Pyrazine formation, pathways

T. Shibamoto and R. A. Bernhard, Investigation of pyrazine formation pathways in glucose-ammonia model systems, Agric. Biol. Chem., 1977, 41, 143-153. 

Shibamoto T. and Bernhard R.A. (1977) Investigation of pyrazine formation pathways in sugar-ammonia model systems. J. Agric. Food Chem. 25, 609-14. 

The alkylated pyrazines formation pathway in amino acid carbohydrate systems was studied by Koehler et al (7 ). 

Among the heterocyclics there is one group which will be thoroughly examined the pyrazines. The compounds belonging to this family play a very important role as contributors of desirable food flavor properties. Structurally, pyrazines are heterocyclic nitrogen compounds and their formation is a quite complicated process. Maga and Sizer (4) present a summary of these formation pathways. 

Although pyrolysis of selected leaf constituents generates pyrazines, the diversity and abundance of pyra-zines in smoke cannot be adequately accounted for by this mechanism alone. Maga and Sizer (2439) and Enomoto et al. (17B12) have reviewed the occurrence of pyrazines in roasted foods and proposed pathways for pyrazine formation. Their summaries present a large array of pyrazines found in the flavor fractions of a number of roasted foods. It is striking that nearly all pyrazines commonly found in tobacco smoke have been identified in at least one roasted food. For example, 2,3-dimethylpyrazine has been found in peanuts, barley, coffee, baked potatoes, mushrooms, lamb fat, and tobacco smoke (1587a). 

Shu, C-K. Pyrazine formation from amino acids and reducing sugars, a pathway other than Strecker degradation J. Agr. Food Chem. 46 (1998) 1515-1517. Smeeton, B. W. Genetic control of tobacco quahty Recent Adv. Tob. Sci. 13 (1987) 3-26. 

Leahy and Reineccius [22] found the influence of water activity on the rate of formation of alkyl pyrazines in a model system to parallel that of classical Maillard reaction. Briefly, the accumulation of pyrazines reached a maximum when heated at an Aw of ca. 0.75 and decreased with either increasing or deCTeasing Aw. This observation suggests that the rate of pyrazine formation is controlled by the initial stages of the Maillard reaction as opposed to an effect on specific pathways of pyrazine formation. 

In addition, interest in combinatorial chemical applications led a team at AMGEN to the recognition of a related but different pathway which afforded tetrahydro tetrazolo[l,5-zz]pyrazine-6-ones 121 (Scheme 22) <2000TL8729>. In this procedure, three starting components, that is, the ketone, the primary amine, and trimethylsilyl azide, as in the previous method, were used, and the fourth component was methyl isocyanoacetate. This reaction also took place under relatively smooth conditions (methanolic solution at room temperature for 6h followed by reflux for 24 h) to yield the products 121 in good to high yields. The reaction obviously proceeds by the formation of intermediate 120. 

Thus, ketone enolates easily substitute chlorine in position 2 of the electrophilic nucleus of pyrazine (1,4-diazabenzene), and even in the dark, the reaction proceeds via the Sj l mechanism (Carver et al. 1981). It is expected that the introduction of the second chlorine in the ortho position to 4-nitrogen in the electrophilic nucleus of pyrazine promotes the ion-radical pathway even more effectively. However, 2,6-dichloropyrazine in the dark or subjected to light reacts with the same nucleophiles by Sr.,2 and not S nI mechanism (Carver et al. 1983). The authors are of the opinion that two halogens in the pyrazine cycle facilitate the formation of a-complex to the extent that deha-logenation of anion-radicals in solution and a subsequent nucleophilic attack of free pyrazine radical become virtually impossible. Thus, the reaction may either involve or exclude the intermediate a-complex, and only special identification experiments can tell which is the true one. 

