2.5- Diphenyl-3,6-dihydropyrazines

Dihydropyrazines may be prepared by the self-condensation of o -(primary amino)carbonyl compounds and some of these syntheses have been described in Sections II.lA (169, 172, 178, 186, 190), Il.lJ (294-298), and II.IL (306). The conversion of a-amino acids through piperazine-2,5-diones (2,5-dihydroxy-3,6-dihydropyrazines) to pyrazines has been described in Section II.IN (93, 95, 101, 282, 312-314a) and Section II.6 (314, 314a) and ring transformations to 2,5-dihydropyrazines in Section II.9 (302, 505a, cf. 1541). 3-Phenylazirine dimerizes on standing to 2,5-diphenyl-3,6-dihydropyrazine (1577). 

An interesting photochemical approach to 4,5-disubstituted N-alkylimidazoles consists of the photolysis of 2,3-dihydro-5,6-disubstituted-pyrazines that can be easily prepared from 1,2-diketones and 1,2-diamino-alkanes. For example, the preparative-scale photolysis, in absolute EtOH with high-pressure Hg lamp (Pyrex filter), of 5,6-dimethyl- or 5,6-diphenyl-2,3-dihydropyrazines 54, yields the corresponding N-methyl-imidazoles 57 in high yields (Scheme 12.16). The reaction mechanism involves the formation of an enediimine intermediate 55, followed by cyclization and re-aromatization [41]. 

Recently Zbiral and Stroh reported that treatment of a-azido-ketones (obtained generally by reaction of the a-halogenoketone with sodium azide) with triphenylphosphine is a convenient route to 2,5-disubstituted pyrazines (Scheme 5). Thus, 2,5-diphenyl-, 2,5-bis(4-methoxyphenyl)-, and 2,5-diisopropylpyrazine have been obtained in 75, 45, and 44% yield, respectively. The intermediate P-iV-ylide undergoes intermolecular condensation to give a 2,5-dihydropyrazine which is subsequently aromatized.122... 

Phenylazirine (178), the photolysis product of a-azidostyrene (177), dimerizes on standing to 2,5-dihydro-3,6-diphenylpyrazine (179). The latter compound, unlike the isomeric 2,3-dihydro-5,6-diphenyl-pyrazine is readily aromatized by treatment with hydrogen peroxide in acetic acid.378 2,5-Dibenzyloxy-2,5-dihydropyrazine is prepared by... 

JV-benzoyl- and jV.V -dibenzoylethylenediamine, 2-phenylimidazo-line, and benzoic acid. The formation of these products is rationalized by mechanisms involving the initial addition of hydrogen peroxide to the dihydropyrazine to give the hydroperoxide. It appears therefore that the earlier report386 that peracetic acid oxidation of 5,6-diphenyl-2,3-dihydropyrazine gives the 1,4-di-iV-oxide is incorrect.386 ... 

Diamino- 1,2-diphenylethane (112) and l,2-dichloro-l,2-bis (p-tolylimino) ethane (113) gave 2,3-diphenyl-5,6-di-p-toluidino-2,3-dihydropyrazine (114) (EtjN, PhMe, 20°C, until thin-layer chromatography (TLC) shows no dichloro synthon 80%) also analogues.979... 

Although both types of pyrazine ethers are easily made, only the nuclear alkoxypyrazines can be used as substrates for nucleophilic displacement reactions. Some epoxides are included in the present discussion. Shape details of cis- and tra y-2,5-dimethoxy-3,6-diphenyl-3,6-dihydropyrazine have been elucidated by X-ray analysis.1243... 

A similar reaction involving co-bromoacetophenone and benzylamine has been studied by Mason and Winder (26). The monophenacylbenzylamine hydrobromide (13) (from the reagents) with potassium hydroxide at 100° was claimed incorrectly to form 1,4-dibenzyl-2,5-diphenyl-l, 4-dihydropyrazine (14) (see p. 344), which gave 2,5-diphenylpyrazine. Bromopyruvic acid with aqueous ammonia and mercuric chloride at 55° gave 2,5-dicarboxypyrazine (236a). 

