Cyanopyrazines

Direct oxidation of ethylpyrazines to the corresponding acetylpyrazines may also be carried out in favourable circumstances using hot chromic acid (75JOC1178). Treatment of 2-ethyl-3-alkylpyrazines with chromic acid yields the corresponding 2-acetyl-3-alkyl-pyrazines in yields of 50-70%. In the absence of the 3-alkyl substituent the yields fall dramatically to less than 10%. Acetylpyrazines are more generally prepared by the inverse addition of a Grignard reagent to a cyanopyrazine. 

Various 4-aminopteridine 3-oxides have recently been obtained by cyclization of 2-amino-3-cyanopyrazine derivatives (81H(15)293). 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

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>. 

The reductive decyanation of cyanopyrazine using H2 and Pt/C under acidic conditions has been reported <2002TL6747>, that is, 2-amino-3-cyano-5-phenylpyrazine 1-oxide 73 is hydrogenated to 2-amino-5-phenylpyra-zine 74 in 90% yield (Equation 11). The double reduction has also been shown to be realized with sodium dithionite. 

Another efficient 1,2-diamine for synthesis of cyanopyrazines is 2,3-diamino-3-phenylthioacrylonitrile 135, an adduct of thiophenol to aminomalononitrile tosylate (Scheme 37). The condensation with phenylglyoxal diethyl acetal affords a mixture of two possible isomers 136 and 137, whose regioselectivity is improved by addition of trifluoroacetic acid finally, the isomer 136 is isolated in 86% yield <2001SC725>. 

The synthetic strategy of preparing pyrazines by condensation of 2-keto aldoximes with a-amino nitriles is well represented by Taylor s pteridine synthesis, in which a variety of 2-amino-3-cyanopyrazine 1-oxides have been prepared by using aminomalononitrile <2002TL6747> as the amino nitriles. In the same fashion, some other a-amino nitriles, which are often the Strecker synthesis products, are converted into 2-aminopyrazine 1-oxides 160 (Scheme 44). The condensations are realized by treatment with iV-methylmorpholine <1993JOC7542>, and... 

Oxidation of one of the nitrogen atoms of 2-chloro-3-cyanopyrazine to form a mono-iV-oxide allows for an identical sequence of reactions to generate the corresponding W-oxide 484 <1999W09957122, 2000JME1586>. 

A direct and versatile synthesis of the thieno[2,3-6 ]pyrazine ring system was found by Schneller and coworkers and consists of the reaction of 2-chloro-3-cyanopyrazine (361) with ethyl a-mercaptoacetate in the presence of sodium carbonate (Scheme 106) (75JHC513, 76JHC273 cf. 79MI31703). The conversion of (362) to thieno[2,3- >]pyrazine (363) is accomplished by straightforward methods. The compound (363) forms colorless crystals with m.p. 44 °C. 

Swern oxidation of 2-(3-cyanopyrazin-2-yl)-6-hydroxymethylperhy-dropyrido[l,2-aJpyrazine at 78 °C gave 6-aldehyde (07USA2007/ 037816). 

The isonipecotinoyl analogues of FA and AP, (592) and (593) respectively, were prepared from 2-amino-5-bromomethyl-3-cyanopyrazine (16b) by an extension of the strategy first developed by Taylor, as depicted in Scheme 3.123 [2491. 

Cyanopyrazine is obtained in 90% yield by the reaction of phos-phoryl chloride and carboxamidopyrazine. The reactants are first kept at room temperature for 5 hours and then heated under reflux for 40 minutes.228 Commercially, cyanopyrazine is prepared by reaction of methylpyrazine with a mixture of ammonia and air in the presence of a catalyst. The catalysts used are Co, Fe, Sn, and Ag vanadates and vanadium phosphotungstate.229 Bromopyrazines are readily converted into cyanopyrazines by treatment with cuprous cyanide in boiling y-picoline.230... 

Reaction of cyanopyrazine and its 6-chloro derivative with hydrazine gives the corresponding amidrazones, these compounds have been prepared for testing as antitubercular agents.262b... 

Cyanopyrazines react with aromatic amines in the presence of aluminum chloride as catalyst at temperatures below 200° and give amidine derivatives in good yield [Eq. (14)].228 Hydrogenation of... 

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... 

Bromination of 2-amino-3-cyanopyrazine in acetic acid gave 2-amino-5-bromo-... 

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

Carbamoyl-3-hydroxypyrazine and phosphoryl chloride have been shown to give 2[Pg.101]

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