5-Amino-3-chloro-2-methylpyrazine

A. Rosowsky and K. K. N. Chen, J. Med. Chem., 1974,17, 1308 describe the preparation of 2-amino-5-chloromethyl-3oxide from aminomalononitrile tosylate and l-chloro-3-hydroxyimino-2-butanone using a method similar to that described (529) for an analogue. 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

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... 

By using thiourea in 2N sulfuric acid, Cullen and Harrison (905) were able to convert 2-chloro-3-methylpyrazine at reflux for 30 minutes to 2-mercapto-3-methylpyrazine (55%), and 3-chloro-2,5-dimethylpyrazine similarly treated gave 3-mercapto-2,5-dimethylpyrazine together with another higher molecular weight compound, postulated as either (60) or (61). 2-Amino-3-chloropyrazine refluxed with thiourea in alcohol, and the thiouronium salt refluxed with aqueous sodium hydroxide, produced 2-amino-3-mercaptopyrazine (535). 2-Chloropyrazine failed to react with thiourea (821) under the mild conditions that converted 2-chloro-quinoxaline to 2-mercaptoquinoxaline (1014). 

Chloropyrazine 1-oxide and 3-chloropyrazine 1-oxide both react with sulfanilamide to give the corresponding sulfanilamidopyrazine 7V-oxides (1032, 1033) 3-chloro-2-methylpyrazine 1-oxide with piperidine at reflux gave 2-methyl-3-piperidinopyrazine I -oxide, and with dimethylamine gave 3-dimethylamino-2-methylpyrazine 1-oxide (793) 2-amino-3-chloropyrazine 1-oxide with aqueous ammonia and copper powder at 140-150 for 18 hours gave 2,3-diaminopyrazine... 

Klein et al. (978) first attempted the alkaline hydrolysis of 3-chloropyrazine 1 -oxide to 3-hydroxypyrazine 1 -oxide, and although spectroscopic evidence indicated the formation of the hydroxy compound, good quality homogeneous material could not be isolated. Later work by Berkowitz and Bardos (1034) has shown that 3-chloropyrazine 1-oxide was hydrolyzed by refluxing with two equivalents of aqueous sodium hydroxide, and treatment of the product with trimethylsilyl chloride and triethylamine gave 3-(trimethylsilyl)oxypyrazine 1-oxide. 3,6-Di-s-butyl-2-hydroxypyrazine 1-oxide has been prepared from the chloro analogue (no details given) (982). Hydrolysis of 2-amino-6-chloro-3-cyano-5-methylpyrazine... 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide with triphenylphosphine in dimethylformamide at 80-90° gave 2-amino-3-cyano-5-(triphenylphosphonio)-methylpyrazine 1-oxide chloride (97) (520) and the 5-bromomethyl analogue reacted similarly with triphenylphosphine in propan-2-ol (542). Compound (97) on hydrolysis with 30% aqueous ethanol containing a small amount of triethylamine gave 2-amino-3-cyano-5-methylpyrazine 1-oxide and thus enabled removal of the chloro substituent from the chloromethylpyrazine (529) compound (97) with triethylamine and acetaldehyde (and other aldehydes) in chloroform at room temperature gave 2-amino-3-cyano-5-(prop-l -enyl)pyrazine 1-oxide (and other alkenyl analogues) (529). 

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-... 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

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