2.5- Dihydroxy pyrazines

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). 

A series of methoxy compounds have been prepared from 2-hydroxy-3-(a-hydroxybenzyl)pyrazines and dimethyl sulfate (1045), and 2-benzyl-3,6-dihydroxy-pyrazine with diethyl sulfate and sodium ethoxide gave the 3,6-diethoxy derivative (1066). 

A comprehensive theoretical smdy of some pyrazolones has been presented. The predicted tautomeric equilibrium constants of these compounds were found to be in good agreement with existing experimental data, indicating that the oxo tautomers are present in aqueous solution whereas, in the main, the hydroxy tautomers predominate in the gas phase. It has been shown that, in solution, the most abundant tautomer of both l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one and its 1-phenyl derivative is dependent on the solvent used, while an NMR study of a number of l(2)//-dihydropyrazolo[3,4-fc]pyridin-6-ones has revealed that they all exist as 2//-tautomers both in solution and in the solid state. DFT and ab initio calculations have been carried out to investigate the stability of different tautomers of 2-hydroxy- and 2,3-dihydroxy-pyrazine in the gas phase and in different media. The data obtained indicated that 2-hydroxypyrazine is more stable than its 2-keto tautomer in the gas phase, whereas in solution the stability order is reversed. For 2,3-dihydroxypyrazine it appears that the intramolecular hydrogen-bonded hydroxyoxo and the a-diketo tautomers are the most stable species at all theoretical levels in the gas phase. Both spectroscopic and theoretical studies of the tautomerism of 2,1,3-benzothiadiazinone 2,2-dioxides and other related fused heterocyclic amides have predicted that the keto form (415) is the most abundant tautomer in the gas phase, whereas the NH hydroxy form (416) is the preferred tautomer in solution and in the solid state. 

Pyrazine, 3-benzyl-2,5-dihydroxy-6-methyl-cycloaddition reactions, 3, 174 Pyrazine, 2,3-bis(3-aminopropyl)-synthesis, 3, 186... 

Pyrazine, 2,5-dichloro-3,6-difluoro-synthesis, 3, 190-191 Pyrazine, dihydro-, 3, 177 Pyrazine, 1,2-dihydro-oxidation, 3, 178 reduction, 3, 177 Pyrazine, 1,4-dihydro-antiaromaticity, 3, 177-178 synthesis, 3, 177 Pyrazine, 2,3-dihydro-oxidation, 3, 178 Pyrazine, 2,5-dihydro-synthesis, 3, 178 Pyrazine, 3,6-dihydro-synthesis, 3, 184 Pyrazine, 2,5-dihydroxy-oxidation, 3, 175 Pyrazine, 2,3-dimethyl-1,4-dioxide... 

E rido[2,3-b]pyrazine, 2,3-dihydroxy-chlorination, 3, 251 Pyrido[2,3-b]pyrazine, 6-hydroxy-formation, 3, 251... 

Two examples were reported for the synthesis of the pyrido[2,3-, ]pyrazine moiety using pyrazine precursors. Thus, amidation of methyl 2-aminopyrazine-3-carboxylate 670 with a substituted acetyl chloride followed by heterocycliza-tion of the formed amide 671 gave 6,8-dihydroxy pyridopyrazine 672 <2004W02004056825>. 

Pyrido[2,3-b]pyrazine, 2,3-dihydroxy-chlorination, 3, 251 Pyrido[2,3-b]pyrazine, 6-hydroxy-formation, 3, 251 Pyrido[2,3-b]pyrazine, 8-hydroxy-tautomerism, 3, 250 Pyrido[2,3-b]pyrazine, methyl-acylation, 3, 253 Pyrido[2,3-b]pyrazine, 2-oxo-oxidation, 3, 250-251... 

The treatment of 4-acetylpiperazinone 323 with LiHMDS, followed by addition of (C02Et)2 gave three condensation products 324-326. Upon addition of excess LiHMDS 8,9-dihydroxy-3,4-dihydro-lH,6H-pyrido [l,2-fl]pyrazine-l,6-dione 327 was obtained in low yield (07BML5595). The major isomer 324 could be izomerized into 325 on the action of TFA in aqueous MeCN, which readily cyclized to pyrido[l, 2-aJpyrazine-l, 6-dione 327. 14C-labeled 327 was also prepared using 14C-labeled diethyl oxalate. 

