Pyrazine-2,3-dicarboxylic acid

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

The electrolytic oxidation of quinoxaline at a copper anode gives pyrazine-2,3-dicarboxylic acid in excellent yield. A similar conversion may be effected with alkaline potassium permanganate, and a list of quinoxaline derivatives which can be oxidized with potassium... 

Quinoxaline Derivatives Which Can Be Oxidized to Pyrazine-2,3-dicarboxylic Acids on a Preparative Scale... 

Stepwise addition of the aniline moieties in analogy to Scheme 7 (Route A) allows the preparation of asymmetrically substituted derivatives.55,56 The use of pyridine-3,4-dicarboxylic acid anhydride similarly results in the formation of mixtures of 5- and 6-azaphthalides.57 Quinoline-2,3-dicarbo-xylic anhydride has also been converted into the corresponding azaphthal-ides in a similar manner.58 Pyrazine-2,3-dicarboxylic acid anhydride yields... 

Pyrazine-2,3-dicarboxylic acid anhydride has also been shown69 to react according to Scheme 8, yielding 4,7-diazaphthalides very similar in... 

Oxidation of methylpyridines in 60-80 % sulphuric acid at a lead dioxide anode leads to the pyridinecarboxylic acid [213]. The sulphuric acid concentration is critical and little of the product is formed in dilute sulphuric acid [214]. In these reactions, electron loss from the n-system is driven by concerted cleavage of a carbon-hydrogen bond in the methyl substituent. This leaves a pyridylmethyl radical, which is then further oxidised to the acid, fhe procedure is run on a technical scale in a divided cell to give the pyridinecarboxylic acid in 80 % yields [215]. Oxida-tionof quinoline under the same conditions leads to pyridine-2,3-dicarboxylic acid [214, 216]. 3-HaIoquino ines afford the 5-halopyridine-2,3-dicarboxylic acid [217]. Quinoxaline is converted to pyrazine-2,3-dicarboxylic acid by oxidation at a copper anode in aqueous sodium hydroxide containing potassium permanganate [218]. 

Pyrazine-2,3-dicarboxylic acid [89-01-0] M 168.1, m 183-185"(dec). Crystd from water. Dried at 100°. 

Pyrazino[2,3-d]pyridazine-5,8-dione (420) can be prepared from pyrazine-2,3-dicarboxylic acid anhydride (419). Condensation of hydrazine with ethyl 5-acylpyridazine-4-carboxylates (421) gives pyridazino[4,5-d]pyridazin-l(2//)-ones (422) (79M365). 

Reaction with pyrazine-2,3-dicarboxylic acid led only to the isolation of a mixed oxidation state complex of stoichiometry AgnAg pyz-2,3-(C02) 2- No stoichiometric product could be isolated with the ligand, pyrazine-2,3,5-tricarboxylic acid. Although a dark brown solid containing Agn was formed after about 10 minutes, longer reaction times led to decomposition of the ligand. 

A combination semiempirical MO and X-ray study of pyrrolo[ 1,2-a]quinoxalines has been conducted [95JHC1317], and X-ray crystal structure reports of 1,2,3,5,6,8a-hexahydro-8,8a-diphenylimidazofl, 2-a]pyrazine [95AX(C)482], adducts of pyrazine-2,3-dicarboxylic acid and... 

The decarboxylation of pyrazine-2,3-dicarboxylic acids may be carried out by heating in vacuo or in glacial acetic acid at 130°-145°,211 or by heating in a solvent of high dielectric constant such as nitrobenzene.212 It is suggested that these solvents promote decarboxylation by zwitterion formation. 

Pyrazinecarboxylic acid has been obtained by selenious acid oxidation in pyridine of methylpyrazine or aqueous permanganate oxidation of ethylpyrazine, in yields of 64 and 48%, respectively.171,218 It has also been obtained in 70% yield by partial decarboxylation of pyrazine-2,3-dicarboxylic acid on heating in vacuo at 210°.219 Aqueous permanganate oxidation of 2,5-distyrylpyrazine gives the 2,5-dicarboxylic acid.220 Pyrazine-2,5-dicarboxylic acid has also been prepared in 45% yield by direct carboxylation of pyrazine with carbon dioxide at 50 atm pressure at 250° for 3 hours in the presence of a potassium carbonate and calcium fluoride catalyst.221 Pyrazine-tricarboxylic acid (57), obtainable in only very poor yields by oxidation of 2,5-dimethyl-3-ethylpyrazine, is prepared in 87% yield by alkaline permanganate oxidation of 2-(D-arabo)tetrahydroxybutyl-quinoxaline (56).222 Decarboxylation of the tricarboxylic acid by... 

