2- Chloropyrazine, displacement reactions

The marked activation of the iV-oxide function on the chlorine atom of 2-chloropyrazine 4-oxide and 2-ehloro-3,6-dimethylpyrazine 4-oxide is also demonstrated by the milder conditions under which these compounds react with ammonia and amines compared with chloro-pyrazine and 2-chloro-3,6-dimethyl pyrazine, respectively. Although 2-chloropyrazine 4-oxide undergoes the expected displacement reaction with ammonia on heating at 115°-120° for 2.5 hours, reaction at 140° for 16 hours gives 2,3-diaminopyrazine, possibly as a result of an addition-elimination reaction on the initially formed 2-amino-pyrazine 4-oxide (Scheme 47).417... 

Palamidessi and Bernardi report the displacement of chloride ion from 2-carboxamido- and 2-amino-6-chloropyrazine with methanolic sodium methoxide.307 In the former case, reaction is carried out for... 

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... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

Hydroxy groups in activated positions are displaced by chlorine using phosphorus chlorides as for the pyridazine (680) (71MI42900). Halogen interchange reactions are to be expected. Bromination of the chloropyrazine (681) can be effected using bromine in chloroform (75JHC451). 

Nucleophilic displacement of halogen in pyrazines and quinoxalines is the most common method for the synthesis of otherwise inaccessible heterocycles, in which, over the past 12 years, the most innovative methodology has been the organometallic catalyzed cross-coupling reaction (Scheme 10). The first example in the pyrazine series was the reductive dechlorination of chloropyrazines... 

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). 

The parent compound (65) has been prepared by the reaction of sodium azide with 2-fluoropyrazine ° and 2-chloropyrazine. Nucleophilic displacement and cyclization occurred readily in refluxing ethanol or ethanolic hydrogen chloride. The diphenyl compound 67 was prepared by diazotization of the hydrazino compound 69 in acetic acid... 

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