Pyrazine, pyridine, pyrimidine

Cobalt trifluoride fluorination corresponds to the electron-transfer mechanism via a radical cation. RF groups attached to the ring enhance the stability of intermediate dienes and monoenes. Perfluoroalkyl pyridines, pyrazines, and pyrimidines were successfully fluorinated but pyridazines eliminated nitrogen. The lack of certain dienes was attributed to the difference in stability of FC=C and RFC=C and steric effects [81JCS(P1)2059]. 

Aldehydes and the corresponding 2-aminopyridine, pyrazine, or pyrimidine are admixed in presence of a catalytic amount of clay (50 mg) to generate iminium intermediate. Isocyanides are subsequently added to the same container and the reactants are further exposed to MW to afford the corresponding imidazo[l,2-a]pyridines, imi-dazo[l,2-a]pyrazines and imidazo[l,2-a]pyrimidines (Scheme 6.48). The process is general for all the three components, e. g. aldehydes (aliphatic, aromatic and vinylic), isocyanides (aliphatic, aromatic and cyclic) and amines (2-aminopyridine, 2-amino-pyrazine and 2-aminopyrimidine). A library of imidazo[l,2-a]pyridines, imidazo[l,2-ajpyrazines and imidazo[l,2-a]pyrimidines can be readily obtained by varying the three components [151]. 

A rapid one-pot synthesis of imidazo-[l,2-a]-pyridines, pyrazines and pyrimidines was described in 1999 by Varma et al. [50], who used recyclable montmorillonite clay Kio under solvent-free conditions and microwave irradiation (Scheme 8.32). 

R.W. Millar, S.E. Philbin, R.P. Claridge, J. Hamid, Studies of novel heterocyclic insensitive high explosive compounds pyridines, pyrimidines, pyrazines and their bicyclic analogues . Propellants Explos. Pyrotech. 81—92. 

Pyrazine and pyrimidine heterocycles, like pyridine, are electron deficient and need the presence of an activating/electron-releasing group to allow efficient electrophilic nitration to occur. An example of this strategy is seen during the synthesis of 2,6-diamino-3,5-dinitropyrazine (ANPz) (183) where one of the chloro groups of 2,6-dichloropyrazine (180) is substituted for a... 

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

Varma, R.S. and Kumar, D., Microwave-accelerated three-component condensation reaction on day solvent-free synthesis ofimidazo[l,2-fl] annulated pyridines, pyrazines and pyrimidines, Tetrahedron Lett., 1999, 40, 7665-7669. 

Nb 0 Aromatic nitrogen (pyridine, pyrazine, and pyrimidine, but not pyridazine)... 

Among the sequence of N-heterocycles, n.b. the 1,2,3,4 N-substituted azabenzenes, the response investigations have focussed on pyridine, pyrazine, pyridazine, pyrimidine, s-triazine, and s-tetrazine [151]. The calculations of phosphorescence of these compounds utilize x type complete active spaces, the general rule of thumb has been to use one correlating x orbital for each occupied x orbital. All azabenzenes, except pyridazine, take the same Hartree-Fock orbital configuration in C2V symmetry Ilai,7b2,2bi,la2, including 18 and 3 doubly occupied a and x orbitals, respectively. For pyridazine it reads 10ai,8b2,2bi,la2. 

Other fundamental characteristics of heteroaromatic systems are their electron-donor and electron-acceptor properties. The energies of the highest occupied (HOMO) and the lowest unoccupied (LUMO) molecular orbitals (the frontier orbitals) can serve as measures of such properties. Pyridine-like heteroatoms lower the energies of all the MOs and compounds containing heteroatoms of this type can be expected to show more -acceptor and less r-donor character. In accord with this expectation (Table 2), -acceptor properties of azines decrease in the sequence l,2,4>5-tetrazine > pyrazine > pyridazine > pyrimidine > pyridine. 

The replacement of CH groups of benzene by nitrogen leads to the azines. Pyridine, pyrazine and pyrimidine have essentially the same stabilization as benzene. Thus, hydrogen transfer reactions between 1,3-cyclohexadiene and the... 

Groebke K, Weber L, Mehlin F (1998) Synthesis of imidazo[l,2-a]annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation. Synlett 661-663... 

Other diimine ligands are shown in (104-106) with systems containing one pyridine and one other heterocyclic mono-aza ligand, and the C atoms of the py ring can be replaced by one or more N atoms to give, for example, (107). Other coupled sets are pyrazole plus pyrazole (108), pyrazole plus imidazole (109), and imidazole plus imidazole (110) together with coupled pyrazines (111), pyrimidines (112), (113), and pyridazines (114). 

Pyrazine is exceptional, by comparison with pyridine, pyrimidine, and pyridazine, in forming a relatively stable anion (592) the ion pair association of pyrazine radical anions with alkali metals has been studied using e.s.r. techniques (593-595) and a study has been made of the kinetics of their dimerization (596). 

Mongin, F., Queguiner, G. Advances in the directed metallation of azines and diazines (pyridines, pyrimidines, pyrazines, pyridazines, quinolines, benzodiazines and carbolines). Part 1 Metallation of pyridines, quinolines and carbolines. Tetrahedron 2001, 57,4059-4090. 

Among the 6-membered heterocombretastatins, where the B ring was replaced by a variety of 6-membered heterocycles (pyridines, pyrimidines, pyridazines, pyrazines, pyridinium salts) the pyridone derivative 14 showed strong antimitotic activity IC50 2 jiiM, the same value of Combretastatin A-4) and cytotoxicity IC50 19.2 nM, versus 8.7 nM of Combretastatin A-4), along with excellent water-solubility. 

Triazine is a very ir-deficient heterocyclic system. Quantitative data on ir-deficiency of azaaromatic compounds obtained by l3C-NMR spectroscopy indicate that 1,2,4-triazines are more electron-deficient compounds than pyridines, pyrimidines, pyrazines, or pyridazines (Scheme 1) (82QMR192). 

The relative nitrogen screening constants of pyridine, pyrazine, pyridazine, pyrimidine, 1,3,5-triazine and 1,2,4,5-tetrazine show a very good linear correlation with theoretical values of the local paramagnetic term calculated by the AEE approximation. (47) A similarly satisfactory... 

A one-pot MW protocol for the synthesis of imidazo[l,2-a]-annulated pyridines, pyrazines and pyrimidines has been developed (Scheme 8.20) that proceeded in the presence of solid catalyst montmorillonite KIO clay under solvent-free conditions. 

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