Ketones Gutknecht pyrazine synthesis

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 has overcome the difficulty of forming the multiple regioisomers that plagued the Staedel and Rugheimer synthesis. The synthesis begins with the reduction of oximino-ketones to... 

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. 

In general, the Gutknecht pyrazine synthesis allows the preparation of a wide variety of pyrazines containing symmetrically placed substituents. Yields are generally above 75%, making the reaction a useful route for preparative work. Oximino ketones derived from aralkyl ketones and p-keto esters have perhaps been used most frequently due the ease with which the ketones may be prepared and nitrosated. 

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. ... 

---