L,2 -Dihydropyrazines

The reactions of glyoxal at 100° and pH 5 with dipeptides (380, 381) and tri-and tetrapeptides (382) to give some 2-oxo-l, 2-dihydropyrazines are summarized in Table 11.8 and discussed in greater detail in Section 7. 

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-... 

Diniethylpiperazine-2,5-dione (34) on treatment with triethyloxonium fluoroborate in dichloromethane gave 5-ethoxy-l,3-dimethyl-2-oxo-l, 2,3.6-tetrahydropyrazine which was oxidized by DDQ in dry benzene to 5-ethoxy-l 3 dimethyl-2-oxo-l,2-dihydropyrazine (35) (1067). l,3,6-Trimethylpiperazine-2,5-dione similarly treated gave three products, one of which was assigned the structure 5-methoxy-l 3,6-trimethyl-2-oxo-l, 2-dihydropyrazine 3-benzyl-5-methoxy-l, 6-dimethyl-2-0X0-1,2-dihydropyrazine was also prepared similarly (1078). When 3,6-diethoxy-2,5"dimethyl-2,5-dihydropyrazine was refluxed with lead tetraacetate in dry benzene it gave a mixture of 2,5-diacetoxy-3,6-diethoxy-2,5-dimethyl-2,5-dihydropyrazine (36) (4 parts) and 2,5-diethoxy-3,6-dimethylpyrazine (1 part) (1068). 

Diisobutyl-3-methoxypyrazine 1,4-dioxide with phosphorus trichloride in ethyl acetate at 40° gave 2,5-diisobutyl-3-methoxypyrazine (and 2,5-diisobutyl-4-methoxy-3-oxo-3,4-dihydropyrazine 1-oxide similarly treated gave 3,6-diisobutyl-I-methoxy-2-oxo-l, 2-dihydropyrazine) (see Section 15) (980). 

In 23-dihydroxypyrazine and derivatives Honzl (853), from measurements of infrared spectra in chloroform and ultraviolet spectra in aqueous alcohol, has proposed that 5,6-dichloro-l-cyclohexyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (pA in water 4.66, 5.66) exists in the form (48). The p.m.r. spectra of some 5- and 6-methyl- and 5- and 6-phenyl-2,3-dihydroxypyrazines have been reported (483). In the 2,5-dihydroxypyrazine series, the infrared spectrum (Nujol) of 2-benzyl-3,6-dihydroxy-5-methylpyrazine has been interpreted as indicating that the major tautomeric form present in the solid state was the dihydroxy form (49), but the ultraviolet spectrum in ethanol was considered consistent with the coexistence of the dihydroxy (49) and oxo-hydroxy form, for example, (50), Although the structure (51) has been proposed for 3-butyl-2,5-dihydroxypyrazine (1092), the evidence in favor of this structure is inconclusive. 

A large number of 2-alkyl-3-methoxypyrazines has been isolated from raw vegetables (59, 60, 64, 65, 69, 80, 1099), bell peppers (60,61) and gambanum oil (49). 2-Isobutyl-3-methoxypyrazine is already finding commercial use as a flavoring material (368) and 2-ethoxy-3-methylpyrazine may be used for pineapple flavor (981). The odor characteristics (367, 368, 976, 977) and structure (977) of some alkoxy alkylpyrazines have been examined. 3-Guanidino-6-hydroxymethyl-l-methyl-2-oxo-l,2-dihydropyrazine has been isolated from seeds of Stizolobium hassjoo and on mild alkaline hydrolysis gave 3-hydroxy-6-hydroxymethyl-l -methyl-2-oxo-l, 2-dihydropyrazine (1060). 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

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-... 

Ribosidation of the trimethylsilyl derivative of 2-hydroxypyrazine (69) (prepared with trimethylsilyl chloride and bistrimethylsilylamine) with 1,2,3,5-tetra-O-acetyl-/J-D-ribofuranose and titanium tetrachloride in 1,2-dichloroethane, followed by deacetylation with sodium methoxide, gave 2-oxo-l-( -D-ribofuranosyl)-l, 2-dihydropyrazine and its 4-oxide was prepared similarly (1035). A similar reaction occurred with the trimethylsilyl derivative of 3-hydroxypyrazine 1-oxide and 1,2,3-tri-<3-acetyl-D-erythrose (1110). 

Ethoxy-l,3-dimethyl-2-oxo-l,2-dihydropyrazine has been shown to undergo ready cycloaddition reactions even with nonactivated double bonds (1067), and also rapidly reacts with oxygen on exposure to air. 

Preparations of some A-substituted 2-oxo-l, 2-dihydropyrazines have been discussed in Section 11.2 from the reactions of di-, tri-, and tetrapeptides with glyoxal (380-382) and Cheeseman and co-workers (1111) have described the preparation of 1-benzyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (83) (and similarly its 1-methyl analogue) from ethyl A-(2, 2 -dimethoxyethyl)oxamate and benzyl-amine through A-benzyl-A -(2, 2-dimethoxyethyl)oxamide (84) by the application of a standard procedure (482). 

Rearrangements of alkoxypyrazines to 1 -alkyl-2-oxo-l, 2-dihydropyrazines have been described in Section 8 (832, 883). 

Honzl (853) has described the preparation of alkyl(or aryl)-2-oxo-l, 2-dihydropyrazines by reaction of A,A -dialkyl(or aryl)piperazine-2,5-diones with phosphorus pentachloride. For example, 1,4-dicyclohexyl(or diethyl)piperazine-2,5-dione (85, R = cyclohexyl, Et) with phosphorus pentachloride in 1,2-dichloroethane gave... 

