Pyrazines Gutknecht synthesis

A limitation of the Gutknecht synthesis lies in the fact that the pyrazine products are necessarily symmetrically substituted. Thus the 2 and 5 substituents must be the same, as must the 3 and 6 substituents. Thus the reaction is not applicable to those situations in which an unsymmetrical pyrazine is the desired product. In addition, the Gutknecht synthesis does not provide a useful preparation of pyrazine itself. ... 

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. ... 

It is not surprising that the pyrazine products of the Gutknecht synthesis have been frequently used as intermediates in the synthesis of biologically active compounds, both pharmaceuticals and agrochemicals. For example, a series of pyrazine derivatives (23, Ri = methyl, ethyl, propyl, wo-propyl, and n-butyl) have recently been examined as heterocyclic nonsteroidal estrogens with selectivity for estrogen receptor subtype ERa over ERp. ... 

The Gutknecht synthesis has also lent itself to the inexpensive, large-scale preparation of pyrazines for specialty engineered materials. Recently a series of 6,12-dihydro-diindeno[l,2-b l, 2 -e]pyrazine derivatives with electroluminescent properties were prepared and studied as deep blue light-... 

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... 

Gutknecht Pyrazine Synthesis Stephen W. Wright 8.3.1 Description... 

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. 

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. 

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