2-Amino-5-carboxypyrazine

Polarographic reduction of 2-aminopyrazine and 2-amino-3-carboxypyrazine to 1,4-dihydro derivatives that give 1,2-dihydro derivatives by acid catalysis has been studied (1190). 

The crystal structures of 2-carboxypyrazine (1298) and 2,3-dicarboxypyrazine dihydrate (1299) have been determined and phase diagrams and data have been measured for the binary systems of 2-carboxypyrazine with benzoic acid (1300) nicotinic, isonicotinic, and picolinic acids (1301). The polarography of 2-carboxypyrazine has been examined (1302). Polarography of 2-amino-3-carboxypyrazine has been carried out in aqueous and nonaqueous solutions the reduction proceeds... 

The brominations of 2-amino-3-carboxypyrazine (804), 2-amino-5-bromo-3-carboxypyrazine (805, 806), and 2-amino-5-bromo-3-methoxycarbonylpyrazine (807) to 2-amino-3,5-dibromopyrazine have been described in Section V.IB (2) nitrations of 2-amino-3-carboxy-5-chloro-6-ethylaminopyrazine to 2-amino-5-chloro-6-ethylamino-3-nitropyrazine (1181) and 2,6-diamino-3,5-dicarboxypyrazine... 

Phthalein type dyes have been prepared from 2,3-dicarboxypyrazine by heating with phenols or aromatic amines and zinc chloride. For example, compound (25) was obtained with resorcinol (1353). Efforts to prepare 2,6-diaminopyrazine through a Curtius-Schmidt reaction on 2-acetamido-6-carboxypyrazine (with sodium azide, sulfuric acid, and trichloroacetic acid) proved unsuccessful (434). The preparation of bicyclic heterocyles from 2-amino-3-carboxypyrazines has been described in Section VIII. 1D(6). 

As expected, amidinopyrazines (431) and guanidinopyrazines (1060) are relatively strong bases. 2-Carboxypyrazine has pA 3.92 (400) and Brown and Jacobsen (431) remark that the possibility that 2-amino-3-carboxypyrazines are zwitterionic cannot be excluded. 

Preparations of carboxypyrazines (1) by primary synthesis have been described in Sections II.lA-C, II.IF, II.II, II.2, II.4, II.5, and II.7. Additional data on the hydrolysis of some pteridines to hydroxylated carboxypyrazines and amino carboxypyrazines are given in Sections VI.1A and VIII.1A(1), respectively. 

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). 

Formylpyrazine (25) undergoes the C annizzaro reaction with 40% sodium hydroxide to yield 2-hydroxymethylpyrazine (26) and 2-carboxypyrazine (1077) and with sulfur dioxide in chloroform gave 2-(l -hydroxy-l -sulfomethyl)pyrazine (1077). The preparation of 2,5-di-(hydroxy-r-butyl)pyrazine from 3-amino-2-hydroxy4,4-dimethyltetrahydrofuran has been described in Section II.9 (500). 

Amino-5-carboxypyrazine in anhydrous dimethylformamide with triethyl-amine and ethyl chloroformate and then diethyl glutamate and stirred at room temperature gave 2-amino-5-(l, 3 -diethoxycarbonylpropyl)carbamoylpyrazine (24) (1244). Similarly a mixture of 2-carboxypyrazine and triethylamine in methylene dichloride with ethyl chloroformate and morpholine gave 2-( -morpholinocarbonyl)-pyrazine (1351). 2-Carboxy-3-hydroxypyrazine refluxed with phosphorus tris(A-methylanilide) in toluene gave 2-hydroxy-3-(A-methyl-A-phenyIcarbamoyl)pyrazine (1055), and 2-hydroxy-3-(A -methyl-A -p-tolylcarbamoyl)pyrazine was prepared similarly (1055). Tetracarboxypyrazine heated with sulfur tetrafluoride (SF4) at 150° gave tetra(trifluoromethyl)pyrazine (899). 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

FormyIpyrazine, which is light sensitive, undergoes the Cannizzaro reaction with aqueous sodium hydroxide to give 2-carboxypyrazine and 2-hydroxymethyl-pyrazine (1077). The direct oxidation of 2-formylpyrazine to 2-carboxypyrazine has not been described but 2-amino-3-formylpyrazine was oxidized by aqueous potassium permanganate to 2-amino-3[Pg.296]

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). 

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). 

For the pyrazine A -oxides, there is a table for each substituent type, and compounds are listed (once only) at the first opportunity. For example, 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide is listed in Table A.31 (aminopyrazine A -oxides) and 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide in Table A.32 (carboxypyrazine A -oxides). 

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