Pyrazines quinoxalines

A feature eommon to the pyrazine, quinoxaline and phenazine ring systems is their remarkable stability in the mass speetrometer and in all eases with the parent heterocyeles the moleeular ion is the base peak. In the ease of pyrazine, two major fragments are observed at mje 53 and 26, and these fragments are eonsistent with the fragmentation pattern shown in Seheme 1. 

Table 3 lists some of the basic physical properties of pyrazine, quinoxaline and phenazine (references are given in the main text). 

Table 3 Physical Properties of Pyrazine, Quinoxaline and Phenazine...

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Pyrazine and quinoxaline fV-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine fV-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine fV-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

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). 

From the foregoing discussion it is evident that the most general methods for the synthesis of pyrazines, quinoxalines and phenazines fall into type A and type B categories, but other methods do exist. Although most of these are not of such general applicability, they are worthy of comment. 

Scarcely a single issue of Chemical Abstracts is published without reference to medicinal compounds containing the pyrazine or quinoxaline ring in some form, and hence it is impractical to list all applications of pyrazines, quinoxalines and phenazines. Some of the more important applications and natural products, particularly the more recent developments, are mentioned in this Section. 

Theoretical calculations have been a successful approach for the description of structures and thermochemistry for a wide variety of chemical substances in fact, the theoretical methods have greatly increased in importance for investigating various properties of pyrazines, quinoxalines, and phenazines <1996CHEC-II(6)233>. In most cases, the calculated results have been discussed in comparison with spectroscopic properties accordingly, in this chapter, such examples are shown in each section on spectroscopy. 

Additional examples of theoretical calculations for pyrazines, quinoxalines, and phenazines are arranged in Sections... 

Reactivity dealt with in the following sections is limited only to that of the heteroaromatic ring of pyrazines, quinoxalines, and phenazines, but exceptionally the reactivity on the benzo moiety of quinoxaline and phenazine is described in the Section 8.03.5.3. In general, any type of substitution reaction on quinoxaline and phenazine should be more facile than with pyrazine because of the resonance stabilization effect of the additional benzenoid ring on the transition states leading to the products. 

Santos-Veiga in 1962 upon pyrazine, quinoxaline, phenazine, and 1,4,5,8-tetraazanaphthalene.35 They failed, however, to observe the anion of pyridine (1) in its stead they found that of 4,4 -bipyridyl in ethereal solvents the ion-pairs of alkali metals and the pyridine anion-radical rapidly dimerize, yielding ultimately 4,4 -bipyridyl whose anion-radical is observed.30,35... 

Besides results for pyridine N-oxides, the paper of Kubota et a/.351 also presents polarographic and ESR data for other azine oxides including the mono- and dioxides of pyrazine, quinoxaline, and phenazine and the oxides of pyridazine, quinoline, and acridine. Their assignment for 105 may be compared with that shown for 22. On account of the molecular asymmetry,... 

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