2-Chloromethyl-5-methylpyrazine oxidation

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... 

Chloromethyl-3-methoxy-5-methylpyrazine 1-oxide (232) and indole-l( )-yl-magnesium bromide (233) (made in situ) gave 3-(3-methoxy-5-methyl-l-oxi-dopyrazin-2-ylmethyl)indole (234) (Et20—PhMe, 0 — 20°C, 12 h 77%).333 Also other examples.1614... 

Chloromethyl-3-ethoxy-5-methylpyrazine 2-Chloromethyl-3-methoxy-5-methylpyrazine 1-oxide 2-Chloromethyl-3-methylpyrazine... 

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). 

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). 

Certain a-chloromethylpyrazine A -oxides have been deoxygenated with phosphorus trichloride. Treatment of 2-amino-5-chloromethyl-3-cyanopyrazine 1-oxide (and 2-amino-3-cyano-5-methoxymethylpyrazine 1-oxide) with phosphorus trichloride at room temperature in tetrahydrofuran resulted in smooth deoxygenation to 2-amino-5-chloromethyl-3-cyanopyrazine (and 2-amino-3-cyano-5-methoxy-methylpyrazine) (529), whereas 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide was best deoxygenated to 3-amino-5-chloromethyl-2-cyanopyrazine by phosphorus trichloride in refluxing tetrahydrofuran (534). The more vigorous conditions necessary for the last reaction may be a reflection of increased steric hindrance at the fV-oxide grouping (529). Use of solvents like chloroform or dioxane led to slow reactions which were accompanied by the formation of numerous unidentified by-products (534). 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide was also deoxygenated by sodium hydrosulfite (dithionite) in boiling water to give a poor yield of 2-amino-5-chloromethyl-3-cyanopyrazine, but 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide under the same conditions underwent both deoxygenation and reductive dehalogenation to 2-amino-3-cyano-6-methylpyrazine (529,534). 

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). 

An analogous series of reactions was observed from 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide and the 2-amino-3-cyano-6-(triphenylphosphonio)-methylpyrazine 1-oxide chloride with aqueous sodium bicarbonate gave the betaine (98) (534). 

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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