Halogenation pyrazines

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

Substitution of the pyrazine ring by electron releasing substituents reduces the reactivity of halopyrazines and more forcing conditions must invariably be employed to bring about displacement of the halogen. 

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

Direct halogenation of quinoxaline appears to be of limited value but pyrazine may be chlorinated in the vapor phase to give monochloropyrazine at 400 °C or at lower temperatures under catalytic conditions 72AHC(14)99, and at higher temperatures tetra-chloropyrazine formation occurs in high yields. Mention has already been made of direct chlorination (see Section 2.14.2.1) of phenazine. 

Sufficient activation was present in 5-ethylamino-2-oxoimidazolo [4,5-6]pyrazine (173) for it to be halogenated in the 6-position by chlorine and bromine in acetic acid or by sulfuryl chloride (69FRP1578366 71BRP1248146). The 2-oxo group could be replaced by chlorine (75KFZ10 76KFZ35). 

Isoxazolo[4,5-6]pyrazine (176) is resistant to electrophilic halogenation because the potentially reactive site is at the ring junction. The 7-oxide, though, was converted into the 6-chloro derivative of 176 on heating with phosphoryl chloride (73JHC181). 

Second only to sulfur-based systems, nitrogen complexes are relatively well represented in the structural literature with 41 complexes reported. Of these, 25 are with I2 as the electron acceptor, 11 are with the interhalogen IC1, three are with Br2, and two are with IBr. As expected, in every case the halogen bond forms between the nitrogen and the softest halogen atom, i.e., iodine, in all of the complexes except those with dibromine. Most N I2 complexes, and all N Br2, N IBr, and N IC1 complexes are simple adducts, mode A. Exceptions for the diiodine complexes include bridging mode (B) observed for diazines, such as pyrazine [86], tetramethylpyrazine [86], phenazine, and quinoxaline [87], and for 9-chloroacridine [89] and the 1 1 complex of diiodine with hexamethylenetetramine [144] and amphoteric bridging mode (BA) observed for 2,2 -bipyridine [85], acridine [89], 9-chloroacridine [89], and 2,3,5,6-tetra-2/-pyridylpyrazine [91]. The occurrence of both B and BA complexes with 9-chloroacridine, and of B and A complexes and an... 

Thus, ketone enolates easily substitute chlorine in position 2 of the electrophilic nucleus of pyrazine (1,4-diazabenzene), and even in the dark, the reaction proceeds via the Sj l mechanism (Carver et al. 1981). It is expected that the introduction of the second chlorine in the ortho position to 4-nitrogen in the electrophilic nucleus of pyrazine promotes the ion-radical pathway even more effectively. However, 2,6-dichloropyrazine in the dark or subjected to light reacts with the same nucleophiles by Sr.,2 and not S nI mechanism (Carver et al. 1983). The authors are of the opinion that two halogens in the pyrazine cycle facilitate the formation of a-complex to the extent that deha-logenation of anion-radicals in solution and a subsequent nucleophilic attack of free pyrazine radical become virtually impossible. Thus, the reaction may either involve or exclude the intermediate a-complex, and only special identification experiments can tell which is the true one. 

The protons of pyrimidines, pyrazines and pyridazines are relatively acidic even without halogen activation, and the three simple heterocycles 240-242 have been lithiated (with varying success) with LiTMP (Scheme 120). ... 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

Palladium-mediated cross-coupling reactions in pteridine chemistry provide for variation at position 6 using halogenated pyrazines or pteridines as substrates (see Section 10.18.7.4). The 6-bromopyrazine 168 is a versatile intermediate leading to pteridine 169 both compounds have been shown to be substrates for palladium-mediated cross-coupling reactions <2000J(P1)89> (Scheme 32). 

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