2-Methyl-6- pyrazine oxidation

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). 

Oxidation, by nitric acid, 48 of aldehyde to carboxyl group, 49 of hydroxyl to carboxyl group, 49 of 2-methylquinoxaline to 2-methyl-pyrazine-5,6-dicarboxylic acid, 89 of quinoxaline to 2,3-pyrazinedicar-boxylic acid, 87... 

Bourguignon and coworkers in their preparation of thieno[2,3-6]pyrazine used methyl-pyrazine (364 Scheme 107) (80JHC257) as starting material. The chlorination of (364) yields 2-chloro-3-methyl- and 2-chloro-6-methyl-pyrazine in a ratio of 80 20. Without separation this mixture is treated with ethyl mercaptoacetate in the presence of sodium ethoxide to give (365) in 91% yield (based on 2-chloro-3-methylpyrazine). Oxidation of the methyl group to an aldehyde function and subsequent base catalyzed ring closure yields (366), which is transformed to (363) by the method depicted already in Scheme 106. 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

This process was undoubtedly developed for the manufacture of pyrazinamide (Zinamide, etc.),1696 a second-line drug for Mycobacterium tuberculosis infections, resistant to more effective and less toxic agents. Thus a mixture of 2-methyl-pyrazine (323), ammonia, oxygen, and steam is passed (at 400°C) over an alumina- or pumice-supported catalyst comprising one to three oxides of Ce, Cr, Mo, Mn, P, Sb, Ti, or (most importantly) V the main product (in up to 90% yield) is 2-pyrazinecarbonitrile (324), easily converted into 2-pyrazinecarboxamide... 

Benzyloxy-5-chloro-6-hydroxymethyl-3-isobutylpyrazine 4-oxide gave 2-benzyloxy-5-chloro-3-isobutyl-6-[(tetrahydropyran-2-yloxy)methyl]pyrazine 4-oxide (150) (3,4-dihydro-2//-pyran, TsOH.H20, CH2C12, 20°C, 1 h 95%).848... 

Both 2-methylpyrazine 1- and 4-oxides (625) (obtained by oxidation of 2-methyl-pyrazine with peroxyacetic acid) on treatment with phosphoryl chloride have been claimed to give 2-chloro-3-methylpyrazine(626)but the 2-methylpyrazine-4-oxide used is now known to have been a mixture of the 1- and 4-isomers (734). More recently other workers (735, 736) have claimed that the mixed 2-methylpyrazine 7V-oxides with phosphoryl chloride gave a mixture of 2-chloro-3-, -5-, and -6-methylpyrazine but Nakel and Haynes (686) have shown that 2-methylpyrazine 1-oxide with phosphoryl chloride followed by sodium methoxide gave 2-methoxy-3-methylpyrazine and 6-methoxy-2-methylpyrazine, and 2-methylpyrazine 4-oxide (3-methylpyrazine 1-oxide) similarly treated gave only 2-methoxy-6-methylpyrazine. 3-Trifluoromethylpyrazine 1-oxide with benzenesulfonyl chloride at 1(X)° has been shown to give 2-chloro-6-trifluoromethylpyrazine (44%) (759). 

Earlier results from the reactions of 2-methylpyrazine 1-oxide and 3-methyl-pyrazine 1-oxide with phosphoryl chloride (626, 735, 736) now appear to have been clarified (686) [see Section 1V.3C(1)]. 

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). 

Reactions of C-alkoxypyrazine A-oxides with phosphoryl chloride have been described in Section V.IG (756, 817, 838, 872, 881). For example, 3-ethoxy-2,5-dimethylpyrazine 1-oxide refluxed with phosphoryl chloride for 10 minutes gave 2-chloro-5-ethoxy-3,6-dimethylpyrazine and 2-chloromethyl-3-ethoxy-5-methyl-pyrazine (872). 

Mcthyl-2-pyrazinecarboxylic acid 4-oxide (118, R = H) gave 2-hydroxyrnethyl-5-methyl pyrazine 4-oxide (119) [BH3.THF, (MeOCH2CH2)2O, 0 20°C, N2,... 

Benzyloxy-5-chloro-6-hydroxymethyl-3-isobutylpyrazine 4-oxide gave 2-benzyloxy-5-chloro-3-isobutyl-6-[(tetrahydropyran-2-yloxy)methyl]pyrazine... 

Using FeS04 (1.67 x 10 M) in conjunction with equimolar amounts of methyl-pyrazine-5-carboxylic acid N-oxide and trifluoroacetic acid, in a water-acetonitrile-benzene (5 5 1 v/v/v) biphasic system, with benzene-H202-FeS04 = 620 60 1, a benzene conversion of 8.6% is achieved (35 °C 4h). Hydrogen peroxide conversion is almost complete (95%) and selectivities to phenol are 97% (based on benzene) and 88% (based on H2O2) [13]. These values are definitely higher than those described in the literature for the classical Fenton system [14], whereas iron complexes with pyridine-2-carboxylic acid derivatives are reported to be completely ineffective in the oxidation of benzene under the well-knovm Gif reaction conditions [15]. 

A ring methyl group condenses with benzaldehydes to yield styryl compounds, but the condensation needs an auxiliary reagent such as acetic anhydride <87S638> or zinc halide, and forcing reaction conditions at reflux or temperatures above 200 °C. In contrast, the condensation of methyl-pyrazine 7V-oxides with benzaldehyde proceeds smoothly by treatment with sodium methoxide in refluxing methanol (Scheme 27) <83JHC169>. 

Treatment of the unsubstituted compound 103 with hydrogen peroxide in glacial acetic acid resulted in the isolation of two iV-oxides. The minor product (8%) was the 4,7-dioxide 105, and the major product (50%) was suggested to be the 4-oxide 104. This assignment was supported by the similarity of the compound s UV spectrum to that of the l-methyl-4-oxide 81, which had been obtained from the pyrazine 87 by an unambiguous route. A 4-oxide was also obtained when the acetylated nucleoside analogue 106 was oxidized with mefa-chloroperbenzoic acid. There has been a recent Russian communication on the chemistry of imidazo[4,5-ft]pyrazine N-oxides. ... 

Additional minor volatile compounds are found in both frying oils and in fried foods, including cis,trans- and trans,trans-2,4-decaderived from oxidized linoleate and 2,4-heptadienal derived from linolenate. The isomers of 2,4-decadienal impart a desirable fried food flavor in fried potatoes when present in small amounts, but excessive amounts of this aldehyde would be expected to cause undesirable rancid flavors. Furfural compounds may be derived from interactions between food sugars and proteins. Minor amounts of sulfur compounds and nitrogen-containing heterocyclic compounds (methyl pyrazine and 2,5-dimethylpyrazine in potatoes) may originate from Maillard reactions (Chapter 11). 

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