2- Methyl-5- pyrazine chloride

Methyl pyrazine-2-carboxylic acid is refluxed with thionyl chloride in anhydrous benzene for approximately 12 hours. Benzene and thionyl chloride excess is removed by distillation. Then some anhydrous dioxane is added and this acid chloride solution is allowed to drop into p-(/3-aminoethyl)-benzenesulfonamide suspension in dioxane and anhydrous pyridine. The resulting mixture is then refluxed for 3 hours. Dioxane is removed by distillation and then the residue is washed with water and acetic acid. The raw acylated sulfonamide is then filtered and crystallized from 95% ethanol, thus obtaining a product of MP 200 to 203 C. 

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-5-hydroxy-3,6-dimethylpyrazine with phosphoryl chloride gave a low yield of 2,5-dichloro-3,6-dimethylpyrazine (312) 3-chloro-5-hydroxy-2-methyl-pyrazine gave 3,5-dichloro-2-methylpyrazine (535) and 2-chloro-5-hydroxy-3,6-diisobutylpyrazine with phosphoryl chloride at 150° for 5 hours gave 2,5-dichloro-3,6-diisobutylpyrazine (101). 

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)]. 

Replacement of the chloro substituent by methoxide has been observed in the following pyrazines 2-chloro-3-methoxycarbonyl (at <5°) (867) 2-chloro-6-methoxycarbonyl (870) 2-chloro-3-methoxycarbonyl-5,6-diphenyl (371, 837) 2-carboxy-6-chloro (869, 871) 2-carbamoyl-5( )-chloro (839) 2-carbamoyl-6-chloro (805, 839) 2-chloro-6-(4 -morpholinocarbonyl) (870) 2-chloro-3-cyano (810, 811) 5-chloro-3-cyano-2-methoxy (reflux 14h) (881) 2-chloro-5-methoxy-3,6-dimethyl (844) 2-chloro-5-isopropyl-6-methoxy-3-methyl (50, 844) 2-chloro-5-methoxy-3,6-diphenyl (1.1 equivalents of 20% methanolic sodium methoxide at 135° for 20h) (797) 2-benzyloxy-6-chloro(at reflux) (832, cf. 883) 2-chloro-3-pyridinio(pyrazine)chloride (or tosylate) (to give 2,3-dimethoxypyrazine) (765) ... 

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). 

Bis-imidoyl chloride 187 reacts with A -methyl imidazole 188 to give bis-cationic diimidazo[l,2- 2, T-c]pyrazine 189 (Equation 46) <2006T731>. The charges are believed to be delocalized over the ring system. 

Two examples were reported for the synthesis of the pyrido[2,3-, ]pyrazine moiety using pyrazine precursors. Thus, amidation of methyl 2-aminopyrazine-3-carboxylate 670 with a substituted acetyl chloride followed by heterocycliza-tion of the formed amide 671 gave 6,8-dihydroxy pyridopyrazine 672 <2004W02004056825>. 

A tetrahydropyrido[3,4-/)]pyrazine nucleus was constructed from 2,3-dimethylpyrazine 687 by chlorination with A-chlorosuccinimide (NCS) to give 2,3-bis(chloromethyl)pyrazine 688, followed by cyclization with diethyl acet-amidomalonate to pyridopyrazine 689. Hydrolysis and decarboxylation of 689 in hydrochloric acid, then esterification by action of thionyl chloride in methanol gave methyl 5,6,7,8-tetrahydropyrido[3,4-. ]pyrazine-7-carboxylate hydrochloride 690 (Scheme 32) <2003BMC433>. 

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