Keto carboxylic acids, reaction

Similar sulfenylation reactions of the 2-subsdtuted cyclic enamines of -keto carboxylic acid anilides are also possible, The trifluoromethanesulfenyl substitution takes place according to ring size Sulfenylation occurs at positions 2 and 5 with five-membered rings, at posibon 6 with six-membered tings, and at position 7 with seven-membered rings [5J (equation 4) (Table 1). Acid hydrolysis of the enamines proceeds readily to form the corresponding keto compounds. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

Pyruvate is first transported from the cytosol into mitochondria or is generated from alanine within mitochondria by transamination, in which the a-amino group is removed from alanine (leaving pyruvate) and added to an a-keto carboxylic acid (transamination reactions are discussed in detail in Chapter 18). Then pyruvate carboxylase, a mitochondrial enzyme that requires the coenzyme biotin, converts the pyruvate to oxaloacetate (Fig. 14-17) ... 

In another synthesis using a preformed pyridine derivative a cyanoacetic acid ester is condensed in a Guareschi-type reaction with an a-substituted /3-keto carboxylic acid ester and an amine to give a hydroxypyridone (18 Scheme 3). These compounds are suitable precursors for an acid catalyzed cyclization to furo[2,3-6]pyridine-6-ones (19). N-Substituted derivatives may also be prepared by this route (64AP754). The aqueous solutions of these furopyridines show an intensive blue fluorescence. 

The carboxylation of pyruvate supplies a significant portion of the thermodynamic push for the next step in the sequence. This is because the free energy change for decarboxylation of /3-keto carboxylic acids such as oxaloacetate is large and negative. The oxaloacetate formed from pyruvate by carboxylation is converted to phosphoenolpyruvate in a reaction catalyzed by phosphoenolpyruvate carboxyki-nase. In many species, including mammals, this reaction involves a GTP-to-GDP conversion. 

Hetero-Diels-Alder reaction of 44 with enol ether 13 as the dienophile gives cycloadduct 45, which is not isolable but reacts with the water formed in the condensation step with loss of acetone and C02 to lactone 15. A suggested mechanism for the formation of lactone 15 is a retro Diels-Alder reaction which leads to the ketene intermediate 46. Ketene 46 adds to the water formed in the previous condensation step, yielding /3-keto-carboxylic acid 47, which then undergoes decarboxylation to 48. 

A microwave-assisted one-pot approach towards 2,4,5-trisubstituted oxazoles employed a hypervalent iodine (III) catalyst to bring about the reaction of ketones, 1,3-diketones and /3-keto-carboxylic acid derivatives with amides [75]. Microwave dielectric heating was also successfully utilized in a solid-supported, solvent-free synthesis of 2-phenyl-oxazol-5-ones (azlac-tones) [76] as well as in a solution phase synthesis of isomeric 2-phenyl-oxazol-4-ones (oxalactims) [77]. 

Treatment of O-acyl esters (2) with l,l-dichloro-2,2-difluoroethylene provides a,a-difluorocarboxylic acids (37) through photolysis, followed by the hydrolysis of the adducts (36) with AgN03 (eq. 8.17) [53]. Eq. 8.18 shows the preparation of a-keto carboxylic acids (40) from carboxylic acids, by means of the radical addition to ethyl acrylate, oxidation to the sulfoxides by mCPBA, the Pummerer reaction with... 

Fig. 6.26. Acylation of alcohols with an acyl Meldrum s acid (A). The reaction product obtained after in situ decarboxylation is a /l-keto carboxylic acid ester D.

A carbonic acid derivative which, surprisingly, also proves to be suitable for the acylation of ketone enolates, is Stiles reagent, i.e., (methoxymagnesium) monomethyl carbonate. In Section 8.2, you saw how this reagent can be obtained. Ketone enolates are carboxylatedby Stiles reagent to furnish a /3-keto carboxylic acid, as shown by the reaction equation below. As this keto acid is initially obtained as the (methoxymagnesium) carboxylate, such an acylation can easily proceed without the extra equivalents of enolate or base mentioned above. 

