2.6- Dimethylpyrazine 1,4-dioxide

Other reactions with their counterparts in the pyridine series are also well known. Thus, 2,3-dimethylpyrazine 1,4-dioxide reacts with acetic anhydride to yield 2,3-bis(acetoxy-methyl)pyrazine (S3) in good yield (72KGS1275). Pyrazine 1-oxide also reacts directly with acetic anhydride to yield 2(ljH)-pyrazinone by way of the intermediate acetate (Scheme 22). The corresponding reaction in the quinoxaline series is not so well defined and at least three products result (Scheme 23) (67YZ942). 

The 6-position in the oxide becomes less activated than the 3- and 5-positions with the result that mixtures of 3-bromo (3-8%) and 3,5-dibromo (56 R = H) (20-30%) products are formed (cf. bromination of 2-aminopyrazine). A sterically demanding substituent such as 2-morpholino gave rise to the 5-bromo derivative exclusively (83JOC1064) (Scheme 48). Annular bromination of 2,3-dimethylpyrazine 1,4-dioxide could not be achieved (72CHE1153). 

Methylpyrazine 1,4-dioxide and 2,3-dimethylpyrazine 1,4-dioxide condense with aromatic aldehydes under mild conditions to give styryl derivatives,418 and treatment of the di-V-oxides with pyridine and iodine gives pyrazinyl methylpyridinium iodides (Scheme 48).419... 

Methyl- and 2,3-dimethylpyrazine 1,4-dioxide when heated with pyridine and iodine undergo King s reaction from 2-methylpyrazine 1,4-dioxide the quaternary salt, 2-pyridiniomethyIpyrazine 1,4-dioxide iodide (41, R = H) was obtained, and this with p-nitrosodimethylaniline in alkaline medium gave the nitrone (42, R = H) (763). 

Pyrazines are formed from transamination reactions, in addition to carbon dioxide and formaldehyde. A requirement is that the carbonyl compound contains a dione and the amino group is alpha to the carboxyl group (16). If the hydrogen on the ct-carbon oI the amino acid is substituted, a ketone is produced. Newell (17) initially proposed a pyrazine formation mechanism between sugar and amino acid precursors. (See Figure 3). The Schiff base cation is formed by addition of the amino acid to the anomeric portion of the aldo-hexose, with subsequent losses of vater and a hydroxyl ion. Decarboxylation forms an imine which can hydrolyze to an aldehyde and a dienamine. Enolization yields a ketoamine, vhich dissociates to amino acetone and glyceraldehyde. 2,5-Dimethylpyrazine is formed by the condensation of the tvo molecules of amino acetone. 

Forexample, good yields of 2-chloropyrazine 4-oxide,391,392 2-carbox-amidopyrazine 4-oxide,392 and 2-methylpyrazine 1,4-dioxide,391 have been obtained by oxidation of the appropriate pyrazine. In general, the preferred product from oxidation of monosubstituted pyrazines at lower temperatures is the monooxide formed by oxidation on the nitrogen remote from the substituent, whereas 1,4-dioxides are obtained by prolonged heating at higher temperatures.155 Pertrifluoro-acetic acid oxidation of 2,5-dichloro-3,6-dimethylpyrazine furnishes the di-iV-oxide, whereas permaleic acid gives only the mono-iV-oxide.393... 

Dimethylpyrazine 1-oxide is converted into 2,5-dimethyl-3-propylmercaptopyrazine on treatment with 1-propanethiol and acetic anhydride, and similarly the 1,4-dioxide yields the bisthio ether (206).409... 

Chloro-3,6-dimethylpyrazine 4-oxide (224) and the 1,4-dioxide [NaB03, AcOH, 80°C, 24 h 56% and a trace, respectively note the difference in orientation of the product (224) from that (220) obtained from an homologous substrate using persulfate].208... 

Dimethyl-2,3-dihydro-2-pyrazinol 1,4-dioxide (307) gave 2,3-dimethylpyrazine... 

Chloro-5,6-dimethylpyrazine 1,4-dioxide 2-Chloro-3,5-dimethylpyrazine 1-oxide 2-Chloro-3,5-dimethylpyrazine 4-oxide... 

Guanidinopropyl)-3-isopropyl-2(l//)-pyrazinone 3,6,AA V,X-Hexamethyl-2,5-pyrazinedicarboxamide 2-Hexylamino-3,6-dimethylpyrazine 2-Hexylamino-3,6-dimethylpyrazine 4-oxide 2-Hexylaminopyrazine 2-Hexylaminopyrazine 4-oxide 2- Hexyl- 3,6-dimethylpyrazine 2- Hexyl- 5,6- dimethy lpy razi ne 2- Hexyl -3,6- dimethy lpy razi ne 1,4- dioxide 2-Hexyl-3-methoxypyrazine 2- Hexyl- 3-methylpyrazine... 

Other oxidations include that of methylpyrazine with selenious acid in pyridine to give 64% of 2-carboxypyrazine (669) and 2,5-dimethylpyrazine with selenium dioxide to 2,5-dicarboxypyrazine (676) a patent (677) claims oxidation of methylpyrazine with sodium dichromate and aqueous phosphoric acid in an autoclave at 225-350° to give 74% 2-carboxypyrazine. likewise, 2,5-dimethylpyrazine gives 67% 2,5-dicarboxypyrazine, and 2,6-dimethylpyrazine gives 59%... 

The strong base-weakening effect of an A-oxide substituent upon a para-situated sp nitrogen atom is exemplified by a comparison of the of pyrazine [0.65 (122)] with that of pyrazine A-oxide [0.05 (745)]. The pKg of 3-methylpyrazine 1-oxide is 0.46 (745). Pyrazine A-oxides form salts thus 2,5-dimethylpyrazine A-oxide forms 1 1 addition products with hydrogen chloride, methyl iodide, and benzyl chloride (625). Thermodynamic parameters for the second protonation of tetramethylpyrazine 1,4-dioxide have been determined from measurements at 25, 40,60,80, and 90° (746). 

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). 

Pyrazine 1-oxide and 1,4-dioxide could not be cyanated at the a-position with potassium cyanide and potassium ferricyanide in protic solvents, even at 130° (755). Attempts to nitrate 2,5-dimethylpyrazine 1,4-dioxide (625) and 3-methylpyrazine 1-oxide (626) were unsuccessful. 

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). 

Dimethylpyrazine 1,4-dioxide 2-Acetoxymethyl-6-methylpyrazine and 2,6-dimethylpyrazine 4-oxide 760... 

Variations in the products obtained from the reaction of 2,5-dimethylpyrazine 1,4-dioxide with acetic anhydride by two groups of workers (625, 760) may be explained by procedural differences. 

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... 

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