5.6- Diphenyl pyrazine

Ein Gemisch von 2,67 g (0,01 mol) 2-Chlor-5,6-diphenyl-pyrazin, 5,60 g (0,1 mol) Kaliumhydroxid und 100m/ Dimethylformamid wird 14h auf 180-190° erhitzt und wie vorstchend heschrieben aufgearbeitet. Das so erhaltene braune Produkt wird aus Methanol umkristallisiert Ausbeute 1,34 g (78%) Schmp. 132-133° (farblose Nadeln). 

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... 

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-... 

Refluxing phosphoms tribromide converted 2-bromo-3-hydroxy-5,6-diphenyl-pyrazine and 2-bromo-5-hydroxy-3,6-diphenylpyrazine to the dibromopyrazines 2,3-dichloro-5,6-dimethylpyrazine and 2,5-dichloro-3-phenylpyrazine to the dibromopyrazines (817) 5-chloro-2,3-diphenylpyrazine (and its 6-ethyl derivative) to 5-bromo-2,3-diphenylpyrazine (and its 6-ethyl derivative) (866) and 2-hydroxy-... 

Hydrolysis of 2-hydroxy-3-nitro-5,6-diphenylpyrazine (11) in aqueous sulfuric acid or aqueous hydrochloric acid-acetic acid afforded 2,3-dihydroxy-5,6-diphenyl-pyrazine (817, 1065), and similar results were obtained with dry hydrogen chloride in glacial acetic acid (841). 

Hydroxy-3-nitro-5,6-diphenylpyrazine heated with aqueous hydrazine gave 2-hydrazino-34iydroxy-5,6-diphenylpyrazine (1124) whereas when refluxed with hydrazine and Raney nickel in methanol it gave 2-amino-3-hydroxy-5,6-diphenyl-pyrazine (1065). 

Chloro-3-methoxycarbonyl-5,6-diphenylpyrazine refluxed with sodium methoxide gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (371) and the attempted Schmidt reaction of 2,5-dimethoxycarbonylpyrazine, in concentrated sulfuric acid with trichloroacetic acid at 60° with subsequent addition of sodium azide, gave 2,5-dicarboxypyrazine (1176). 2-Methoxy-3-methoxycarbonyl-5,6-diphenylpyrazine, when refluxed with cuprous chloride in dry dimethylformamide, gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (10%) 2-hydroxy-3-methoxycarbonyl-5,6-diphenyl-pyrazine similarly treated gave 5-hydroxy-2,3-diphenylpyrazine (30%) (837). 

Dicyanopyrazine with sodium methoxide in methanol with ammonia at reflux gave 5,7-diimino-6//-pyrrolo[3,4-i)]pyrazine (65) (1442) and 2,3-dicyano-5,6-dimethyl(and 5,6-diphenyl)pyrazine with hydrazine by the procedure of Patel and Castle (1339) gave 2,3-dimethyl(and 2,3-diphenyl)-5,8-diaminopyrazino[2,3-rfJ-pyridazine(s) (66) (1435). Fusion of 2-chloro-3-cyano-5,6-diphenylpyrazine with urea and thiourea was reported to give 4-amino-2-hydroxy(and mercapto)-6,7-diphenylpteridine (848). 

A number of other pteridinones and pteridinethiones have been obtained by similar methods, for example the use of phenylisothiocyanate as the one-carbon unit with 3-amino-5,6-diphenyl-pyrazine-2-thiocarboxamide gives 2-anilino-6,7-diphenylpteridine-4(3/f)-thione (2).139... 

Die Dihydro-Derivate sind bei diesen Potentialen offenbar bestandig das 2,3-Diphcnyl-5,6-dihydro-pyrazin jedoch wird bei —1,4 V (vs. SCE) unter Ar%y>nzum2,3-Diphenyl-1,4,5,6-tetrahydro-pyrazin weiterreduziert (an Quecksilber in geteilter Zelle 70% d. Th. F 106°). 2,3-Diphenyl-pyrazin (-1,75 V 15% d. Th.) und 2,5-Di-phenyl-l,2-dihydro-pyrazin (- 1,55 V 59% d. Th.) wird im selben basischen Milieu dagegen za 2,3-Diphenyl-bzw. 2,5-Diphenyl-piperazin reduziert1 ... 

In waGrig-alkalischem Methanol kann 5-Methoxy-2,3-diphenyl-pyrazin zum 5-Meth-oxy-2,3-diphenyl-3,6-dihydro-pyrazin (34% d.Th. F 125° EK = —1,7 V) reduziert wer-den2 (zur analogen Reaktion von 2-Pyrazonen s. S. 602) ... 

Aus 5-Hydroxy-2,3-diphenyl-pyrazin wird auf analoge Weise 5-Oxo-2,3-diphenyl-... 

