2- -3-hydroxy-6-methoxypyrazine

Diethoxy-3-(l-hydroxy-l-methylethyl)pyrazine (155) gave 2,5-diethoxy-3-isopropenylpyrazine (156) (TsOH, PhH, molecular sieves, reflux 80%) 6 2-(l-hydroxy-2-methylpropyl)-6-iodo-3-methoxypyrazine gave 2-iodo-5-methoxy-6-(2-methylprop-l-enyl)pyrazine (157) (TsOH, PhMe, reflux with H20 removal, 6 h 65%).1588... 

Reductive debenzylation. 2-Benzyloxy-3,6-diisobutyl-5-methoxypyrazine 4-oxide (21) gave 3,6-diisobutyl-5-methoxy-2(l//)-pyrazinone 4-oxide (22) (H2, Pd/C, EtOH, h 90% structure confirmed by X-ray analysis) 310 2,5-dibenzy-loxy-3,6-diphenylpyrazine likewise gave 5-hydroxy-3,6-diphenyl-2(l//)-pyrazinone (23) (43%).82... 

Acetoxy-3,6-dibenzyl-5-methoxypyrazine gave 3,6-di benzyl-5-methoxy-2(l//) -pyrazinone (29) (K2C03, MeOH—H20, reflux, 30 min > 95%) 312 2,5-diace-toxy-3,6-dimethylpyrazine gave 5-hydroxy-3,6-dimethyl-2(l//)-pyrazinone (30) (KHC03, MeOH, reflux, 50 min 53%).1386... 

Isobutyl-3-methoxypyrazine (123, R = H) gave 2-(l-hydroxy-2-methylpropyl)-3-methoxypyrazine (123, R = OH) (PiTNLi, Et20—C6H14, N2, -78 20°C,... 

Hydroxy-2-methylpropyl)-5-isobutyl-6-methoxypyrazine 4-oxide 2-(l-Hydroxy-2-methylpropyl)-... 

V-Hydroxy-6-propylthio-2-pyrazinecarboxamide V-Hydroxy-6-propylthio-2-pyrazinecarboxamidine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisobutylpyrazine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisobutylpyrazine 4-oxide 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisopropylpyrazine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisopropylpyrazine 4-oxide 2- (3-Hydroxyprop-1 -ynyl)-3,6-dimethylpy razi ne 2-(3-Hydroxyprop-1 -y nyl)-3,6-dimethylpyrazine 4-oxide 2-(3-Hydroxyprop-l-ynyl)-3,5-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-3,6-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-5,6-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-5,6-diphenylpyrazine 4-oxide 2-(3-Hydroxyprop-l-ynyl)-6-methoxy-5-(2-methylprop-l-enyl)pyrazine 2- (3-Hydroxyprop-1 -ynyl )-6-methoxypyrazine N-Hydroxy-2-pyrazinecarboxamide Af-Hydroxy-2-pyrazinecarboxamide 4-oxide... 

Demethylation of 5-(2 -hydroxy-2 -methylpropyl)-2-isobutyl-3-methoxypyrazine occurred on refluxing with 10% hydrochloric acid to give 3-hydroxy-5-(2 -hydroxy-2 -methylpropyl)-2-isobutylpyrazine but 2-isobutyl-3-methoxy-5-(2 -methylprop-l -enyl)pyrazine and 3-hydroxy-24sobutyl-5-(2 -methylprop-l -enyl)pyrazine were also produced (113b). 

Other hydrolyses with sodium hydroxide have been described as follows. 2-Benzyloxy-6-chloropyrazine in ethanol with 3.5N sodium hydroxide at reflux for 4.5 hours gave 2-chloro-6-hydroxypyrazine (832), 2-chloro-6-metho)Qrpyrazine with aqueous ethanolic sodium hydroxide gave 2-chloro-6-hydroxypyrazine (43%) possibly containing a small amount of 2-hydroxy-6-methoxypyrazine) (883), and 2,6-dimethoxypyrazine with aqueous ethanolic sodium hydroxide at reflux for 24 hours formed 2-hydroxy-6-methoxypyrazine (832). 

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-... 

A number of alkoxypyrazines have been prepared from hydropyrazines. 5-(4 -Amino-3, 5 -dibromobenzenesulfonylimino)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetra-hydropyrazine (32) refluxed with 2N sodium hydroxide gave 2-(4 -amino-3, 5-dibromobenzenesulfonamido)-3-hydroxy-6-methoxypyrazine (881). Rperazine-2,5-dione (33) with an excess of triethyloxonium fluoroborate in dichloromethane gave... 

