Pyrazine 1,4-dioxide

Pyrazine 1,4-dioxides are available by the direct self-condensation of 1,2-hydroxyaminooximes (70JOC2790). 1,2-Nitrooximes are obtained by the isomerization of alkene initrogen trioxide adducts, which are reduced with palladium on charcoal to the hydroxyaminooximes which undergo acid-catalyzed auto-condensation to the pyrazine 1,4-dioxides (Scheme 19). 

Ring transformation of pyrido[2,3-f]furoxan 676 with 1,3-diketones or /3-keto esters was catalyzed by silica gel, alumina, or molecular sieves to give mainly the corresponding pyrido[2,3- ]pyrazine 1,4-dioxides 677 in addition to pyrido[2,3- ]pyrazine 1-oxides 678 in a low yield (Equation 57) <1997H(45)107>. 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Pyrazine 1,4-dioxide reacts exothermically with phosphoryl chloride if, after the initial reaction has subsided, reaction is completed by heating under reflux, 2,6-dichloropyrazine is obtained.301,362 Elina and Musatova report that reaction of the dioxide with benzene sulfonyl chloride gives 2-chloropyrazine 1-oxide, m.p. 131°-132°, in low yield.406 A melting point of 140w—146° has been reported by previous workers for this compound.398... 

Thin-layer chromatography indicates that prolonged reaction of pyrazine 1,4-dioxide with acetic anhydride gives the mono-iV-oxide, together with other unidentified products.406 Pyrazine mono-A-oxide is also formed on reaction of pyrazine-2-carboxylic acid 4-oxide with acetic anhydride.408... 

Little is known about the chemistry of pyridylfuroxans, but reaction of the [l,2,5]oxadiazolo[3,4-Z>]pyridine oxides (126) and (127) with activated methylene synthons provides pyrido[2,3-6]pyrazine-1,4-dioxides (130) in moderate yields (Beirut reaction) (Table 4, Scheme 21) <80M407, 82AF10). The actual reactive species is presumed to be the bis(nitroso)pyridine isomer (128). Direct oxidation... 

Pyrazine gave pyrazine 1,4-dioxide (Na2W04, H202 no details).995... 

Methylpyrazine 1,4-dioxide (297) gave 2-[2-(pyridin-2-yl)vinyl]pyrazine 1,4-dioxide (298) [2-pyridinecarbaldehyde, NaOH, MeOH—H20, N2, 80°C, 5 min 96%] isomers and analogues likewise.81... 

Mel, AcMe, or EtOH , sealed, 100°C, 4 h 95%) 286 homologues were made likewise 286 and similar treatment of pyrazine 1,4-dioxide gave a separable ( ) mixture of 1-methylpyrazinium iodide and its 4-oxide in approximately equal amounts.286... 

The kinetics and mechanism for photochemical rearrangement of pyrazine 1,4-dioxide (41) into 5-hydroxy-2(l//)-pyrazinonc (42) have been studied.869... 

Pyrazine 1-oxide is also conveniently prepared by vacuum distillation of 3-carboxypyrazine 1-oxide at 250° and pyrazine 1,4-dioxide by treating 2-carboxy-pyrazine with hydrogen peroxide in acetic acid (744). 

The polarographic behavior of the 1-oxides and 1,4-dioxides of pyrazine, 2,5-dimethylpyrazine, and tetramethylpyrazine at various pH values has been investigated. It was assumed that at lower pH values, the A -oxide group was reduced in its protonated form. In acid media the 1-oxides exhibited double waves, the first of which is attributable to the reduction of jV-oxide groups and the second to that of the pyrazine nucleus (production of 1,4-dihydro compounds). Reduction of both A -oxide groups of pyrazine-1,4-dioxide proceeded simultaneously (588). Half-wave potentials of the voltammetric oxidation and reduction of pyrazine mono- and di-A -oxides have been measured in dimethylformamide, and in acetonitrile by the technique of a rotating platinum electrode (750). 

Infrared absorption spectra of pyrazine A -oxides and alkylpyrazine A -oxides have been recorded and discussed (575, 625, 626). The ligand 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide and its complexes with cobalt(II), nickel(II), and copper(II) have been prepared and are polymeric octahedral in structure (754). 

