Pyrazines from 2-aminoketones

A number of reductive procedures have found general applicability. a-Azidoketones may be reduced catalytically to the dihydropyrazines (80OPP265) and a direct conversion of a-azidoketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 55) has been reported to proceed in moderate to good yields (69LA(727)23l). Similarly, a-nitroketones may be reduced to the a-aminoketones which dimerize spontaneously (69USP3453279). The products from this reaction are pyrazines and piperazines and an intermolecular redox reaction between the initially formed dihydropyrazines may explain their formation. Normally, if the reaction is carried out in aqueous acetic acid the pyrazine predominates, but in less polar solvents over-reduction results in extensive piperazine formation. 

An alternative approach to the use of a-aminoketones involves acetals (72JOC221) and pyrazine-2,3-diones have been synthesized by this route (Scheme 58). The acetals are readily available from the phthalimido derivatives via the a-chloroketones. Hemiacetals have also served as a starting point for pyrazine synthesis, although in most cases hemiacetals are too labile to be easily prepared examples are common in the 2-amino-2-deoxy sugar series 2-amino-2-deoxy-D-glucose for example dimerizes to the pyrazine (101) when generated in situ from the hydrochloride salt (68JAP6813469). 

G A S T A L 0 I Pyrazine Synthesis Pyrazme synthesis from a-oximmokeiones via a-aminoketones... 

Several mechanisms have been proposed for the formation of pyrazines in food flavours [18, 23, 25], but the major route is from a-aminoketones, which are products of the condensation of a dicarbonyl with an amino compound via Strecker degradation (Scheme 12.3). Self-condensation of the aminoketones, or condensation with other aminoketones, affords a dihydropyrazine that is oxidised to the pyrazine. 

Also acetic acid may arise from a reaction of this type. Most important compounds of this pathway are pyruvic aldehyde, diacetyl, hydro-oxyacetone and hydroxydiacetyl which can easily react with amino acids. The Strecker degradation is a reaction where the amino acid is de-carboxylated and loses its amino group. Reaction products are the Strecker aldehyde and - as an intermediate - an aminoketone which forms a pyrazine by dimerization. This pathway is considered to be most important for the origin of pyrazines in thermal aromas. However, only limited knowledge is available about the fate of the Strecker aldehydes. As we will demonstrate they are very reactive. 

Many other examples are known of acid-catalyzed intermolecular Schiff reactions18 to give cyclic dimers. Thus, condensation of two molecules of a-aminoketones gives 2,5-dihydropyrazines (e.g., 9 from l-aminopropan-2-one), most of which can be converted into pyrazines by oxidation with mercuric chloride (i.e., the Gutknecht pyrazine synthesis19). The same type of self-condensation occurs on heating... 

Pyrazine synthesis from a-oximinoketones via a-aminoketones (see 1st edition)... 

Symmetrical pyrazines result from the spontaneous self condensation of two mol equivalents of a 2-aminoketone, or 2-aminoaldehyde, followed by an oxidation. 

In addition to the pyrazines (7, 10) formed in the early Neber rearrangements (which are theoretically accessible from any a-aminoketone), several other heterocycles have been prepared using this reaction as a key... 

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