1.2- Dihydropyrido pyrazines

Heating 2-cyanopyridine and 2-bromoacetophenoneat 90 °C for 2 h, and then the treatment of the aqueous solution of the reaction mixture with KPF6 gave 1 -oxo-3-phenyl-l,2-dihydropyrido[l,2-fl]pyrazin-5-ium hexafluorophosphate [06AX(E)2438]. 

Heating l-hydroxy-3-oxo-3,4-dihydropyrido[l,2-a]pyrazin-5-ium betaine in H20 afforded the ring-opened product [67JCS(C)2391], Heating cis-... 

Treatment of 3-hydroxy-2,3-dimethylperhydropyrido[l,2-a]pyrazine-l,4-dione with ethanethioi in CHC13 in the presence of ZnCl2 gave the 3-ethylthio derivative (74CB2804). Heating l-imino-l,4-dihydropyrido[l,2-a]-pyrazin-5-ium bromide in 48% HBr gave l-oxo-l,2-dihydropyrido [l,2-a]pyrazin-5-ium bromide [67JCS(C)2391]. 

By the same treatment ethyl A -(3-nitro-2-pyridyl)aminoacetate (3) yields 1-hydroxy-3,4-dihy-dropyrido[2,3-/>]pyrazin-2(l//)-one.6 The complete reduction of the 3-nitro group in 3 by tin(II) chloride7 or hydrogen/palladium on carbon129,133-134 is followed by cyclization to give 3,4-dihydropyrido[2,3-/j]pyrazin-2(l 7/)-one (4).7... 

Enolizable a-dioxo compounds, such as biacetyl and 1-phenylpropane-l, 2-dione, condense with iV2-phenylpyridine-2,3-diamine (20) in refluxing ethanol to give 2-methyl-3-methylene-4-phenyl-3,4-dihydropyrido[2,3-6]pyrazine (21a) and 3-methylene-2,4-diphenyl-3,4-dihydropyrido[2,3-A] pyrazine (21b), respectively, in low yield.21... 

The reaction of pyridine-2,3-diamine with hexafluoropropenc oxide gives 2-fluoro-2-(trifluo-romethyl)- . 2-dihydropyrido[2.3-/r]pyrazin-3(4//)-one (25) as the main product. 

In the absence of mineral acids the condensation of alloxane with pyridine-2,3-diamines in aqueous solution yields yellow 3-oxo-3,4-dihydropyrido[2,3-h]pyrazine-2-carboxyureide (26 R = H) or 4-alkyl derivatives, together with small amounts of the corresponding 2-oxo-l,2-di-hydropyrido[2,3-h]pyrazine-3-carboxyureide.23 27 28... 

Ethyl 3-Oxo-3,4-dihydropyrido[2,3-6]pyrazine-2-carboxylate and Ethyl 2-Oxo-l,2-dihydropyrido[2,3-A]-pyrazine-3-carboxylate Typical Procedures 23... 

A solution of pyridine-2,3-diamine (4 g, 36.6 mmol) and diethyl mesoxalate (10 mL) in EtOH (80 mL) and H20 (60 mL) was refluxed for 2 h, and the material which crystallized from the cold solution was collected. Recrystallization (EtOH) gave a mixture (5 g, 62%), which was separated by fractional crystallization (EtOH) into ethyl 3-oxo-3,4-dihydropyrido[2,3-6]pyrazine-2-carboxylate, pale-yellow, flat needles yield 2.5 g (31%) mp213-214°C, and ethyl 2-oxo-l,2-dihydropyrido[2,3-6]pyrazine-3-carboxylale, pale-yellow plates yield 0.09 g (1 %) mp 247-254°C (dec.). 

Dihydropyrido[2,3-6]pyrazin-2(l//)-one (4) is aromatized by iodine in aqueous potassium iodide solution to give pyrido[2,3-6]pyrazin-2(l//)-one (5), whereas potassium hcxacyanofer-rate(III) will oxidize further to pyrido[2,3-6]pyrazine-2,3(l//,4//)-dione (fry1... 

The dihydropyrido[2,3-7>]pyrazine (0.03 g) was dissolved in hot anhyd MeOH (10 mL), and FeCl3 (2 g), dissolved in McOH (20 mL) was added. After 15 min reflux the mixture was cooled and poured into an excess of H20. The precipitated product was collected and recrystallized (EtOH). 

