6- Phenyl-2 -pyrazinone

Isobutyl-5-phenyl-2(17/)-pyrazinone 3-Isobutyl-6-phenyl-2(17/)-pyrazinone 2-Isobutyl-3-propionylpyrazine 2-Isobutyl-5-propionylpyrazine... 

Alternatively, 3-phenyl pyrazinone was prepared via Suzuki reaction, when a polymer-bound pyrazinone was irradiated with 4 equiv of phenylboronic acid, 5 equiv of Na2C03 and 20 mol % of Pd[P(Ph)3]4 as the catalyst in DMF as the solvent (Scheme 36). Contrary to the results obtained in solution phase [29], all attempts to drive the reaction toward the formation of disub-stituted compound, using higher equivalents of reagents or longer reaction times, were unsuccessful. Apphcation of aqueous conditions afforded mixtures of 3-mono and 3,5-disubstituted pyrazinones. 

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

Greater para than ortho deactivation is seen in the hydrolysis (HCl in AcOH, 100°, 1 hr) of the nitro group in 5,6-diphenyl-2-nitro-3-pyrazinone (218) but not in 6-phenyl- or 3,6-diphenyl-2-nitro-5-pyrazinone (219). Similarly, acid hydrolysis of a 2-bfomo substituent in 3-pyrazinone, but not in 5-pyrazinone, is readily accomplished. All flve of these pyrazinones are stable in strong alkali or alkoxide as a result of complete anionization. Decreased reactivity of... 

Condensation of phenylalaninenitrile, prepared from phenyl acetaldehyde, with 1-oxime of pyruvaldehyde afforded the pyrazine N-oxide, which was further rearranged to give the N-acetyl pyrazinone. The acetyl groups were removed by treatment with hydrazine to give the target 6-aminopyrazinone. 

Hydroxypyrazines or 2(l//)-pyrazinones are also subject to electrophilic halogenation. A new result is that 1-benzyl- or 1-phenyl-substituted 2(l//)-pyrazinones undergo bromination with NBS or A -iodosuccinimide (NIS) to give the 5-bromo or iodo-2(l//)-pyrazinones in 66-82% yields <2004TL1885, 2005T3953>. 

The simple phenyl-substituted pyrazines do undergo nitration in the phenyl ring for example, 2-phenylpyrazine yields the 4-nitrophenyl derivative (mixed acid), although 5-phenyl-2-pyrazinone forms the 3-nitropyra-zinone under similar conditions (75MI1). However, 2,5-dimethyl-3,6-diphenylpyrazine and its /V,A -dioxide are both reported to be nitrated to give the bis-(3-nitrophenyl) products (55JCS3094). 

Heating with phosphoryl chloride converted 1 -hydroxy-3-phenyl-2( 1H )-pyrazinone (52) into the 2,5-dichloro derivative (53) via the 5-monochIoro species. It had been expected that chlorination would take place at C-6, but this occurred only to a minor extent. The observed chloride attack /3 to the oxygen function might be accounted for in terms of the sequence illustrated in Scheme 46 (86JHC149). Reaction mechanisms have been proposed to explain the observed a- and /3-chlorination when 2- and 3-substituted pyrazine Af-oxides are subjected to the Meisenheimer reaction. /3-Chlorination was rationalized in terms of electron withdrawal by the unoxidized nitrogen atom [84JCR(S)318] (Scheme 46). 

As already mentioned, hydroxypyrazines exist in tautomeric equilibria with the corresponding pyrazinones which are normally the predominant species in the equilibria. Some of the reactions of hydroxypyrazines are reminiscent of those of phenols they can, for example, be coupled with diazonium salts and brominated and nitrated in either the ortho or para position to the hydroxyl group. Coupling with diazonium salts occurs in neutral or weakly alkaline solution, but if the reaction is carried out in 1 M sodium hydroxide solution, arylation of the pyrazine ring takes place. From hydroxy-pyrazine and benzenediazonium chloride 47% 2-hydroxy-3-phenyl-and 4% 2-hydroxy-3,6-diphenylpyrazine are obtained. 

