2.6- Dihydroxy-3,5-diphenylpyrazine

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)]. 

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

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-... 

Other methylations with diazomethane are as follows 2,6-dihydroxy-3,5-diphenylpyrazine formed a mixture of products from which only 2,6-dimethoxy-... 

Dihydroxy-5,6-diphenylpyrazine refluxed with aqueous hydrazine hydrate gave 2-hydrazino-3-hydroxy-5,6-diphenylpyrazine, which was also obtained by heating 2-hydroxy-3-nitro-5,6-diphenylpyrazine with aqueous hydrazine (1124). Distillation of the compound claimed by Japp and Knox (317) to be 3-hydroxy-2,5-diphenylpyrazine (317, cf. 282) with zinc dust produced 2,5-diphenylpyrazine (317) reduction of the former with hydriodic acid and red phosphorus at 200 for 6 hours gave what was regarded as 2,5-diphenyl-3,4-dihydropyrazine (317). 

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). 

A solution of 2-hydroxy-3-nitro-5,6-diphenylpyrazine in dry pyridine treated dropwise with thionyl chloride gave a slightly exothermic reaction and after standing for 18 hours gave the zwitterion of 24iydroxy-5,6-diphenyl-3-pyridinio-pyrazine (12) (863) and 23-dihydroxy-5,6-diphenylpyrazine with boiling 50% aqueous hydrazine gave 2-hydrazino-3-hydroxy-5,6-diphenylpyrazine (13) (which was also prepared from 2-hydroxy-3-nitro-5,6-diphenylpyrazine) (1124). 

Hydroxy-3-nitro-5,6-diphenylpyrazine was converted with 72% sulfuric acid at 82° to benzil (24%), 23-dihydroxy-5,6-diphenylpyrazine (41%), and an unidentified solid (20%) (1065). The formation of benzil under these conditions was proof that neither of the phenyl groups in the starting material was nitrated (1065). 2-Hydroxy-3-nitro-5,6-diphenylpyrazine refluxed with acetic-6Af hydrochloric acid (1 1) for 1 hours also gave 2,3-dihydroxy-5,6-diphenylpyrazine (94%) (817). 

The title compounds are stable tautomers of the corresponding 2-hydroxypyrazine 1-oxides, and in fact l-acetoxy-2(lH)-pyrazinones, not 2-acetoxypyrazine A -oxides, are obtained on treatment with acetyl chloride in the presence of pyridine at room temperature <87JHC187>. Nevertheless, these compounds resemble the N-oxides in most of their reactions. Representative examples are deoxidative acetoxylation and chlorination. Treatment of l-hydroxy-3,5-diphenyl-2(l//)-pyr-azinone (100) with a refluxing mixture of acetic anhydride and acetic acid affords 2,6-diacetoxy-3,5-diphenylpyrazine (101), which is deacetylated with potassium hydrogen carbonate to give 2,6-dihydroxy-3,5-diphenylpyrazine (102) (or tautomer) (Scheme 23) <7UCS(C)2977>, Acetoxylation of a methyl substituent occurs exclusively and then that of the pyrazine ring is suppressed completely. 

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