3.6- Dimethyl-2 -pyrazinone

Alkylation of pyrazinones and quinoxalinones may be carried out under a variety of conditions and it is usually observed that while O-alkylation may occur under conditions of kinetic control, to yield the corresponding alkoxypyrazines or alkoxyquinoxalines, under thermodynamic control the A-alkylated products are formed. Alkylation using trialkyl-oxonium fluoroborate results in exclusive O-alkylation, and silylation under a variety of conditions (75MI21400) yields specifically the O-silylated products. Alkylation with methyl iodide or dimethyl sulfate invariably leads to A-methylation. 

Fig. 39 Microwave-assisted synthesis of pyridinones from resin-bonnd 2(iH)-pyrazinones. Reagents and conditions a dimethyl acetylenedicarboxylate, chlorobenzene, reflux (132 °C), 1-2 days or 1,2-dichlorobenzene, MW 220 °C, 20-40min b bromobenzene, reflux (156 °C), 2h or 1,2-dichlorobenzene, MW 220 °C, 10min R = OC2H4C2H c TFA, reflux (72 °C), 20-24 h or TFA/Ch2Cl2, MW 120 °C, 10-40min. R=OMe or Ph, R = methoxyphenyl. All microwave-assisted reactions were rim in sealed vessels...

However, most of the reactions are reported to be slow, taking up to 12 h for complete conversion of the starting materials. A Diels-Alder reaction of the pyrazinone scaffold with dimethyl acetylenedicarboxylate (DMAD) [57] has been studied in view of investigating the swiftness of this cycloaddition-fragmentation protocol (Scheme 20). The authors investigated the reaction with DMAD (lOequiv) under microwave irradiation at an elevated temperature of 190 °C, using small amounts of ionic liquid (bmimPFe) in... 

As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

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. 

A rather different route to hexadentate ligands containing 3-hydroxy-2-p5rridinone units is based on the reaction of an appropriate pyrazinone with dimethyl acetylene dicarboxylate, which replaces one of the ring-nitrogen atoms by carbon (82). 

Ring nitrogens in pyrazines and the benzo derivatives react with electrophiles to form quaternary ammonium species such as iV-alkylpyrazinium salts and pyrazine iV-oxides. N-Alkylation has generally been performed by treatment with a reactive alkyl iodide. The N-1 nitrogen in 2(l//)-pyrazinone 5 is methylated using chloro(chloromethyl)dimethyl-silane followed by desilylation with cesium fluoride to yield l-methyl-2(l//)-pyrazinone <2000TL4933>. 

As can be seen in the intramolecular cycloaddition (Section 8.03.5.1), the intermolecular Diels-Alder reactions between functionalized 2(l/f)-pyrazinones 83 and dimethyl acetylenedicarboxylate (DMAD) forming bicyclo adducts 84 has been shown to be significantly rate enhanced and increased in yields by using controlled microwave irradiation compared to the conventional thermal protocols (Scheme 21) <2002JOC7904>. The microwave-assisted Diels-Alder reactions of substituted 2(l//)-pyrazinones with ethene are significantly more effective utilizing prepressurized (up to 10 bar) reaction vessels <20040BC154>. 

Since 1,4-dihydropyrazine itself is unknown, various substitutions of the ring system are required to produce stable isolable molecules. Carbonyl-stabilized 1,4-dihydropyrazines are synthesized by self-condensation of 3-chloromethyl-5,6-dihydro-l,5,5-trimethyl-2(l//)-pyrazinone <1998J(P1)289>. Another carbonyl-stabilized example is provided by WA -BOC-protected 1,4-dihydropyrazine 102, which can undergo Michael addition with nucleophiles such as 1,2,4-triazole, 3-formylindole, 4-bromothiophenol, benzylamine, or sodium methoxide to yield tetrahydropyrazines 103 (Scheme 26) <2004T8489>. Treatment of the di- and tetrahydropyrazines with trifluoroacetic acid leads to cleavage of BOC groups and/or elimination of the nucleophile to both afford dimethyl 2,5-pyrazinedicarboxylate 104. 

Scheme 7.45 Intermolecular 2(liT)-pyrazinone Diels-Alder reactions on solid support. Reagents and conditions (i) CS2CO3, DMF, MW, 70° C, 5 min (ii) dimethyl acetylene dicarboxylate (DMAD), 1,2-dichlorobenzene, MW, 220°C, 20-40 min (iii) TFA-CH2C12 (1 4 or 1 9), MW, 120°C, 10-40 min.

