Cyanopyrazine

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>. 

Wieser, M., Heinzmann, K., and Kiener, A. 1997. Bioconversion of 2-cyanopyrazine to 5-hydroxypyrazme-2-carboxylic acid with Agrobacterium sp. DSM 6336. Applied Microbiology and Biotechnology, 48 174—6. 

The replacement of nitrile groups by amino groups is exemplified by the reaction of 2,3-dicyano-pyrazine (272) with an aqueous solution of methyl-amine to give 3-methylamino-2-cyanopyrazine (273) (86JHC1299 see also... 

Amino-2-carbamoyl-5-hydroxypyrazine in dimethylformamide with phosphoryl chloride gave 3-amino-5-chloro-2-cyanopyrazine (538). 

Displacement of the chloro substituent from pyrazines by the cyano group has not been satisfactorily accomplished (866), but many cyanopyrazines have been prepared from the bromo analogues. Karmas and Spoerri (866) prepared 11 cyanopyrazines with mono-, di-, or trialkyl or phenyl substituents from the corresponding bromo compounds and cuprous cyanide in refluxing dry 4-picoline, but the procedure was not suitable for the preparation of 2-cyanopyrazine (866). It was prepared in 29% yield when the reaction was performed in pyridine (866). Another preparation of 2-cyano-3-phenylpyrazine from the bromo analogue has also been reported (1024). 

Certain a-chloromethylpyrazine A -oxides have been deoxygenated with phosphorus trichloride. Treatment of 2-amino-5-chloromethyl-3-cyanopyrazine 1-oxide (and 2-amino-3-cyano-5-methoxymethylpyrazine 1-oxide) with phosphorus trichloride at room temperature in tetrahydrofuran resulted in smooth deoxygenation to 2-amino-5-chloromethyl-3-cyanopyrazine (and 2-amino-3-cyano-5-methoxy-methylpyrazine) (529), whereas 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide was best deoxygenated to 3-amino-5-chloromethyl-2-cyanopyrazine by phosphorus trichloride in refluxing tetrahydrofuran (534). The more vigorous conditions necessary for the last reaction may be a reflection of increased steric hindrance at the fV-oxide grouping (529). Use of solvents like chloroform or dioxane led to slow reactions which were accompanied by the formation of numerous unidentified by-products (534). 

Amino-3-cyanopyrazine 1,4-dioxide was selectively monodeoxygenated with phosphorus trichloride in tetrahydrofuran at 25° to 3-amino-2-cyanopyrazine 1 -oxide (538). 

Cyanopyrazine with concentrated aqueous ammonia was converted through 2-[A(-(C-imino-C-pyrazin-2-ylinethyl)amidino]pyrazine (43) to 2-carbamoylpyrazine (985), and 2-chloro-6-cyanopyrazine reacted similarly (985). 2-Ethoxy-6-(C-ethoxy-C-iminomethyl)pyrazine was found to be a by-product of the reaction of 2-chloro-6-cyanopyrazine with concentrated ethanolic ammonia and 2-ethoxy(or methoxy)-6-[C-ethoxy(or methoxy)-C-iminomethyl]pyrazine was obtained from 2-chloro-6-cyanopyrazine by the action of ethanol (or methanol) in the presence of triethylamine (985). 2-Cyanopyrazine treated in water with hydroxylamine hydrochloride and sodium carbonate at 70-75° gave 2-(C-amino-C-hydroxyiminomethyl)-pyrazine (62), and 2aluminum chloride at 140-220° gave 2-(C-anilino-C-iminomethyl)pyrazine (and similar preparations were carried out with other aromatic amines) (1334,1410). 

Cyanopyrazine with dicyanodiamide [(NH2CN)2] gave the 2-(4, 6 -diamino-triazin-2 -yl)pyrazine (63), with o-phenylenediamine in the presence of poly-phosphoric acid at 250 gave 2-(benzimidazol-2 -yl)pyrazine, and with hydrazine gave 2-(C-hydrazino-C-iminomethyl)pyrazine, which condensed with benzil to 2-(5, 6 -diphenyl-as-triazin-3 -yl)pyrazine (64) (1441). 

