2-Chloro-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. 

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... 

Chloro-3,6-diethylpyrazine (119, R = H) gave 2,5-diethyl-3-methylpyrazine (118) [Me3Al, Pd(PPh3)4, dioxane—C6H14, A, reflux, 2 h 88%] 280 2,5-dichloro-3,6-diethylpyrazine (119, R = Cl) gave 2,5-diethyl-3,6-dimethyl-pyrazine (120) (likewise but reflux, 4 h 93%) 280 and many homologues and their TV-oxides were made similarly.280,282... 

Chloro-3,6-dimethylpyrazine (124) gave 2-ethyl-3,6-dimethylpyrazine (125) [Et2Zn, NiCl2.(Ph2PCH2)2CH2, THF, A, 20°C, 3 h 71%] 55 2-ethyl-3,6-di-methylpyrazine 1-oxide (126) (46%) was made similarly 1594 and analogues likewise.551594... 

Chloromethyl-3-methoxy-5-methylpyrazine 1-oxide (28, R = H) gave 2-chloro-6-chloromethyl-5-methoxy-3-methylpyrazine 1-oxide (28, R = Cl) OV-chIorosuccinimide, Me2NCHO, 20°C, 12 h 90%).333 Also other examples.321,599,1460... 

Chloro-5,6-dimethylpyrazine 4-oxide (49) gave a mixture of 2,3-dichloro-5,6-dimethylpyrazine (50) and 2-chloro-5-chloromethyl-6-methylpyrazine (51) (POCl3, reflux, 30 min 38 and 19%, respectively, after separation).1272... 

Chloro-5,6-diethylpyrazine 1-oxide (219) (K2S2Os, H2S04, 20°C, 24 h 84%) 1250 2-chloro-3-isobutyl-6-methylpyrazine 1-oxide (220) (likewise 78%) 295 and 2-fluoropyrazine 1-oxide (likewise 40%).276... 

Chloro-3-isobutyl-6-isopropylpyrazine 1 -oxide 2-Chloro-3-isobutyl-6-isopropylpyrazine 4-oxide 2-Chloro-6-isobutyl-3-isopropylpyrazine 4-oxide 2-Chloro-3-isobutyl-6-methylpyrazine 2-Chloro-6-isobutyl-3-methylpyrazine 2-Chloro-3-isobutyl-6-methylpyrazine... 

Chloro-5-methylpyrazine 2-Chloro-6-methylpyrazine 6-Chloro-A,-methyl-2-pyrazinecarboxamidine 6-Chloro-5-methyl-2-pyrazinecarboxylic acid 5-Chloro-6-methyl-2-pyrazinecarboxylic acid 1-oxide... 

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

Ethyl 5-bromo-2-pyrazinecarboxylate 2-(2-Ethylbut-1 -enyl)-6-methylpyrazine Ethyl 5-carbamoyl-2-pyrazinecarboxylate Ethyl 5-chloro-2-pyrazinecarboxylate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboximidate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboxylate Ethyl 3,5-diami no-6-chloro-2-pyrazi necarboximidate Ethyl 6-diethylamino-2-pyrazinecarboxylate 2-Ethyl-3,6-diisobutyl-5-methylpyrazine 2-Ethyl-3,6-diisobutylpy razi ne 2-Ethyl-3,6-diisobutylpyrazine 1 -oxide 2-Ethyl-3,6-diisobutylpyrazine 4-oxide 2-Ethyl-3,6-diisopropylpyrazine /V-Ethyl-AyV -dimethyl-3,5-bismethylamino-2,6-pyrazinedicarboxamide Ethyl 3,6-dimethyl-5-oxo-4,5-dihydro-2-pyrazinecarboxylate... 

A. Rosowsky and K. K. N. Chen, J. Med. Chem., 1974,17, 1308 describe the preparation of 2-amino-5-chloromethyl-3oxide from aminomalononitrile tosylate and l-chloro-3-hydroxyimino-2-butanone using a method similar to that described (529) for an analogue. 

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). 

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). 

Chloro-2-methylpyrazine 1-oxide 2-Chloro-3-hydroxymethyIpyrazine (after hydrolysis) 737... 

Chloropyrazine 1-oxide and 3-chloropyrazine 1-oxide both react with sulfanilamide to give the corresponding sulfanilamidopyrazine 7V-oxides (1032, 1033) 3-chloro-2-methylpyrazine 1-oxide with piperidine at reflux gave 2-methyl-3-piperidinopyrazine I -oxide, and with dimethylamine gave 3-dimethylamino-2-methylpyrazine 1-oxide (793) 2-amino-3-chloropyrazine 1-oxide with aqueous ammonia and copper powder at 140-150 for 18 hours gave 2,3-diaminopyrazine... 

Klein et al. (978) first attempted the alkaline hydrolysis of 3-chloropyrazine 1 -oxide to 3-hydroxypyrazine 1 -oxide, and although spectroscopic evidence indicated the formation of the hydroxy compound, good quality homogeneous material could not be isolated. Later work by Berkowitz and Bardos (1034) has shown that 3-chloropyrazine 1-oxide was hydrolyzed by refluxing with two equivalents of aqueous sodium hydroxide, and treatment of the product with trimethylsilyl chloride and triethylamine gave 3-(trimethylsilyl)oxypyrazine 1-oxide. 3,6-Di-s-butyl-2-hydroxypyrazine 1-oxide has been prepared from the chloro analogue (no details given) (982). Hydrolysis of 2-amino-6-chloro-3-cyano-5-methylpyrazine... 

The reaction of 3-chloro-2-methylpyrazine 1-oxide with glacial acetic acid and acetic anhydride to give (after treatment with aqueous sodium hydroxide) 2-chloro-... 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide with triphenylphosphine in dimethylformamide at 80-90° gave 2-amino-3-cyano-5-(triphenylphosphonio)-methylpyrazine 1-oxide chloride (97) (520) and the 5-bromomethyl analogue reacted similarly with triphenylphosphine in propan-2-ol (542). Compound (97) on hydrolysis with 30% aqueous ethanol containing a small amount of triethylamine gave 2-amino-3-cyano-5-methylpyrazine 1-oxide and thus enabled removal of the chloro substituent from the chloromethylpyrazine (529) compound (97) with triethylamine and acetaldehyde (and other aldehydes) in chloroform at room temperature gave 2-amino-3-cyano-5-(prop-l -enyl)pyrazine 1-oxide (and other alkenyl analogues) (529). 

Methyl-2-oxo-l, 2-dihydropyrazine with phosphorus pentasulfide in pyridine at reflux was converted into l-methyl-2-thio-l,2-dihydropyrazine (18) (821,1100), and 3-chloropyrazine 1-oxide with sodium hydrogen sulflde in ethanol at room temperature gave 3-mercaptopyrazine 1-oxide (19) (1035). Whereas 3-chloro-2,5-dimethyipyrazine 1-oxide reacted slowly with thiourea in ethanol, and the use of water in place of ethanol caused some increase in reaction rate, the reaction in 2A sulfuric acid at reflux for 30 minutes gave 3-mercapto-2,5-dimethylpyrazine 1-oxide (85%), and 3-mercapto-2-methylpyrazine 1-oxide was prepared similarly (905). 

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-... 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

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