2- -3-methylpyrazine oxidation

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. 

Bromination using NBS has been used to provide acetylpyrazine derivatives from the corresponding ethylpyrazines. Bromination of 2-ethyl-3-methylpyrazine gives 2-bromoethyl-3-methylpyrazine in quantitative yield this may be oxidized using the sodium salt of 2-nitropropane or with pyridine AT-oxide to yield 2-acetyl-3-methylpyrazine in yields of 66 and 25% respectively (Scheme 14). 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Lonza, for example, has commercialized processes for highly chemo- and regioselective microbial ring hydroxylation and side-chain oxidation of heteroaromatics (see Fig. 2.32 for examples) (Kiener, 1995, 1999). The pharmaceutical intermediate 5-methylpyrazine-2-carboxylic acid, for example, is manufactured by microbial oxidation of 2,5-dimethylpyrazine. Many conversions of the type shown in Fig. 2.32 would not be possible by conventional chemical means. 

Methylpyrazine-2- Acipimox Anti-lipolytic Oxidation Pseudomonas putida Single-stage fermentation [6]... 

This 2-carbamoyl-5-methylpyrazine (7.0 g) in glacial acetic acid (30 ml) and 35% (w/v) hydrogen peroxide (20 ml) was heated with stirring at 70°C for 7 h. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine-4-oxide (5.5 g), melting point 206°-208°C. 

Carbamoyl-5-methylpyrazine 4-oxide (5.0 g) was added to 10% by weight sodium hydroxide (50 ml) and then refluxed for 30 min. The reaction mixture was acidified with dilute hydrochloric acid and extracted in a continuous extractor with ethyl acetate. The ethyl acetate extract was concentrated to small volume and gave, after filtration 2-carboxy-5-methylpyrazine 4-oxide (3.2 g), melting point 178°-180°C. 

Pyrazines occur naturally, although not in appreciable quantities. Fusel oil contains 2,5-dimethyl-, 2,5-diethyl-, trimethyl-, and tetra-methylpyrazine. The last compound has been isolated from cultures of Bacillus natto and B. subtilis and from fermented soybeans.4-6 Emimycin (pyrazine-2-one-4-oxide), a powerful antibiotic, has been obtained from Streptomyces No. 2020-1.7,8... 

The sodio derivative of methylpyrazine (20) reacts with aldehydes and ketones to give secondary and tertiary pyrazine carbinols, respectively.175, 178 Yields in the range 21-99% are obtained when the molar ratio of methylpyrazine sodamide carbonyl compound used is 2 2 1. Oppenauer oxidation of 1-phenyl-2-pyrazylethand (21), the aldol addition product of methylpyrazine and benzaldehyde, gives phenacylpyrazine (22) in 18% yield.176... 

Oxidation of alkyl- or arylpyrazines with dichromate or permanganate yields pyrazinecarboxylic acids. Thus, Beck reported that on heating 2-methylpyrazine with aqueous dichromate and phosphoric acid in an autoclave at 225°-300°, pyrazinecarboxylic acid was obtained in 74% yield.216 Pyrazine-2,5- and -2,6-dicarboxylic acids... 

Pyrazinecarboxylic acid has been obtained by selenious acid oxidation in pyridine of methylpyrazine or aqueous permanganate oxidation of ethylpyrazine, in yields of 64 and 48%, respectively.171,218 It has also been obtained in 70% yield by partial decarboxylation of pyrazine-2,3-dicarboxylic acid on heating in vacuo at 210°.219 Aqueous permanganate oxidation of 2,5-distyrylpyrazine gives the 2,5-dicarboxylic acid.220 Pyrazine-2,5-dicarboxylic acid has also been prepared in 45% yield by direct carboxylation of pyrazine with carbon dioxide at 50 atm pressure at 250° for 3 hours in the presence of a potassium carbonate and calcium fluoride catalyst.221 Pyrazine-tricarboxylic acid (57), obtainable in only very poor yields by oxidation of 2,5-dimethyl-3-ethylpyrazine, is prepared in 87% yield by alkaline permanganate oxidation of 2-(D-arabo)tetrahydroxybutyl-quinoxaline (56).222 Decarboxylation of the tricarboxylic acid by... 

Chloro-3-methylpyrazine undergoes the expected reactions with aniline, methylaniline, sodium phenoxide, and sodium thiophen-oxide.304 Normal products of substitution are also obtained with piperidine and other heterocyclic amines such as pyrrolidine.305 However, when 2-chloro-3-methylpyrazine (98) is treated with sodamide in liquid ammonia 2-chloro-3-(3 -methyl-2 -pyrazylmethyl)-pyrazine (99) is produced as indicated (Scheme 29) in 70% yield.304... 

The isomeric 2-amino-5-methyl- and 2-amino-6-methylpyrazines are obtained by Hofmann degradation of 2-carboxamido-3-hydroxy-5-and 6-methylpyrazines, respectively, followed by phosphoryl chloride treatment and catalytic dechlorination (Scheme 35).324 Two methods for the preparation of 2-aminopyrazine-5-carboxylic acid have been reported. One of these is based on the permanganate oxidation of 2-acetylaminoquinoxaline (see Section V,B), the other on pyrazine 2,5-dicarboxylic acid.325,326 The required transformations are illustrated in Scheme 36. 

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... 

Pyrazine 1-oxide, 2-methylpyrazine 4-oxide, and 2,6-dimethyl-pyrazine 4-oxide are unreactive toward acetic anhydride, but 2,5-dimethylpyrazine 1-oxide, 2,6-dimethylpyrazine 1-oxide, and 2,3,5,6-tetramethylpyrazine 1-oxide react to give 2-acetoxymethyl derivatives. The following mechanism (Scheme 44) is consistent with the observation that an acetoxymethyl derivative is only formed when a methyl group is adjacent to the AT-oxide function.407 However, in... 

Chloro-3-methylpyrazine 4-oxide (210) reacts with thiourea (preferably in 2 N sulfuric acid) to give a high yield of the corresponding thione (211), but the reaction of 2-chloro-3-methylpyrazine itself with thiourea gives only a moderate yield of the thione, thus further illustrating the activating effect of the iV-oxide function.415 The... 

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... 

Only methyl groups seem to cause little steric hindrance, and hence 2-methylpyrazine was converted by peracetic acid into a 3 2 mixture of 1- and 4-oxides (78JOC3367), the preponderance of the former arising from the +1, + M effects of methyl. The 2,6-dimethyl compound has been variously reported to form a 1 1 mixture of monoxides, with a small amount of dioxide (59JA5160), or a 1 2 mixture of 1- and 4-oxides (83JHC311). Both the 2,3-(82JHC465) (32 R = Me) and 2,5-dimethyl isomers (58JOC1603), and... 

Alkoxy groups again direct attack to the more remote nitrogen site, probably for steric reasons. Thus, 2-ethoxypyrazine gave 45% and 2-methoxy-3-methylpyrazine 82% of the 4-oxides (64JOC2623). Isolation of an almost quantitative yield of 4-oxide from 2-methoxy-3-phenylpyrazine oxidation... 

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