1.4- Dihydropyrazines

Dihydropyrazines are relatively stable, although they are easily oxidized. They are usually formed via the addition of organometallic reagents to the pyrazine ring. Similarly, 2,3-dihydropyrazines are usually easily oxidized to pyrazines and are formed during type A synthesis (see Section 2.14.3.2). 

Condensation of 1,2-bishydroxylamines (84) with 1,2-dicarbonyl compounds leads to derivatives of 2,3-dihydropyrazine-l,4-dioxides (85) (255), whereas the reaction with ninhydrin gives [1,2-b] pyrazine N,N -dioxides (86) (Scheme 2.32)... 

Among the four isomers of dihydropyrazines, the 2,3-dihydro isomers are most explored because these reduced pyrazines have been easily prepared by condensation of 1,2-diamines and 1,2-dicarbonyl compounds. This class of compounds is unexpectedly unstable resulting in dimerization at room temperature. Thus, 2,3-dihydropyrazine 97 (R = = Me) gradually dimerizes to form tricyclic system 98, fused with two tetrahydropyrazine units... 

Acetyl-protected 1,2,3,4-tetrahydropyrazines 105, which are prepared by treatment of 2,3-dihydropyrazine with acetic anhydride and zinc (Scheme 27), undergo photooxidation to produce new dioxetanes 106 <1995JA9690>. Upon thermolysis, the dioxetanes 106 decompose quantitatively to tetraacyl ethylenediamines 107. Dimethyldioxirane oxidation of tetrahydropyrazine 105 affords novel epoxide 108, which is also generated by deoxygenation of dioxetane 106 with dimethyl sulfide. In 2,3,4,5-tetrahydropyrazine 1-oxide 109, which is prepared... 

The condensation of an a-diketone or its synthetic equivalent (e.g. aroyl cyanide (87S914)) with a 1,2-diaminoalkane gives 2,3-dihydropyrazines (Scheme 41), which like their 2,5-analogues can be oxidized by air, or better by Mn02 in ethanolic KOH, to pyrazines (78MI21400). 

Although hexamethyl-2,3-dihydropyrazine 1,4-dioxide (166) does not exhibit typical nitrone properties, oxaziridines are nevertheless formed on photolysis with light of wavelength greater than 300 nm, only the monooxaziridine (167) is formed, whereas with light of wavelength down to 200 nm, cis- (168) and trans- (169) dioxaziridines are obtained.148... 

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]. 

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 ... 

The photolysis of 2,3-dihydro-5,6-diphenylpyrazine and related 2,3-dihydropyrazines gives imidazoles. Reaction proceeds through a diazahexatriene intermediate (196) as illustrated. The major product,... 

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... 

Bis(hydroxyamino)-2,3-dimethylbutane (160) and glyoxal gave 2,2,3,3-tetramethyl-2,3-dihydropyrazine 1,4-dioxide (161) (H20—EtOH, reflux, 10 min 83% naturally not subject to facile oxidation).702 Also other examples.1,86 237 414,466,483 588 988 1108... 

Af-Benzylidene-AKdiphenylmethyl)amine N-oxide (288) gave 2,2,3,3,5,6-hexa-phenyl-2,3-dihydropyrazine (290) via the isomeric anions (289) (LiPh, Et20, A, 20°C, 10 min 30%).1112... 

Tetramethyl-2,3-dihydropyrazine 1,4-dioxide (303) gave 2,2,3,3-tetram-ethyl-l,4-piperazinediol (304) (NaBH4, H20, 20°C, 24 h 81% homologues likewise).702 Also analogous reductions.702... 

Both pyrazine iV-oxides and 2,3-dihydropyrazines rearrange photochemically to imidazoles. Irradiation of the 2,5-disubstituted oxides (187) gives mixtures of the imidazole products (188, 189), probably through the intermediacy of oxaziridine intermediates (Scheme 109). 

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). 

The preparation of some 2,3-dihydropyrazines from a, -dicarbonyl compounds with a,0-diamino compounds has been recorded in Section 11.2 (330, 330a, 331, 333, 334, 338-344, 349, 356, 357), with further data given in references 6, 337, 345, and 1547-1549. In addition hexamethyl-2,3-dihydropyrazine (16) has been prepared from 2,3-diamino-2,3-dimethylbutane and butane-2,3-dione (1550). Condensation of oxalyl chloride with diiminosuccinonitrile (10) in ether has been shown to give 2,3-dichloro-2,3-dicyano-5,6-dihydroxy-2,3-dihydropyrazine (17) (383). 

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-... 

Fluorination of tetrafluoropyrazine with a mixture of cobalt and calcium fluorides at 80° gave 2,2,3,3,5,6-hexafluoro-2,3-dihydropyrazine (22) (886), and chlorination of tetrafluoropyrazine gave 10% 5,6-dichloro-2,2,3,3-tetrafluoro-2,3-... 

Dehydrogenations of some 2,3-dihydropyrazines to the corresponding pyrazines have been effected as follows 2,3-dimethyI-5,6-dihydro [reflux with potassium hydroxide in ethanol (333) heat in ethylene glycol at 197° (653, 1558) reflux with potassium hydroxide and manganous oxide in ethanol (633a) vapor phase reaction in the presence of a catalyst, such as copper chromite, and clay (472) heat... 

Irradiation of /rans-2,3,5,6-tetraphenyl-2r3-dihydropyrazine in benzene gave cis-2,3,5,6-tetraphenyl-2,3-dihydropyrazine (1556). 

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). 

The photorearrangement of 2,3-dihydropyrazines to imidazoles has been described (1547, 1563, 1564). For example, 2,3-dimethyl-5,6-dihydropyrazine gave... 

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

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