The synthesis of 2-chloromethyl-5,6-diphenyl-2,3-dihydropyrazine from 1,2-diamino-3-chloropropane and benzil has been described (349) in Section II.2 and 2,5-bis(trichloropropenyl)pyrazine from 2,5-dimethylpyrazine and chloral (708) in Section lV.2C(5)(a). 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

Pyrolyses and thermal stabilities of 2-hydroxy-, 2-ethoxy-, and 2-isopropoxy-pyrazines have been studied. 2-Hydroxypyrazine was very stable, but the alkoxy-pyrazines underwent thermal elimination of olefin to yield 2-hydroxypyrazine (668a). Electrochemical reductions of l-methyl-2-oxo-5,6-diphenyl-l,2-dihydro-pyrazine and 54iydroxy(and 5-methoxy)-2,3-diphenylpyrazine are reported to involve the intermediate enamine, for example, 6-hydroxy-1-methyl-2,3-diphenyl-1,4-dihydropyrazine (54) (1096, cf. 1097). When tested on mice 2-carbamoyl-5-methoxypyrazine had less anti tubercular activity than did pyrazinamide (1098). 

Hydroxy-2,5-diphenylpyrazine, methyl iodide, and methanol and some potassium hydroxide heated in a sealed tube at 100° for 10 hours formed the methiodide of 1 -methyl-3,6-diphenyl-2-oxo-l, 2-dihydropyrazine (1104) [3-hydroxy-... 

Dihydroxy-5,6-diphenylpyrazine refluxed with aqueous hydrazine hydrate gave 2-hydrazino-3-hydroxy-5,6-diphenylpyrazine, which was also obtained by heating 2-hydroxy-3-nitro-5,6-diphenylpyrazine with aqueous hydrazine (1124). Distillation of the compound claimed by Japp and Knox (317) to be 3-hydroxy-2,5-diphenylpyrazine (317, cf. 282) with zinc dust produced 2,5-diphenylpyrazine (317) reduction of the former with hydriodic acid and red phosphorus at 200 for 6 hours gave what was regarded as 2,5-diphenyl-3,4-dihydropyrazine (317). 

Hydrolysis of 2-amino-3-hydroxy-l-methylpyrazinium toluenesulfonate (87) with aqueous sodium hydroxide at 95° afforded 3-hydroxy-l-methyl-2-oxo-l, 2-dihydropyrazine which was also prepared in poor yield from the action of nitrous acid on 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (832) and hydrolysis of 6-chloro-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine with boiling methanolic sodium methoxide (followed by acidification) gave 6-hydroxy-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine (873). 1,3,6-Trimethyl-2-oxo-1,2-dihydropyrazine methiodide has been converted through l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahy dropy razine and 3-benzoylmethylene-1,4,6-trimethyl-2-oxo-1,2,3,4-tetra-hydropyrazine (in water) to 1,4,6-trimethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine (1129). 

Electrochemical reduction of l-methyl-2-oxo-5,6-diphenyl-l, 2-dihydropyrazine has been discussed in Section 6F (1096, 1097). Direct amination of the oxo group appears to be unexplored, and little is known of the action of phosphorus halides except that a number of 1-alkyl-3,5,6-trichloro-2-oxo-l,2-dihydropyrazines has been prepared from 1,4-dialkylpiperazine-2,5-diones and phosphorus pentachloride (853) Section 9A(4)]. 

Mason and Winder (26) reported that the base-catalyzed cyclodehydration of JV-phenacylbenzylamine hydrobromide (1) gave 1,4-dibenzyl-2,5-diphenyl-1,4-dihydropyrazine (2) but Chen and Fowler (1535) showed that the product was l,2-dibenzyl-3,6-diphenyl-l,2-dihydropyrazine (3) (20%). Further investigation by... 

