2-Aminopyrazine bromination

As might be expected from a consideration of electronic effects, an amino substituent activates pyrazines, quinoxalines and phenazines to electrophilic attack, usually at positions ortho and para to the amino group thus, bromination of 2-aminopyrazine with bromine in acetic acid yields 2-amino-3,5-dibromopyrazine (Scheme 29). 

The presence of an N-oxide function in pyrazine is not sufficient in itself to promote electrophilic halogenation, and even the presence of other weak donor groups may fail to promote reaction unless they can act in concert. Although 2-methoxypyrazine 1-oxide could not be bromi-nated, the 3-methoxy isomer [and 3-aminopyrazine 1-oxide (54)] was bro-minated in the 2- and 6-positions (ortho to oxide and ortho or para to the amino group cf. Scheme 47). Similarly, 2-aminopyrazine was brominated more readily than its Af-oxide (55 R = H) where the two groups are in opposition [83JOC1064 84H(22) 1195]. 

The 6-position in the oxide becomes less activated than the 3- and 5-positions with the result that mixtures of 3-bromo (3-8%) and 3,5-dibromo (56 R = H) (20-30%) products are formed (cf. bromination of 2-aminopyrazine). A sterically demanding substituent such as 2-morpholino gave rise to the 5-bromo derivative exclusively (83JOC1064) (Scheme 48). Annular bromination of 2,3-dimethylpyrazine 1,4-dioxide could not be achieved (72CHE1153). 

The amino substituent attached to the pyrazine ring facilitates electrophilic attack at the ring carbon atoms in the ortho and para positions. Thus, bromination of aminopyrazine in glacial acetic acid... 

Aminopyrazines, like aminopyridines and aminopyrimidines, form p-aminobenzenesulfonyl derivatives, and one of these, 2-sulfanilamido-3-methoxypyrazine (11), is clinically used as an antibacterial agent.320 Bromination of compound 11 in methanol gives a product (114)321,322 which was originally incorrectly formulated as a hydrate.323 The correct structure follows from spectroscopic evidence and alkaline... 

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). 

The diazotization of aminopyrazines has been described in earlier sections. Section V.IH records the preparation of 2-fluoropyrazine from 2-aminopyrazine in fluoroboric acid containing copper powder with sodium nitrite (882, 884) and Section V.ll the preparation of iodopyrazines from some aminopyrazines via isodiazotate salts (30) (887). These salts were assigned the isodiazotate structure, on the basis of their inability to couple with 0-naphthol in alkaline solution (887) and they were characterized by hydrolysis in cold 40% aqueous sulfuric acid to the hydroxypyrazine (887). Section V.I K describes the conversion of aminopyrazines to bromopyrazines (798, 800, 807, 890-892) for example, 2-amino-3-methoxy-carbonylpyrazine with hydrobromic acid, bromine, and sodium nitrite in water gave 2-bromo-3-methoxycarbonylpyrazine (798, 890). The diazotization of aminopyrazines to hydroxypyrazines has been described in Section VI. 1C, to alkoxy-pyrazines in Section V1.3C, and to oxopyrazines in Section V1.9A(5). 2-Amino-pyrazine with isopentyl nitrite in benzene gave 2-phenylpyrazine (45%) and some 2-isopentoxypyrazine and 2,2 -dipyrazinyl amino isomers (1211). 

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