Pyrazine N-oxides

Condensation of phenylalaninenitrile, prepared from phenyl acetaldehyde, with 1-oxime of pyruvaldehyde afforded the pyrazine N-oxide, which was further rearranged to give the N-acetyl pyrazinone. The acetyl groups were removed by treatment with hydrazine to give the target 6-aminopyrazinone. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Monocyclic oxadiazepines have not been isolated in reactions of this type but it has been proposed that the 1,2,6-system (508) is an intermediate in the formation of (509) from the pyrimidine AT-oxide (507) (69TL4899), and that the 1,2,5-systems (511) and (512) are intermediates in the formation of the imidazoles (513) and (514) from the pyrazine N-oxide (510) (67TL1197). 

A behavior similar to that of pyridine and pyrazine N-oxides is exhibited by complexes of pyridines with hexafluoroacetone. Such complexes are expected to enhance the acidity of the pyridine hydrogens by oxygen-lithium chelating effects and therefore direct 2-deprotonation. In fact, treatment of f-butylpyridine (495) with LiTMP/THF-Et20/- 107°C generated, via the known complex 507, the stable 2-lithio species 508 which, upon reaction with electrophiles, furnished 2-substituted pyridines 509 (Scheme 154) (83JOC4156). 

A similar difference in reactivity is evident in the N-oxides pyrazine N-oxide is even more reactive than pyrimidine or pyridine N-oxide. Substituents in the 3-position appear to act mainly through their inductive effects (Table 10.3). Log k2 varies linearly with p/Ca, and the carbanion mechanism probably operates (there is, however, doubt about the mode of substitution at C-6 in pyrazine N-oxides) (70JOC3467). All four hydrogens of pyrazine N,AT-dioxide are exchanged in MeOD at 65°C (68MI2). 

Second-Order Rate Coefficients for Base-Catalyzed Deuterium-Hydrogen Exchange in 3-Substituted Pyrazine N-Oxides ... 

Far fewer cases of linkage isomerism occur in which the ligands are neutral molecules, although such complexes are theoretically possible for ligands such as pyrazine N-oxide. This molecule has the structure... 

This minor route to pyrazine N-oxides involves either reductive or hydrolytic debenzylation of l-benzyloxy-2(l//)-pyrazinones, often available by primary synthesis. 

Note It should be remembered that deoxygenation of pyrazine N-oxides is not usually achieved by treatment with hydrogen or formate ion in the presence of palladium or platinum catalysts.290 1283... 

All the major routes to pyrazinecarbonitriles have been discussed already by primary synthesis in Chapters 1 and 2 by cyanolysis of halogenopyrazines in Sections 4.2.8 and 4.4 by deoxidative cyanation of pyrazine N-oxides in Section 5.5.2.4 by the rare cyanolysis of nitropyrazines in Section 7.1.2 by cyanolysis of trimethylammoniopyrazine salts no recent examples by dehydration of pyrazinecarboxamides in Section 8.4.2 and by passenger introduction of a cyano group in a variety of ways, for example, by cyanoalkylation. 

PYRAZINE N-OXIDES, THEIR C-ALKYL AND C-ARYL DERIVATIVES... 

Both pyrazine N-oxides and 2,3-dihydropyrazines rearrange photochemically to imidazoles. Irradiation of the 2,5-disubstituted oxides (187) gives mixtures of the imidazole products (188, 189), probably through the intermediacy of oxaziridine intermediates (Scheme 109). 

Tetrafluoropyrazine is not completely protonated either in concentrated sulfuric acid or in fluorosulfuric acid (FS03H) it is estimated to have a pKa value of approximately —13.67b The pKa of pyrazine N-oxide is 0.05, it is thus a considerably weaker base than the parent heterocycle.67 ... 

It is obvious that simple pyrazine N-oxides cannot undergo 0-alkylation or acylation. However, tautomeric N-oxides, for example, (262), can do so. The following examples will illustrate conditions required and results to be expected ... 

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