Lown and Akhtar (1536) revealed a second product from this reaction, namely l,2-dibenzyl-2,5-diphenyl-1,2-dihydropyrazine (59%) (4). Lown and Akhtar(1537) also showed that the self-condensation of A -isopropylphenacylamine at room temperature gave 1,2-diisopropyl-2,5-diphenyl-1,2-dihydropyrazine (and proposed l,4-diisopropyl-2,5-diphenyl-l,4-dihydropyrazine as an intermediate). In a similar series of reactions of A -alkylphenacylamines, the thermally induced selfcondensations were followed by regiospecific 1,3-shifts to substituted carbon atoms to give in good yields l,2-dialkyl-2,5-diphenyl-l,2-dihydropyrazines at temperatures ranging from ambient to 140° (1536). 

The reactions of A -benzyl-A, A-diphenacylamine hydrobromide with benzylamine at 120-130° was also reported to give 1,4-dibenzyl-2,6-diphenyl-l, 4-dihydropyrazine... 

Condensation of diiminosuccinonitrile (10) with 3-methylbutan-2-one gave 5,6-dicyano-2,2,3-trimethyl-l,2-dihydropyrazine (II) (11%) and 4,5-dicyano-l-isopropyl-2-methylimidazole (7.6%) (383). Cyclization of a-cyanoalkyldiamino-maleonitiiles (12, e.g., R = Me) with phosphorus pentoxide in refluxing ethanol has been shown to give 5,6-dicyano-3-hydroxy(-2-substituted)-l, 2-dihydropyrazines(I3, e.g., R = Me) (489, 490) and the conversion of benzylidenediaminomaleonitrile to 5-carbamoyl-6-cyano- and 6-carbamoyl-5-cyano-2,3-diphenyl-l, 2-dihydropyrazines has been described in Section II.3 (395a). 

Pyrolysis of 1,2-dibenzyl-3,6-diphenyl-1,2-dihydropyrazine (3) gave a mixture of 2,5-diphenylpyrazine, 3-benzyl-2,5-diphenylpyrazine, 2,5-dibenzyl-3,6-diphenyl-pyrazine, and toluene (1535), and pyrolysis of l,2-dibenzyl-3,5-diphenyl-l,2-dihydropyrazine formed a mixture of 2,6-diphenylpyrazine and 2-benzyl-3,5-diphenylpyrazine (1535). l-Benzyl-2,3,5-triphenyl-l,2-dihydropyrazine refluxed with palladium on charcoal in benzene gave 2,3,5-triphenylpyrazine (1542) and the... 

Ultraviolet irradiation (1551, 1552) and thermolysis (1552) of 2,6,8-triphenyl-l,5-diazabicyclo[5,l,0]octa-3,5-diene (18) formed a mbcture containing 2,5-diphenyl-trans-3-styryl-2,3-dihydropyrazine and irradiation of endo- and exo-2,4,6-triphenyl-1,3-diazabicyclo[3,l, 0]hex-3-ene in benzene at 50° gave c -2,3,5-triphenyI-... 

Diphenyl-5,6-dihydropyrazine reacts with alcoholic alkali to form 2,3-... 

It has been claimed (25) that 2,3-diphenyl-5,6-dihydropyrazine when heated with acetic or benzoic anhydride gives a derivative of the 1,4-dihydropyrazine ring system, but this has been shown by Chen and Fowler (1562) to be in error [the products have been shown to be 1,4-diacetyl(or dibenzoyl)-5,6-diphenyl-l,2,3,4-tetrahydropyrazine (26, R = Me or Ph), respectively, together with 23-diphenyl-pyrazine]. Hexamethyl-2,3-dihydropyrazine cannot undergo oxidation to a pyrazine, but it rapidly dimerized in air in the presence of hydrochloric acid to give compound (27, X = Cl) (also prepared as the iodide with iodine in ether) (1550). 

Electrochemical reductions of 2,3-dihydropyrazines have been investigated (1549, 1567) 2,3-diphenyl-5,6-dihydropyrazine was reported to give 2,3-diphenyl-... 

Diphenyl-5,6-dihydropyrazine reacts with diethyl fumarate to give diethyl 1,2-diphenyl-1,3-dihydro-3,7-diazabicyclo[2,2,2]octane-5,6-dicarboxylate (31) (1568), and a similar reaction was observed with Af-methylmaleimide (1569). 2,3-Diphenyl-... 

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