A systematic study to identify solid oxide catalysts for the oxidation of methane to methanol resulted in the development of a Ga203—M0O3 mixed metal oxide catalyst showing an increased methanol yield compared with the homogeneous gas-phase reaction.1080,1081 Fe-ZSM-5 after proper activation (pretreatment under vacuum at 800-900°C and activation with N20 at 250°C) shows high activity in the formation of methanol at 20°C.1082 Density functional theory studies were conducted for the reaction pathway of the methane to methanol conversion by first-row transition-metal monoxide cations (MO+).1083 These are key to the mechanistic aspects in methane hydroxylation, and CuO+ was found to be a likely excellent mediator for the reaction. A mixture of vanadate ions and pyrazine-2-carboxylic acid efficiently catalyzes the oxidation of methane with 02 and H202 to give methyl hydroperoxide and, as consecutive products, methanol and formaldehyde.1084 1085... 

Another reaction pathway is observed in methanol [117]. Irradiation of a methanolic solution of 134 led to imidazoline 147 in 60% yield, with a possible intermediate being azomethine ylide 146 (Scheme 1.44). However, two pathways for the formation of imidazoline 147 are possible. The first one is via initial formation of an enediimine 141 (such reaction is known as a nonphotochemical process [118, 119]). The fact that addition of methanol to compound 141 obtained by irradiation of cis-d i h yd ro pyrazine or trans-dih yd ro pyrazi ne 140... 

In the mechanism proposed to explain the formation of /l,y difluoro amines and a-fluoro ketones, two main, competing pathways are possible, after protonation of the 2//-azirine 1. One pathway leads to the / ,/ -difluoro amine 7 via the intermediates 2 and 6. A second possibility, via 2, 3 and 4, gives the observed a-fluoro ketone 5. Pyrazines are formed by the intermoleciilar reaction of the intermediates corresponding to 3, lo give diprotonated intermediates, e.g. 8. 

In the folate pathway, the ribosyl moiety of GTP supplies the carbon atoms required for the formation of a second heterocyclic ring, thus affording the first committed intermediate, dihydroneopterin triphosphate. A motif with close structural similarity to the dihydroneopterin motif is a structural part of molybdopterin the problem, however, is that the two carbon atoms required for the formation of the pyrazine ring plus the carbon atoms of the position 6 side chain add up to 6, and the ribosyl moiety of GTP is obviously insufficient to supply them all. 

Photochemical isomerizations of perfluoropyridazines proceed in a manner different from the thermal. Here, perfluoropyrazines (259) are formed in high yields and their formation was postulated to involve intermediate Dewar-diazabenzenes and diazaprismane. Irradiation of perfluoro-4,5-diisopropylpyridazine gives the corresponding pyrazine (301), twice as much of a para-bonded valence-isomer (300). The mechanistic pathway was... 

Manley et al. (1974) suggested that cyclopentapyrazines may result from the condensation of 2-hydroxy-3-methylcyclopent-2-en-l-one (D.68) with glyoxal or pyruvaldehyde and amino acids, and a mechanism of formation has also been suggested from a study on popcorn flavor by Walradt et al. (1970). Vitzthum and Werkhoff (1975) reported 17 new alkylated five-and six-membered bicyclic pyrazines in roasted coffee the mass spectra of these new constituents and particularly the fragmentation pathways of 2-methyl-(O.50) and of 6,7-dihydro-5-methyl-5//-cyclopentapyrazine (0.51) are discussed in detail. 

A more original pathway for formation of dihydrocyclopentapyrazines has been proposed by Flament (1981). The reaction of 2,3-dihydropyrazines with aldehydes and ketones allowed the preparation of numerous and original trisubstituted pyrazines. When a, (3-unsaturated carbonyl compounds were used, the formation of bicyclic pyrazines was observed. Transitory 2,3-dihydropyrazines which certainly result from the trimolecular condensation of an a-dicarbonyl fragment with a diol in the presence of ammonia can condense with a, 3-unsaturated compounds, giving 6,7-dihydro-5//-cyclopentapyrazine (0.49) and various alkylated homologs. 

---