Pyrazinecarboxylic acids

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). 

CjjHjjOj 35363-65-6) see Dimethisterone methyl pyrazine-2-carboxylate (QH N202 6164-79-0) see Pyrazinamide 5-methyl-2-pyrazinecarboxylic acid (QHfiN202 5521-55-1) see Adpimox Glipizide 5-methylpyrazine-2-carboxylic acid see under 5-methyl-2-pyrazinecarboxylic acid... 

Most pyrazines are thermally stable, but pyrazinecarboxylic acids undergo decarboxylation at high temperature above 200 °C. This reaction is practically utilized for the synthesis of alkyl- or arylpyrazines, pyrazinones, and pyrazinamines from the corresponding pyrazinecarboxylic acids (Section 8.03.7.1). 

The pyrazine ring is stable toward permanganate oxidation, and this explains a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines or benzo-fused quinoxalines. In contrast, alkyl side chains on pyrazines are effectively oxidized by permanganate, selenious acid, selenium dioxide, or dichromate to afford the corresponding carboxylic acids (Section 8.03.7.1). Oxidation of pyrazines with hydrogen peroxide or percarboxylic acids gives pyrazine A -oxides and/or A, A -dioxides (Section 8.03.5.2). 

An interesting report is the hydroxylation of pyrazinecarboxylic acid 38 with biocatalysts <1994SL814>, where all isomers of hydroxypyrazinecarboxylic acids can be prepared by the use of three individual wild-type microorganisms in whole-cell biotransformations. The enzymatic hydroxylation is most practical for the synthesis of... 

A useful reaction involving substitution of carbon functionalities is decarboxylation of pyrazinecarboxylic acids. This conversion is readily achieved by heating directly or in high-boiling solvent, or distillation over copper compounds. Fusion under reduced pressure has been occasionally effective for the transformation <2002JOC556>. 

Azirines are dimerized under various conditions to dihydropyrazines or their dehydrogenated products, namely pyrazines (Section 8.03.9.5). Quinoxalines are oxidized with potassium permanganate to afford 2,3-pyrazinedicarboxylic acids, and pteridines are hydrolyzed to give 3-amino-2-pyrazinecarboxylic acid derivatives. Condensation of 3,4-diamino-l,2,5-thiadiazole 176 with a-diketones produces l,2,5-thiadiazolo[3,4- Jpyrazines 177, which are reduced to provide 2,3-diaminopyrazines 178 (Scheme 51) <1997JCM250>. 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

Carboxylic acids, acyl chlorides, and sulfonyl chlorides used for deri-vatization of 4-aminophenylalanine and >-4-am i n op h e ny I a I a n i n e are as follows 5-hydantoinacetic acid, / ran, v - 4 - co t i n i n ec a r b o xy I i c acid, isonicotinic acid, 3-pyridinepropionic acid, 4-hydroxyphenylacetic acid, 2-butynoic acid, 2-pyrazinecarboxylic acid, cyclopropanecarboxylic acid, 3-hydroxy-2-qui-noxaline carboxylic acid, 5-bromovaleric acid, propargyl chloroformate, 3,4-dimethoxybenzoyl chloride, 2-thiophenesulfonyl chloride, 3-thiophene-carboxylic acid, 2-thiophenecarboxylic acid, 2-methylbutyric acid, 2-thio-pheneacetyl chloride, benzoic acid, furylacrylic acid, 4-nitrophenyl acetic acid, 2,5-dimethoxyphenylacetic acid, p-toluenesulfonyl chloride, 4-(di-methylamino)phenylacetic acid, 3-indolepropionic acid, phenoxyacetic acid, 3-(dimethylamino)benzoic acid, cyclohexanecarboxylic acid, naphtha-lenesulfonyl chloride, 4-bromophenylacetic acid, 4-bromobenzoic acid, 2-phenoxybutyric acid, 3,4-dichlorophenylacetic acid, (l-naphthoxy)acetic acid. 

Kubisova, L ., Sabolova, E., Schlosser, ., Martak, J. and Kertesz, R. (2004) Mass-transfer in membrane-based solvent extraction and stripping of 5-methyl-2-pyrazinecarboxylic acid and co-transport of sulphuric add in HF contactors. Desalination, 163, 27. 

Chemical Name 2-Pyrazinecarboxylic acid, 5-methyl-, 4-oxide... 

Condensation of 1,2-diaminopropane and 2,3-dioxobutane similarly gives 5,6-dihydro-2,3,5-trimethylpyrazine which is oxidized to the corresponding pyrazine in 58% yield by treatment with potassium hydroxide pellets.111 Hydroxypyrazines are very conveniently prepared from a,j8-dicarbonyl compounds and a-amino acid amides [Eq. (1)],30,112 and pyrazinecarboxylic acids have been prepared by condensation of an a,)5-diketone with an a,/ -diaminocarboxylic acid, followed by oxidation (Scheme 2). Thus, condensation of benzil and... 

The greater stability of the pyrazine ring to oxidation compared with that of benzene enables pyrazinecarboxylic acids to be prepared by permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring is more stable than the pyrimidine ring to acid and alkaline hydrolysis. Thus, pteridine is converted into 2-amino-3-formylpyrazine on treatment with dilute sulfuric acid and N-(3-formyl-2-pyrazinyl)formamidine oxime on treatment with sodium carbonate and hydroxylamine (Scheme 11).136 Aminopyrazines and... 

Oxidation of alkyl- or arylpyrazines with dichromate or permanganate yields pyrazinecarboxylic acids. Thus, Beck reported that on heating 2-methylpyrazine with aqueous dichromate and phosphoric acid in an autoclave at 225°-300°, pyrazinecarboxylic acid was obtained in 74% yield.216 Pyrazine-2,5- and -2,6-dicarboxylic acids... 

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. 

Benzamidopropionic acid (95) underwent unsymmetrical self-condensation and aminolysis to give l-benzoyl-2,5-dimethyl-6-methylimino-3-phenyl-l,2,5,6-tetrahydro-2-pyrazinecarboxylic acid (97), possibly via intermediate (96) (MeNH2-POCl3, CHC13, reflux, 5 h 43%) several analogues were made similarly.1098... 

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