Oxo-5,8-dihydropyrido[2,3-/)]pyrazine-7-carboxylic acids having various substituents in the 3-position are alkylated by the appropriate bromo or iodo compounds in aqueous dimethyl-formamide/potassium carbonate at the N5 atom.62... 

Substituted 8-Oxo-5,8-dihydropyrido[2,3-6]pyrazine-7-carboxylic Acids 6 General Procedure 62... 

By refluxing in aqueous sodium hydroxide, 5-ethyl-3-(methylsulfanyl)-8-Oxo-5,8-dihydropyrido-[2,3-6]pyrazine-7-carboxylic acid (20) is converted into 5-ethyl-3,8-dioxo-3,4,5,8-tetrahydropy-rido[2,3-6]pyrazine-7-carboxylic acid (21).62... 

A mixture of 5-ethyl-3-(methylsulfanyl)-8-oxo-5,8-dihydropyrido[2,3-6]pyrazine-7-carboxylate (20 265 mg, 1 mmol) and the appropriate amine (1.5 2 mmol) in EtOH (20 mL) was heated at 95-105 rC for 7 h in a sealed tube. The solvent was evaporated and the crystalline residue was recrystallized from DMF to yield the products. 

Alkyl, vinyl, and phenyl Grignard compounds add to pyndo[2,3-6]pyrazine 1 and its 7-bromo derivative to give the corresponding /ra i -2,3-disubstitutcd l,2,3,4-tetrahydropyrido[2,3-/>]pyrazines 2.67,68 The 3-phenyl compound 3 yields the 2-substituted 1,2-dihydropyrido[2.3-/ijpyrazine 4 in low yield 2,3-diphenylpyrido[2,3-/>]pyrazines 5 add one mole of Grignard compound to give the 6-substituted 5,6-dihydro derivatives 6.68... 

Both pyrido[2,3-/)]pyrazine and its 2,3-dimethyl derivative undergo Reissert compound formation by treatment with trimethylsilyl cyanide, benzoyl chloride, and a catalytic amount of aluminum trichloride. The Reissert compound from pyrido[2,3-f>]pyrazine, 5-benzoyl-5,6-dihydropyrido-[2,3-/)]pyrazine-6-carbonitrile, is bismethylated in the 6- and 8-positions by iodomethane in dimethylformamide in 22% yield.88... 

Mcthylpyrido[2,3-7>]pyrazinium iodide is reduced by potassium borohydride to give the air-sensitive 5-methyl-5,6-dihydropyrido[2,3-6]pyrazine in 60% yield14 (cf. Section 7.2.3.1.1.3.). 

The Raney nickel catalyzed hydrogenation of ethyl (3-nitro-4-pyridyl)aminoacetate (3a) in ethanol yields 57% of l,2-dihydropyrido[3,4-h]pyrazin-3(4//)-one (4a). From methyl 2-[(3-nitro-4-pyridyl)amino]propanoate (3b), the corresponding 2-methyl derivative 4b is obtained in 19% yield.97... 

After hydrogenation with Raney nickel at room temperature and 1 atmosphere pressure, an ethanolic suspension of diethyl 4-(acetonylamino)-3-nitropyridine-2,6-dicarbamate (8) cyclizes to afford diethyl 3-methyl-l,2-dihydropyrido[3,4-6]pyrazine-5,7-dicarbamate (9) in 65% yield.98... 

Aminomethyl phenyl ketone oximes, such as ethyl 6-amino-5-nitro-4- [2-(hydroxyimino)-2-phenylethyl]amino pyridine-2-carbamate, bearing various substituents in the phenyl group are converted into the corresponding ketones 12, and then cyclized by hydrogenating the nitro function to yield 5-amino-3-aryl-1,2-dihydropyrido[3,4-5]pyrazine-7-carbamates 13.104 1°9... 

By refluxing [6-amino-3-(ethoxycarbonyl)pyrazin-2-yl]- or (6-amino-3-cyanopyrazin-2-yl)-malononitriles in acetic acid/hydrochloric acid, the malononitrile moiety is converted into the corresponding malonamide. This cyclizes with one of its amido groups with the ortho substituent to give eventually 2-amino-7-hydroxy-5-oxo-5,6-dihydropyrido[3,4-/)]pyrazine-8-Carbox-... 

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