2-Amino-3-carbamoyl-5 pyrazine

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). 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

Cyano-6-methylaminopyrazine was also prepared from the chloro compound with methylamine hydrochloride and sodium hydroxide in aqueous dioxane (945) and 2-cyano-6-(2, 2 -dimethylhydrazino)pyrazine was prepared similarly (945). 2-Chloro-6-cyanopyrazine with methanol (and similarly with ethanol) and triethylamine gave 2-methoxy-6-(C-methoxyformidoyl)pyrazine (32) [see Section 5D(2)], and 2-chloro-6-carbamoylpyrazine with concentrated aqueous ammonia at 170-175° gave 2 -amino-b-carboxypyrazine (744). 2-Chloro-3-cyano-5,6-diphenylpyrazine with ammonium hydroxide and potassium iodide formed 2-amino-3-carbamoyl-5,6-diphenylpyrazine, but on fusion with ammonium acetate it gave 2-amino-3-cyano-5,6-diphenylpyrazine (848). 

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)]. 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

C yanoethyl)carbamoyl-3-formylamino-5-methylpyrazine boiled with N sodium hydroxide for 30 seconds gave 3-amino-2-cyanoethylcarbamoyl-5-methyl-pyrazine (435) 2,3-dichloro-5-formamido-6-formylpyrazine was readily deformyl-ated under acid or alkaline conditions (e.g., 2A( sodium carbonate at 20°) (430) and 2-formamido-3-(iniidazol-2-yl)pyrazine was deformylated by refluxing with 0.1 A hydrochloric acid for 4 hours and its 5,6-dimethyl derivative reacted similarly (455a). 

Carbamoylpyrazine was methylated to 3-carbamoyl-l -methylpyrazinium iodide by methyl iodide in methanol at reflux (138) and by methyl iodide in dimethyl sulfoxide at room temperature (666) under the latter conditions the rate of methylation relative to pyrazine was 0.53 (666). 3-Carbamoyl-l-methylpyrazinium iodide reacted with liquid ammonia at — 40° to give 2-amino-5-carbamoyl-l-methyl-1,2-dihydropyrazine (46) (609). With nitromethide ions in liquid ammonia, none of the carbon addition reaction was found (721), but with ethanethiolate ion in liquid ammonia it gave 5-carbamoyl-2-ethylthio-l-methyl-1,2-dihydropyrazine (721). 2-(4 -Morpholino)carbonylpyrazine with methyl iodide gave 3-(4 -morpholino)-carbonyl-1-methylpyrazinium iodide (870). 

A -Alkyl(thiocarbamoyl)]pyrazines have also been obtained by heating the 2-(A -alkylcarbamoyl)pyrazine with phosphorus pentasulfide and potassium sulfide in xylene at 100° (1268) and 2-amino-3-carbamoyl-5,6-diphenylpyrazine refluxed with phosphorus pentasulfide in pyridine gave 2-amino-5,6-diphenyl-3-thiocarbamoylpyrazine and the 3-A -butyl(thiocarbamoyl) analogue was prepared similarly (455). 2-Amino-5-chloro-3-(C-imino-C-methylthiomethyl)pyrazine with hydrogen sulfide in pyridine gave 2-amino-5-chloro-3-thiocarbamoylpyrazine (1218). 

Hydrolyses of carbamoylpyrazine A -oxides to carboxypyrazine IV-oxides have been described in Section 8A(2), deoxygenation and chlorination of carbamoylpyrazine A -oxides (A -unsubstituted carbamoyl compounds gave the nitrile) in Section V.IG, and deoxygenation of carbamoylpyrazine A -oxides (which also contained amino groups) in Section VIII.3C(4). In addition, 4-methyl-2-A -methyl-A -phenylcarbamoyl-3-oxo-3,4-dihydropyrazine 1-oxide refluxed with aqueous ethanolic sodium dithionite gave 4-methyl-2-Af-methyl-Af-phenylcarbamoyl-3-oxo-3,4-dihydropyrazine (1137), and 3,5-bis(methylamino)-3-A -methylcarbamoyl-pyrazine 1-oxide was deoxygenated by heating at 190-200° and 0.25 mm (462). 

Various bicyclic heterocycles have been prepared from carbamoylpyrazine V-oxides 2-amino-5-chloro-3-7V-methyIcarbamoylpyrazine 1-oxide refluxed with triethyl orthoformate and acetic anhydride gave 6-chloro-3-methyl-4-oxo-3,4-dihydropteridine 8-oxide (1222) 2-amino-3-carbamoyl-5-methyl(or phenyl)pyrazine 1-oxide with triethyl orthoformate, or with ethyl chloroformate followed by cyclization of the intermediate urethane, gave 6-methyl(or phenyl)-4-hydroxy-pteridine 8-oxide (537). 

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