2-Hydroxy-3-isobutylpyrazine

An equimolar glyoxal-glycine mixture heated under reflux for 4 hours has been shown to give pyrazine and various methylpyrazines (310), but L-leucine and glyoxal sodium bisulfite gave 2-hydroxy-3-isobutylpyrazine (311). 

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-... 

Dimethylamino-7V-hydroxy-2-pyrazinecarboxamide 6-Dimethylamino-7V-hydroxy-2-pyrazinecarboxamidine 2-Dimethylamino-5-iodopyrazine 2-Dimethylamino-6-iodopyrazine 2-Dimethylamino-5-iodopyrazine 4-oxide 2-Dimethylamino-3-isobutylpyrazine 2-Dimethylamino-6-isobutylpyrazine 2-Dimethylamino-5-methoxy-3,6-dimethylpyrazine 2-Dimethylaminomethyl-3,6-bismethylthiopyrazine 2-Dimethylamino-6-methyl-5-phenylpyrazine 4-oxide 2-Dimethylamino-3-methylpyrazine 2-Dimethylamino-6-methylpyrazine 2-Dimethylamino-3-methylpyrazine 4-oxide Dimethyl 5-amino-6-oxo-1,6-dihydro-2,3-pyrazinedicarboxylate 2-Dimethylamino-5-phenylpyrazine 2-(3-Dimethylaminopropyl)-6-methylpyrazine... 

Bromination of 5-s-butyl-3-hydroxy-2-isobutylpyrazine (deoxyaspergillic acid) in aqueous solution or acetic acid gave 2-bromo-3-s-butyl-5-hydroxy-6-isobutylpyrazine (bromodeoxyaspergjllic acid) (87) bromination of 2-s-buty-3-hydroxy-5-isobutyl-pyrazine in acetic acid gave 2-bromo-6-s-butyl-5-hydroxy-3-isobutylpyrazine (93) and 3-hydroxy-2,5-diphenylpyrazine behaved similarly (282). This procedure with bromine in acetic acid was unsatisfactory when applied to simpler hydroxypyrazines (817), and bromination of 3,6(and 5,6)-disubstituted-2-hydroxypyrazines and 2-... 

Bromodesoxyaspergillic acid (2-bromo-3-s-butyl-5-hydroxy-6-isobutylpyrazine) with zinc dust in glacial acetic acid gave a product thought to be 3-s-butyl-6-isobutylpiperazine-2,5-dione (87). 

Dichloro-3,6-dimethylpyrazine 1,4-dioxide with 0.5 sodium hydroxide at 20° for 5 hours gave 2-chloro-5-hydroxy-3,6-dimethylpyrazine 1,4-dioxide which resisted further alkaline hydrolysis (842) (possibly due to anion formation, whereas sodium ethoxide and sodium benzyloxide rapidly displaced both chloro substituents). Similarly bromoaspergillic acid (3-bromo-2-s-butyl-6-hydroxy-5-isobutylpyrazine... 

Diazotization of 2-aminopyrazine with nitrous acid in dilute or concentrated sulfuric acid gave 2 hydroxypyrazine (to 67% yield) (86, 477, 720, 818). Many such conversions have been described, mostly using nitrosylsulfuric acid in concentrated sulfuric acid solution. Preparations of hydroxypyrazines from the aminopyrazines are summarized as follows 2-hydroxy-3-methylpyrazine (sodium nitrite in concentrated sulfuric acid-acetic acid) (681), 2Jiydroxy-3,5-dimethylpyrazine (aqueous nitrous acid, then at 60°) (524), 3-hydroxy-2,5-dimethylpyrazine (477), 2,5-diethyl-3-hydroxypyrazine (aqueous nitrous acid) (478), 2-hydroxy-6-phenyl-pyrazine (365a), 24iydroxy-3,5-diphenylpyrazine (nitrous acid in N hydrochloric acid) (524), 3-hydroxy-2,5-diphenylpyrazine (282), 2-s-butyl-3-hydroxy-5-isobutyl-pyrazine (93), 5TS-butyl-3 hydroxy-2-isobutylpyrazine (92, 536), 2,5-di-s-butyl-3-hydroxypyrazine (89, 720), 3-hydroxy-2-isobutyl-5-isopropylpyrazine (103, 525), 2,3-dihydroxypyrazine (from 2 amino-3-hydroxypyrazine) (757, 1055) and its... 

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). 

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 2-hydroxy-3,5-diphenylpyrazine 1-oxide was heated under reflux with an excess of acetic anhydride, a crystalline triacetoxy compound was obtained which was thought to have an open chain structure [AcO-CH=CPh-N=CPh-C(OAc)=N-OAc], but when the 2-hydroxypyrazine-l-oxide was boiled with a mixture of acetic anhydride and acetic acid, 2,6-diacetoxy-3,5-diphenylpyrazine was obtained (873) which was hydrolyzed by potassium hydrogen carbonate in methanol to 2,6-dihydroxy-3,5-diphenylpyrazine (873). 2-Hydroxy-5-methyl-3-phenylpyrazine 1-oxide behaved differently and when refluxed with acetic anhydride gave 5-acetoxymethyl-2-hydroxy-3-phenylpyrazine (100) and 2-hydroxy-3-methyl-5-phenylpyrazine 1-oxide similarly gave 3-acetoxymethyl-2-hydroxy-5-phenylpyrazine (873). When 2- l-hydroxy-2 -methylpropyl)-5-isobutylpyrazine 1-oxide was heated with a mixture of acetic anhydride and sodium acetate on a water bath 2-(l -acetoxy-2 -methylpropyl)-5-isobutylpyrazine 1 oxide was obtained (760a). 

Hydroxy-5-(1 -hydroxy-2 -methylpropyl)-2-isobutylpyrazine 1,4-dioxide was deoxygenated by titanium trichloride in dry tetrahydrofuran under nitrogen at room temperature to give 2-hydroxy-6-(r-hydroxy-2 -methylpropyl)-3-isobutyl-pyrazine 1 oxide (DL-neohydroxyaspergillic acid) (760a). 

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