5-Chloro-2,3-diphenylpyrazine

Perhaps the most convincing evidence for nucleophilic attack at an unexpected ring position comes from the direct observation of intermediate Meisenheimer complexes in the NMR spectrum. When 2-chloro-3,6-diphenylpyrazine is treated with KNH2 in liquid ammonia, the intermediate (29) was observed directly (Scheme 8). It was postulated that this initially formed complex rearranges to (30) which gives the observed product by elimination of a chloride ion (73RTC708). 

Amination of 2-chloro-3,6-diphenylpyrazine with potassium amide in liquid ammonia yields 2-amino-3,6-diphenylpyrazine 102 (73RTC449). It is of interest to mention that, although addition of the amide ion initially forms the C-5 adduct 101 (as proved by NMR-spectroscopy), this C-5 adduct is stable and does not undergo ring opening (73RTC708). It isomerizes slowly into the C-2 amino adduct 100 (via an equilibrium with 2-chloro-5,6-diphenylpyrazine) in which a rapid chloride expulsion takes place (Scheme 11.47). 

Chloro-3,6-diphenylpyrazine (119, R = Cl) gave 2-ethoxy-3,6-diphenylpyra-zine (119, R = OEt) (EtONa, EtOH, reflux, 4 h 89%)82 or 2-phenoxy-3, 6-diphenylpyrazine (119, R = OPh) [(PhO)3PO, KOH, Me2NCHO, reflux, 1 h 81% substituted-phenoxy analogues were made likewise].192... 

Chloro-5,6-diphenyl-2-pyrazinecarbohydrazide 5-Chloro-3,6-diphenyl-2-pyrazinecarbonitrile 3-Chloro-5,6-diphenyl-2-pyrazinecarboxamide 2-Chloro-3,5-diphenylpyrazine 1 -oxide 2-Chloro-3,6-diphenylpyrazine 1-oxide 2-Chloro-3,6-diphenylpyrazine 4-oxide 2-Chloro-5,6-diphenylpyrazine 1-oxide... 

After addition of the amide ion at C-6, fission of the pyrazine ring occurs with elimination of chloride. This produces the cyanoaza-1,3-diene 8 which recyclizes to the pyrazine 6 or to the imidazole 7. In the case of 2-chloro-3,6-diphenylpyrazine 9, the intermediate existence of a Meisenheimer complex 10 has been demonstrated, which then converts into 11 prior to product formation (12) ... 

Carrying out the same reaction with N-labeled potassium amide/liquid ammonia, the aminodechlorination leads to 100% incorporation of the label in the ring of 95. This exclusive enrichment of the nitrogen of the ring in 95 means that the replacement of the 2-chloro substituent starts by an exclusive nucleophilic attack at C-4 and formation of the C-4 adduct 93. Ring opening to 2-iminobenzoyl-3-cyanamino-5,6-diphenylpyrazine (94) and subsequent recyclization yield 95. 

Chloro-5,6-diphenylpyrazine (136) gave successively dimethyloxosulfonium 5,6-diphenylpyrazin-2-ylmethylide (137) [H2CS(=0)Me2, THF, N2, reflux, 5 h 93%], acetyl dimethyloxosulfonium 5,6-diphenylpyrazin-2-ylmethylide (138) (Ac20, dioxane, 0°C, 90 min 91%), and 2-acetonyl-5,6-diphenylpyrazine (139) (Raney Ni, MeOH, reflux, 30 min 60%).91... 

Diphenylpyrazine 1,4-dioxide (46) gave a separable mixture of 2,3-dichloro-5,6-diphenylpyrazine (47) and (unexpectedly) 2-chloro-5,6-diphenylpyrazine... 

Chloro-3,5-diphenylpyrazine (118, R = Cl) gave 2-methoxy-3,5-diphenyl-pyrazine (118, R = OMe) (MeONa, MeOH, reflux, 3 h 97%) homologues likewise.1307... 

Chloro-3,5-diphenylpyrazine 1-oxide (266) gave 2-acetoxy-6-chloro-3, 5-diphenylpyrazine (267) (neat Ac20, reflux, 1 h 81%).1307... 

