From Carbamoylpyrazines

Aminopyrazines may be prepared from carbamoylpyrazines by the Hofmann degradation. Gabriel and Sonn (397) first prepared 2-aminopyrazine from 23-dicarbamoylpyrazine with potassium hypobromite through 2-amino-3-carboxy-pyrazine, which was decarboxylated when heated above its melting point (or in refluxing nitrobenzene) (397, 477). 2,3-Dicarbamoylpyrazine with 2 mol of 

5-Bis(azidocarbonyl)pyrazine heated with anhydrous benzyl alcohol at 180° for 30 minutes, and then at 220° for 15 minutes gave 2,5-bis(benzyloxycarbonyl-amino)pyrazine (5), which with concentrated sulfuric acid foUowed by pouring onto ice afforded 2,5-diaminopyrazine (1176) but 2,5-bis(azidocarbonyl)pyrazine refluxed with ethanol gave 2,5-bis(ethoxycarbonylamino)pyrazine, which could not be converted into the amine with (fuming) hydrochloric acid to 210°, with concentrated sulfuric acid, or with potassium hydroxide (1172). 

2-Hydrazinocarbonyl-5-phenylpyrazine treated with aqueous nitrous acid gave 2-azidocarbonyl-5-phenylpyrazine, converted by heating in benzyl alcohol at 150° to 2-benzyloxycarbonylamino-5-phenylpyrazine, and with 30% hydrobromic acid in glacial acetic acid gave 2-amino-5-phenylpyrazine (376). 2-Hydrazinocarbonyl-6- 

Hydrogenation of 3-(benzyloxycarbonylamino)-2,5-dimethoxypyrazine in ethanol over palladium-charcoal gave 3-amino-2,5-dimethoxypyrazine and 2-amino-3,5-dimethoxypyrazine was prepared similarly (881). 

5-Diisocyanatopyrazine (7) was stable toward (fuming) hydrochloric acid or potassium hydroxide (1172). 

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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). 

Homolytic amidation of pyrazine to 2-carbamoylpyrazine can be effected in > 80% yield by using concentrated sulfuric acid with carbamoyl radicals ( CONH2) generated from the action of hydrogen peroxide and ferrous sulfate on formamide (611). 

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). 

Urethanes may be prepared from azidocarbonyl compounds by heating with anhydrous alcohols [see Section 1A(6)]. In this way 2,5-bisazidocarbonylpyrazine (with benzyl alcohol at 180-220°) gave 2,543is-Af-benzyloxycarbonylaminopyrazine (5) (1176) 2-azidocarbonyl-5-carbamoylpyrazine (at 150°) gave 2-A -benzyloxy-carbonylamino-5-carbamoylpyrazine (676, 1249) 2-azidocarbonyl-5-ethoxy-... 

Aminopyrazine 1-oxide has been prepared from 3-carbamoylpyrazine 1-oxide with sodium hypobromite (108, 547a), and the interaction of iminodiacetonitrile ... 

Many carbamoylpyrazines and related compounds such as IV-hydroxyamides (hydroxamic acids), hydrazides, cyanamides, guanidinocarbonyl-, guanidino-carbamoyl-, and ureidocarbonylpyrazines have been prepared from pyrazinecarboxylic esters. The amides were usually prepared with ammonia in methanol (or other alcohols) but also under other conditions. 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

Cyanopyrazine with concentrated aqueous ammonia was converted through 2-[A(-(C-imino-C-pyrazin-2-ylinethyl)amidino]pyrazine (43) to 2-carbamoylpyrazine (985), and 2-chloro-6-cyanopyrazine reacted similarly (985). 2-Ethoxy-6-(C-ethoxy-C-iminomethyl)pyrazine was found to be a by-product of the reaction of 2-chloro-6-cyanopyrazine with concentrated ethanolic ammonia and 2-ethoxy(or methoxy)-6-[C-ethoxy(or methoxy)-C-iminomethyl]pyrazine was obtained from 2-chloro-6-cyanopyrazine by the action of ethanol (or methanol) in the presence of triethylamine (985). 2-Cyanopyrazine treated in water with hydroxylamine hydrochloride and sodium carbonate at 70-75° gave 2-(C-amino-C-hydroxyiminomethyl)-pyrazine (62), and 2aluminum chloride at 140-220° gave 2-(C-anilino-C-iminomethyl)pyrazine (and similar preparations were carried out with other aromatic amines) (1334,1410). 

Carbamoylpyrazine A-oxides are also prepared from the corresponding esters. 3-Methoxycarbonylpyrazine 1-oxide with ammonium hydroxide at reflux gave 3-carbamoylpyrazine 1-oxide (1266) and similarly with hydroxylamine gave 3-N-hydroxy carbamoylpyrazine 1-oxide (1266). 2-Amino-5-chloro-3-methoxycarbonyl-pyrazine 1-oxide with methylamine gave 2-amino-5-chloro-3-A-methylcarbamoyl-pyrazine 1-oxide (876). 

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