The pyrazinecarboxylic acids have properties similar to the pyridinecarboxylic acids and aromatic carboxylic acids in general. The pKa of pyrazine-2-carboxylic acid is 2.92 it is thus considerably stronger than pyridine-2-carboxylic acid (pff0 5.52), and comparable in acidic strength to pyridazine-3-carboxylic acid (pKa 3.0). The pKa values of pyrazine-2,3-dicarboxylic acid are 0.9 and 3.57.231 Pyrazinecarboxylic acids form colored salts with Fe11 ions and they are readily esterified and decarboxylated. 

Reference has already been made to the partial decarboxylation of pyrazinedicarboxylic acids.219 Both pyrazine itself,232 and 2,3-dimethylpyrazine,207 are conveniently prepared by decarboxylation of the appropriate dicarboxylic acids. The decarboxylation of pyrazine-2,3-dicarboxylic acid is carried out by heating in din-butyl phthalate and gives pyrazine in 90% yield. The 2,3-dicarboxylic acid forms an anhydride in the normal way. Pyrolysis of the anhydride at 800°/0.05 mm through a silica tube gives in 80% yield an approximately 1 1 mixture of maleonitrile and fumaronitrile (Scheme 19). 2,3-Dehydropyrazine is thought to be an intermediate in this reaction and a strong peak of m/e 78, corresponding to the dehydropyrazine ion, is observed in the mass spectrum of the anhydride.233... 

The O-carboxyhydroxamic acid, prepared by treatment of pyrazine 2,3-dicarboxylic acid anhydride with hydroxy la mine, gives an O-benzoyl derivative. This forms a sodium salt which is isolated as a methanolate and which on heating in boiling toluene gives a mixture of 24% 3-aminopyrazine 2-carboxylic acid and 55% of the corresponding methyl ester (Scheme 20a).253a... 

Pyrazine-2,3-dicarboxylic acid anhydride (180) serves as the basis for the preparation of a series of pyrrolo[3,4-6]pyrazine derivatives <89JSC233>. Thus, treatment with a series of amino acids yields compounds of the type (181) (Equation (62)). 

Consistent with the photolytic result, radiolysis of solutions of pyrazine gave only 1,4-dihydropyraziniumyl radical (17) in acidic or neutral conditions and no paramagnetic products in alkaline media.196 However, pyrazine-2,3-dicarboxylic acid gave the 1-hydropyrazinyl-2,3-dicarboxylate (63) in strongly alkaline solution.196... 

C6H3BrN408S 6-bromo-2,4-dinitrobenzenediazonium hydrogen 65036-47-7 465.15 40.546 1,2 6363 C6H3N302 pyrazine-2,3-dicarboxylic acid imide 4933-19-1 338.65 28.626 1,2... 

Synthesis of a tetracyclic analog of 294 is also reported from the anhydride of pyrazine-2,3-dicarboxylic acid and a tetralin derivative under Friedel-Crafts conditions (85JCR(S)338). A representative of the o-quinonoid system (296) was prepared from 2,3-dichloro-1,4-naphthoquinone and o-phenyl-enediamine (63JOC1019). 

Figure U.1D. Nicotinamide analogs tested in pellagra or animal models of pellagra. The active compounds include (1,2, 6, 11, 12, 13,15,18, and 20). Compounds active in some models or in pellagrainclude (7,17,21), pyrazine-2,3-dicarboxylic acid, NAD, pyridyl-3-aldehyde,pyridyl-3-carbi-nol, tryptophan, and 3-hydroxyanthranilicacid. The inactive compounds are (3,4,5,8,9,10,14,16, 19), 3-arninopyridine,thiazole-5-carboxylicacid, 2-methylpyridine, 3-methylpyridine, 2,6-dimethyl-pyridine-3,5-dicarboxylic acid, pyridine-3,5-dicarboxylic acid, kynurenine, 3-hydroxykynurenine, and formylkynurenine. This figure is from Ref 33 and is used with permission.

For oxidation of quinoxaline to pyrazine-2,3-dicarboxylic acid, Jones and McLaughlin" took permanganate in 20% excess of the theory, and evidently it was... 

The unidentate carboxylato groups in Na2Cu(0Ac)4(H20) give IR bands at 1607, 1583 cm-1 (vasC02), 1405, 1344 cm 1 (vsC02).369 The IR spectra of Cu(L), Cu(HL)2 and Cu(HL)2(L,)2, where H2L = pyrazine-2,3-dicarboxylic acid, L = 3-pyridylmethanol, show that the carboxylates are unidentate.370 Similar results were obtained for Cu2(3,5-Cl2sal)4.H20 and related species (where sal = salicylate).371... 

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