Pyrazine chlorination

Imidazo[4,5-6]pyrazine, 2-methyl-synthesis, 5, 645 I midazo[ 1,2-a]pyrazines reaaions, 5, 624 sjmthesis, 5, 642-643 Imidazo[l,5-a]pyrazines chlorination, 5, 625 reactions, 5, 625-626 synthesis, 5, 644-645 Imidazo[4,5- 6]pyrazines reactivity, 5, 626-627 synthesis, 5, 645-646... 

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

Treatment of both pyrazine 1-oxide and quinoxaline 1-oxide with POCI3 results in the formation of the corresponding chlorinated derivatives (SO) and (SI). However, in the case of quinoxaline 1-oxide the 2-chloroquinoxaline is accompanied by 6-chloroquinoxaline (S2) (67YZ942). 

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. 

Imidazo[4,5-6]pyrazin-2(3H)-one, 1,5,6-trimethyl-chlorination, 5, 626 lmidazo[ 1,2-a ]pyrazin-3(2H) -ones synthesis, 5, 642... 

Pyrazine, 2-amino-5-(3-indoloyl)-synthesis, 3, 180, 181 Pyrazine, 2-amino-3-methoxycarbonyl-chlorination, 3, 163... 

Pyrazine, 2-methoxy-3-sulfanilamido-plasma half-life, 1, 162 Pyrazine, methyl-chlorination, 3, 168 oxidation, 3, 168 reactions... 

E rido[2,3-b]pyrazine, 2,3-dihydroxy-chlorination, 3, 251 Pyrido[2,3-b]pyrazine, 6-hydroxy-formation, 3, 251... 

The chlorination of phosphonic and phosphinic acids and esters are of considerable importance. PCI5 can also act as a Lewis acid to give 6-coordinate P complexes, e.g. pyPClf, and pyz-PCI5, where py = C5H5N (pyridine) and pyz = cyclo-1, 4-C4H4N2 (pyrazine). ... 

When thieno[2,3- ]pyrazine was chlorinated, the reaction resembled the corresponding pyridine and pyrimidine (152) analogues in that 13-substitution in the thiophene ring was observed (80JHC1019). 

A mixture of 1- and 3-chloro, 1,3-dichloro, and 1,3,5-trichloro derivatives was obtained on chlorination of imidazo[l, 5-a]pyrazine (172). Bromination gave similar results (75JHC207,75JOC3373 84MI24). The 8-chloro compound is best made from the 8-oxy derivative of 172. When the 1-bromo-3-methyl derivative of 172 was treated in turn with aqueous bromine and excess dilute caustic soda, the pyrazine ring was destroyed to give 4-bromo-2-methylimidazole-5-aldehyde (75JOC3373). 

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). 

Pyrazine (1,4-diazine) will bridge two OsNCLt fragments in [Cl4NOs(pyrazine)OsNCl4]2- where the chlorines are bent slightly away from the terminal N (IR l-(Os-N) 1105cm-1, Os-N 1.63 A) [190],... 

It has been discovered that direct chlorination of pyrazines can be accomplished and this has also been used to make candidate drugs. For example, when 2-methylpyrazine (120) is heated with chlorine in carbon tetrachloride, a mixture of the 3-chloro (121) and the 6-chloro derivatives result. After separation, 121 is heated with piperidine to give modaline (122), an antidepressant. 6... 

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. 

Deoxidative chlorination of alkyl- or aryl-substituted pyrazine A -oxides with refluxing phosphoryl chloride for 1 h provides 76-78% yields of the chloropyrazines <1997MI1076>. 

Chlorine gas was reported to rupture the disulfide bond of the fused 1,2,3-dithiazolidine ring of tricycle 108 to give [l,2,5]thiadiazolo[3,4-7]pyrazine 109 (Scheme 83) <1999JA969>. 

A tetrahydropyrido[3,4-/)]pyrazine nucleus was constructed from 2,3-dimethylpyrazine 687 by chlorination with A-chlorosuccinimide (NCS) to give 2,3-bis(chloromethyl)pyrazine 688, followed by cyclization with diethyl acet-amidomalonate to pyridopyrazine 689. Hydrolysis and decarboxylation of 689 in hydrochloric acid, then esterification by action of thionyl chloride in methanol gave methyl 5,6,7,8-tetrahydropyrido[3,4-. ]pyrazine-7-carboxylate hydrochloride 690 (Scheme 32) <2003BMC433>. 

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