Ultraviolet irradiation of 4,5-dichloro-3,6-difluoropyridazine similarly gives 2,5-dichloro-3,6-difluoropyrazine. Lemal and his co-workers consider that this result also eliminates the prismane mechanism for pyridazine-pyrazine interconversion.140a Methyl-, 2,5-dimethyl-, 2,6-dimethyl-, and trimethylpyrazine are formed when cis-3,7-dihydroxy-octahydro-l,5-diazocine is passed over hot alumina [Eq. (4)].141... 

The thieno[3,4-h][l,4]dioxins (341) have been obtained from the 3,4-dihydroxy thiophenes (340) by the two routes shown in Scheme 25. The use of ethane-1,2-diamine allows the synthesis of the tetrahydrothieno[3,4-6][l,4]pyrazine system <91JHC1449>. 

One such epidioxypiperazinedione has been reduced to a regular pyrazine. Thus l,4-dibenzyl-2,3-dioxa-5,7-diazabicyclo[2.2.2]octane-6,8-dione (86) underwent reduction by sodium borohydride in ethanol at 20°C during 1 h to afford 3,6-dibenzyl-3,6-dihydroxy-3,6-dihydro-2,5( l//, 4//)-pyrazincdione (86a) in 65% yield, confirmed in structure by dehydration to 3,6-dibenzylidene-3,6-dihydro-2,5(1 H, 4//)-pyrazincdionc (86b).5... 

Pyrazino[2,3-d]pyridazin 5,8-Dihydroxy- E9c, 366 [2,3-(COOR)2 —pyrazin + N2H4] Pyridazino 4,5-c]pyridazin ... 

Benzimidazol 1 -Methyl-2-nitrosami-no-E8c, 371 (NH2 - NH-N02) Phthalazine 5,7-Diamino-l, 4-dihydroxy- E9a, 752 [3,5-(NH2)2 —phthalanhydrid/N2H4] Pyrazin 5-Amino-6-cyan-3-metho-xycarbonyl-2-methyl- E9b/2,... 

Some unusual zwitterionic pyrazines have been prepared by dehydrogenation of 1,4-disubstituted piperazine-2,6-diones. Honzl et al. (476a) prepared theanhydro-2,6-dihydroxy-l, 4-diphenyl-3,5-bis(phenylthio)pyrazinium dihydroxide [s/c] (92) (which yields adducts by dipolar cycloaddition of maleic anhydride or formaldehyde) by the reaction of 1,4-diphenylpiperazine-2,6-dione with benzenesulfonyl chloride in pyridine. Tanaka et al. (476b), from I,4-diphenylpiperazine-2,6-dione with benzoyl chloride, and tosyl chloride in pyridine at reflux, obtained the anhydro - 3 - benzoyl - 2,6 -dihydroxy -1,4 -diphenyl - 5 - (p - toly lthio)pyrazinium dihydroxide [src] (93), together with some of the S-p-tolyl analogue of (92). 

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-... 

Hydrolysis of 2,6-diacetoxy-3,5-diphenylpyrazine (9) (from 2-hydroxy-3,5-diphenylpyrazine 1 -oxide by refluxing with acetic acid-acetic anhydride) with potassium hydrogen carbonate in methanol gave 2,6-dihydroxy-3,5-diphenylpyrazine (873), and 2-acetoxy-6-methoxycarbonylpyrazine (from 3-methoxycarbonyl-pyrazine 1-oxide with acetic anhydride) with methanolic hydrogen chloride gave 2-hydroxy-6 -methoxycarbonylpyrazine (838). 

Hydrolysis of 2-hydroxy-3-nitro-5,6-diphenylpyrazine (11) in aqueous sulfuric acid or aqueous hydrochloric acid-acetic acid afforded 2,3-dihydroxy-5,6-diphenyl-pyrazine (817, 1065), and similar results were obtained with dry hydrogen chloride in glacial acetic acid (841). 

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-... 

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