2-Amino-6-chloropyrazine

Dihaloquinoxalines are extremely reactive and both halogen atoms are replaceable, on occasions explosively (59RTC5), whereas in the case of dihalopyrazines, and tri- or tetra-halopyrazines, there is frequently a considerable difference in reactivity of the halogen atoms. When 2,3-dichloropyrazine is treated with ammonia at 130 °C, only one chlorine atom is displaced, giving 2-amino-3-chloropyrazine (66FES799). 

Besides furo[2,3-d]pyrimidines, 6-substituted 5H-pyrrolo[2,3-h]pyrazines have also been obtained in a microwave-promoted one-pot process starting from N-mesyl protected 2-amino-3-chloropyrazine (Scheme 60) [74]. The... 

The readily available 2-amino-3-chloropyrazine 247 has been coupled with phenylacetylene using palladium-catalyzed conditions to give 2-amino-3-phenylethynylpyrazine 248, which subsequently is cyclized to pyrrolo[2,3-. ]pytazine 249 (Scheme 23) <2004TL8087, 2004TL8631, 2005TL1845>. 

Regioselectivity in the chlorination of pyrazine /V-oxides with phosphoryl chloride depends upon the substituent on the C-3 carbon. Thus, 3-aminopyrazine 1-oxide is chlorinated with loss of the /V-oxide oxygen to give 2-amino-3-chloropyrazine as the sole product whereas 3-methoxy and 3-chloropyrazine 1-oxides form approximately equal amounts of 3-chloro- and 6-chloro-2-substituted pyrazines along with a trace of the 5-chloro derivatives. 

Only one halogen is frequently displaced in the reactions of dihalo-genopyrazines with nucleophiles. Thus, 2-amino-3-chloropyrazine is isolated in 85% yield from the reaction of 2,3-dichloropyrazine and aqueous ammonia in an autoclave at 130° for 14 hours.270 Similarly Cragoe and his colleagues report a series of displacements in which the chlorine para to the electron-attracting carbomethoxy group in the dichloropyrazine (96) is preferentially displaced.309,310 These are illustrated in Scheme 31. The reaction of 2,6-dichloropyrazine with... 

Aminopyrazine with bromine in acetic acid gave 2-amino-3,5-dibromopyrazine (804, 810, 811), also obtained from bromination of 2-amino-3-bromopyrazine in aqueous hydrobromic acid (806, 807), and 5-amino-2,3-dimethylpyrazine with bromine in acetic acid gave 2-amino-3-bromo-5,6-dimethylpyrazine (812). 2-Amino-5-phenylpyrazine with bromine and pyridine in chloroform at 20 gave 2-amino-3-bromo-5-phenylpyrazine (365a), and 2-amino-3-chloropyrazine with 20% hydrobromic acid and bromine gave 2-amino-5-bromo-3-chloropyrazine (806,807). 

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... 

Aminopyrazine was oxidized by hydrogen peroxide in acetic acid at 20° to 3-aminopyrazine 1 -oxide and at 50° for 15 hours to 2-aininopyrazine 1,4-dioxide (51%) (also obtained by similar oxidation of 3-aminopyrazine 1-oxide) (1189). m-Chloroperoxybenzoic acid was also used for the oxidation of 2-aminopyrazine to its 1-oxide (1258). The following aminopyrazine TV-oxides have been prepared by oxidation (reagent and conditions) 2-amino-3-methoxycarbonylpyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (880, 1222) 2-amino-5-chloro-3-methoxycarbonyl(and methylcarbamoyl)pyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (1222) 2-amino-5-bromo-3-methoxycarbonylpyrazine 1-oxide (wperoxyacetic acid) (906) 2-amino-3-bromo-5,6-dimethylpyrazine 1-oxide (peroxyacetic acid) (907) and 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide (hydrogen peroxide in sulfuric acid at room temperature) (754). 

An attempt to diacylate an o-chlorophenylhydroxylamine with acetic anhydride-pyridine gave instead a cyclized product in which pyridine had been incorporated. A cleaner sample of the same product was obtained by stirring the diacetate in pyridine at ambient temperature. 2-Amino-3-chloropyrazines may react with a 2-unsubstituted pyridine at ambient temperature to form a fused imidazole system in which the pyridine is also fused. The presence of substituents on the pyridine ring may necessitate the use of DMF as solvent and heat to be suppli. ... 

Reaction of compound 8 with a-halo nitriles (R CHHalCN) gave the 3-amino compounds 7 after cyclization of the intermediate S-alkylated products 12 with aqueous potassium hydroxide. Similarly reaction of 2-amino-3-chloropyrazine (13) with the mercapto esters 14 in the presence of sodium ethoxide gave the 3-oxo derivatives 16 on refluxing in dioxan. The intermediates 15 are involved in the reaction. The most convenient synthesis of these compounds involves reaction of 2-amino-3-chloropyrazines with thioglycollic acid in alkali and acid-catalyzed cyclization of the carboxymethylthio derivative. ... 

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