2-Chloro-5-hydroxy-3,6-dimethylpyrazine

Chloro-5-hydroxy-3,6-dimethylpyrazine with phosphoryl chloride gave a low yield of 2,5-dichloro-3,6-dimethylpyrazine (312) 3-chloro-5-hydroxy-2-methyl-pyrazine gave 3,5-dichloro-2-methylpyrazine (535) and 2-chloro-5-hydroxy-3,6-diisobutylpyrazine with phosphoryl chloride at 150° for 5 hours gave 2,5-dichloro-3,6-diisobutylpyrazine (101). 

Chloro-3-hydroxy-5(and 6)-methylpyrazine with ammonium hydroxide, copper, and cupric chloride at 125° for 15 hours gave 2-amino-3-hydroxy-5(and 6)-methylpyrazine (373, 835), but 2-chloro-5-hydroxy-3,6-dimethylpyrazine was recovered unchanged after treatment with alcoholic ammonia under drastic conditions (312) and 2-chloro-3-hydroxy-5,6-diphenylpyrazine with pyridine and its hydrochloride at reflux gave the betaine (33) from 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (863). Replacement of the chloro substituent occurred... 

Cheeseman and Godwin (883) repeated the literature preparation of 2,5-dimethoxy-3,6-dimethylpyrazine (797) and obtained the dimethoxy compound in the expected yield together with 2-chloro-5-hydroxy-3,6-dimethylpyrazine (25%). Although no rigorous precautions were taken to exclude moisture, the formation of the last compound was attributed to the attack by methoxide ion at the extra-nuclear methoxycarbon atom (883). 

Dichloro-3,6-dimethylpyrazine 1,4-dioxide with 0.5 sodium hydroxide at 20° for 5 hours gave 2-chloro-5-hydroxy-3,6-dimethylpyrazine 1,4-dioxide which resisted further alkaline hydrolysis (842) (possibly due to anion formation, whereas sodium ethoxide and sodium benzyloxide rapidly displaced both chloro substituents). Similarly bromoaspergillic acid (3-bromo-2-s-butyl-6-hydroxy-5-isobutylpyrazine... 

Diacetyl-3,6-dibenzylpiperazine-2,5-dione (15) reacted with sulfur in dimethyl-formamide and triethylamine to form, after hydrolytic removal of the acetyl groups, 3-benzyl-6-benzylidenepiperazine-2,5-dione (16) (1068). 2-Chloro-5-hydroxy-3,6-dimethylpyrazine heated with solid potassium hydroxide gave 3-hydroxy-2,5-dimethylpyrazine (312), and 2-chloro-6-hydroxy-3,5-diphenylpyrazine with an excess of methanolic sodium methoxide at 150° formed 2-hydroxy-3,5-diphenylpyrazine (873). Decarboxylation of 2-carboxy-3-hydroxypyrazine gave 2-hydroxypyrazine (420) and in this way 24iydroxy[2- C]pyrazine (823) and 2-hydroxy[l- N]pyrazine (822) have been prepared. 

Chloro-2,S-dimethylpyrazine was not isolated from the reaction of DL-alanine anhydride with a mixture of phosphoryl chloride and phosphorus pentachloride, but the reaction gives a poor yield of (48, X = Q) and a small quantity of (48, X = OH). Gallagher et al. (282) found that DL-phenylglycine with phosphoryl chloride gave 2,5-dichloro-3,6-diphenylpyrazine and 3-hydroxy-2,5-diphenyl-pyrazine (presumably formed by loss of the elements of hydrogen chloride from an intermediate 2-chloro-5-hydroxy-3,6-diphenyldihydropyrazine) and Dunn et al. (95) from DL-leucine anhydride and phosphoryl chloride prepared flavacol, 3-hydroxy-2,5-diisobutylpyrazine, and a mature of chloropyrazines, whereas Ohta (101) used phosphoryl chloride and phosphorus pentachloride and obtained flavacol and a little 2[Pg.26]

Ramsay and Spring (548) found that treatment of a-chloro-a-hydroxyimino-acetone (13) with sodium hydrogen sulfite gave the bisulfite derivative of pyruvo-hydroxamic acid, which after purification from sodium hydrogen sulfite condensed with aminoacetone to give 2-hydroxy-3,6-dimethylpyrazine 1-oxide (14). 

Many chloropyrazines have been prepared from hydroxypyrazines by reaction with mixed phosphorus pentachloride-phosphoryl chloride as follows 2-hydroxy-pyrazine to 2-chloropyrazine (818), 2-hydroxy-3-phenylpyrazine to 2-chloro-3-phenylpyrazine (535), 2-hydroxy-6-methyl- and 5-hydroxy-23-[Pg.102]

Refluxing phosphoms tribromide converted 2-bromo-3-hydroxy-5,6-diphenyl-pyrazine and 2-bromo-5-hydroxy-3,6-diphenylpyrazine to the dibromopyrazines 2,3-dichloro-5,6-dimethylpyrazine and 2,5-dichloro-3-phenylpyrazine to the dibromopyrazines (817) 5-chloro-2,3-diphenylpyrazine (and its 6-ethyl derivative) to 5-bromo-2,3-diphenylpyrazine (and its 6-ethyl derivative) (866) and 2-hydroxy-... 

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-... 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature gave 2-cyano-5-ethoxy-3,6-dimethylpyrazine and 2-cyano-5-hydroxy-3,6-dimethylpyrazine (288). Reactions of 2-chloro-6-cyanopyrazine with sodium methoxide have been described in Sections 1 A(2)(c). 

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