Pyrimidine and Pyrazine Derivatives

A linear relationship was obtained between the logarithmic interfacial formation constant (log / ,) for PdL+-diazine derivative complexes and the logarithmic ratio of the distribution constant (A D) to the acid-dissociation constant (Ka) for the two groups. PdL+-pyridazine derivative complexes showed much higher stability at the interface than pyrimidine and pyrazine derivative complexes. This result suggests that pyridazine derivative complexes become more... 

Adams, A.D. and Santini, C. (2007) Pyridine, pyrimidine and pyrazine derivatives as CXCR3 receptor modulators. W02007100610. 

Preparation and use of amphiphilic oximes, derivatives of pyridine, pyridazine, pyrimidine, and pyrazine 98CFY469. 

IR spectral data for most known 1,2,4-triazines have been published. The absorption of the 1,2,4-triazines in the IR region are those expected for this system. The IR spectrum of the parent compound (1) shows three absorption bands for the C—H stretching vibrations at 3090, 3060 and 3030 cm-1, five bands for C=N and C=C stretching vibrations at 1560, 1529,1435,1380 and 1295 cm-1, three for the C—H in-plane deformations at 1163,1135 and 1113 cm-1, two for the characteristic ring skeleton vibrations at 1050 and 995 cm-1 and three bands for the C—H out-of-plane deformation vibrations at 851,768 and 713 cm-1 (68CB3952). These values are in good agreement with similar bands for pyridine, pyridazine, pyrimidine and pyrazine. Alkyl and aryl derivatives of 1,2,4-triazine show similar bands in their IR spectra, with additional bands from the substituents. 

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy. 

The l,2-diamino-4-methylthiazole 73 with phosgeniminium chloride gives the thiazolo[3,2-A [l,2,4]triazole derivative 74 (Scheme 45) <1973AGE806>. Reaction of the sulfimide 75 with nitrile oxides forms [l,2,4]triazolo[l,5- ] pyridine 3-oxides 76 in good yields (Scheme 46). This method is applicable to analogous pyrimidines and pyrazines <1976J(P1)2166, 1978BCJ563>. 

Pyrimidines, (I), and pyrazine derivative, (II), effective as GSK3 inhibitors were prepared by co-author Nuss (2,3), respectively, in earlier investigations. 

The three diazines, pyridazine, pyrimidine, and pyrazine are stable, colourless compounds that are soluble in water. The three parent heterocycles, unlike pyridine, are expensive and not readily available and so are seldom used as starting materials for the synthesis of their derivatives. There are only four ways in which a benzene ring can be fused to a diazine cinnoline, phthalazine, quinazoline and quinoxaline are the bicyclic systems thus generated. 

Ring systems containing two heteroatoms tend to feature less in the vapor-phase literature. This is partly because of the greater reactivity (i. e. reduced aromaticity) of these heterocyclic compounds. In addition, there has been less commercial incentive to develop catalyzed processes for these smaller-volume niche products. As an example, both pyrimidine (26) [51] and pyrazine (27) [52] can be made by catalyzed vapor-phase methods they can also be recovered from the pyri-dine- ff-picoline reaction. In principle, pyrimidine and pyrazine could then serve as platforms-much like pyridine does-for preparing a wide range of derivatives. The market for these derivatives is, however, best met by traditional convergent syntheses in the liquid phase. 

Reactions of Imidazoles. Thermolysis of 1-triphenylmethylimidazole results in migration of the imidazolyl group to yield compound (286). Sensitized photo-oxygenation of 4,5-diphenylimidazole in methanol affords a mixture of the imidazolinone (287) and the imidazolidinone (288). The imidazole (289 R = H) undergoes lithiation at C-5 subsequent treatment with diphenyl disulphide gives the di(phenylthio)-derivative (289 R = PhS). Copyrolysis of 2,4-dimethylimidazole and chloroform results in a complex mixture, containing imidazole and methyl-, dimethyl-, and chloromethyl-pyrimidines and -pyrazines. The confusion about the structures of N-methyl derivatives of iodo-nitro-imidazoles has been cleared up the supposed 1-methyl-2,5-di-iodoimidazole is actually the 4,5-di-iodo-compound it yields 4-iodo-l-methyl-5-nitroimidazole on nitration. The reaction of the bromo-... 

Olefins could also be used as reactants in these radical alkylations, and the resulting products such as 8 are similarly converted to suitable derivatives. Other variously substituted pyridines, pyrimidines, and pyrazines could be alkylated, in some cases giving mixtures which were separated to give additional subjects for our study. 

Fragmentation Same as for the corresponding monocyclic heteroaromatics pyridazine, pyrimidine, and pyrazine. Characteristic for pyridazine, cinnoline, and phthalazine is the elimination of N2 (Am 28) and of N2H (Am 29) from their alkyl derivatives. Phthalazine loses HCN (Am 27) twice. 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

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