Pyrazines, Pyrimidines, and Pyridazines

Direct evidence for the existence of anionic a-adducts for pyrazine, pyrimidine, and pyridazine (155-157) was first presented by Zoltewicz and Helmick (72JA682). They obtained H-NMR spectra of the adducts formed by mixing the diazine in liquid ammonia with sodium or potassium amide. Upheld shifts (2.2-4.5 ppm) were typical indicators of adduct formation. In an excess of diazine, both free and complexed diazine were evident in the spectrum, while in an excess of amide, the spectrum did not indicate the presence of free diazine. 

Pyrazine gave a spectrum consistent with 2-amino-1,2-dihydropyrazinide (18). Pyrimidine may form adducts in three positions, but the major adduct observed was 4-amino-l, (or 3), 4-dihydropyrimidinide (19). Two cr-adducts are possible for pyridazine, but the structure found was 4-amino-l,4-dihydropyridazinide (20). At — 70°C, the cr-adducts were stable for days. 

Work has also been done on the amination of alkoxypyridazines. Treatment of 3,6-dimethoxypyridazine (162) and 3-methoxypyridazine (163) with potassium amide in liquid ammonia, followed by the addition of potas- 

2-isopropylpyrimidine increased to 30 and 45%, respectively. In the case of 2-tert-butylpyrimidine, where no deprotonation occurs, the yield of aminated product was 60% (87JHC1377). 

The variation of results for the amination of 29 in liquid ammonia and in m-xylene is attributed to adduct formation. In the hydrocarbon, once the nucleophilic attack on C-2 and C-6 occurs (the rate-determining step), the elimination step takes place immediately, making isomerization virtually impossible. 

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As with other haloaromatic systems, Barbier reactions are also suitable for heterocyclic systems. For example, the lithio derivatives formed in situ from iodide 187 upon sonication reacted immediately with electrophiles such as benzaldehyde, hexanal and diphenyl disulfide, to give good yields of 188 <00T3709>. Similar chemistry was also successful with pyrazines, pyrimidines, and pyridazines. 

Tsuchiya, T., Kurita, J. and Takayama, K. (1980) Studies on diazepines. XIII. Photochemical behaviour of pyrazine, pyrimidine, and pyridazine N-imides. Chemical el Pharmaceutical Bulletin, 28 (9), 2676-2681. 

Fig. 1 Schematic representation of (from left to right) pyrazine, pyrimidine, and pyridazine. Open and closed circles represent CH groups and N atoms, respectively.

The spectra of pyrazine, pyrimidine, and pyridazine, all in cyclohexane, are compared by Albert (1462). They show two bands with associated fine structure, the peaks for pyrazine center around 260 and 328 nm. The near-ultraviolet spectrum of pyrazine has been measured in several solvents [and at various pH values (1463)] and the transitions assigned (1474, 1482). The diffuse system at 260 nm has been attributed to rr->-7r transitions whereas the sharp system at 328 nm has been ascribed to n rr transitions (1467, 1474). Semiempirical calculations have been made on the electronic structure of pyrazine with reference to its -> rr transition (1483-1486), calculations have been made of transition energies in N-... 

Recently, more complex heterocyclic nitrogen bases such as A-methylpyrrole, 2-chloropyridine, quinoline, pyrazine, pyrimidine, and pyridazine have been tested as reliable probes to obtain information about the surface acidity of Si02, Ti02, Zr02, Si02-Al203, H-mordenite, and sepiolite [22-25]. 

Benzothiazoline thione Substituted dimercapto-thiadiazole Imidazolidine dimethylene bis phosphoro dithioate Derivatives of pyridine, pyrazine, pyrimidine and pyridazine and their fused ring derivatives Triaryl phosphates Triphenyl phosphate Tritolyl phosphate... 

Excluding pyrimidine derivatives electrophilic fluorination of other diazines was almost not studied. To the best of our knowledge there is no examples of electrophilic fluorination of pyridazines and only 1 paper and 1 patent devoted to fluorination of pyrazines and quinoxaline. Chambers and co-workers described fluorination of quinoxalines 29 in good yields using elemental fluorine-iodine mixtures at room temperature (Scheme 8). Mono- (30) and difluorinated products 31 were formed in different ratio depending on amount of fluorine used in the reaction. It should be noted that pyrazine, pyrimidine and pyridazine were recovered unchanged using similar condition [42]. 

