2- Methoxy-3- pyrazine bromination

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]. 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

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). 

The bromine atom in 2-bromopyrazino[2,3-6]pyrazines may be replaced by the methoxy or methylsulfanyl group under nucleophilic conditions.246 Unexpectedly, 6,7-dimethyl-2,3-bis(methylsulfanyl)pyrazino[2,3-h]pyrazine is formed (with introduction of a second methylsulfanyl group) when 2-bromo-6.7-dimethylpyra7ino[2,3-/>]pyrazine is treated with methanethi-ol in a solution of sodium methoxide in methanol at 201C for 4 hours [yield 19% mp 240-242 °C (cyclohexane)].246... 

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