Mcthyl-5-phenyl-2(l//)-pyrazinone (4) gave 2-chloro-3-methyl-5-phenylpyra-zine (5) (P0C13,175°C, sealed, 18 h 92% beware of pressure within the tube even when cooled ) 57 such a sealed reaction also converted 5-chloro-3-phcnyl-2( l//)-pyrazinone into 2,5-dichloro-3-phenylpyrazine (6) (185°C, 5 h 92%).1382... 

Methylthioethyl)-5-phenyl-2(l//)-pyrazinone (20) gave 2-chloro-3-(2-methylthioethyl)-5-phenylpyrazine (21) (COCl2, PhMe—THF, reflux, 4 h >95%) 315 2-chloro-3-isobutyl-5-phenylpyrazine (>80%) similarly.632... 

Benzyl-3,5-dichloro-6-phenyl-2(l//)-pyrazinone (91, R = Cl) gave 1-benzyl-5-chloro-3-(o-iodoanilino)-6-phcnyl-2(l//)-pyrazinonc (91, R = NHC6H4I-o) (H2NC6H4I-o, NaH, THF, N2, 20°C, 30 min substrate J, reflux, <5 h 78%) 1607 analogues likewise.1607 Also other examples.481,1063... 

Chloro-3-isobutylpyrazine 4-oxide gave 3-isobutyl-2( I // )-pyrazinone 4-oxide (111, R = Hu ) (5 M NaOH, reflux, 2 h 39%) 86 2-chloro-3-phenylpyrazine 4-oxide gave 3-phenyl-2( I //(-pyrazinone 4-oxide (111, R = Ph) (KOH, H20—EtOH, reflux, 1 h 30%) 1290 also analogues likewise.1290... 

L-Benzyl-6-(l-bromo-2-methylpropyl)-5-chloro-3-phcnyl-2(l//)-pyrazinonc (256, R = Br) gave 6-(l-azido-2-methylpropyl)-l-benzyl-5-chloro-3-phenyl-2(l//)-pyrazinone (256, R = N3) (NaN3, Mc2NCIIO, 60°C, 5 h 62%).53... 

Hydrolysis. 2-Methoxy-3-methyl-5-phenylpyrazine (16) gave 3-methyl-5-phenyl-2(l//)-pyrazinone (17) (6 M HC1, reflux, 3 h 97%) 1307 other products like 3,6-diisopropyl-2( I //(-pyrazinonc (18, R = Pr ) (97%)1311 and 3,6-diphenyl-2(l/7)-pyrazinone (18, R = Ph) (84%)82 were made similarly. Hydriodic acid may also be used.1307... 

The polarographic reduction of 6-methyl-3-phenyl-2(l//)-pyrazinone (105) has been studied.983... 

Dichloro- l-phenyl-2(l//)-pyrazinone (207) and dimethyl acetylenedicarboxy-late gave an unisolated adduct (208) that immediately underwent competitive retro-Diels-Alder reactions to afford dimethyl 2,6-dichloro-3,4-pyridinedicar-boxylate (209) and dimethyl 5-chloro-6-oxo-l-phenyl-l,6-dihydro-2,... 

Amino-6-phenyl-2-pyrazinecarboxamide from its 4-oxide (257) (Na2S204, H20, reflux, 24 h 97%) 1517 also substituted-phenyl analogues likewise.1517 6-Phenyl-2( I //(-pyrazinone from its 4-oxide (258) (Na2S204, EtOH—H20, reflux, 30 min then more Na2S204, reflux, 30 min 59%).88 Also other examples.1457... 

Acetoxy methyl- 5-phenyl- 2(1 77)-pyrazinone 5-Acetoxy methyl- 3-phenyl- 2(1 77)-pyrazinone 2-(l-Acetoxy-2-methylpropyl)-3-chloro-5-isobutylpyrazine... 

Amino-6-phenyl-2,3-pyrazinedicarbonitrile 3-Amino-5-phenyl-2(177)-pyrazinone 3-Amino-5-(prop-l-enyl)-2-pyrazinecarbonitrile 3-Amino-6-(prop-l-enyl)-2-pyrazinecarbonitrile 3-Amino-5-(prop-l-enyl)-2-pyrazinecarbonitrile... 

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