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). 

Iminodipropiononitrile (53) gave 6-hydroxy-3,5-dimethyl-3,4-dihydro-2(l//)-pyrazinone (54) (HCl/EtOH, 0°C, 12 h then Na2C03—H20 18% by a yet unconfirmed mechanism).577 Also other examples 436 747,749,1180,1284... 

Dimethylamino-2,2-dimethyl-2//-azirine (27) and 4-isopropyl-2-trifluo-romethyl-5-oxazolinone (28) gave 5-dimethylamino-3-isopropyl-6,6-di-methyl-3,6-dihydro-2(l//)-pyrazinone (29) (MeCN, reflux, N2, 1 h 60% a rational mechanism was suggested) 944 analogues, like 3-allyl-5-dimethy-lamino-6,6-dimethyl-3-phcnyl-3,6-dihydro-2(l//)-pyrazinone (44%),958 were made similarly.944 958... 

C-Acetylformamido)-4-isopropyl-3-methyl-4,5-dihydro-5-isoxazolone (55) gave 6-isopropyl-3,5-dimethyl-2 (1 //)-pyrazinone (56) [Lindlar catalyst (Pd/CaC03/trace Pb), H2, EtOH, 20°C, 10 h 90%] also several homologues likewise and in comparable yields.227... 

Acetoxy-3,6-dibenzyl-5-methoxypyrazine gave 3,6-di benzyl-5-methoxy-2(l//) -pyrazinone (29) (K2C03, MeOH—H20, reflux, 30 min > 95%) 312 2,5-diace-toxy-3,6-dimethylpyrazine gave 5-hydroxy-3,6-dimethyl-2(l//)-pyrazinone (30) (KHC03, MeOH, reflux, 50 min 53%).1386... 

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,... 

For example, I -bcnzyloxy-2(l //)-pyrazinone (217, R = H) afforded 70% of 1-hydroxy-2( I //)-pyrazinone (218, R = H) [sometimes written as its tautomer, 2-pyrazinol 1-oxide (218a, R = H) on catalytic hydrogenation over palladium-on-charcoal in methanol for 20 min.588 The homologous l-benzyloxy-5,6-dimethyl-2( I //(-pyrazinone (217, R = Me) gave l-hydroxy-5,6-dimethyl-2(l//)-pyrazinone (218, R = Me), either by a similar hydrogenation (76%) or by hydrolysis in acetic acid-hydrogen bromide under reflux for 10 min (81%, as hydrobromide).588 1085... 

Diethyl-5-methyl-3,6-dihydro-2(l//)-pyrazinone 4-oxide (301) gave dimethyl 4,4-diethyl-3a-methyl-6-oxo-4,5,6,7-tetrahydro-3a/7-isoxazolo[2,3-a]pyrazine-2,3-dicarboxylate (302) (Me02CC CC02Me, CHC13, reflux, 3 h 64%) 544 homologues likewise.544... 

Aminopentanoyl)ethyl]-l-benzyloxy-5,6-dimethyl-2(l//)-pyrazinone (311) and a coligand afforded a gallium complex that showed promise for extraction of primary ammonium ions.179... 

Amino-2,5-dimethylpyrazinium iodide 4-oxide 3-Amino-5,6-dimethyl-2(177)-pyrazinone... 

Benzyloxy-5,6-diphenyl-2(l//)-pyrazinone 5- Benzyloxy-1 -hydroxy 3,6-dimethyl-... 

Benzyloxy-6-hydroxymethyl-3-isobutylpyrazine 4-oxide 2-Benzyloxy-6-iodomethyl-3-isobutyl-5-methoxypyrazine 4-oxide 2-Benzyloxy-3-isobutyl-6-mesyloxy-methyl-5-methoxypyrazine-4-oxide 1 - Benzyloxy-3 - (2-methoxycarbonyl-ethyl)-5,6-dimethyl-2(l/7)-pyrazinone... 

Bromo-5,6-dimethyl-2(177)-pyrazinone 5-Bromo-3,6-dimethyl-2(l 77)-pyrazinone 5-Bromo-2-dimethylsulfimidopyrazine 2-Bromo-5,6-diphenyl-3-propylpyrazine 2-Bromo-3,5-diphenylpyrazine... 

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