Dihydroxypyrazines

Dialkoxypyrazines and 2,5-dihydroxypyrazines have been shown to add to singlet oxygen to yield peroxy adducts such as (75) in high yields (76CC417, 79JCS(P1)1885 and the reaction is believed to be important in the biosynthesis of the antibiotic bicyclomycin (76)... 

Dioxopiperazines have been converted into the corresponding dihydroxypyrazines by base catalyzed isomerization of the corresponding arylidene derivatives (Scheme 64) (70JCS(C)980), although this reaction appears to be limited to the synthesis of benzyl- or aryl-substituted benzylpyrazines. 

Mycelianamide (114) clearly bears a structural resemblance to pulcherrimic acid and it seems probable that both are derived from the corresponding dihydroxypyrazines (115)... 

DFT and post-Hartree-Fock ab initio studies on the different tautomers and rotamers of 2-hydroxy- (94) and 2,3-dihydroxypyrazine (95) indicate that the former species is stabilized by about -3 kcal/mol with respect to its keto tautomer in the gas phase [99JST229]. In solution the opposite appears to be true. For 95, the hydroxyoxo 95b and diketo tautomers 95c are most stable in the gas phase (Scheme 61). 

Ether cleavage in methoxypyrazines is effected by TMS-I, whereby 3,6-disubstituted 2,5-dimethoxypyrazines are converted into the corresponding 2,5-dihydroxypyrazines (Scheme 69) (86JHC1677). 

Benzyl-6-methyl-2,5-dihydroxypyrazine (144) undergoes Diels-Alder addition with dimethyl acetylenedicarboxylate on heating the... 

There is no longer any real doubt that simple tautomeric pyrazinones like 2(1//)-pyrazinone (1) exist predominantly in their oxo forms. However, largely confirmatory theoretical,1042,1430,1623,1675 NMR,1424 and IR studies1398 on such pyrazinones have appeared recently in addition, 2,3(1 H,AH)-pyrazinedione (9) appears to exist substantially as such,1623,1675 whereas the 2,5-isomer [2,5(l//,6A)-pyrazinedione ] appears to prefer an equilibrium mixture (10) of 2,5-dihydroxypyrazine and... 

Adachi and Sato (483) have prepared six dihydroxypyrazines (103, R and R = H, Me, Ph) by condensation of a-aminoketals (100) with ethyl oxamate (101) to oxamoylamino ketones (102), which were subsequently cyclized in acetic acid to give excellent yields of the 23-dihydroxypyrazines. 

Dichloropyrazines have also been prepared from the corresponding hydroxy compounds as follows 2,3-dihydroxypyrazine with phosphoryl chloride containing pyridine (481, 757) [see Schneller and May (828) re the use of phenylphosphonic dichloride at 150-170°] 2,3-dihydroxypyrazine and its methyl, dimethyl, phenyl, diphenyl, and 5-methy 1-6-phenyl derivatives with phosphoryl chloride (483, 829) [N.B. error in work of Minovici and Bente (830)] 2-chloro-5-hydroxypyrazine with phosphoryl chloride (831) 2-chloro-6-hydroxypyrazine with phosphoryl chloride at reflux for 6hours (832) and 2,5-dihydroxy-3-phenylpyrazine and3,5-dihydroxy-2-phenylpyrazine with phosphoryl chloride at 180-200° (829). 

Some chlorinations have been reported with thionyl chloride. 23-Dicyano-5,6-dihydroxypyrazine refluxed with thionyl chloride in pyridine was reported to give 23-dichloro-5,6-dicyanopyrazine (862) and 2-hydroxy-3-nitro-5,6-diphenyl-pyrazine with thionyl chloride gave 2-chloro-3-hydroxy-5,6-diphenylpyrazine (817, 841) but with thionyl chloride and pyridine it gave the betaine of 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (5) (863), which was hydrolyzed in acid to 2,3-dihydroxy-5,6-diphenylpyrazine (863). No product could be isolated from 2-methylpyrazine when refluxed with thionyl chloride (864). 1,4-Dimethylpiperazine-... 

Bredereck and Schmotzer (1044), from diaminomaleonitrile (DAMN hydrogen cyanide tetramer) and oxalyl chloride, prepared 2,3-dicyano-5,6-dihydroxy-pyrazine but Stetten and Fox (1049) could not prepare 23-diamino-5-hydroxy-pyrazine from glycine amide and oxamide. Section 11.3 lists preparations from a, -diamino or a, -diimino compounds and reagents other than a,0-dicarbonyl compounds (384) with additional data (1050) and oxidation of 23-dichloro-quinoxaline with hot aqueous potassium permanganate gave 23-dicarboxy-5,6-dihydroxypyrazine (1051). 

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... 

Cleavage of pyrazine diethers by sodium methoxide has been developed as a method of preparing o- and p-dihydroxypyrazines and hydroxypyrazine ethers (797). Such a procedure offers no advantage over mineral acid cleavage for the simple monoethers but with diethers stepwise reaction can be achieved by this method (797). 

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-... 

In 23-dihydroxypyrazine and derivatives Honzl (853), from measurements of infrared spectra in chloroform and ultraviolet spectra in aqueous alcohol, has proposed that 5,6-dichloro-l-cyclohexyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (pA in water 4.66, 5.66) exists in the form (48). The p.m.r. spectra of some 5- and 6-methyl- and 5- and 6-phenyl-2,3-dihydroxypyrazines have been reported (483). In the 2,5-dihydroxypyrazine series, the infrared spectrum (Nujol) of 2-benzyl-3,6-dihydroxy-5-methylpyrazine has been interpreted as indicating that the major tautomeric form present in the solid state was the dihydroxy form (49), but the ultraviolet spectrum in ethanol was considered consistent with the coexistence of the dihydroxy (49) and oxo-hydroxy form, for example, (50), Although the structure (51) has been proposed for 3-butyl-2,5-dihydroxypyrazine (1092), the evidence in favor of this structure is inconclusive. 

Dihydroxypyrazine with hexamethyldisilazane in the presence of ammonium sulfate produced 2,3-bis(trimethylsilyloxy)pyrazine (1111), and 2-amino-3-hydroxypyrazine behaved similarly (1111). 23-Bis(trimethylsilyloxy)pyrazine with 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide and silver perchlorate in benzene gave 1,4-bis(2, 3, 4, 6 -tetra-0-acetyl-/J-D-glucopyranosyl)-2,3-dioxo-l, 2,3,4-tetrahydropyrazine, and other similar reactions have also been described (1111). 

Reduction of 2-carbamoylpyrazine in ethanol over palladium-charcoal at atmospheric pressure gave 2-carbamoylpiperazine (870, 1269, 1352), and the 2-carbamoyl-3-carboxy (1269) and 2,3-dicarbamoyl (1269, 1352) analogues were prepared similarly, but 2,3-dicarboxypyrazine imide gave 50% 2,3-dicarboxy-1,4,5,6-tetrahydropyrazine imide (1269). 2-Hydroxy-3-V-phenylcarbamoylpyrazine oxidized with hydrogen peroxide in acetic acid at 50° for 96 hours did not give an 7V-oxide but only a tar and 2,3-dihydroxypyrazine (1055). 

Dibenzyl-3,6-dihydroxypyrazine with singlet oxygen gave 2,5-dibenzyl-2,5-epidioxy-3,6-dihydroxy-2,5-dihydropyrazine (3,6-dibenzyl-3,6-epidioxypiperazine-... 

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