Aminopyrazines halogenation

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

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]. 

There are many examples from the work of Cragoe and his colleagues on the activating effect of a para-amino group on the halogenation of pyrazines. Thus, treatment of methyl 3-aminopyrazine 2-carboxylate... 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides. A methoxy group is also displaced with phosphoryl chloride to yield chloropyrazine when the period of reaction is prolonged or the reaction is carried out at higher temperatures <78JHC665>. Chloro- and bromopyrazine N-oxides are obtained by diazotization of aminopyrazine A-oxides in concentrated hydrochloric acid and hydrobromic acid, respectively (see Section 6.03.5.4.2). 

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