Dihydropyrazines, Gutknecht synthesis

Less frequently, dioximes have been used as starting materials in the Gutknecht synthesis. Formation of a dihydropyrazine from a dioxime could occur by hydrolysis of an oxime or imine intermediate to a diketone under... 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

Gutknecht pyrazine synthesis. Cyclization of a-amino ketones produced by reduction of isoni-troso ketones the dihydropyrazines formed are dehydrogenated with Hg20 or CuS04, or sometimes with atmospheric oxygen. 

The Gutknecht pyrazine synthesis constitutes the cyclization of an a-oximino carbonyl compound to ultimately form a pyrazine. The a-oximino carbonyl compound is reduced to afford an a-amino carbonyl compound, which undergoes cyclocondensation to a dihydropyrazine. Oxidation of the dihydropyrazine to the pyrazine may occur spontaneously or may be carried out in a second step. It is mechanistically related to the Stadel and Rugheimer and Erdmann syntheses, which involve the cyclization of a-haloketones with ammonia and a-hydroxyketones with ammonia, respectively. 

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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