2-Amino-3-methylpyrazine chloride

The isomeric 2-amino-5-methyl- and 2-amino-6-methylpyrazines are obtained by Hofmann degradation of 2-carboxamido-3-hydroxy-5-and 6-methylpyrazines, respectively, followed by phosphoryl chloride treatment and catalytic dechlorination (Scheme 35).324 Two methods for the preparation of 2-aminopyrazine-5-carboxylic acid have been reported. One of these is based on the permanganate oxidation of 2-acetylaminoquinoxaline (see Section V,B), the other on pyrazine 2,5-dicarboxylic acid.325,326 The required transformations are illustrated in Scheme 36. 

Phenylpyrazine 1-oxide, 2,3-diphenylpyrazine 1-oxide and 2,5-diphenylpyrazine 1 -oxide have been deoxygenated in good yield by aqueous chromium(ll) chloride in methanol, acetone, and chloroform at room temperature (761), and deoxygenation of 5-(substituted aminomethyl)-2-amino-3-cyano-6-methylpyrazine 1-oxide by triethyl phosphite in hot dimethylformamide has been described (762). 

Chloro-3-hydroxy-5(and 6)-methylpyrazine with ammonium hydroxide, copper, and cupric chloride at 125° for 15 hours gave 2-amino-3-hydroxy-5(and 6)-methylpyrazine (373, 835), but 2-chloro-5-hydroxy-3,6-dimethylpyrazine was recovered unchanged after treatment with alcoholic ammonia under drastic conditions (312) and 2-chloro-3-hydroxy-5,6-diphenylpyrazine with pyridine and its hydrochloride at reflux gave the betaine (33) from 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (863). Replacement of the chloro substituent occurred... 

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... 

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). 

Reduction of 2-hydroxy-3,6-dimethyl-5-phenylazopyrazine (8) with sodium hydrosulfite (dithionite) gave 2-amino-5-hydroxy-3,6-dimethylpyrazine (872), and vigorous reduction of the disodium salt of 2-(p-sulfophenylazo)-3-methyI-5-hydroxypyrazine with stannous chloride and hydrochloric acid gave 2-amino-5-hydroxy-3-methylpyrazine (434). 2-Hydroxy-5,6-diphenyl-3-phenylazopyrazine in methanol was reduced with hydrogen over Raney nickel to 2-amino-3-hydroxy-5,6-... 

Amino-3-methylpyrazine heated with triethyl orthoformate and ethanolic hydrogen chloride to 145° gave 2-ethoxymethyleneamino-3-methylpyrazine (46) 1195). 

Dimethoxy-2-methoxycarbonylpyrazine boiled with phosphoryl chloride and phosphorus pentachloride gave the acid chloride, which, treated with aqueous hydrazine, gave 2-hydrazinocarbonyl-3,5-dimethoxypyrazine (881). 2-Methoxy-3-methoxycarbonyl-5-methylpyrazine with methylmagnesium iodide in ether gave 3-(l -hydroxy-r-methylethyl)-2-methoxy-5-methylpyrazine (39) (844). Thebromi-nation of 2-amino-5-bromo-3-methoxycarbonylpyrazine in 30% hydrobromic acid to 2-amino-3,5-dibromopyrazine has been described in Section V.IB (2) (807). 

Formyl derivatives 12 were obtained on Vilsmeier formylation of the 2-amino-3-methylpyrazines 11 with three molar quantities of phosphoryl chloride Although it seems reasonable to suggest that the reaction proceeds through intermediates such as 2 and 3, attempts to formylate... 

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