2- Carbamoyl-6-hydroxypyrazine

Carbamoyl-3-hydroxypyrazine and phosphoryl chloride have been shown to give 2[Pg.101]

Carbamoyl-3-hydroxypyrazine refluxed with aniline gave 2-hydroxy-3-7V-phenylcarbamoylpyrazine (1055) and 2-amino-3-carbamoyl-5,6-diphenylpyrazine refluxed with benzylamine gave 2-amino-3-A -benzylcarbamoyl-5,6-diphenylpyrazine but a similar reaction with piperidine was unsuccessful (451). 3-Methylamino-2-yV-methylcarbamoyl-5-phenylpyrazine was unchanged when heated with liquid ammonia in dry ethanol at 210° for 2 hours (453). 2,6-Diamino-3-carbamoyl-5-chloropyrazine in isopropanol with 1 mol of potassium hydroxide and 1 -amidino-... 

Jones (361) introduced a very convenient variation of this reaction for the preparation of hydroxypyrazines (55) in which a,/3-dicarbonyl compounds (49) were condensed with a-amino acid amides (54). In this way aminomalonamide (54, R = CONHj) with glyoxal in aqueous sodium hydroxide gave 3-carbamoyl-2-... 

Amino-2-carbamoyl-5-hydroxypyrazine in dimethylformamide with phosphoryl chloride gave 3-amino-5-chloro-2-cyanopyrazine (538). 

Amino-2prepared from 2-amino-3-cyanopyrazine 1-oxide by reflux with acetic acid-acetic anhydride followed by ready deacetylation by refluxing in methanol (538), and in a similar manner 3-amino-2-ethoxycarbonyl-5-hydroxypyrazine has been prepared from 2-amino-3-ethoxycarbonylpyrazine 1 -oxide through 3-acetamido-2-ethoxycarbonyl-5 ydroxy-pyrazine (538), and 2-amino-3-carbamoyl-6-hydroxy-5-methylpyrazine from 2-amino-3-cyano-5-methylpyrazine 1-oxide (538). The preparation of 24 ydroxy-6-methoxycarbonylpyrazine (10) has been claimed from 3-methoxycarbonylpyrazine 1-oxide with acetic anhydride followed by hydrolysis (1057) [cf. Nov Cek et al. (839), who claim it to be the 5-isomer, and Foks (744)]. 

Pyrolyses and thermal stabilities of 2-hydroxy-, 2-ethoxy-, and 2-isopropoxy-pyrazines have been studied. 2-Hydroxypyrazine was very stable, but the alkoxy-pyrazines underwent thermal elimination of olefin to yield 2-hydroxypyrazine (668a). Electrochemical reductions of l-methyl-2-oxo-5,6-diphenyl-l,2-dihydro-pyrazine and 54iydroxy(and 5-methoxy)-2,3-diphenylpyrazine are reported to involve the intermediate enamine, for example, 6-hydroxy-1-methyl-2,3-diphenyl-1,4-dihydropyrazine (54) (1096, cf. 1097). When tested on mice 2-carbamoyl-5-methoxypyrazine had less anti tubercular activity than did pyrazinamide (1098). 

Oxidation of nuclear and extranuclear hydroxypyrazines (and derivatives) to their Af-oxides has been achieved with hydrogen peroxide in acetic acid, and with m-chloroperoxybenzoic acid in 1,2-dichIoroethane. 3-Hydroxy-2,5-diisobutyl-pyrazine was oxidized with 30% hydrogen peroxide in acetic acid at 70 to 3-hydroxy-2,5-diisobutylpyrazine 1-oxide (101), 3-hydroxy-2-(Af-methyl-A -phenyl-carbamoyl)pyrazine 1-oxide (90) was also prepared from the conesponding pyrazine [its A -4-methyl derivative was prepared similarly and also by methylation of (90) (1055)], and 3-hydroxy-2-(A -methyl-AAp-tolylcarbamoyl)pyrazine 1-oxide (1055) was synthesized analogously. 

Hydroxypyrazine 1 oxide was reduced with hydrogen at atmospheric pressure over Raney nickel to 2-hydroxypyrazine (108) [but failed to react with phosphorus trichloride in chloroform (108)], and 3-hydroxy-2-isobutyl-5-isopropylpyrazine 1,4-dioxide was reduced with hydrogen over nickel to 3-hydroxy-2-isobutyl-5-isopropylpyrazine (740a). 2-(A -Anilino-yV-methylcarbamoyl)-4-methyl-3oxo-3,4-dihydropyrazine 1 oxide with sodium dithionite produced 3-(A -anilino-A -methyl-carbamoyl)- -methyl-2oxo-l, 2-dihydropyrazine (1137). 

Aminopyrazine jV-oxides may rearrange and acetylate in the presence of acetic anhydride. Thus 2-amino-3with acetic anhydride and acetic acid at reflux for 2 hours gave 3.acetamido-2-carbamoyl-5-hydroxypyrazine (25), 2-amino-3[Pg.216]

Carboxypyrazine A -oxides have been prepared by hydrolysis of carbamoyl- and alkoxycarbonylpyrazine A(-oxides as follows (reagent and conditions) 2-carbamoyl-pyrazine 1-oxide (10% NaOH/reflux/12h) (838) 3-carbamoylpyrazine 1-oxide (10% NaOH/reflux/30 min) (1266, cf. 838) 3-A(-acetylcarbamoylpyrazine 1-oxide (10% NaOH/heat) (1057) 3-morpholinocarbonylpyrazine 1-oxide (18% HQ/reflux/ 8h) (870) 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/20-25°/ 20min) (739) 3-hydroxy-5-methoxycarbonylpyrazine 1-oxide (KOH/22 /2h gave 3-carboxy-5-hydroxypyrazine 1-oxide, which interfered with the growth of Streptococcus faecium Escherichia coli at 6 x lO and 4 x 10" M, respectively) (1035) 2-amino-3-benzyloxycarbonyl-5-methyIpyrazine 1-oxide 2N NaOH/reflux/ 30min) (365c) and 2-amino-5-chloro-3-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/heat) (876,1222). 

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