Pyrazine reactions with radicals

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

Homolytic acylation of the pyrazine cation with aldehyde radicals have been reported (616). A mixture of pyrazine, acetaldehyde, aqueous acetic acid, sulfuric acid, r-butyl hydroperoxide, and ferrous sulfate gave 2,5-diacetylpyrazine, and similar reactions occurred with propionaldehyde and benzaldehyde (616). 

The product of reaction of pyrazinecarboxamide with Cr + is a dark green complex of chromiumCiii) and the pyrazinecarboxamide radical ion, first characterized in 1965 (see ref. 118 and references cited therein). Evidence has now been presented to show that in reactions with various cobalt(ni) complexes, the effective reducing agent is, not the radical-ion complex but free Cr + present in equilibrium with it (Pz = substituted pyrazine) ... 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

Electron-spin resonance (e.s.r.) spectra with characteristic hyperfine structure have been recorded during the initial stages of the Maillard reaction between various sugar and amino compounds. The products responsible for the spectra appear to be IV, Af -disubstituted pyrazine radical cations. The pyrazine derivatives are assumed to be formed by the bimolecular condensation of two- and three-carbon enaminol compo-... 

Silyl radicals (Si) obtained by reaction of 2 or 4 with thermally generated t-BuO radicals add readily to pyrazine and nitroalkanes to form the corresponding adducts 27 and 28 for which EPR spectra have been recorded [13]. 

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. 

The results of analyses of the ESR spectra of various reaction systems are summarised in Table II. It was shown that all spectra have in common the splittings arising from two equivalent nitrogens (about 8.2 G) and four equivalent protons (about 3.0 G), and additionally from an even number of equivalent protons with different splitting constants. These assignments let to the reasonable assumption that the radical products are N,N -disubstituted pyrazine cation radical derivatives, as shown in Fig. 4. This assumption was strongly supported by the fact that the hyperfine structure as well as the g-value of the ESR... 

Figure 4. N,N -Disubstituted pyrazine cation radicals with assignments for hyperfine structures of the ESR spectra in the Maillard reaction mixtures.

Formation of novel free radical products at an early stage of the Maillard reaction was demonstrated by use of ESR spectrometry. Analyses of the hyperfine structures for various sugar-amino compound systems led to the conclusion that the radical products are N,N -disubstituted pyrazine cation radicals. These new pyrazine derivatives are assumed to be formed by bimolecular condensation of a two-carbon enaminol compound involving the amino reactant residue. The presence of such a two-carbon product in an early stage reaction mixture of sugar with amine was demonstrated by isolation and identification of glyoxal dialkylimine by use of TLC, GLC, NMR, MS and IR. 

Lipid-Protein-Carbohydrate Interactions. Evidence for such complex interaction was recently reported by Huang et al (36) who observed that the addition of corn lipids to zein and corn carbohydrates enhanced the formation of alkylpyrazines, indicating that lipid-derived free radicals may accelerate the rate of Maillard reactions. Two of the alkylpyrazines, identified in such mixtures after heating for 30 minutes at 180°C, have 5-carbon alkyl substitution at the pyrazine ring and could only be explained by interaction of lipid or lipid decomposition products. These authors suggested that condensation of amino ketones, formed by protein-carbohydrate interaction, may yield 3,6-dihydropyrazine which would in turn react with pentanal, a lipid oxidation product, to form 2,5-dimethyl-3-pentylpyrazine. 

Reduction of pyrazine with potassium in 1,2-diethoxyethane at — 70° gives the paramagnetic radical anion. Anions have also been generated from the low-temperature reaction of pyrazine, methyl-pyrazine, 2,5- and 2,6-dimethylpyrazines with sodium or potassium in tetrahydrofuran or 1,2-dimethoxyethane. From measurements of their ESR spectra, ion-pair formation is proposed between the alkali metal cation and the pyrazine anion.96-101... 

Pyrazines form diquaternary salts on treatment with triethyloxonium fluoroborate. Using this reagent the 1,4-diethylpyrazinium difluoro-borates of pyrazine, 2,5-dimethyl-, and 2,6-dimethylpyrazines have been obtained in 96, 97, and 46% yield, respectively. The reaction is subject to considerable steric hindrance since the yield of diquaternary salt from tetramethylpyrazine is only 6%. The diquaternary salts are extremely reactive substances and that of the parent compound is shown by ESR measurements to be readily reducible to the radical cation [Eq. (7)].150... 

Radical nucleophile oxidation based on one-electron oxidation, known as the Minisci reaction, is employed for the functionalization of /V-heterocycles with acidic hydrogen peroxide in the presence of iron(II) salts (Figure 3.112).472 A range of A-heterocycles (pyridines, pyrazines, quinolines, etc.) which are activated towards attack by nucleophilic radicals when protonated are suited to this chemistry. The Minisci reaction is suitable for the preparation of carboxylic amides (from formamide), carboxylic esters (from pyruvic esters via a hydroxyhydroperoxide), aldehydes (from 1,3,5-trioxane) and alkylated pyridines (either from carboxylic acids or from alkyl iodides in dimethyl sulfoxide).473 The latter reaction uses dimethyl sulfoxide as the source of methyl radical (Figure 3.112). 

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