Pyrazine quaternization

The quaternization of pyrazine compounds has not been extensively studied, and, therefore, a detailed discussion of the effect of substituents is not possible. Recently Cheeseman has shown, from spectroscopic evidence, that 2-amino- and 2-diethylamino-pyrazine (50, Y = NH2 and NEt2) quatemize at N-4, although protonation occurs at position-1. Other substituted pyrazines from which quaternary salts of structure 51 are formed include 2-chloro- and 2-... 

The principal means for preparation of unreduced pyrazino[2,3- ]pyrazines and their fused and quaternized analogues involve the reaction of a 1,2-diamine with a 1,2-bis-electrophile, as reported in CHEC(1984) <1984CHEC(3)329> and CHEC-11(1996) <1996CHEC-11(7)737>. Additional examples of the condensation of dichloropyrazines with diamines have been reported since the appearance of CHEC-11(1996) <1997CHE1352,... 

Pyrazines (see Sections II, V,B,2, and D). Both 2-amino- and 2-methylpyrazine react with Mel to give isomers. The observed isomer ratios are very close to those predicted by considering relative reactivities of the appropriately 2- and 3-substituted pyridines.62 The observation159 that 2-aminopyrazine undergoes quaternization... 

Triazanaphthalene. Quaternization of 1,4,5-triazanaphthalene (59) with Mel in DMSO gives a single product resulting from reaction at N-5, a result expected from a consideration of the reactivities of pyridine and pyrazine.41... 

The aza substituent constants (vide supra) reflect the fact that electron-withdrawing annular nitrogens decrease the reactivity of any other ring nitrogen in the order ortho meta < para. For this reason, pyrazines should quaternize more readily than pyrimidines and pyridazines, and all three diazines should react faster than triazines. When the diazines are included in a Hammett plot for the methylation of substituted pyridines (p = —2.3), the positive deviations showed that they were all more reactive than indicated by their pK values. Relative rates compared with pyridine were pyridazine, 0.25 pyrimidine, 0.044 and pyrazine, 0.036 (72JA2765). Pyridazine in particular appears to be much more reactive than one would expect. (See Section III, A below). 

The isomer ratios estimated for a series of pyrazines, pyridazines, and pyrimidines are in good agreement with experiment (72T1983) they provide not only reasonable predictions of isomer ratios of quaternization products but also a method for rectifying many of the previously contradictory statements in the literature. 

Various l-alkylimidazo[l,2-a]pyrazine 7-oxide quaternary salts have also been synthesized from imidazoles (71JCS(C)2748). Two approaches were used. Quaternization of the oximes (462) with a-bromocarbonyl compounds gave salts (463) which cyclized in strong acid to the 7-oxides (464), and quaternization of the acetals (465) with bromoacetaldehyde oxime afforded salts (466) which were treated with concentrated sulfuric acid. 

Dimethylaminoethyl)pyrazine was quaternized by methyl iodide to give 2-(2 -trimethylammonioethyl)pyrazine iodide (48) (which with aqueous sodium hydroxide gave 2-vinylpyrazine) (657) and 2-hydroxy-3-nitro-5,6-diphenylpyrazine... 

The 7-oxides of thiazolo[3,2-a]pyrazin-4-ium salts are available by analogous methods to those used for pyrido[l,2-a]pyrazines. The N-oxide (25) of the parent was obtained by quaternization of the ethylene acetal 22 (R = H) with bromoacetaldehyde oxime (23) followed by the cyclization of the quaternary compound 24 with concentrated sulfuric acid. Attempts to quaternize the acetal 22 (R = Me) with bromoacetaldehyde oxime were unsuccessful. 

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