Aryl pyruvates

An alternate route to 90 commenced with the Robinson annelation of the aryl pyruvic acid 97 with methylvinyl ketone followed by dehydration and dissolving metal reduction of the resulting mixture of unsaturated acids to provide the cis-keto acid 98 (Scheme 7) (112b). Transformation of 98 to the rrans-ketal ester 99... 

The reaction also works with an aryl pyruvic acid, but the decarboxylation is more difficult to organize without pyridoxal. 

Very little information is available about the species which react in the further decomposition of ascorbic add. Apparently, both dehydroascorbic acid and 2,3-diketogulonic acid can be oxidized directly, since both oxalylthreonic acid and the same two free acids have been identified. The former would result from oxidative fission of the chain while the lactone ring was intact. Even less is known of the oxidation mechanism. The oxidation occurs with iodine and with acid permanganate (H12) and also with oxygen or peroxide (R23). Recent studies on the similar decomposition of the enols of aryl pyruvates to aryl aldehydes plus oxalic acid identified these reactions as examples of the direct attack... 

Pll. Pitt, B. M., A model for oxygenase reactions. The oxygenolysis of aryl pyruvates to aromatic aldehydes and oxalate. Abstr. Am. Chem. Soc. 138th Meeting pp. 7C-8C (1960). 

The use of the 4tt diene participation of vinylnitroso compounds in Diels-Alder reactions in the preparation of aryl pyruvate oximes,76a c e 8>h amino acids,76a,c 8 y-hydroxynitriles,76ad 8 y-lactones,76dg pyridine N-ox-ides,76f and pyrroles77 is summarized in Scheme 9-III. The intramolecular Diels-Alder reactions of in situ generated and unactivated vinylnitroso compounds have been shown to proceed readily employing electron-rich olefins, and the course of the reaction has been shown to proceed preferentially through an endo transition state [Eq. (36)].79... 

Udine (SAMP) finally gave the aryl pyruvate SAMP-hydrazone and its higher homologue as pale yellow solids in almost quantitative yield [41] (scheme 13). 

In 1991, Pattenden exploited the inherent regioselectivity of nucleophilic additions on P-methoxy maleic anhydrides to prepare gomphidic acid (30) by two different routes (Scheme 1.10) [63]. The first one involves an HWE reaction between phosphonate 80 and aryl pyruvate 81 [63b], and the second one is based on a Reformatsky-type reaction of 77 with zinc enolates derived from aryl acetate 79 [63cj. 

In 1883, Bottinger described the reaction of aniline and pyruvic acid to yield a methylquinolinecarboxylic acid. He found that the compound decarboxylated and resulted in a methylquinoline, but made no effort to determine the position of either the carboxylic acid or methyl group. Four years later, Doebner established the first product as 2-methylquinoline-4-carboxylic acid (8) and the second product as 2- methylquinoline (9). Under the reaction conditions (refluxing ethanol), pyruvic acid partially decarboxylates to provide the required acetaldehyde in situ. By adding other aldehydes at the beginning of the reaction, Doebner found he was able to synthesize a variety of 2-substituted quinolines. While the Doebner reaction is most commonly associated with the preparation of 2-aryl quinolines, in this primary communication Doebner reported the successful use of several alkyl aldehydes in the quinoline synthesis. 

Substitution in position 4 displays a more complex influence. Cyclization of the 4-methyl- and 4-ethyl-thiosemicarbazones of phenylpyruvic acid and of the 4-methylthiosemicarbazone of phenyl-glyoxylic acid (103) was readily achieved (104), whereas it was not possible to cyclize the analogous 4-methyl derivatives of pyruvic and glyoxylic acids. It thus appears that cyclization is hindered by substitution in position 4 and that this unfavorable effect can be partly relieved by the known favorable effect of an aryl or aralkyl group in the a-position. 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Hydralazine 219 is a good precursor for that ring system. Its reactions with pyruvic acid (75JOC2901), arylidene pyruvic acids (81AP1030), and 4-aryl-2-oxo-butanoic acids (87JHC63) gave the respective hydrazones... 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

In some cases a choice of multicomponent or linear protocol for the treatment of pyruvic acids, aminoazole, and aldehydes allows obtaining different heterocycles. For instance, MCR involving 5-aminopyrazoles or sequence pathway via preliminary synthesis of arylidenpyruvic acids led to positional isomers 36 and 37, respectively (Scheme 15) [4, 61, 68]. It is interesting to note that the same strategy applied to 3-amino-l,2,4-triazole or to amino-W-aryl-lH-pyrazole-4-carboxamide reactions gave no effect and the final compound for both the protocols were the same [52, 61, 62]. 

The direction of MCR involving pyruvic acid, aldehyde, and l-aryl substituted l,2,4-triazole-3,5-diamine was different from the directions of all other processes that were discussed earher. It was established [53] that this treatment yielded 3-(5-ammo-lH-l,2,4-triazol-3-ylamino)furan-2(5H)-one 39 instead of triazolopyri-midine carboxylic acids 38 (Scheme 16). 