The plasma half-life of cathinone is 1.5 hours. The primary metabolites are norpseudoephedrine, norephedrine, 3,6-dimethyl-2,5-diphenyl-pyrazine, and l-phenyl-l,2-propanedione (Szendrei 1980 Brenneisen etal. 1986 Guantai and Maitai 1983). However, norpseudoephedrine and norephedrine also originate directly from the leaves, as well as being metabolic products (Widler et al. 1994). Maximal plasma concentrations of norephedrine and norpseudoephedrine are reached at about 3.3 and 3.1 hours, respectively. These two drugs have a much longer duration of action than cathinone, where terminal half-lives could not be calculated after 10 hours. 

Zu erwahnen sind schlicBlich die photochemische Umlagerung von 2,4-Dimethyl- bzw. 2,4-Diphenyl-pyrazin-l-oxid, die zu 2,4(5 )-Dimethyl- (15%) bzw. 2,4(5)-Diphenyl-imidazol (29%) fiihrt429, und die ebenfalls photochemische Herstellung von Imidazolen aus 2,3-Dihydro-pyr-azinen (s.Bd. IV/5b, S. 1107-1108). 

The self-condensation of the bisulfite addition compound of an a-oximinoketone followed by reaction with potassium cyanide and hydrochloric acid yields 3,6-dicyano-2,5-dialkylpyrazines or, in the case of oximinoacetophenone, a mixture of 3-cyano-2,5-diphenyl-pyrazine and 3,6-dicyano-2,5-diphenylpyrazines.227... 

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... 

IIydroxy-3,6-diphenyl-2(l//)-pyrazinonc (84) gave 2,5-diacetoxy-3,6-diphenyl-pyrazine (85) (AC2O, AcOH, reflux, 4 h 65%).1386 Also other examples.118,734 1347 1392 1695... 

During the isolation of cathinone, 3,6-dimethyl-2,5-diphenyl pyrazine (3) was also found (14). This is doubtless an artifact, the product of oxidative dimerization of cathinone which involves the formation of condensation product 4 as an intermediate (18). Also found was the diketone (5) and the cinnamoyl compound (6) (14), later shown to have the (S) stereochemistry illustrated and named merucathinone (6,19,20). Merucathine (7) has also been isolated (6,21,22), and this and merucathinone are minor components. (-)-Norephedrine (8) also occurs in khat (14), and its iV-formyl derivative (9) has been found in plant material of South Arabian origin (23). Despite earlier positive reports, ephedrine and pseudoephedrine have not been verified as components of khat (14). HPLC has been employed to separate and quantify mixtures of the khatamines cathinone, (+)-norpseudoephedrine, and (—)-norephedrine in connection with a study of their distribution in different parts of the khat plant and in specimens of different geographical origin (20,21). 

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]

An interesting series of reactions for 2,5-dimethyl(and 2,5-diphenyl)pyrazine... 

Bromo-3-hydroxy-5,6-dimethylpyrazine and 2-bromo-5-hydroxy-3,6-diphenyl-pyrazine with phosphoryl chloride afforded 2,3-dichloro-5,6-dimethylpyrazine and 2,5-dichloro-3,6-diphenylpyrazine, respectively (817) and the bromo substituent in 2-amino-3-bromo-5,6-dimethylpyrazine and its p-aminobenzenesulfonyl derivative have been replaced by chlorine on treatment with aqueous hydrochloric acid in ethanol (812). 

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-... 

Khydroxypyrazine (which was converted into its jV -dimethyl derivative by treatment with dimethyl sulfate and alkali) gave, on reaction with an excess of ethereal diazomethane a mixture of its N,N-, 0,N-, and 0,0-dimethyl derivatives (58-60) (832). 2-Hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenylpyrazine with ethereal diazomethane gave predominantly 2,5-dimethoxy-3,6-diphenyl-pyrazine and only minor amounts of A -methylated products (832). Methylation of 2-hydroxy-6-methoxypyrazine with ethereal diazomethane produced a mixture of 0- and A -methyl derivatives in which the 0-methyl derivative predominated but the corresponding reaction of 2-benzyloxy-6-hydroxypyrazine gave almost exclusively the 0-methyl derivative (832) [the results of these methylations were correlated with the carbonyl stretching frequency (1103) in the parent lactam (832)]. 

When heated with aqueous potassium hydroxide, 2,5-dicyano-3,6-dimethyl(and diphenyOpyrazine gave 2-carboxy-5-hydroxy-3,6-dimethyl(and diphenyl)pyrazine (286-288) and the diethyl analogue was prepared similarly (287). 2-ChIoro-6-cyanopyrazine refluxed with three equivalents of sodium methoxide for 2 hours gave 2-carboxy-6-methoxypyrazine, also obtained from 2-chloro-6-cyanopyrazine with one equivalent of sodium methoxide through 2-(C-imino-C-methoxymethyl)-6-methoxypyrazine (2), which, refluxed with 15% sodium hydroxide, gave 2-carboxy-6-methoxypyrazine (986). 

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... 

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). 

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