2-Cyano-3-methylpyrazine

Ethyl 5-bromo-2-pyrazinecarboxylate 2-(2-Ethylbut-1 -enyl)-6-methylpyrazine Ethyl 5-carbamoyl-2-pyrazinecarboxylate Ethyl 5-chloro-2-pyrazinecarboxylate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboximidate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboxylate Ethyl 3,5-diami no-6-chloro-2-pyrazi necarboximidate Ethyl 6-diethylamino-2-pyrazinecarboxylate 2-Ethyl-3,6-diisobutyl-5-methylpyrazine 2-Ethyl-3,6-diisobutylpy razi ne 2-Ethyl-3,6-diisobutylpyrazine 1 -oxide 2-Ethyl-3,6-diisobutylpyrazine 4-oxide 2-Ethyl-3,6-diisopropylpyrazine /V-Ethyl-AyV -dimethyl-3,5-bismethylamino-2,6-pyrazinedicarboxamide Ethyl 3,6-dimethyl-5-oxo-4,5-dihydro-2-pyrazinecarboxylate... 

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). 

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... 

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). 

Amino-2prepared from 2-amino-3-cyanopyrazine 1-oxide by reflux with acetic acid-acetic anhydride followed by ready deacetylation by refluxing in methanol (538), and in a similar manner 3-amino-2-ethoxycarbonyl-5-hydroxypyrazine has been prepared from 2-amino-3-ethoxycarbonylpyrazine 1 -oxide through 3-acetamido-2-ethoxycarbonyl-5 ydroxy-pyrazine (538), and 2-amino-3-carbamoyl-6-hydroxy-5-methylpyrazine from 2-amino-3-cyano-5-methylpyrazine 1-oxide (538). The preparation of 24 ydroxy-6-methoxycarbonylpyrazine (10) has been claimed from 3-methoxycarbonylpyrazine 1-oxide with acetic anhydride followed by hydrolysis (1057) [cf. Nov Cek et al. (839), who claim it to be the 5-isomer, and Foks (744)]. 

The preparation of extranuclear alkoxypyrazines from extranuclear halogeneo-pyrazines has been described in Section V.6A (654, 672,679,685, 687,688,694, 756, 872, 1027). 2-Amino-3-cyano-5-methoxymethylpyrazine 1-oxide with phosphorus trichloride in tetrahydrofuran afforded 2-amino-3-cyano-5-methoxy-methylpyrazine (529) and 3-(bromoacetamido)-l-ethoxy4-oxopentane (44) with alcoholic ammonia gave 5-hydroxy-3-(2 -ethoxyethyl)-2-methylpyrazine (45) (248). 

Amino-3-cyano-5-methylpyrazine 1,4-dioxide (91) refluxed for several minutes with acetic anhydride formed 3-acetamido-2-cyano-5-hydroxy-6-methylpyrazine 1-oxide (92) (24%) (532) and 2-acetoxymethyl-5-methylpyrazine 1,4-dioxide refluxed with acetic anhydride afforded a mixture of2,5-di(acetoxymethyl)pyrazine 1-oxide, with some 2,5-diacetoxymethylpyrazine and a monoxide of 2-acetoxy-methyl-5-methylpyrazine (625). 2-Formylpyrazine hydrate 1,4-dioxide with aqueous sodium hydroxide or bicarbonate at < 37° in an unusual reaction gave 3-carboxy-pyrazine 1-oxide mixed with 5 [Pg.188]

Alkoxypyrazine A-oxides may also be prepared by oxidation of the alkoxypyrazine with peroxyacetic acid. In this way the following have been prepared 3-ethoxypyrazine 1-oxide (100°/20h) (978) 3-(trideuteromethoxy)pyrazine 1-oxide (757l9h) (975) 3-ethoxy-2-methylpyrazine 1-oxide (65-75724h) (978) 3-methoxy-2-phenylpyrazine 1-oxide (55720 h) (817) 3-ethoxy-2,5-dimethyl-pyrazine 1-oxide (56716 h) (872) 3-carbamoyl-2-methoxypyrazine 1-oxide (80720h) (881) and 2-cyano-5-ethoxy-3,6-dimethylpyrazine A-oxide (55720h) (288). 

Amino-3with sodium methoxide overnight has been shown to give 3-amino-2-cyano-5-methoxy-6-methylpyrazine 1-oxide (532). 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

The preparation of 2-aminopyrazine 1-oxides from a-amino nitriles and a-hydroxyiminocarbonyl compounds has been described in Section Ill.l (92, 93, 103, 377, 524-542). Armarego and Schou (1255) utilized known chemical procedures (531, 532) and prepared 2namino-6-deuterio-3-ethoxycarbonyl-5-(partial)-trideuteriomethylpyrazine 1-oxide and 2-amino-3-cyano-6-deuterio-5-trideuterio-methylpyrazine 1-oxide. 

Methylpyrazine with ammonia and air over an alumina catalyst containing vanadium pentoxide and potassium sulfate at 350° for 10 hours gave 2-cyano-pyrazine (726), also obtained similarly under other conditions (1437). 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

The oxidations of 2-amino-3-cyanopyrazine 1-oxides to the 1,4-dioxides are described in Section VIII.3A(4) and deoxygenations of some 2-amino-3-cyano-pyrazine 1-oxides and 1,4-dioxides with phosphorus trichloride or sodium dithionite in Section VIII.3C(4). Deoxygenation and chlorination of aminocyanopyrazine 1-oxides are reported in Section V.IG, and deoxygenation and acetoxylation or alkoxylation of 2-amino-3-cyano-5-methylpyrazine 1,4-dioxide in Section VIII.3C(5). Hydrolysis of cyanopyrazine Y-oxides to carbamoylpyrazine Af-oxides are given in Section 10A(3) and ring closure reactions of 2-amino-3-cyanopyrazine 1-oxides to pteridine 8-oxides in Section V11I.3C(3). 

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. 

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