2-Chloromethyl-5-methylpyrazine hydrolysis

Chloromethyl-5-methylpyrazine (242) gave either 2-acetoxymethyl- (243) (AcOK, EtOH, reflux, 6 h 65%) or 2-hydroxymethyl-5-methylpyrazine (224) (AcOK, KHC03, EtOH, reflux, 6 h 74%) 221 the acetoxymethyl intermediate was confirmed as such by alkaline hydrolysis to the product (244) (NaOH, no details 85%).1353... 

Hydrolysis of 2-chloromethyl-3-ethoxy-5-methylpyrazine with aqueous potassium hydroxide gave 3-ethoxy-2-hydroxymethyl-5-methylpyrazine (872), but attempted acid hydrolysis of 2-chloromethyl-3-ethoxy-5-methylpyrazine (and 3-ethoxy-2-ethoxymethyl-5-methylpyrazine) was unsuccessful (872). Attempts to convert 2-chloromethylpyrazine to 2-hydroxymethylpyrazine were also unsuccessful (679). 

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). 

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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