A study of the a-arylation of diazine mono iV-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very substantial improvement in yield <06AG(I)7781>. 

Pyrazines have considerable aromatic character and therefore in the majority of their reactions tend to revert to type. The main features of their reactivity may be predicted by regarding them as pyridines into which a nitrogen has been inserted in the para position. Pyrazines also show close similarity in their reactions to the other diazines, pyrimidines, and pyridazines. 

The aza substituent constants (vide supra) reflect the fact that electron-withdrawing annular nitrogens decrease the reactivity of any other ring nitrogen in the order ortho meta < para. For this reason, pyrazines should quaternize more readily than pyrimidines and pyridazines, and all three diazines should react faster than triazines. When the diazines are included in a Hammett plot for the methylation of substituted pyridines (p = —2.3), the positive deviations showed that they were all more reactive than indicated by their pK values. Relative rates compared with pyridine were pyridazine, 0.25 pyrimidine, 0.044 and pyrazine, 0.036 (72JA2765). Pyridazine in particular appears to be much more reactive than one would expect. (See Section III, A below). 

In order to generate an appropriate number of solute-solvent clusters to be used in the NMR calculations a series of classical MD simulations of pyrazine, pyrimidine or pyridazine in aqueous solution has been carried out. All the details of the force fields used for the diazines and water as well as computational details of the MD simulation can be found in Ref. [31]. Every 1 ps an MD configuration was dumped so as to obtain 600 different molecular configurations. Then, a spherical cut-off distance equal to 12 A was applied so as to obtain the final cluster including 230-240 water molecules together with the solute. 

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). 

The photoelectron spectrum of pyridazine is similar to those of pyrazine, pyrimidine, and triazine i.e., the lowest ionization potential corresponds to ionization of a lone-pair electron. The ionization potential is in agreement with the calculated value. These spectra were recorded also of pyridazine 1-oxide and 1,2-dioxide, and it was found that the perturbation of the t-system by the N—O group results in the separation of the lower excited states of the AT-oxide ions. ... 

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

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

Corsaro and co-workers studied the reaction of pyridazine, pyrimidine, and pyrazine with benzonitrile oxide and utilized H NMR spectral analysis to determine the exact structure of all the cyclized products obtained from these reactions <1996T6421>, the results of which are outlined in Table 1. The structure of the bis-adduct product 21 of reaction of pyridazine with benzonitrile oxide was determined from the chemical shifts of the 4- and 5-isoxazolinic protons at 3.76 and 4.78 ppm and coupled with the azomethine H at 6.85 ppm and with the 5-oxadiazolinic H at 5.07 ppm, respectively. They determined that the bis-adduct possessed /(-stereochemistry as a result of the large vicinal coupling constant (9.1 Hz). Similarly, the relative stereochemistry of the bis-adducts of the pyrimidine products 22-25 and pyrazine products 26, 27 was determined from the vicinal coupling constants. 

The copper-catalysed V-arylation of diazinones by aryl halides, but mainly using 2-fluoro-4-iodoaniline, was described as part of a paper devoted primarily to pyridones. Pyrazin-2-one, pyrimidin-4-one and pyridazin-3-one all reacted successfully but pyrimidin-2-one failed to give any product <06TL7677>. 

Recent literature examples involve the use of the Suzuki protocol for the highspeed decoration of various heterocyclic scaffolds of pharmacological or biological interest, including pyrimidines [45], pyridazines [46], pyrazines [47], chromanes [48], and pyrazoles [49] (Scheme 6.19). 

Ring Synthesis of Fused Pyridazines, Pyrimidines, and Pyrazines with Oxygen, Sulfur,... 

In 1886 the first examples of compounds containing two adjacent nitrogen atoms in a six-membered ring were reported [ 1 ] The preparation of the parent system pyridazine or 1,2-diazine (1) was described as early as 1895 by Tauber [2]. Compared with the 1,3- and the 1,4-diazine systems (pyrimidine and pyrazine), however, the pyridazine system for a long period attracted little attention in medicinal chemistry. 

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