3.5- Dichloro-2-methylpyrazine

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... 

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... 

In a similar manner, 3-isobutyl-6-methyl-3,6-dihydro-2,5(l//,4//)-pyrazinedione (9, R = Me) gave 2-chloro-3-isobutyl-6-methylpyrazine (10, R = Me), 2-chloro-6-isobutyl-3-methylpyrazine (11, R = Me), and 2,5-dichloro-3-isobutyl-6-methylpyrazine (12, R = Me) (27, 21, and 4%, respectively).295... 

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... 

Acetoxymethyl- -chloropyrazine 2-Acetoxymethyl-3,6-dichloro-5-methylpyrazine 2-Acetoxymethyl-3,6-dichloro-5-methylpyrazine 1-oxide 2-Acetoxymethyl-3-ethoxypyrazine 2-Acetoxymethyl-5-isobutyl-3-methoxypyrazine 2-Acetoxymethyl-5-isobutyl-3-methoxypyrazine 1-oxide 2-Acetoxymethyl-3-methoxy-5-methylpyrazine 2-Acetoxymethyl-5-methoxy-6-methylpyrazine 2-Acetoxymethyl-3-methoxy-5-methylpyrazine 1-oxide 2-Acetoxymethyl-3-methylpyrazine 2-Acetoxymethyl-5-methylpyrazine... 

Dimethylbut-l-enyl)-6-methylpyrazine 2-(2,3-Dimethylbutyryl)pyrazine Dimethyl 5-chloro-6-methoxy-2,3-pyrazinedicarboxylate Dimethyl 5,6-diamino-2,3-pyrazinedicarboxylate Dimethyl 5,6-dichloro-2,3-pyrazinedicarboxylate... 

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). 

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). 

Some chlorinations have been reported with thionyl chloride. 23-Dicyano-5,6-dihydroxypyrazine refluxed with thionyl chloride in pyridine was reported to give 23-dichloro-5,6-dicyanopyrazine (862) and 2-hydroxy-3-nitro-5,6-diphenyl-pyrazine with thionyl chloride gave 2-chloro-3-hydroxy-5,6-diphenylpyrazine (817, 841) but with thionyl chloride and pyridine it gave the betaine of 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (5) (863), which was hydrolyzed in acid to 2,3-dihydroxy-5,6-diphenylpyrazine (863). No product could be isolated from 2-methylpyrazine when refluxed with thionyl chloride (864). 1,4-Dimethylpiperazine-... 

Dichloro-3,6-dimethylpyrazine 1,4-dioxide with phosphoryl chloride at 170° gave 2,5-dichloro-3,6-bis(chloromethyl)pyrazine and 2,5-dichloro-3-chloromethyl-6-methylpyrazine 1-oxide and 2,5-dichloro-3,6-dimethylpyrazine 1-oxide gave 2,5-dichloro-3-chloromethyl-6-methylpyrazine (756). 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

In 23-dihydroxypyrazine and derivatives Honzl (853), from measurements of infrared spectra in chloroform and ultraviolet spectra in aqueous alcohol, has proposed that 5,6-dichloro-l-cyclohexyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (pA in water 4.66, 5.66) exists in the form (48). The p.m.r. spectra of some 5- and 6-methyl- and 5- and 6-phenyl-2,3-dihydroxypyrazines have been reported (483). In the 2,5-dihydroxypyrazine series, the infrared spectrum (Nujol) of 2-benzyl-3,6-dihydroxy-5-methylpyrazine has been interpreted as indicating that the major tautomeric form present in the solid state was the dihydroxy form (49), but the ultraviolet spectrum in ethanol was considered consistent with the coexistence of the dihydroxy (49) and oxo-hydroxy form, for example, (50), Although the structure (51) has been proposed for 3-butyl-2,5-dihydroxypyrazine (1092), the evidence in favor of this structure is inconclusive. 

C yanoethyl)carbamoyl-3-formylamino-5-methylpyrazine boiled with N sodium hydroxide for 30 seconds gave 3-amino-2-cyanoethylcarbamoyl-5-methyl-pyrazine (435) 2,3-dichloro-5-formamido-6-formylpyrazine was readily deformyl-ated under acid or alkaline conditions (e.g., 2A( sodium carbonate at 20°) (430) and 2-formamido-3-(iniidazol-2-yl)pyrazine was deformylated by refluxing with 0.1 A hydrochloric acid for 4 hours and its 5,6-dimethyl derivative reacted similarly (455a). 

Methylpyrazine heated with dimethylformamide and sulfur in o-dichloro-benzene at about 150-180° (with and without iodine as catalyst) gave 2-N-methyl(thiocarbamoyl)py razine and 2-A, yV-dimethyl(thiocarbamoyl)pyrazine (1268,... 

All tables include relevant C-alkyl derivatives of the type of pyrazine listed. For example, Table A.2 (aminopyrazines) contains aminopyrazines and A -substituted analogues, as well as C-alkyl derivatives and Table A.21 (carboxy halogenopyrazines) lists 2,6-dichloro-3 -cyano-5 -methylpyrazine. 

Acetoxybenzyl-3,6-dichloro-5-methylpyrazine 1,4-dioxide (232) and an inseparable mixture of the (mono) 1- and 4-oxide [80% H2O2, F3CCO2H, 2, 6-Bu 2-4-Me-phenol (radical inhibitor), 0°C, 30 min then substrate J, 0°C, 24 h 36% (dioxide) initially but 74% after reoxidation of the mono-. V-oxidcs). ... 

In the synthesis of (III. 15) and (III.16) by Rosowsky and Chen [21], which was an application of the regioselective Taylor pteridine synthesis [22-24], 2-amino-5-chloromethyl-3-cyano-6-methylpyrazine A-oxide was condensed with diethyl A-[4-(A-methylamino)benzoyl]-L-glutamate, the A-oxide group was removed with triethyl phosphite in DMF at 125 °C, and the resultant pyrazine amino nitrile was condensed with gujmidine. Brief hydrolysis (15 min, 1 M NaOH in refluxing EtOH) led to (III. 15), and chlorination of (III.15) at 5 °C afforded the 3, 5 -dichloro derivative (III.16). Ultraviolet absorption spectra of (III. 15) and (III. 16) in 0.1 M NaOH were consistent with those reported in the literature for MTX and DCM, except for small... 

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