2-Azido-6- pyrazine

In sehr guten Ausbeuten verlauft die thermische Umlagerung von 2-Azido-pyrazinen zu 1-Cyan-imidazolen bei 200-240°426,427. Diese Synthese ist breit anwendbar und fiihrt nach hydrolytischer Abspaltung der 1-Cyan-Gruppe (> 90% Ausbeute) zu den 1-unsubstituier-ten Imidazolen. 2-Azido-pyrazine konnen durch Umsetzung der entsprechenden 2-Chlor-pyrazine mit Natriumazid in Dimethylformamid hergestellt werden (62 84% Ausbeute). 

Azido-pyrazin-l-oxid reagiert in einer verwandten Reaktion bereits beim Kochen in Benzol in 83% Ausbeute zu 2-Cyan-l-hydroxy-imidazol4 28. 

Dichlorooxadiazolo[3,4-3]pyrazine 181 forms the tricyclic tetrazole derivative 182 on reaction with sodium azide (Equation 44). The 7-azido group readily undergoes nucleophilic substitution <1997CHE977>. 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Cyclic dimerization of the a-amino ketone, which is formed by reduction of a-azido ketone 149 with triphenylphosphine, leads to the formation of a pyrazine derivative 150 (Scheme 40) <1994JOC6828>. Reduced Te also dimerized a-keto azide 149 to give pyrazine 150 <2006JOG2797>. 

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

An important preparation of pyrazines (303) is from a-amino ketones RCOCH2NH2 or their monooximes which spontaneously condense to give 2,5-dihydropyrazines (302). The a-amino ketones are often prepared in situ by reduction of isonitroso ketones, and the dihydropyrazines are usually oxidized to pyrazines before isolation icf Section 3.2.2.3.3). Catalytic reduction of a-azido ketones also leads to 2,5-dihydropyrazines (80OPP265). Similarly, a-nitro ketones may be reduced to the a-amino ketones which dimerize spontaneously (69USP3453278). 

Conversion of a-azido ketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 42) proceeds in moderate to good yields (69LA(727)23l). 

Irradiation of azido-substituted pyrazines and pyrimidines bearing strong electron-donating substituents in the presence of a base, such as MeONa or diethylamine, resulted in ring expansion with formation of 1,3,5-triazepines (Scheme 38) <1990CC723>. A similar transformation was observed on irradiation of a series of 6-azidouracils in the presence of a primary or a secondary amine <1984J(P1)1719>. 

Recently Zbiral and Stroh reported that treatment of a-azido-ketones (obtained generally by reaction of the a-halogenoketone with sodium azide) with triphenylphosphine is a convenient route to 2,5-disubstituted pyrazines (Scheme 5). Thus, 2,5-diphenyl-, 2,5-bis(4-methoxyphenyl)-, and 2,5-diisopropylpyrazine have been obtained in 75, 45, and 44% yield, respectively. The intermediate P-iV-ylide undergoes intermolecular condensation to give a 2,5-dihydropyrazine which is subsequently aromatized.122... 

Thermolytic conversions of aromatic pyridines into pyrazines have been reported, albeit in minute yield. Thus vacuum pyrolysis of 4-dichloroamino-2,3,5,6-tetrafluoropyridine (69) at 550°C gave at least 12 products in which 2,3,5,6-tetrafluoropyrazine (70) could be identified 1320 and flow thermolysis of 4-azido-2,3,5,6-tetrafluoropyridine in nitrogen at 300°C gave l,2-difluoro-l,2-bis(3,5,6-trifluoropyrazin-2-yl)ethylene (71), isolated in 0.1% yield.1322... 

Just as pyrazine. V-oxides may be converted into C-halogeno- (Section 4.1.3) or C-acyloxypyrazines (Section 5.5.2.3), so they can afford C-amino-, C-azido-, C-cyano-, or C-alkylthiopyrazines, although such reactions are not well developed yet. The following examples will illustrate such procedures as used in recent literature ... 

The major and recently used preparative routes to azidopyrazines have been covered already by azidolysis of halogenopyrazines (Sections 4.2.6 and 4.4) and by treatment of hydrazinopyrazines with nitrous acid (Section 7.4). In addition, direct C-azidation of pyrazines has been used for example, the lithio intermediate (225), generated in THF by treatment of 2-methoxypyrazine (224) with lithium 2,2,6,6-tetramethylpiperidine, gave 2-azido-3-methoxypyrazine (226) (87%) on subsequent treatment with p-toluenesulfonyl azide.232... 

Since the excellent 1973 summary of azido—tetrazolo valence-tautomerism in nitrogenous heterocycles,1713 little has been added to our knowledge of factors governing such tautomerism (227 228) in the pyrazine series. However, it has been shown by NMR studies that 2-azidopyrazine 4-oxide (229) exists as such in chloroform, as tetrazolo[l,5-a]pyrazine 7-oxide (230) in dimethyl sulfoxide, and as a mixture in acetone.272 For obvious pragmatic reasons, all such compounds are named as azidopyrazines in this book, irrespective of their predominant structures. 

Diazidopyrazine (236) gave a separable mixture of 2-azido-6-(4,5-dimethoxycarbonyl-l,2,3-triazol-l-yl)pyrazine (237) and 2,6-bis(4,5-dimethoxycarbonyl-l,2,3-triazol-l-yl)pyrazine (237a) [Me02CC=CC02Me, MeOCH2OCH2OMe( ), reflux, 19 h 18 and 15%, respectively].1124... 

Bridging ligands such as cyano and azido are used to form one-, two-, and three-dimensional polymeric systems and represent a fast growing research field because of their interesting magnetic properties. In addition to the polymeric binary dicyanamide and azide systems, for example, [Mn N(CN)2 2], [Mn N(CN)2 3], and [Mn(N3)3]-, ancillary organic ligands, such as pyrazine, 4,4 -bipy and 2,2 -bipy have been extensively used to create other lattice types. 

Amino- E9b/2, 372 (4-CN-5-NH2 — imidazol + Guanidin] Pyrazin 3-Azido-2-methyl- E9b/2,... 

Bis-[2-methyl-propyl]-l-cyan-E16c, 218 (aus Azido-pyrazinen) l-Cyan-2,5-dibutyl- E8c, 91 3,5-(C4H9)2 — 2-Nj-pyrazin/A ... 

In the solid state (57) and its derivatives prefer the tetrazolo form whereas in solution an equilibrium exists (73S123). As in the other systems described here, the substituent on the pyrazine ring can greatly influence the position of the tetrazolo-azido equilibrium (81MI41500). 

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