Matsuura and co-workers (756) have reexamined the reactions of the A -oxides of 2,5-dimethylpyrazine and found that 2,5-dimethylpyrazine di-A -oxide (29) when heated with phosphoryl chloride at 160° gave 2,5-dichloro-3,6-dimethylpyrazine (6%) (30), 3-chloro-2,5-dimethylpyrazine 1-oxide (5%) (31), and 5-chloromethyl-2-methylpyrazine 1 -oxide (9%) (32). In addition small amounts of other chlorinated products, 3-chloro-2-chloromethyl-5-methylpyrazine (33) and 2,5-bischloromethyl-pyrazine (34), were identified. These authors also examined the action of p-tosyl chloride, methane sulfonyl chloride, and mixtures of phosphoryl chloride and concentrated sulfuric acid, but state that these did not give good results. Pyrazine 1-oxide and phosphoryl chloride have been shown to give 2reaction conditions it gave 2-chloropyrazine 1-oxide (757). Pyrazine 1,4-dioxide and benzenesulfonyl chloride also gave a low yield of 2-chloropyrazine 1-oxide (758). 

Methylpyrazine 1-oxides react with benzaldehyde to give styrylpyrazine 1-oxides. Thus tetramethylpyrazine 1,4-dioxide, p-dimethylaminobenzaldehyde, and 37% hydrochloric acid at 140° for 15 hours gave 2,3,5,6-tetra(p-dimethyIaminostyryl)-pyrazine 1,4-dioxide (713) 2,5-dimethylpyrazine 1,4-dioxide, benzaldehyde, and sodium hydroxide gave 2,5-distyrylpyrazine 1,4-dioxide, and 2,5-dimethylpyrazine... 

Bromination of 23-diniethylpyrazine 1,4-dioxide in dioxane in the presence of benzoyl peroxide gave 2-(bromomethyl)-3-methyl- and 2,3-bis(bromomethyl)-pyrazine 1,4-dioxide (739), and 2-methylpyrazine 1,4-dioxide gave 2-bromo-... 

D. By Reaction of Pyrazine 1,4-Dioxide with Phosphoryl Chloride (and Other Acid Chlorides)... 

The preparation of certain halogenopyrazine 7V-oxides from pyrazine 1,4-dioxide with phosphoryl chloride (and othe r acid chlorides) has been described in Section 1G. 

Peroxyacetic acid oxidation of 2-acetoxymethyl-5-methylpyrazine gave the 1,4-dioxide which hydrolyzed in 0.1% sulfuric acid to 2-hydroxymethyl-5-methyl-pyrazine 1,4-dioxide (625) and 2,3-di(acetoxymethyl)pyrazine 1,4-dioxide was subjected to transesterification with lower alcohols in the presence of a catalytic amount of alkali to give 2,3-di(hydroxymethyl)pyrazine 1,4-dioxide (739). 

Qeavage of the ether linkage occurred when 3,6-diisobutyl-l-methoxy-2-oxo-1,2-dihydropyrazine (93) was heated with methylmagnesium iodide at 150° and gave 2-hydroxy-3,6-diisobutyIpyrazine I-oxide (980). 2,5-Diisobutyl4-methoxy-3-0X0-3,4-dihydropyrazine 1-oxide and 2,5-diisobutyl-3-methyoxypyrazine 1,4-dioxide similarly treated are both reported to have given 3-hydroxy-2,5-diisobutyl-pyrazine 1,4-dioxide (980). 

The Vilsmeier reaction on 2-methylpyrazine has been described in Section IV.2C(7) (717), and King s reaction on 2-methyl(and 23-dimethyl)pyrazine 1,4-dioxide has been described in Section IV.3C(7) (763). Pyrazine with A, jV-dimethyl-acetamide, ammonium peroxydisulfate, and ferrous sulfate gave 2-(A -acetyl-iV-methylaminomethyl)pyrazine (1188). 

Aminopyrazine was oxidized by hydrogen peroxide in acetic acid at 20° to 3-aminopyrazine 1 -oxide and at 50° for 15 hours to 2-aininopyrazine 1,4-dioxide (51%) (also obtained by similar oxidation of 3-aminopyrazine 1-oxide) (1189). m-Chloroperoxybenzoic acid was also used for the oxidation of 2-aminopyrazine to its 1-oxide (1258). The following aminopyrazine TV-oxides have been prepared by oxidation (reagent and conditions) 2-amino-3-methoxycarbonylpyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (880, 1222) 2-amino-5-chloro-3-methoxycarbonyl(and methylcarbamoyl)pyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (1222) 2-amino-5-bromo-3-methoxycarbonylpyrazine 1-oxide (wperoxyacetic acid) (906) 2-amino-3-bromo-5,6-dimethylpyrazine 1-oxide (peroxyacetic acid) (907) and 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide (hydrogen peroxide in sulfuric acid at room temperature) (754). 

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