2- -3-methoxycarbonylpyrazine

Pd-catalyzed carbonylation of 2-chloropyrazine 1-oxide failed, whereas that of 3-chloropyrazine 1-oxide (40) proceeded without deoxygenation of the IV-oxide function to give 3-methoxycarbonylpyrazine 1-oxide (73). This observation was in accord with the failure of Stille reactions of 2-chloropyrazine 1-oxide [9,18]. 

Chlorination of 2-amino-3-methoxycarbonylpyrazine in aqueous acetic acid at about 40° has been shown to give 5-chloro-2-chloroamino-3-methoxycarbonyl-pyrazine and thence 2-amino-5-chloro-3-methoxycarbonylpyrazine (150, 378a, 432a, 778-787), but in the presence of polar aprotic solvents (such as acetonitrile and dichloroethane) at temperatures between room temperature and reflux it gave 2-amino-5,6 -dichloro-3 -me thoxycarbonyIpyrazine (788). 

Chlorination of 2-methoxycarbonyl-3-methylaminopyrazine gave 2,3-dichloro-5-methoxycarbonyl-6-methylaminopyrazine (789), 5-chloro-2-(2 -dimethylamino-ethylamino)-3-methoxycarbonylpyrazine at room temperature gave 2,3-dichloro-5-... 

Patents describe the preparation (by chlorination) of 2,3,5-trichloro-6-cyano-pyrazine (794,795) and the chlorination of 2-methoxy-3-methoxycarbonylpyrazine (product not stated) has been described (155). 

Bromination of 2-amino-3-methoxycarbonylpyrazine in acetic acid gave 2-amino-5-bromo-3-methoxycarbonylpyrazine (787, 798) and the 2-methylamino analogue... 

Many derivatives of carboxy chloropyrazines have been prepared by the action of phosphoryl chloride on the corresponding hydroxypyrazine. In this way were prepared 2-chloro-3-methoxycarbonylpyrazine (371, 423, 836), 2-chloro-3-methoxycarbonyl-5,6-diphenylpyrazine (but the corresponding hydroxy compound did not react with phosphorus tribromide) (837), and 3-chloro-2-methoxycarbonyl-... 

Amino-3-hydroxypyrazine with phosphoryl bromide at 140-150° for 20 minutes gave 2-amino-3-bromopyrazine (807) and 2-hydroxy-6-methoxycarbonyl-pyrazine with phosphoryl bromide at 125° for 10 minutes gave 2-bromo-6-methoxycarbonylpyrazine (867). 

Ellingson and Henry (798) first showed that 2-amino-3-methoxycarbonylpyrazine... 

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Bromo-3-methoxycarbonylpyrazine with 2,3-dimethylaniline in refluxing toluene gave 2-(2, 3 -dimethylphenyl)amino-3-methoxycarbonylpyrazine (950) [hydrolysis of this product with sodium hydroxide in ethanol gave 2-carboxy-3-(2, 3 -dimethylphenyl)aminopyrazine, which was also obtained by treatment of l-(2, 3 -dimethylphenyl)lumazine with sodium hydroxide in refluxing ethanol (950)]. 3-Bromo-2-hydroxy-5-phenylpyrazine with ammonium hydroxide and copper at 150° gave 3-amino-2-hydroxy-5-phenylpyrazine (365a). Replacement of the iodo substituent from 2-amino-5-iodo-3,6-dimethylpyrazine has been effected with ammonium hydroxide (887). 

In reactions with amines the 2-halogeno substituent was replaced from 2,5-dihalogeno-3-methoxycarbonylpyrazines (35) and 2,3-dichloro-5-methoxycarbonyl-... 

Hydrolysis of 2,6-diacetoxy-3,5-diphenylpyrazine (9) (from 2-hydroxy-3,5-diphenylpyrazine 1 -oxide by refluxing with acetic acid-acetic anhydride) with potassium hydrogen carbonate in methanol gave 2,6-dihydroxy-3,5-diphenylpyrazine (873), and 2-acetoxy-6-methoxycarbonylpyrazine (from 3-methoxycarbonyl-pyrazine 1-oxide with acetic anhydride) with methanolic hydrogen chloride gave 2-hydroxy-6 -methoxycarbonylpyrazine (838). 

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)]. 

Hydroxymethylpyrazines may be prepared by reduction of carboxylic acid derivatives. Thus reduction of 2-amino-3-methoxycarbonylpyrazine with lithium aluminum hydride in tetrahydrofuran gave 2-amino-3-hydroxymethylpyrazine (1074, 1075) the imide from 23-dicarboxypyrazine (20) with sodium borohydride in tetrahydrofuran gave 2-carbamoyl-3-hydroxymethylpyrazine (21), and the methylcarbamoyl analogue was prepared similarly (1076). 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

Diazotization of 2-amino-3-alkoxycarbonylpyrazine foDowed by treatment with alcohols gave 2-alkoxy-3-alkoxycarbonylpyrazines (890) and 2-amino-5with methanol formed 5-chloro-2-methoxy-3-methoxycarbonylpyrazine (799,892). 

When 2-amino-5-chloro-3-methoxycarbonylpyrazine was refluxed with aniline and concentrated hydrochloric acid in acetone for 16 hours, the anil, 5-anilino-2-isopropylideneamino-3-methoxycarbonylpyrazine (22) was formed (432, 778, 780), and 2-amino-5-chloro-3-methoxycarbonyl-6-(l -methylhydrazino)pyrazine with benzaldehyde in ethanol gave 2-amino-6-(2 -benzylidene-r-methylhydrazino)-5-chloro-3-methylcarbonylpyrazine (23) (809). A series of hydrazones has been prepared by refluxing equimolar quantities of 2-hydrazinopyrazine and carbonyl compounds in the presence of catalytic quantities of p-toluenesulfonic acid in benzene (1195). Other preparations of similar hydrazones have been described (1196). 

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