2- Chloro-6-methylpyrazine

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. 

Treatment of methylpyrazine with chlorine in carbon tetrachloride at 40° gives two products and the total yield of monochloro derivatives is 65%.281-283 The major product is 2-chloro-3-methylpyrazine and the minor product, originally thought to be the isomeric 2-chIoro-5-methyl derivative, was later shown to be 2-chloro-6-methylpyrazine [Eq. (16)].284 2,5-Dimethylpyrazine also undergoes ring substitution... 

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... 

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... 

Methylimidazole (51) with chloroform in the vapor phase gave, among other products, 2-chloro-3-methylpyrazine (52) (550°C, flow system 17%) n other such reactions with imidazole, methylimidazoles, and methylimidazo-... 

Chloro-3-methylpyrazine (154, R = Cl) gave 2-methyl-3-methylthiopyrazine (154, R = SMe) MeSNa, EtOH, 20°C reflux, 2 h 92%), 2-ethoxycar-bonylmethylthio-3-methylpyrazine (154, R = SCH2C02Et) [NaSCH2C02Et (made in situ), likewise 91%), or analogues.1126... 

Chloro-l -methyl-2,3(1 //,4//) -pyrazinedione 2-Chloro-3-methylpyrazine 1-oxide 2-Chloro-3-methylpyrazine 4-oxide... 

Chlorination of 2-methylpyrazine in acetic acid at 100° gave 2-trichloromethyl-pyrazine (685, 686), whereas 2-chloro-3-methylpyrazine under similar conditions gave 2-chloro-3-dichloromethylpyrazine (685, 687, 688). Chlorine bubbled into a stirred solution of 3-dimethylamino-2,5-dimethylpyrazine in chloroform gave the 6[Pg.80]

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). 

Vapor phase chlorination of methylpyrazine in carbon tetrachloride (10%w/w) at 545° with 15 times the molar ratio of chlorine for 13 sec has been claimed to give tetrachloropyrazine (776) and chlorine passed into a refluxing solution of 2-chloro-3-methylpyrazine in acetic acid gave 2-chloro-3-dichloromethylpyrazine (688). 

Chloro-3-methylpyrazine (101,535) and 2-chloro-5-phenylpyrazine (363, 365a, 377, 824, 825) have been prepared from the corresponding hydroxy compound and phosphoryl chloride, 2-chloro-6-methylpyrazine from 2-hydroxy-6-methylpyrazine and phosphoryl chloride with one drop of dimethylformamide (681), and 2-benzyl(or s-butyl, isobutyl, or isopropyl)-3phosphoryl chloride with a trace of concentrated sulfuric acid (80). 2-Chloro-6-methyl-3-propyl- (826), 3[Pg.99]

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

Chloro-3-methylpyrazine with fV-methylaniline at reflux gave 50% 2-methyl-... 

A -methylanilino)pyrazine and 37% 2-anilino-3-methylpyrazine, but 2-chloro-3-methylpyrazine and diphenylamine at reflux failed to react. In an attempt to prepare 2-(fV,fV-diphenylamino)-3-methylpyrazine, 2-chloro-3-methylpyrazine was allowed to react with sodium diphenylamine (from sodium hydride and diphenylamine) and gave various products depending on the conditions. At room temperature, these reagents gave only recovered diphenylamine and a self-coupling product of 2-chloro-3-methylpyrazine, namely, 2-chloro-3-(3 -methylpyrazin-2 -ylmethyl)pyrazine (28), but if this reaction mixture was refluxed for 24 hours it gave some 2- A, A -diphenylamino)-3-methylpyrazine (929). 

Castle and co-workers (1013) showed that 2-chloro-3-methylpyrazine with phosphorus pentasulfide in boiling pyridine afforded 2-mercapto-3-methylpyrazine, and 3-chloro-2,5-dimethylpyrazine similarly treated gave 3-mercapto-2,5-dimethyl-pyrazine. 

By using thiourea in 2N sulfuric acid, Cullen and Harrison (905) were able to convert 2-chloro-3-methylpyrazine at reflux for 30 minutes to 2-mercapto-3-methylpyrazine (55%), and 3-chloro-2,5-dimethylpyrazine similarly treated gave 3-mercapto-2,5-dimethylpyrazine together with another higher molecular weight compound, postulated as either (60) or (61). 2-Amino-3-chloropyrazine refluxed with thiourea in alcohol, and the thiouronium salt refluxed with aqueous sodium hydroxide, produced 2-amino-3-mercaptopyrazine (535). 2-Chloropyrazine failed to react with thiourea (821) under the mild conditions that converted 2-chloro-quinoxaline to 2-mercaptoquinoxaline (1014). 

Dichloropyrazine in anhydrous ether with methyl magnesium iodide at 10° gave 2-chloro-6-methylpyrazine and 2,6-dimethylpyrazine and 2,3-dimethyl-pyrazine was likewise obtained from 2-chloro-3-methylpyrazine (687). A Grignard derivative has been prepared from 2-chloro-3,5,6-trimethylpyrazine and magnesium turnings in tetrahydrofuran and on treatment with diethyl sulfate produced 2-ethyI-3,5,6-trimethylpyrazine (330). 

Fluoropyrazine refluxed with aqueous sodium sulfite for 2 hours gave the sodium salt of 2-sulfopyrazine (ca. 70%) (882,884), whereas 2-chloropyrazine with aqueous sodium sulfite at 150° for 12 hours gave only 44% of the desired product (819, 884). 2-Chloro-3-methylpyrazine (71) with magnesium (and a little methyl iodide) in tetrahydrofuran with phenyldimethylchlorosilane (72) gave 2-methyl-3-dimethylphenylsilylpyrazine (73) (929). 

Alkylpyrazines with other substituents have been oxidized to carboxylic acids as follows 2-acetamido-6-methylpyrazine was oxidized in aqueous magnesium sulfate with potassium permanganate to 2-acetamido-6aqueous potassium permanganate at room temperature to 2-carboxy-3-chloropyrazine, which was also obtained by oxidation of 2-chloro-3-methylpyrazine with selenium dioxide in boiling aqueous pyridine (947). Oxidations of 2-methoxy-3-methyl-... 

---