Decarboxylation of /?-keto acids

In addition to the above-mentioned reactions, metal complexes catalyze decarboxylation of keto acids, hydrolysis of esters of amino acids, hydrolysis of peptides, hydrolysis of Schiff bases, formation of porphyrins, oxidation of thiols, and so on. However, polymer-metal complexes have not yet been applied to these reactions. 

Acyl radicals. Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of -keto acids react selectively at the - or -position to the nitrogen of protonated pyridines, quinolines, pyrazines, and quinoxalines, in yields typically in the range 4070% for example, 4-cyanopyridine gives 2-benzoyl-4-cyanopyridine in 96% yield <2003JHC325>. Similarly, pyridines can be carbamoylated in acid media at C(2)/C(4) (Scheme 53). 

Decarboxylation of carboxymethyl groups. Pyridines with an - or -carboxymethyl group (e.g., 721) undergo easy decarboxylation by a zwitterion mechanism (722 647) somewhat similar to that for the decarboxylation of -keto acids (cf. Section 3.2.3.1.1). Carboxymethylpyridines often decarboxylate spontaneously on formation thus, hydrolysis of 723 gives 724. The corresponding 2- and 4-pyridone and 2- and 4-pyrone acids are somewhat more stable, e.g., 725 decarboxylates at 170C. 3-Pyridineacetic acid shows no pronounced tendency to decarboxylate. 

The thermal decarboxylation of -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. 

Decarboxylation reactions are common in Nature and they are involved in many pathways, including decarboxylation of keto acids, amino acid conversions, and carbohydrate synthesis. Many decarboxylases use cofactors such as metal ions, pyridoxal 5 -phosphate, biotin, and flavin, but a small subset, for example, orotidine 5 -phosphate decarboxylase (ODCase) and methyhnalonyl CoA decarboxylase do not utilize any cofactor. ODCase catalyzes the decarboxylation of orotic acid (shown in Figure 8), and it generates one of the largest rate enhancements known to be produced by any enzyme (rate of the reaction is enhanced by a factor of Several... 

This is the decarboxylation of a (3-keto acid which undergoes smoothly even in the absence of an enzyme. Thus, it can be said that the mother nature utilizes an organic reaction with a low activation energy. The second step of the decarboxylation is the conversion of a-ketoglutaric acid to succinic acid (Fig. 3). This is the same type of reaction as the decarboxylation of pyruvic acid. 

Pyruvic acid is the simplest homologue of the a-keto acid, whose established procedures for synthesis are the dehydrative decarboxylation of tartaric acid and the hydrolysis of acetyl cyanide. On the other hand, vapor-phase contact oxidation of alkyl lactates to corresponding alkyl pyruvates using V2C - and MoOa-baseds mixed oxide catalysts has also been known [1-4]. Recently we found that pyruvic acid is obtained directly from a vapor-phase oxidative-dehydrogenation of lactic acid over iron phosphate catalysts with a P/Fe atomic ratio of 1.2 at a temperature around 230°C [5]. 

Recently, an example of cycloamylose-induced catalysis has been presented which may be attributed, in part, to a favorable conformational effect. The rates of decarboxylation of several unionized /3-keto acids are accelerated approximately six-fold by cycloheptaamylose (Table XV) (Straub and Bender, 1972). Unlike anionic decarboxylations, the rates of acidic decarboxylations are not highly solvent dependent. Relative to water, for example, the rate of decarboxylation of benzoylacetic acid is accelerated by a maximum of 2.5-fold in mixed 2-propanol-water solutions.6 Thus, if it is assumed that 2-propanol-water solutions accurately simulate the properties of the cycloamylose cavity, the observed rate accelerations cannot be attributed solely to a microsolvent effect. Since decarboxylations of unionized /3-keto acids proceed through a cyclic transition state (Scheme X), Straub and Bender suggested that an additional rate acceleration may be derived from preferential inclusion of the cyclic ground state conformer. This process effectively freezes the substrate in a reactive conformation and, in this case, complements the microsolvent effect. 

