Pyrazine cyanates

PYRAZINE CYANATES, ISOCYANATES, THIOCYANATES, ISOTHIOCYANATES, AND CARBONITRILE OXIDES (H 301)... 

Reactions of Pyrazine Ketones Pyrazine Cyanates, Isocyanates, Thiocyanates, Isothiocyanates, and Carbonitrile Oxides... 

Chemoselective cyanation in the C-3 position of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one has been described by Van der Eycken et al. [27]. The procedure is similar to that reported by Alterman and Hallberg. The only difference is that CuCN was selected as transmetal-lating agent instead of Zn(CN)2. When a mixture of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one and CuCN in DMF, using Pd(PPh3)4 as a catalyst, was irradiated for 15 min at 200 °C, the desired 5-chloro-3-cyano-N-(4-methoxybenzyl)pyrazin-2(lff)-one could be isolated with a 68% yield (Scheme 69). 

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>. 

Pd-catalyzed cyanation of 2-methylpyrido[3,4- ]pyrazine 95 with Zn(CN)2 in the presence of Pd2(dba)3 and dppf gave the 5-cyano derivative 96 (dba = dibenzylideneacetone). Amination, without using any base, with benzylamine converted 95 into adduct 97 in excellent yield. Hydrolysis of 95 in aqueous formic acid provided the 5-oxo derivative 98 (Scheme 4) <2003H(60)925>. 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

All the major routes to pyrazinecarbonitriles have been discussed already by primary synthesis in Chapters 1 and 2 by cyanolysis of halogenopyrazines in Sections 4.2.8 and 4.4 by deoxidative cyanation of pyrazine N-oxides in Section 5.5.2.4 by the rare cyanolysis of nitropyrazines in Section 7.1.2 by cyanolysis of trimethylammoniopyrazine salts no recent examples by dehydration of pyrazinecarboxamides in Section 8.4.2 and by passenger introduction of a cyano group in a variety of ways, for example, by cyanoalkylation. 

Pyrazine 1-oxide and 1,4-dioxide could not be cyanated at the a-position with potassium cyanide and potassium ferricyanide in protic solvents, even at 130° (755). Attempts to nitrate 2,5-dimethylpyrazine 1,4-dioxide (625) and 3-methylpyrazine 1-oxide (626) were unsuccessful. 

Sato, N., Shimomura, Y., Ohwaki, Y., and Takeuchi, R., Studies on pyrazines. Part 22. Lewis acid-mediated cyanation of pyrazine A-oxides with trimethylsilyl cyanide. New route to 2-substituted 3-cyanopyrazines, J. Chem. Soc., Perkin Trans. 1, 2877, 1991. 

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