Amino-pyrazines, basicity

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... 

Oakley and co-workers reported the transformation of l,2,5-thiadiazolo[3,4-/ ]pyrazines into tricyclic rings 55 and 57. Titanocene 55 was prepared by reaction of 5,6-dithiol derivative 54 with Cp2TiCl2 under basic conditions (Scheme 37) <1998JA352>, and 6-amino-5-thiol 56 was condensed with sulfur monochloride to give the 1,2,3-dithiazolidine derivative 57 in excellent yield (Scheme 38) <1999JA969>. 

Aminopyrazine is a yellowish crystalline solid with m.p. 118-120 (420). It is a weak base with reported pAj, values of 3.14 (123) and 2.96 (821) (others are recorded in Chapter X). The similarity in the ultraviolet spectra (in water) of the neutral molecules of 2-amino-, 2-methylamino-, and 2-dimethylaminopyrazines, and of their monocations, and their similar basic strengths (2.96,3.42,3.27) (821) supports the conclusion that in aqueous solution 2-aminopyrazine exists mainly in the amino form (20) (821). The ultraviolet spectrum of 2-aminopyrazine cation differs from that of the neutral molecule of pyrazine, thus indicating that protonation does not take place at the extranuclear nitrogen atom (821) 2-aminopyrazine in fact protonates at Ni (see below). 

Aminopyrazine is a stronger base than pyrazine moreover, 2-amino-, 2-methylamino-, and 2-dimethylaminopyrazine have closely similar basic strengths, which supports the conclusion that, in aqueous solution, 2-aminopyrazine exists mainly in the amino form (1) (821). Ultraviolet spectral evidence (see Section VIII. 1C) indicates that the protonation does not take place at the extranuclear amino group (821). This and other evidence (p.m.r.) (1136) are consistent with monoprotonation of 2-aminopyrazine at Ni, and the second protonation at N4. 2,3-Diaminopyrazine (pAg 4.88) is a much stronger base than 2-aminopyrazine, but... 

The vinyl triflate of Kornfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(A-rerr-butoxycarbonyl-A-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [257], A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [258], Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in Chapter 10 (pyrazines) [259], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 240 with arenes [260]. Subsequent desulfurization and hydrolysis furnishes 2-arytmethylindoles 241. Bis-indole 242 was also prepared in this study. Aryl iodides couple with indole under basic conditions to afford 2-arylindoles [261]. 

The mechanism of Gutknecht pyrazine synthesis has been studied and is well understood. Reduction of the a-oximino ketone affords an a-amino ketone. If the reduction is carried out under acidic conditions, the a-amino ketone may be isolated as an acid salt. These acid addition salts are entirely stable. In these salts the ketone carbonyl may be hydrated, and this is particularly true for a-amino aldehydes. However, as soon as the free base of the amine is generated, either from the salt or during reduction of the oxime if this is carried out under neutral or basic conditions, rapid bimolecular imine formation occurs, which is then followed by rapid intramolecular formation of a second imine to afford a dihydropyrazine. Oxidation to the pyrazine may occur spontaneously upon exposure to air, particularly in the presence of transition metals, and it is this facile aerobic oxidation that doubtless accounts for the isolation of pyrazines by early workers in the field. 

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