Pyrazine, 2,5-dimethyl-3,6-diphenyl

Imidazolidine, 4,5-dichloro-l,3-diacetyl-imidazo[4,5-6]pyrazine synthesis from, 5, 646 Imidazolidine, 1,3-dimethyl-conformation, 5, 355 Imidazolidine, diphenyl-dehydrogenation, 5, 427 Imidazolidine, 2-imino-1-substituted nitration, 5, 427... 

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). 

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]. 

Different aromatic residues have been substituted for the pyrazine and phenyl groups in 9 in order to undertake a systematic investigation of this type of compound. Nakanishi et al. have examined the solid-state photochemistry of l,4-bis[p-pyridyl-(2)-vinyl]benzene (10), p-phenylenediacrylic acid dimethyl ester (11), diethyl ester (12) and diphenyl ester (13), and p-phenylenedi[a-cyanoacrylic... 

MePTZ = lO-methylphenothiazine 2,3-dpp = 2,3-bis (2-pyridyl)pyrazine 2,9-Me2-4,7-Ph2-phen = 2,9-dimethyl-4,7-diphenyl-l,10-phenanthrolme 2,9-Me2-phen = 2,9-dimethyl-1,10-phenanthroline 3,4,7,8-Me4-phen = 3,4,7,8-tet-ramethy 1-1,10-phenanthroline 4,4 - NH2 2-bpy = 4,4 -dia-mino-2,2 -bipyridine 4,4 -Me2-bpy = 4,4 -dimethyl-2,2 -bipyridine 4, 4 -Ph2-bpy = 4,4 -diphenyl-2,2 -bipyridine 4, 4 - Bu2-bpy = 4,4 -di-tert-butyl-2,2 -bipyridine 4,7-Me2-phen = 4,7-dimethyl-l,10-phenanthroline 4-MeOPh-HPh bpy = 4 -(4-methoxyphenyl)-6 -phenyl-2,2 -bipyridine 4-Me-phen = 4-methyl-1,10-phenanthroline 5,6-Me2-phen = 5,6-dimethyl-l,10-phenanthroline 5-Ph-phen = 5-phenyl-1,10-phenanthroline bimy = benzimidazol-2-ylidene biq = 2,2 -biquinoline bpy = 2,2 -bipyridine bpy-dvb-bpy = 1,4-bis[2-(4 -methyl-2,2 -bipyrid-4-yl)ethenyl]benzene bpy-pyrl = 4-(2-pyrrol-l-ylethyl)-4 -methyl-2,2 -bipyridine bpy-pyr2 = 4,4 -bis((3-pyrrol-l-ylpropyloxy)carbonyl)-2,2 -bipyridine BSA = bovine serum albumin BTA = bis(trimethylsilyl)acetylene chrysi = 5,6-chrysenequinone diimine COD = 1,5-cyclooctadiene DAB = 1,4-diaza-1,3-butadiene DFT = density functional theory dmb =1,8-diisocyano-/ -menthane dmb-tol = 4-methyl-4 -(iV-methyl-/ -tolylaminomethyl)-2,2 -bipyridine dmpe = l,2-bis(di-methylphosphino)ethane dmpm = bis(dimethylphosphino) methane dpmp = bis(diphenylphosphinomethyl)phenylphos-phine dppb = l,2-bis(diphenylphosphino)benzene dppe = l,2-bis(diphenylphosphino)ethane dpp-HCNN = 2,9-di-... 

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). 

Other reducing conditions have also been widely used. Thus zinc and sodium hydroxide has been utilized for the conversion of 1-hydroxyimino-l-phenylacetone to 2,5-dimethyl-3,6-diphenylpyrazine (191) dithionite for the conversion of a-benzoyl a-hydroxyiminoacetanilide to 2,5-diphenyl-3,6-bis(7V-phenylcarbamoyl)-pyrazine (192) sodium amalgam for benzil monoxime to tetraphenylpyrazine (193) aluminum amalgam for hydroxyiminoacetoacetic ester to 2,5-bisethoxy-carbonyl-3,6-dimethylpyrazine (194) and sodium and alcohol for benzil dioxime to tetraphenylpyrazine (195). 

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

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Replacement of the chloro substituent by methoxide has been observed in the following pyrazines 2-chloro-3-methoxycarbonyl (at <5°) (867) 2-chloro-6-methoxycarbonyl (870) 2-chloro-3-methoxycarbonyl-5,6-diphenyl (371, 837) 2-carboxy-6-chloro (869, 871) 2-carbamoyl-5( )-chloro (839) 2-carbamoyl-6-chloro (805, 839) 2-chloro-6-(4 -morpholinocarbonyl) (870) 2-chloro-3-cyano (810, 811) 5-chloro-3-cyano-2-methoxy (reflux 14h) (881) 2-chloro-5-methoxy-3,6-dimethyl (844) 2-chloro-5-isopropyl-6-methoxy-3-methyl (50, 844) 2-chloro-5-methoxy-3,6-diphenyl (1.1 equivalents of 20% methanolic sodium methoxide at 135° for 20h) (797) 2-benzyloxy-6-chloro(at reflux) (832, cf. 883) 2-chloro-3-pyridinio(pyrazine)chloride (or tosylate) (to give 2,3-dimethoxypyrazine) (765) ... 

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)]. 

The following nitriles have been used to prepare carboxypyrazines 2-cyano-3-phenyl [NaOH/ethylene glycol/reflux (1274) or heated with H2S04/NaN02 (1024)] 3-cyano-2,5-dimethyl (NaOH/EtOH/reflux) (1015) 3-cyano-2,5-diphenyl (NaOH) (286) 2,3-dicyano [NaOH/EtOH (354) aq. KOH/EtOH (353) NajOj (357)] 2,6-dicyano (5% NaOH/10072h)(865) 23-dicyano-5,6-dimethyl(Na202) (357) 2-cyano-6-ethylthio(propylthio or phenylthio) (NaOH/EtOH/reflux) (992) 2hydrochloric acid to 2-(3 -carboxy-3 -phenylpropyl)pyrazine (731). 

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). 

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). 

Heating of l,4-dicyano-2,3-dinitroso-2,3-diphenylpiperazine ( ) (1572, cf. 1573) in mesitylene is claimed to give l,4-dicyano-2,3-diphenyl-1,4,5,6-tetrahydro-pyrazine (1572), and l-carbamoyl-3-hydroxy-2,3-diphenylpiperazine ( )(1572, cf. 1573) with methyl iodide and potassium carbonate in methanol is claimed to give 4-carbamoyl-l,l-dimethyl-2,3-diphenyl-l,4,5,6-tetrahydropyrazinium iodide (1572). 2-Diethylamino-l,4-dimethylpiperazine on thermal treatment gives 1,4-dimethyl-l,2,3,4-tetrahydropyrazine, which was methoxycarbonylated to 5-methoxycarbonyl-1,4-dimethyl-l, 2,3,4-tetrahydropyrazine (1593). 

---