Pyrazines applications

Pyrazino[l,2-a]pyrazine, octahydro-spectra, 3, 340 Py razino[2,3- h]pyrazine applications, 3, 368 cations... 

Cerium(IV) ammonium nitrate in methanol has been used to oxidize phenazine to the mono-N-oxide (41) in good yield (75JCS(P1)1398), but no other reports on the application of this reagent to the pyrazine or quinoxaline series have appeared. 

A number of reductive procedures have found general applicability. a-Azidoketones may be reduced catalytically to the dihydropyrazines (80OPP265) and a direct conversion of a-azidoketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 55) has been reported to proceed in moderate to good yields (69LA(727)23l). Similarly, a-nitroketones may be reduced to the a-aminoketones which dimerize spontaneously (69USP3453279). The products from this reaction are pyrazines and piperazines and an intermolecular redox reaction between the initially formed dihydropyrazines may explain their formation. Normally, if the reaction is carried out in aqueous acetic acid the pyrazine predominates, but in less polar solvents over-reduction results in extensive piperazine formation. 

From the foregoing discussion it is evident that the most general methods for the synthesis of pyrazines, quinoxalines and phenazines fall into type A and type B categories, but other methods do exist. Although most of these are not of such general applicability, they are worthy of comment. 

Scarcely a single issue of Chemical Abstracts is published without reference to medicinal compounds containing the pyrazine or quinoxaline ring in some form, and hence it is impractical to list all applications of pyrazines, quinoxalines and phenazines. Some of the more important applications and natural products, particularly the more recent developments, are mentioned in this Section. 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

At present, other CL amplifiers are recommended for the detection of superoxide in cells and tissue such as coelenterazine (2-(4-hydroxybenzyl)-6-(4-hydroxyphenyl)-8-benzyl-3,7-dihydroimidazo[l,2-a]pyrazin-3-one]) and its analogs CLA (2-methyl-6-phenyl-3,7-dihydroi-midazo[l,2-a]pyrazin-3-one]) and MCLA [2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimi-dazo[l,2-a]pyrazin-3-one]). It has been suggested that the origin of CL produced by these compounds is the oxidation of the acetamidopyrazine moiety [69,70]. Unfortunately, to our knowledge, there are still no reliable thermodynamic and kinetic data to validate the application of the above CL amplifiers for superoxide detection. Reichl et al. [71] proposed to use the photoprotein pholasin for the detection of superoxide and myeloperoxide activity in stimulated neutrophils. 

For the practical application to nonlinear optics, further, noncentrosymmetric LB films are required to possess not only large nonlinear optical response but excellent optical quality and thickness appropriate to optical devices. In this study, a family of pyrazine derivatives was found to be an LB film-forming material applicable to waveguide devices. The optical nonlinearity in the pyrazine LB films and the application of the pyrazine LB films to a frequency-doubling waveguide device is demonstrated in the latter part. 

Sato et al. carried out detailed studies on the possibilities of transformation of tetrazolo[l,5-tf]pyrazines 54 to 2-aminopyrazines 56 < 1994S931 >. These authors found that the generally used methods for this conversion fail because the starting compound exists in the stable bicyclic form 54, whereas partial formation of the azide valence bond isomer 55 would be necessary for the success of the transformation. Application of special reaction conditions succeeded, however hydrogenation over palladium catalyst in the presence of ammonium hydroxide or treatment with stannous chloride in a mixture of methanol and hydrochloric acid solved this problem. Thus, a great number of derivatives of 54 was reduced to the corresponding 2-aminopyrazine 56 in medium to high yields (45-100%). 

A research team at Rhone-Poulenc reported a four-component procedure for the synthesis of variously substituted heteroaromatic tetrazolo[l,5-zz]pyrazines <1998TL2735>. Thus, aldehydes, primary amines, trimethylsilyl azide, and methyl /3-(iV,iV-dimethylamino)-a-isocyanoacrylates 117 were reacted in a methanolic solution at room temperature to yield the product 119 in high yields. The reaction was rationalized to proceed via the formation of intermediate 118. The procedure proved to be efficient for combinatorial chemical applications. 

In addition, interest in combinatorial chemical applications led a team at AMGEN to the recognition of a related but different pathway which afforded tetrahydro tetrazolo[l,5-zz]pyrazine-6-ones 121 (Scheme 22) <2000TL8729>. In this procedure, three starting components, that is, the ketone, the primary amine, and trimethylsilyl azide, as in the previous method, were used, and the fourth component was methyl isocyanoacetate. This reaction also took place under relatively smooth conditions (methanolic solution at room temperature for 6h followed by reflux for 24 h) to yield the products 121 in good to high yields. The reaction obviously proceeds by the formation of intermediate 120. 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

Aminotriazoles which are appropriately substituted at the C(5)-position are important intermediates for the synthesis of 8-azapurines. These reactions have been reviewed <86AHC(39)ll7>. The pharmaceutically useful acyclonucleosides bearing 1,2,3-triazolines and 8-azapurines have been synthesized <888879). 4,5-Diaminotriazoles react with 1,2-dicarbonyl reagents to give 1,2,3-triazolo[4,5- )]pyrazines. 4,5-Diamino-2-phenyltriazole and sulfur monochloride afford the triazolo[4,5-c][l,2,5]thiadiazole (855) <86AHC(40)129>. The synthesis of triazolopyridines from triazoles has been described in a review <83AHC(34)79>. For further applications of substituted triazoles in preparations of complex heterocycles, see Section 4.01.4. 

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