2-Hydroxy-6-methoxy pyrazine methylation

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

Kinetic parameters k, often also and AS, occasionally AV ) for formation and dissociation of several pentacyanoferrate(II) complexes [Fe(CN)5L]" have been established. Ligands L include several S- and A-donor heterocycles,4-methyl- and 4-amino-pyridines, a series of alkylamines, 3- and 4-hydroxy- and 3- and 4-methoxy-pyridines, several amino acids, nicotinamide, " 4-pyridine aldoxime, 3-Me and 3-Ph sydnones, several bis-pyridine ligands,neutral, protonated, and methylated 4,4 -bipyridyl, 1,2-bis(4-pyridyl)ethane and traTO-l,2-bis0-pyridyl)ethene, pyrazine- 4,4 -bipyridyl- and bis(4-pyridyl)ethyne-pentaammine-cobalt(III), edta-ruthenium(III), and pentaammineruthenium-(II)and-(III) complexes of... 

Reaction of 4-aryl-7-iodoperhydropyrido]2,l-c][l,4]oxazin-6-ones (07USA2007/0117839, 08WOP2008/013213) and 7-iodo-6-oxo-4-(3,4,5-tri-fluorophenyl)perhydropyrido[2,l-a]pyrazine-2-carboxylate (07USA2007/ 0117839) with P(OEt)3 at 120 °C for 2 h afforded 7-phosphonic acid diethyl esters. 3-Hydroxy-6-arylperhydropyrido[2,l-c][l,4]oxazin-4-ones first were reacted with triphenylphosphonium bromide in refluxing MeCN, then with 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde at ambient temperature in the presence of NEt3 to provide (Z)-3- l-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]methylidene] derivatives (07USA2007/ 0117798, 08USA2008 /0207900). 

Pyrazin 2-(bzw. 4)-(4-Methyl-anilinocarbonyl)- E5, 1017 (N3 -v CO-NH-Ar) Pyridazine 4-Cyan-6-hydroxy-5-methyl-3-phenyl-4,5-dihydro-E9a, 570 (4-Oxo -4-Ar-3-CN-2-CH3 —butanoic Acid + N2H4) Pyridin 2-Methoxy-5-phenylazo-E16d, 57 (R-NH2 + R-NO) Pyrrol 2-Amino-3-cyan-1 -(4-methyl-phenyl)- 5-oxo-4,5-dihydro-E15/2, 1946 (Cl-CH2-CO-NR2 + NC-CH2-CN) Quinolin... 

The first lithiopyrazine derivative was prepared by Hirschberg et al. (1015) from 3-iodo-2,5-dimethylpyrazine and butyllithium in ether subsequent reaction with (a) carbon dioxide gave 3-carboxy-2,5-dimethylpyrazine, and (b) several aromatic aldehydes gave the carbinols (62, R = H, p-methoxy, m-nitro) (1015). Similar reactions were observed when 2-formylpyridine and 2-acetylpyridine (1016) were used as the carbonyl compounds, but with acetaldehyde attempted reactions were unsuccessful (1015). A patent also describes the preparation of many carbinols from 2,5-disubstituted 3-iodopyrazines (164). The lithio reagent derived from 3-iodo-2,5-dimethylpyrazine (with butyllithium in hexane) with 2-nitrobenzaldehyde gave 2,5-dimethyl-3[ 1 -hydroxy-1 (2"-nitrophenyl)methyl] pyrazine (1017). 

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-... 

Methylation (666, 912) of 2-methoxypyrazine with methyl iodide in dimethyl sulfoxide at room temperature gave 3-methoxy-l-methylpyrazinium iodide with a rate of methylation relative to pyrazine of 1.05 (666). 2-Methoxypyrazine with tetracyanoethylene oxide gave a small yield of 3 ethoxypyrazinium dicyano-methylide (53) (1094). Alkylation of 2-methoxypyrazine with ethyl methyl ketone in the presence of sodium in liquid ammonia to give 2-s-butyl-6-methoxypyrazine (17%) has been described (614). The reactions of 3-hydroxy-2,5-dimethylpyrazine and alkylhalides have been examined (1095). 

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). 

Khydroxypyrazine (which was converted into its jV -dimethyl derivative by treatment with dimethyl sulfate and alkali) gave, on reaction with an excess of ethereal diazomethane a mixture of its N,N-, 0,N-, and 0,0-dimethyl derivatives (58-60) (832). 2-Hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenylpyrazine with ethereal diazomethane gave predominantly 2,5-dimethoxy-3,6-diphenyl-pyrazine and only minor amounts of A -methylated products (832). Methylation of 2-hydroxy-6-methoxypyrazine with ethereal diazomethane produced a mixture of 0- and A -methyl derivatives in which the 0-methyl derivative predominated but the corresponding reaction of 2-benzyloxy-6-hydroxypyrazine gave almost exclusively the 0-methyl derivative (832) [the results of these methylations were correlated with the carbonyl stretching frequency (1103) in the parent lactam (832)]. 

Methylation of 2-hydroxy-3-7V-phenylcarbamoylpyrazine with dimethyl sulfate and potassium carbonate in boiling acetone gave l-methyl-2-oxo-3-A -phenylcarbamoyl-1,2-dihydropyrazine and the 3-(A -methyl-Af-phenylcarbamoyl) analogue was prepared likewise (1055). Similar methylation of 2-hydroxy-3-(o-methylaminophenyl)pyrazine produced 1 -methyl-3-(o-methylaminophenyl)-2-oxo-1,2-dihydropyrazine (1055). A series of 24iydroxy-3-(a-hydroxybenzyl)pyrazines has been methylated with dimethyl sulfate in aqueous sodium hydroxide to the 2-methoxy analogues (1045) and 2-benzyl-3,6-dihydroxy-5-methylpyrazine with diethyl sulfate and sodium ethoxide formed 2-benzyl-3,6-diethoxy-6-methylpyrazine (1066). 

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