The reaction of the /3-keto carboxylic acid resulting from the acidic workup of this carboxy-lation with diazomethane affords the corresponding /3-ketoester (method Figure 2.33). 

One remarkable process is the photochemical synthesis of 3,4-dihydro-2H-l,3-oxazin-4-ones from a-sulfonyloxy-(3-keto amides (obtained by coupling of P-keto-carboxylic acids with amines, followed by treatment with an iodanyl mesylate). This allows the regioselective oxidation of less-activated C—H bonds and a C—O bond formation which is unusual for a Norrish-Yang reaction [69]. The formation of a 1,6-0—C biradical has been postulated as an intermediate (Scheme 9.42). 

The first C6-C7-aldol reactions were reported by Nicolaou s group with the dianion of keto-carboxylic acid 5 (Scheme 12). Aldehydes 29a, 29b and 20b give the desired aldols 62, 63 and 66 in high yields ( ) at —78 °C. As expected, excellent control of the enolate configuration had taken place to result in a perfect C6-C7 syn relationship. Nevertheless, there was no or mini-... 

Like /f-keto carboxylic acids 5 undergoes decarboxylation at "high temperatures. As a result 5 is transformed into 18 by setting free CO. Aldehyde 18 reacts with the hydrochloride salt 6 to iminium ion 19. The. subsequent Pictet-Spengler reaction provides tetrahydro-/ -carboline 7. ... 

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

The oxidation of methyl ketones to a-keto carboxylic acids is rare and is accomplished by treatment with a cold solution of potassium permanganate. However, the reaction is not general acetophenone, p-methyl-acetophenone, and 3,4-dimethylacetophenone are oxidized all the way to the corresponding benzoic acids. On the other hand, 2,4-dimethylaceto-phenone, when shaken with approximately 1% aqueous potassium permanganate at room temperature, gives 6 72% yields of 2,4-dimethyl-phenylglyoxylic acid [555, 559],... 

Even after SO years of continuous development carbonylation chemistry has still not achieved its full potential and new reactions are still being discovered, a good recent example being double carbonylation leading to a-keto carboxylic acids, a-keto esters and a-keto amides. ... 

The reaction of a diamine with one terminal keto-function of a triketone, keto-phenol or keto-carboxylic acid leads to the formation of a SB having available adjacent dissimilar coordination compartments. Condensation at the central carbonyl was not observed. 

For the perfluorooctyl substituent, the reaction yields 60% of the acid (tcrt-butanol, H20, Ca(OH)2, 120°C, 50-bar CO, 24 hr, CT 75) (319a). Alkyl halides react with carbon monoxide and aqueous lithium hydroxide to give carboxylic acids and a-keto carboxylic acids according to... 

Pudovik, A.N., Samitov, Y.Y., Gur yanova, I.V, and Banderova, L.V., Reaction of phosphonic and phosphinic acid esters with the nitriles of a-keto carboxylic acids, Khim. Org. Soedin. Eosfora., Akad. Nauk SSSR, 45, 1967 Chem. Abstr., 69, 67489j, 1968. 

Anions of type (4), for example (7), react with carbon dioxide at —70° to give 1,3-dithianes of a-keto carboxylic acids (11) in 70-75% yield. The reaction of carboxylic acid derivatives is more complex, but the reaction with nitriles to give 1,3-dithianes of 1,2-diketones such as (12) usually proceeds without complication.4... 

Synthesis of fi-lactones. Dichloroketene (generated in situ from dichloroacetyl chloride and triethylamine) reacts with aliphatic and aromatic aldehydes in ether at low temperatures (<20°) to give a,a-dichloro-/3-lactones.4 Esters of a-keto-carboxylic acids also undergo the reaction. 

This alcoholysis of carboxylic esters under the influence of alkaline catalysts is important for the preparation of esters of long-chain alcohols with heat-sensitive carboxylic acids, e.g., with /ff-keto carboxylic acids,858-864 and of esters of acid-sensitive alcohols860-863 that cannot be subjected to the usual methods of esterification. For such reactions sodium alkoxides,853 sodium hydroxide,854 855 and potassium carbonate856 have proved useful as catalysts. 

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