation, or loss of CO2, is not a typical reaction of carboxylic acids under ordinary conditions. However, j8-ketoacids are unusually prone to decarboxylation for two reasons. First, the Lewis basic oxygen of the 3-keto function is ideally positioned to bond with the carboxy hydrogen by means of a cyclic six-atom transition state. Second, this transition state has aromatic character (Section 15-3), because three electron pairs shift around the cyclic six-atom array. The species formed in decarboxylation are CO2 and an enol, which tautomerizes rapidly to the final ketone product. 

Furanones have been prepared by treatment of y-ketoacids with acetic anhydride. Furanones have also been formed by hydrolysis and dehydrobromination of j8,y-dibromoacids (B-50MI31200). The furan-3(2//)-one system (164) has been prepared by intramolecular cyclization of the diazoketones (163) (74TL3073). Some natural 3(2//)-furanones are known furaneol (166), occurring in strawberries and pineapples, is obtained by acid or base treatment of the dihydroxydiketone (165) (73JOC123). 

Decarboxylation of /3-Dicarboxylic Acids (Section 17.9B) The mechanism of decarboxylation of a j8-dicarboxylic acid is similar to that for decarboxylation of a jS-ketoacid. 

Steps 1 and 2 bring about a crossed Claisen or Dieckmann condensation to give a 8-ketoester. Steps 3 and 4 bring about hydrolysis of the j8-ketoester to give a 8-ketoacid, and Step 5 brings about decarboxylation to give a ketone. 

The product of Claisen and Dieckmann condensation reactions can be treated with aqueous base (saponification) followed by acidification to convert the j8-ketoester group into a )8-ketoacid that is then heated to cause decarboxylation to give a ketone product and CO2. 

Relatively acidic carbon acids such as malonate esters and )8-ketoesters were the first class of carbanions for which reliable conditions for alkylation were developed. The reason for this was that these carbanions are formed by easily accessible alkoxide ions. The preparation of 2-substituted j8-ketoesters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.4 is useful for the synthesis of ketones and carboxylic acids. Both jS-ketoacids and malonic acids undergo facile decarboxylation ... 

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