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). 

Methylfluorosulfonate and 1 -methyl-2-oxo-l, 2-dihydropyrazine gave a quantitative yield of 1,4-dimethyl-2-oxo-l, 2-dihydropyrazinium fluorosulfonate, which reacted instantaneously and exothermically at room temperature and in high yields with hydroxide ion, hydrosulfide ion, and ammonia to give interesting new cage systems (1130). 

Irradiation of 1,3,5,6-tetramethyl-2-oxo-l, 2-dihydropyrazine (88) in tetrahydro-furan produced an unstable photoisomer which can be trapped by hydrogenation to 1,2,4.6-tetramethyl-3-oxo-2,5-diazobicyclo[2,2,0lhexane (89) (1131). 

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)]. 

The reactions in the decomposition of 13,6-trimethyl-2-oxo-l, 2-dihydropyrazine methiodide with alkali metal hydroxide to give 1,4,6-trimethyl-3-methylene-2-oxo-1,2,3,4-tetrahydropyrazine (1105) and its reaction with benzenediazonium chloride or phenylhydrazine to give l,4,6-trimethyl-2-oxo-3-phenylazomethylene-l,2,3,4-tetrahydropyrazine (1105,1132) have been described. 

Boron tribromide in dry chloroform was used to convert 3-isobutyl-6-isopropyl-1-methoxy-2-oxo-l, 2-dihydropyrazine to 2-hydroxy-3-isobutyl-6-isopropylpyrazine 1-oxide, and 6-isobutyl-3-isopropyl-l-methoxy-2-oxo-l, 2-dihydropyrazine behaved similarly (740a). Ohta (843) reports the preparation of 2-hydroxy-3,6-diisobutyl-pyrazine 1-oxide from 3,6-diisobutyl-l-methoxy-2-oxo-l, 2-dihydropyrazine (as intermediate) and hydrogen iodide. 

Hydroxypyrazine 1 oxide was reduced with hydrogen at atmospheric pressure over Raney nickel to 2-hydroxypyrazine (108) [but failed to react with phosphorus trichloride in chloroform (108)], and 3-hydroxy-2-isobutyl-5-isopropylpyrazine 1,4-dioxide was reduced with hydrogen over nickel to 3-hydroxy-2-isobutyl-5-isopropylpyrazine (740a). 2-(A -Anilino-yV-methylcarbamoyl)-4-methyl-3oxo-3,4-dihydropyrazine 1 oxide with sodium dithionite produced 3-(A -anilino-A -methyl-carbamoyl)- -methyl-2oxo-l, 2-dihydropyrazine (1137). 

Methyl-2-oxo-l, 2-dihydropyrazine with phosphorus pentasulfide in pyridine at reflux was converted into l-methyl-2-thio-l,2-dihydropyrazine (18) (821,1100), and 3-chloropyrazine 1-oxide with sodium hydrogen sulflde in ethanol at room temperature gave 3-mercaptopyrazine 1-oxide (19) (1035). Whereas 3-chloro-2,5-dimethyipyrazine 1-oxide reacted slowly with thiourea in ethanol, and the use of water in place of ethanol caused some increase in reaction rate, the reaction in 2A sulfuric acid at reflux for 30 minutes gave 3-mercapto-2,5-dimethylpyrazine 1-oxide (85%), and 3-mercapto-2-methylpyrazine 1-oxide was prepared similarly (905). 

The ultraviolet spectra in aqueous solution (821) of the methiodides isolated from the methylation of 2-amino- and 2-dimethylaminopyrazines with methyl iodide in methanol (821) differed from those obtained by protonation of 2-amino-and 2-dimethylaminopyrazine, respectively. This methiodide of 2-aminopyrazine was rapidly decomposed by aqueous alkali but did not form l-methyl-2-oxo(or imino)-l, 2-dihydropyrazine or 2-methylaminopyrazine (821). These and other observations were consistent with protonation of 2-amino(2-methylamino or 2-dimethylamino)pyrazine at N, and with the methiodides isolated involving quater-nization at N4 (821). It has been claimed from studies of ultraviolet and infrared spectra and from reactions with cyanoguanidine that in 2-aminopyrazine p-toluenesulfonate, the amino group is protonated (1189). 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

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). 

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). 

Treatment of (2a,3o(,6a,7o )-2,3.5,7-tetraphenyl-l,4-diazabicyclo[4,l,0]hept-4-ene (14) with potassium r-butoxide in benzene has been reported to give 1-benzyl-2,3,5-triphenyl-l, 2-dihydropyrazine (1542). 

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... 

Treatment of 2-benzylideneamino-l-phenylvinyl benzoate (47) with sodium methoxide produced one major product which was assigned as 2,5-dibenzoyI-3,6-diphenyl-1,4-dihydropyrazine (48) (1585). Dimerization of a series of a-arylamino ketones (49) in toluene with p-toluenesulfonic acid gave the symmetrical 1,4-diaryl-1,4-dihydropyrazine (50), not the corresponding l,4-diaryl-l,4-dihydropyrazines (51) or l-aryl-l,2-dihydropyrazines (52). Thus w-(4-chloroanilino)acetophenone gave 1,4-bis(p-chlorophenyl)-2,6-diphenyl-1,4-dihydropyrazine (1546). 

The preparation of piperazin-2-ones by reduction of 2-oxo-l,2-dihydropyrazines has been described in Section V.5A(1) (853). 

---