Keto carboxylic acid derivatives

Various approaches can be used to synthesize pyridines and partially saturated pyridines on insoluble supports. Dihydropyridines can be readily prepared by cyclocondensation of amines with ketones and aldehydes (Hantzsch pyridine synthesis, Figure 15.12). This synthesis proceeds particularly smoothly when using a 3-keto carboxylic acid derivative as the ketone component. This cyclocondensation has been realized on... 

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]. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

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. 

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. 

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. 

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. 

In this section sequences are described in the course of which 7-hydroxy carboxylic acid derivatives are formed and immediately cyclized to 7-lactones. For instance, 7-keto ester (195) is reduced with super hydride to give the dkoxide ester (196) with 7 1 selectivity (equation 73) (1 >6) cannot be isolated, due to the rapid formation of lactone (197). Similarly, cuprates add to 7-aldehydo esters with high selectivity to form tra s-4,5-disubstituted 7-lactones after acidification (equation 74). ... 

Internal alkynes yield carboxylic acids and a-diketones when oxidized with the MTO/H2O2 system [22]. Rearrangement products are observed only for aliphatic alkynes. Terminal alkynes give carboxylic acids, derivatives thereof and a-keto acids as the major products. The yields of these products vary with the solvent used [22]. 

Coppola, G.M., Hardtmann, G.E., and Pfister, O.R., Chemistry of 2//-3,l-bcn/.oxazinc-2,4(l//)-dione (isatoic anhydride). Part 2. Reactions with thiopseudoureas and carbanions, J. Org. Chem., 41, 825,1976. Kabachnik, M.L, Rossiiskaya, P.A., and Shepeleva, E.S., Esters of a-keto phosphonic acids. Part 3. Two types of carboxylic acid derivatives, Izv. Akad. Nauk SSSR, Ser. Khim., 163, 1947 Chem. Abstr, 42, 4132i, 1948. 

Kabachnik, M.L, Rossiiskaya, P.A., and Shepeleva, E.S., Esters of a-keto phosphonic acids. Part 3. Two types of carboxylic acid derivatives, Izv. Akad. Nauk SSSK, Ser. Khim., 163, 1947 Chem. Abstr, 42, 4132i, 1948. 

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... 

A related cyclization process has been reported to give the isoindole carboxylic acid derivative as its hydroxylammonium salt when the keto acid 37 is refluxed in aqueous ethanol with two molar equivalents of hydroxyl-amine.58 A plausible pathway is indicated. 

The carboxylic acids derived from sucrose may find some use in pharmaceutical and agricultural chemistry. The uronic and 2-keto-aldonic acids obtained by hydrolysis of these compounds represent a great industrial... 

Isotetronic acids were readily assembled through an organocatalyzed domino aldol-lactonization reaction starting from a-keto carboxylic acids and aldehydes [5]. As chiral organocatalyst, the proline-derived benzimidazol pyrrolidine 8 was employed, which proved superior to proUne itself Electron-poor aldehydes were both more reactive and selective. Thus, as a typical example, pyruvate was converted into isotetronic acid 10 in 77% yield and 83% ee upon treatment with para-nitrobenzyldehyde (9) and 10mol% 8 (Scheme 8.3). 

Derivatives of this type can usnally be isolated without difficulty, but a further reaction can occur to give a 1,3,2 dioxaphospholane derivative (6.344). This is believed to proceed through an ionised tetrahedral form of the molecule as indicated. Similar type derivatives can be obtained by reacting phosphites with a keto carboxylic acids at low temperatures in polar solvents (6.345). 

---