2.6- Dihydroxy-3,5-diphenylpyrazine methylation

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-... 

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)]. 

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

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). 

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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