Replacement of Halogeno Substituents by Hydroxyl Groups

The reactivity of 2-fluoropyrazine with aqueous sodium hydroxide to give 2-hydroxypyrazine has been investigated (882, 884). In 1.07N sodium hydroxide at 26° the reaction followed pseudo-first-order kinetics with a half-life of 43 minutes, whereas under the same conditions 2-chloropyrazine had a half-life of 18 days, and 2-iodopyrazine and 2-fluoropyridine remained unchanged (882, 884). Thus, under the above conditions, 2-fluoropyrazine was 640 times more reactive than 2-chloropyrazine (882). Hydrolysis of 2-fluoropyrazine in 61V hydrochloric acid proceeded at a much slower rate with a half-life of 4 days at room temperature (884). Some literature preparations of hydroxypyrazines by hydrolysis of halogenopyrazines (chloropyrazines with aqueous sodium or potassium hydroxide unless otherwise specified) are as follows 2-hydroxy (150°) (818) 2-hydroxy-3-methyl (reflux) (680) 2-hydroxy-3,5-dimethyl (reflux) (978) 3-hydroxy-2,5-dimethyl (reflux) (98, 312, 680, 740) [at 120° (978)] 3-hydroxy-2,5-di- -butyl (powdered potassium 

6- dichloropyrazine with sodium hydroxide in aqueous tetrahydrofuran at reflux (832) and also from 2-chloro-6-fluoropyrazine (883)] 2-bromo-6-hydroxy (865) 2-chloro-5-hydroxy-3,6-dimethyl (potassium hydroxide in aqueous dioxane at reflux) (312) 2,5-di-s-butyl-3-chloro-6-hydroxy (powdered potassium hydroxide at 160-180°) (312) 2,3,5-trifluoro-6-hydroxy (from tetrafluoropyrazine with potassium hydroxide in r-butanol at reflux) (851) 5,6-dichloro-l-cyclohexyl-3-hydroxy-2-0X0-1,2-dihydropyrazine (from 3,5,6-trichloro-l-cyclohexyl-2-oxo-l, 2-dihydropyrazine with N sodium hydroxide in dioxane at 70-80°) (853) 2-amino-5-bromo-3-hydroxy (from 2-amino-3,5-dibromopyrazine by hydrolysis with 2N sodium hydroxide (804) and 3.57V sulfuric acid) (807) 2-amino-3-carbamoyl-5-cyano-6-hydroxy (from 2-amino-6-chloro-3,5-dicyanopyrazine) (484) 2-amino-3-hydroxy-5,6-bis(methoxycarbonyl) (aqueous sodium hydroxide at 20° or concentrated sulfuric acid at 40°) (409) and 2-amino-3-carboxy-5-chloro-6-hydroxy (from 2-amino-5,6-dichloro-3-methoxycarbonylpyrazine) (809, 858). 2-Benzyloxy-6-chloropyrazine with 3.57V sodium hydroxide in aqueous ethanol at reflux gave 2-chloro-6-hydroxypyrazine (32%), 2-benzyloxy-6-hydroxypyrazine (2%), 2-benzyloxy-6-ethoxypyrazine, and minor amounts of 2-chloro-6-ethoxypyrazine and 

6- diethoxypyrazine (883) and 2-benzylthio-6-chloropyrazine with 3.57V sodium hydroxide at reflux gave, after oxidation with potassium permanganate in acetic acid, 2,6-di(benzylsulfonyl)pyrazine (883). 2-Bromo-3-hydroxy-5,6-dimethyl(and diphenyl)pyrazine refluxed with 48% hydrobromic acid gave 2,3-dihydroxy- 

6- dimethyl(and diphenyl)pyrazine (817) and 2-amino-5-bromo-3-chloropyrazine refluxed with 3.57V sulfuric acid gave 2-amino-5-bromo-3-hydroxypyrazine (807). Slow addition of water to a solution of tetrafluoropyrazine in sulfuric acid left it unchanged whereas addition of methanol gave 2,3,5-trifluoro-6-methoxypyrazine (851). 

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). 

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