Pyrazine radical substitution

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 adduct of silyl radicals to 4-substituted pyridines and pyrazine monitored by EPR results from the attack at the nitrogen atom to give radicals 52 and 53, respectively [68,69]. The rate constant for the addition of Et3Si radical to pyridine is about three times faster than for benzene (Table 5.3) [24]. 

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>. 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

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 SRN1 mechanism (Carver, Komin, et al. 1981). It might be expected that the introduction of the second chlorine in the ortho position to another nitrogen in the electrophilic nucleus of pyrazine promotes the ion radical pathway even more effectively. However, 2,6-... 

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. 

A theoretical/NMR study of keto-enol tautomerism in 2-(2-methoxycarbony-lacetyl)pyrazine (277/278) and other similarly substituted azines has been undertaken the foregoing pyrazine exists in its enolic form (278) to the extent of 35% in deuterochloroform.411 l,4-Diacetyl-l,4-dihydropyrazine (279) gave the persistent radical cation (279) + on one-electron oxidation (cyclic voltammetry in MeCN— Bu4NC104).167... 

Acylpyrazines, constituents in foodstuffs and pheromones, have been prepared by the Minisci-type radical reactions of pyrazines even though these methods often suffer from poor regioselectivity of aromatic substitution. Alternatively, synthesis of acetylpyrazines and propionylpyrazines 33 was achieved via a Stille coupling of bromopyrazines 31 with tributyl-(l-ethoxyalkenyl)tin (32), followed by acidic hydrolysis of the ether derivative [24]. 

Homolytic aromatic substitution of pyrazines is a rare reaction. Early workers in the field have updated their work on radical addition of oxidized formamide to pyrazine (250). The new procedure affords pyrazine-2-car-boxamide (251) in 96% yield (85T4157). 

Nncleophilic radicals add readily to diazines under Minisci conditions. Additions to pyrimidine often show little selectivity, C-2 versus C-A, but a selective Minisci reaction on 5-bromopyrimidine provided a convenient synthesis of the 4-benzoyl-derivative on a large scale. Similar reactions on pyridazines shows selectivity for C-4, even when C-3 is unsubstituted. Pyrazines can, of course, substitute in only one type of position. 

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