Other Substituted Aminopyrazines

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. 

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]. 

This section covers primary, secondary, tertiary, and quaternary aminopyrazines (both nuclear and extranuclear) but not (functionally substituted amino)pyrazines such as hydrazino-, hydroxyamino-, or azidopyrazines. General discussions have appeared on the spectra of 2-pyrazinamine,255 257 991 the proton-sponge properties of 2,3,5,6-tetra(pyridin-2-yl)pyrazine in relation to its fine structure,925 the fluorescene properties of 3,6-diamino-2,5-pyrazinedicarboxylic acid derivatives in relation to their fine structures,1646,1659 the basic properties of aminopyrazines and other such azines in relation to their electronic structures,412,928 and the fine structures of 3-amino-2-pyrazinecarboxylic acid1340 and l,4-diacetyl-2,3-diphenylpiperazine.559... 

These (substituted-amino)pyrazines and piperazines have proved to be useful intermediates for subsequent cyclizations and other reactions. Their formation from aminopyrazines and a few cyclizations are illustrated in the following examples ... 

Comparative A -oxide activation was likewise observed when other amines such as hexylamine, aniline, benzylamine, piperidine, and dimethylamine were used. It was also noted, in every example studied, that amination of the chloropyrazine A -oxide or alkylchloropyrazine 7V-oxide at elevated temperatures in a sealed vessel gave mixtures containing greater or lesser amounts of deoxygenated halogeno-pyrazine or aminopyrazine (921). Similar enhanced activation by theTV-oxide group was observed when 3-chloro-2,5-dimethylpyrazine and its 1-oxide in reaction with various amines were compared, although dialkyl substitution further retarded overall aminolysis (793,921). 

Dipole moments of 3-aminopyrazine 1-oxide (3.43D, dioxane) (749) and 3,5-bisdimethylaminopyrazine 1-oxide (4.87, benzene) (663) have been measured. Second-order rate constants for hydrogen-deuterium exchange of H2 and in sodium deuteroxide-deuterium oxide solutions of 3-amino- and 3-dimethylaminopyrazine 1-oxides have been determined as 2.3 x 10 , 1.1 x 10 , and 3.3 x 10 and 4.5 x 10 l/mol min, respectively. These results (and those of other 3-substituted pyrazine 1-oxides) have been correlated with o constants, and the log of the H2 exchange rates has been shown to be linearly related to the p/fa values of these compounds (745). 

Pteridine, and substituted pteridines, are generally very thermally stable. However, because of the ready reaction with water, and other nucleophilic species, pteridines are unstable in hot solutions. Pteridine undergoes ring fission of the pyrimidine ring in aqueous acid to yield 3-aminopyrazine-2-carbaldehyde 11 (aqueous base yields 10). Such ring fission has been reviewed,28,29 and is discussed further in Section 7.3.1.4.7.2. 

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