Cyanopyrazine treated with a Grignard solution of methylmagnesium bromide in ether followed by treatment with dilute hydrochloric acid formed 2-acetyl-pyrazine (138). In a similar manner, 2-acetyl-5(and 6)-methylpyrazine (1327), 5-acetyl-2,3-diphenylpyrazine (866), and 2-acetyl-3,5,6-trimethylpyrazine (866) were prepared. 2-Cyanopyrazine with phenylma esium bromide has been reported to give 2-(C-imino-C-phenylmethyl)pyrazine (1220). 

The preparation of acetylpyrazines from cyanopyrazines and Grignard reagents proceeded in the usual manner. 2-Cyanopyrazine with methylmagnesium bromide in ether followed by treatment with dilute hydrochloric acid gave 2-acetylpyrazine (138, 1447). In a similar way the following pyrazines were prepared 2-acetyl-5-methyl (1327) 2-acetyl-6-methyl (1327) 5-acetyl-23-diphenyl (866) 2-acetyl-3,5,6-trimethyl (886) and 2-benzoyl (1447). 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

Cyanopyrazine A -oxides have been prepared from a-amino nitriles and a-hydroxyimino carbonyl compounds as summarized in Section III. 1 (528-530, 532-534, 537, 540, 542). Oxidation of 2-cyanopyrazine with perhydrol gave 3-cyanopyrazine 1-oxide (575), 2-cyano-5-ethoxy-3,6-dimethylpyrazine with 30% hydrogen peroxide in acetic acid at 55° gave 2-cyano-5-ethoxy-3,6-dimethylpyrazine iV-oxide (288), and the oxidations of 2-amino-3-cyanopyrazine 1-oxide (538) and... 

Numerous 3-substituted 2-cyanopyrazines and quinoxalines are synthesized by reaction of the corresponding 3-substituted iV-oxides with TMS-CN in the presence of triethylamine (Section... 

The product had already been synthesized by Kushner et al. (1952), and Smith (V.K.) and Kushner (1954) and Shindo (I960), in relation with a study on the antituberculous activity of pyrazina-mide, an aza-analog of nicotinamide (Cote et al., 1953). A preparation procedure was also described by Wolt (1975a). The synthesis is usually performed by dehydration of the commercially available pyrazinamide into 2-cyanopyrazine followed by a Grignard reaction (Ohloff et al., 1985). 

Figure 11.8 Reaction sequence analogies of 3-cyanopyridine 1 degradation and 2-cyanopyrazine 4 transformation (through nicotinic acid 2 and 6-hydroxy-nicotinic acid 3 or pyrazinecarboxylic acid 5 and 5-hydroxypyrazine-2-carboxylic acid 6 respectively). Figure reproduced from [49] with kind permission from Springer Science and Business media.

Reddy, B.M., Kumar, M.V., and Manohar, B. Vanadium phosphorus oxide catalysts for ammoxidation of 3-picoline to nicotinonitrile and 2-methylpyrazine to 2-cyanopyrazine. In Catalysis of Organic Reactions, Scaros, M.G. Prunier, M.L., Eds. Marcel Dekker New York, 1995 pp. 487 91. 

FIGURE 7.7 Catalytic results of the ammoxidation of 2MP using various LaVO x catalysts with varying La V ratios X-MP = conversion of 2MP Y-CPy = yield of 2-cyanopyrazine Y-CO = yields of CO and CO STY = space-time-yield [96, 98]. 

DhachapaUy, N., Kalevaru, V.N., Brtlckner, A., and Martin, A. Metal vanadate catalysts for the ammoxidation of 2-methylpyrazine to 2-cyanopyrazine. Appl Catal A 443-444, 111-118(2012). 

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