The immediate precursor of pentachlorothiophenol was assumed to be S-(PCP)Cys. Cysteine C-S lyase enzymes that convert S-aryl and S-alkyl derivatives of cysteine to pyruvate and a thioalcohol have been detected in some plant species (24,. When the... 

More drastic hydrolysis conditions of unsaturated oxazolones 448 leads to further hydrolysis of the intermediate 2-acylamino-2-alkenoic acid 449 and produces the corresponding a-keto acids 450. For example, phenylpyruvic acid " and other aryl(heteroaryl)pyruvic acids of biological interest have been obtained in this manner (Scheme 7.148). 

Since fluoro-carbonyl compounds are such useful and versatile synthetic intermediates, much effort has been devoted to their preparation [124], but only in a few instances has elemental fluorine been used directly. One of the earliest successful direct fluorinations of a simple carbonyl compound was the fluorina-tion of pyruvic acid derivatives which have a high enol content (R = Aryl, Acyl) (Fig. 47) [125] in the solvent being used (mixtures of CF2C1CFC12 and acetonitrile). However, in derivatives where the enol content was low (R = Alkyl), complicated mixtures of products were obtained. 

Hinsburg first reported that various a-dicarbonyl compounds (256) condensed with thiodiglycolic esters in the presence of alcoholic sodium ethoxide to give various substituted thiophene-2,5-dicarboxylic esters (257). R1 and R2 in (256) could be H, OH, alkyl, OR, aryl or carboxyl groups o-quinones will also condense. If the condensation is carried out in aqueous alcohol, as is the case when glyoxal (256 R1 = R2 = H) is used, the thiophene-2,5-dicarboxylic acid is isolated directly. Pyruvic acid gives the half-ester of (257 R1 = Me, R2 = OH). The earlier work has been reviewed (52HC(3)l). 

In presence of a stoichiometric quantity of triethylamine, pyruvic acid was hydrogenated by the complex [Rh(cod)(BPPFOH)]+ in an optical yield of 83% to lactic add (equation 55).278 The same ligand has been used to hydrogenate aryl aminoalkyl ketones with optical yields of up to 89% (equation 56).279... 

A general route to aryl-substituted pyruvic acids (e.g. phenylpyruvic acid, Expt 5.175) is the acid hydrolysis of 2-acetamido-3-arylacrylic acids (19), which are themselves formed by hydrolysis of the corresponding azlactones (18) (cf. Expt 8.21) with water. 

Participation of proton-donors other than hydroxonium ion has been observed, e.g. for phenylglyoxylic (59) and pyruvic (60) acids, for substituted benzaldehydes (61—63), unsaturated acids (49, 64), N-nitros-amines (65), nitrones (66), unsaturated ketones (67), aryl alkyl ketones (68) and various heterocyclic compounds (69, 70). Consecutive dissociation has been observed for maleic and fumaric acids (48), for phthalic acid (50) and for pyridoxal derivatives (71). 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

In cases where the natural amino acid side chains of enzymes are insufficient to carry out a desired reaction, the enzyme frequently uses coenzymes. A coenzyme is bound by the enzyme along with the substrate, and the enzyme catalyses the bimolecular reaction between the coenzyme and the substrate (cf. Section 2.6.3). A simple model for a-amino acid synthesis by transamination was developed by substituting /I-cyclodextrin with pyridoxamine. Pyridoxamine is able to carry out the transformation of a-keto acids to a-amino acids even without the presence of the cyclodextrin, but with the cyclodextrin cavity as well, the enzyme model proves to be more selective and transaminates substrates with aryl rings bound strongly by the cyclodextrin much more rapidly than those having little affinity for the cyclodextrin. Thus (p-le/f-butylphenyl) pyruvic acid and phenylpyruvic acid are transaminated respectively 15 000 and 100 times faster then pyruvic acid itself, to give (p-le/f-butylphenyl) alanine and phenylalanine (Scheme 12.5). 

A three-component condensation of 5-aminotetrazole with pyruvic acid and aromatic aldehydes was developed as a procedure for the synthesis of 5-aryl-5,8-dihydrotetrazolo[l,5- ]pyrimidine-7-carboxylic acids 414 (Equation 75) <2005S2597>. 

Fischer disconnection of the indole 30a (chapter 39) gives methyl pyruvate and an aryl hydrazine that would have to be made from the corresponding diazonium salt that would have to be protected on the other amino group 36. They decided to take a short cut by using the Japp-Klingemann reaction on the same diazonium salt with the easily made acetoacetate 35. 

Some simple dithiolethiones, including the parent (3b) and 5-aryl derivatives, have been isolated from Brassica species, and some Streptomyces strains produce four antibiotics which possess pyrrolo[3,2-c][l,2]dithiole skeletons (174a-d). Some of these have been synthesized (B-66MI43100,77JOC2891). Lipoic acid (29) is a growth factor and an essential component of enzyme systems involved in oxidative decarboxylation of pyruvic and related acids (B-61MI43101). 

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