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). 

Examination of the basic ionization constants (820) and ultraviolet spectra (821, 1081) of 2-hydroxypyrazine and its TV- and D-methyl derivatives (Table VI.1) (820, 821,1082) has revealed that the neutral species of2-hydroxypyrazine exists in aqueous solution as the amide form (46) but, in the absence of a common cation, tautomeric ratios could not be determined (821, 1083). The infrared spectra of 2-hydroxypyrazine in the solid state and in chloroform solution led to a similar conclusion (1084, 1085). Infrared spectra (680) for 2-hydroxy-3-methyIpyrazine and pjn.r. spectra (979,1086) of 2-hydroxy-and 2-methoxypyrazines also indicate that the hydroxy compounds exist in the amide form, and are further supported by MO[Pg.172]

However, in 2,3,5-trifluoro-6-hydroxypyrazine (47), the infrared spectrum of the solid was reported to show no absorption attributable to the carbonyl group, and its ultraviolet spectrum (in ethanol) was similar to that of 23,5-trifluoro-6-methoxypyrazine, thus indicating that it was a true hydroxy compound (851). A similar phenomenon has been observed in the pyridine (1087-1089) and pyrimidine (1090) series, but differs from observations in the pyridazine series (1091). 

Crystal structures of 3,5,6-tri-t-butyl-2-hydroxypyrazine (1093) 2,5-dichloro-3-methoxypyrazine (915) and 2,3-dichloro-5-ethylamino-6-methoxypyrazine (916) have been determined. The dipole moment of 2-amino-5-bromo-3-methoxypyrazine (2.94D in benzene) is consistent with the S-cis configuration (52) (749) and the polarographic behavior of 3-hydroxy(and methoxy)-2,5-dimethylpyrazine (and their A(-oxides) at various pH values has been investigated (588). 

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). 

A large number of 2-alkyl-3-methoxypyrazines has been isolated from raw vegetables (59, 60, 64, 65, 69, 80, 1099), bell peppers (60,61) and gambanum oil (49). 2-Isobutyl-3-methoxypyrazine is already finding commercial use as a flavoring material (368) and 2-ethoxy-3-methylpyrazine may be used for pineapple flavor (981). The odor characteristics (367, 368, 976, 977) and structure (977) of some alkoxy alkylpyrazines have been examined. 3-Guanidino-6-hydroxymethyl-l-methyl-2-oxo-l,2-dihydropyrazine has been isolated from seeds of Stizolobium hassjoo and on mild alkaline hydrolysis gave 3-hydroxy-6-hydroxymethyl-l -methyl-2-oxo-l, 2-dihydropyrazine (1060). 

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)]. 

Cleavage of the Me-0 bond in 3,6-diisobutyl-l-methoxy-2-oxo-l,2-dihydro-pyrazine (93) with methylmagnesium iodide at 150° gave 2-hydroxy-3,6-diisobutyl-pyrazine 1-oxide (94) and the 1,4-dioxide was prepared similarly from 2,5-diisobutyl4-methoxy-3-oxo-3,4-dihydropyrazine 1-oxide and also from 2,5-diisobutyl-3-methoxypyrazine 1,4-dioxide (980). 

Diazomethane methylation of 3-hydroxy-2,5-diisobutylpyrazine 1,4-dioxide has been shown to give the 4-methoxypyrazine 1-oxide, 2,5-diisobutyl4-methoxy-3-0X0-3,4-dihydropyrazine 1-oxide (96) (843, 980) [and some 3-methoxy-2,5-diisobutylpyrazine 1,4-dioxide (4 l)(980)] 5-s-butyl-3-hydroxy-2-isobutylpyrazine... 

When heated with aqueous potassium hydroxide, 2,5-dicyano-3,6-dimethyl(and diphenyOpyrazine gave 2-carboxy-5-hydroxy-3,6-dimethyl(and diphenyl)pyrazine (286-288) and the diethyl analogue was prepared similarly (287). 2-ChIoro-6-cyanopyrazine refluxed with three equivalents of sodium methoxide for 2 hours gave 2-carboxy-6-methoxypyrazine, also obtained from 2-chloro-6-cyanopyrazine with one equivalent of sodium methoxide through 2-(C-imino-C-methoxymethyl)-6-methoxypyrazine (2), which, refluxed with 15% sodium hydroxide, gave 2-carboxy-6-methoxypyrazine (986). 

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