Chloro-5-dimethylamino-3, 6-difluoropyrazine 2-Chloro-6-dimethylamino-3, 5-difluoropyrazine 2-Chloro-5-dimethylamino-3, 6-diisobutylpyrazine 2-Chloro-5-dimethylamino-3,6-diisopropylpyrazine 2-Chloro-5-dimethylamino-3,6-dimethylpyrazine 2-Chloro-6-dimethylamino-3,5-diphenylpyrazine... 

Chloro-3-isopropyl-5,6-dimethylpyrazine 2-Chloro-3-isopropyl-5,6-diphenylpyrazine 2-Chloro-3-isopropyl-5-methylpyrazine 2-Chloro-3-isopropyl-6-methylpyrazine 2-Chloro-6-isopropyl-3-methylpyrazine 2-Chloro-3-isopropyl-6-methylpyrazine 1 -oxide 2-Chloro-6-isopropyl-3-methylpyrazine 1-oxide 2-Chloro-3-isopropylpyrazine... 

Chloro-3-methoxy-2-pyrazinamine 2-Chloro-3-methoxypyrazine 2-Chloro-5-methoxypyrazine 2-Chloro-6-methoxypyrazine 6-Chloro-3-methoxy-2-pyrazinecarbonitrile 6-Chloro-3-methoxy-2-pyrazinecarboxamide 2-Chloro-6-methylamino-3,5-diphenylpyrazine 2-Chloro-3-methylaminopyrazine 6-Chloro-3-methylamino-2-pyrazinecarboxamide 5-Chloro-6-methylamino-2,3-... 

Chloro-2,S-dimethylpyrazine was not isolated from the reaction of DL-alanine anhydride with a mixture of phosphoryl chloride and phosphorus pentachloride, but the reaction gives a poor yield of (48, X = Q) and a small quantity of (48, X = OH). Gallagher et al. (282) found that DL-phenylglycine with phosphoryl chloride gave 2,5-dichloro-3,6-diphenylpyrazine and 3-hydroxy-2,5-diphenyl-pyrazine (presumably formed by loss of the elements of hydrogen chloride from an intermediate 2-chloro-5-hydroxy-3,6-diphenyldihydropyrazine) and Dunn et al. (95) from DL-leucine anhydride and phosphoryl chloride prepared flavacol, 3-hydroxy-2,5-diisobutylpyrazine, and a mature of chloropyrazines, whereas Ohta (101) used phosphoryl chloride and phosphorus pentachloride and obtained flavacol and a little 2[Pg.26]

Chloro-3-methylpyrazine (101,535) and 2-chloro-5-phenylpyrazine (363, 365a, 377, 824, 825) have been prepared from the corresponding hydroxy compound and phosphoryl chloride, 2-chloro-6-methylpyrazine from 2-hydroxy-6-methylpyrazine and phosphoryl chloride with one drop of dimethylformamide (681), and 2-benzyl(or s-butyl, isobutyl, or isopropyl)-3phosphoryl chloride with a trace of concentrated sulfuric acid (80). 2-Chloro-6-methyl-3-propyl- (826), 3[Pg.99]

Many derivatives of carboxy chloropyrazines have been prepared by the action of phosphoryl chloride on the corresponding hydroxypyrazine. In this way were prepared 2-chloro-3-methoxycarbonylpyrazine (371, 423, 836), 2-chloro-3-methoxycarbonyl-5,6-diphenylpyrazine (but the corresponding hydroxy compound did not react with phosphorus tribromide) (837), and 3-chloro-2-methoxycarbonyl-... 

Whereas 2-hydroxy-3-nitro-5,6-diphenylpyrazine with phosphoryl chloride at reflux has been shown to give a mixture of 2-chloro-3-hydroxy- and 2,3-dichloro-... 

Some chlorinations have been reported with thionyl chloride. 23-Dicyano-5,6-dihydroxypyrazine refluxed with thionyl chloride in pyridine was reported to give 23-dichloro-5,6-dicyanopyrazine (862) and 2-hydroxy-3-nitro-5,6-diphenyl-pyrazine with thionyl chloride gave 2-chloro-3-hydroxy-5,6-diphenylpyrazine (817, 841) but with thionyl chloride and pyridine it gave the betaine of 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (5) (863), which was hydrolyzed in acid to 2,3-dihydroxy-5,6-diphenylpyrazine (863). No product could be isolated from 2-methylpyrazine when refluxed with thionyl chloride (864). 1,4-Dimethylpiperazine-... 

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