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

Although metal ions do not catalyze the decarboxylation of monocarboxylic acids in solution, a variety of metal ions catalyze the decarboxylation of oxaloacetic acid anion, leading to the formation of pyruvic acid (27). The metal ions involved were cupric, zinc, magnesium, aluminum, ferric, ferrous, manganous, and cadmium, approximately 10-2 to 10-3 M (27). Of these, the aluminum, ferric, ferrous, and cupric ions were the most efficient sodium, potassium, and silver ions were inactive. This process involves the decarboxylation of a / -keto acid, which undergoes a relatively facile uncatalyzed decarboxylation. However, not every decarboxylation of a / -keto acid is catalyzed by metal ions—only those... 

The mechanism for synthesis of alcohols and aldehydes from amino acids has been discussed in a review by Morgan (1976). Both S. lactis and its malty variant can reversibly form keto acids from the amino acids valine, leucine, isoleucine, methionine, and phenylalanine. However, unlike S. lactis, S. lactis var. maltigenes can decarboxylate these keto acids to form aldehydes and reduce the aldehydes to their corresponding alcohols through the action of alcohol dehydrogenase in the presence of NADH. 

Decarboxylation of pyruvic acid and its isomers, including the enol tautomers and enantiomeric lactone structures, has been investigated at the B3LYP/6-311+- -G(3df, 3pd) level.18 It has been found that a keto form with trans CmethyiCketoCacidOhydroxyi and cis CketoCacidOH, and with one methyl hydrogen in a synperiplanar position with respect to the keto oxygen, is the most stable. 

Synthetic complexes modeling a-keto carboxylate-dependent enzymes have played a key role in furthering our understanding of these enzymes. Several [Fe (L)(a -keto acid)] complexes have been reported as functional models using tetradentate and tridentate ligands. All of the model complexes that react with O2 afford quantitative yields of the decarboxylated a-keto acid, but in only two cases was the active oxidant trapped. Intermolecular olefin epoxidation has been observed in the case of [Fe (Tp )(BF)j complex. This complex reacts with O2 to form a species capable of stereospecific oxidation of cA-stilbene to its oxide as the product. However trans -stilbene is not epoxidized, suggesting that the active oxidant is capable of steric discrimination. 

The reactive intermediate is probably a chelate complex with one carboxylate group and the keto oxygen as ligands. The electron-withdrawing effect of the metal ion in the complex facilitates rupture of the bond between methylene carbon and the free carboxylate group. A similar reaction is the decarboxylation of dimethyloxaloacetic acid catalyzed by the ions Zn2+ and Mn2+ [269]. 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

This vitamin is synthe.sized by most green plants and microorganisms. The precursors are y-ketoisovaleric acid and /S-alanine. The latter originates from the decarboxylation of aspartic acid. y-KetoLsovalcric acid is converted to keto-pantoic acid by Ar.W" -methyIenetetrahydrofolic acid then, on reduction, pantoic acid is formed. Finally, pantoic acid and alanine react by amide formation to form pantothenic acid. 

The decarboxylations described in this section are, with one exception, of keto acids. 

It may not, however be necessary for decarboxylation of the amino acid to occur. A condensation with the amino acid similar to that above wmuld give the same result if decarboxylation occurred after condensation. Similarly an aldehyde component need not be present as such a potential aldehyde, such as a keto or imino acid, also condenses readily (e.g., 334, 337). Again the same product is obtained by subsequent decarboxylation. Transamination is known to occur in plants (e.g., 931) and the occurrence of keto acids is to be expected. Both amino and keto acids could of course be formed from the amino acid by oxidative deamination. 

As an alternative to prior deprotonation of the parent carbonyl compounds, enolates can also be generated in situ from allyl /(-koto carboxylates or allyl enol carbonates by decarboxylation with simultaneous production of a 7i-allylpalladium complex 1-12. A similar utilization of / -keto acids has also been described13. The following diagram illustrates the reaction course for an allyl jS-keto carboxylate. 

Synthesis of / -Keto Acids, Esters, Amides, Imides and Nitriles and Decarboxylation... 

A variety of metal ions have been found to increase markedly the rate of decarboxylation of several jS-keto acids, but to have no effect on the decarboxylation of ketomonocarboxylic acids such as acetoacetic acid. Moreover, only those fl-keto acids having a second carboxylic acid group adjacent to the /3-keto group are affected by the presence of metal ions, e.g., oxaloacetic or oxalosuccinic acids (90, 116, 166, 170, 190, 191, 208). 

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