2-Amino-3-cyanopyrazine

Various 4-aminopteridine 3-oxides have recently been obtained by cyclization of 2-amino-3-cyanopyrazine derivatives (81H(15)293). 

The reductive decyanation of cyanopyrazine using H2 and Pt/C under acidic conditions has been reported <2002TL6747>, that is, 2-amino-3-cyano-5-phenylpyrazine 1-oxide 73 is hydrogenated to 2-amino-5-phenylpyra-zine 74 in 90% yield (Equation 11). The double reduction has also been shown to be realized with sodium dithionite. 

The synthetic strategy of preparing pyrazines by condensation of 2-keto aldoximes with a-amino nitriles is well represented by Taylor s pteridine synthesis, in which a variety of 2-amino-3-cyanopyrazine 1-oxides have been prepared by using aminomalononitrile <2002TL6747> as the amino nitriles. In the same fashion, some other a-amino nitriles, which are often the Strecker synthesis products, are converted into 2-aminopyrazine 1-oxides 160 (Scheme 44). The condensations are realized by treatment with iV-methylmorpholine <1993JOC7542>, and... 

The isonipecotinoyl analogues of FA and AP, (592) and (593) respectively, were prepared from 2-amino-5-bromomethyl-3-cyanopyrazine (16b) by an extension of the strategy first developed by Taylor, as depicted in Scheme 3.123 [2491. 

The replacement of nitrile groups by amino groups is exemplified by the reaction of 2,3-dicyano-pyrazine (272) with an aqueous solution of methyl-amine to give 3-methylamino-2-cyanopyrazine (273) (86JHC1299 see also... 

Bromination of 2-amino-3-cyanopyrazine in acetic acid gave 2-amino-5-bromo-... 

Amino-2-carbamoyl-5-hydroxypyrazine in dimethylformamide with phosphoryl chloride gave 3-amino-5-chloro-2-cyanopyrazine (538). 

The synthesis of 2-amino-5-chloromethyl-3-cyanopyrazine 1-oxide (529) from aminomalononitrile and chloromethyl hydroxyiminomethyl ketone, and of 2-amino-6-chloromethyl(and chloroalkyl)-3-cyanopyrazine 1-oxide (534) from aminomalononitrile and -chloro-a-hydroxyiminopropionaldehyde (prepared from the addition of nitrosyl chloride to acrolein) has been described in Section III.l. 

Cyano-6-methylaminopyrazine was also prepared from the chloro compound with methylamine hydrochloride and sodium hydroxide in aqueous dioxane (945) and 2-cyano-6-(2, 2 -dimethylhydrazino)pyrazine was prepared similarly (945). 2-Chloro-6-cyanopyrazine with methanol (and similarly with ethanol) and triethylamine gave 2-methoxy-6-(C-methoxyformidoyl)pyrazine (32) [see Section 5D(2)], and 2-chloro-6-carbamoylpyrazine with concentrated aqueous ammonia at 170-175° gave 2 -amino-b-carboxypyrazine (744). 2-Chloro-3-cyano-5,6-diphenylpyrazine with ammonium hydroxide and potassium iodide formed 2-amino-3-carbamoyl-5,6-diphenylpyrazine, but on fusion with ammonium acetate it gave 2-amino-3-cyano-5,6-diphenylpyrazine (848). 

Chloro-3-dichloromethylpyrazine with sodium methanethiolate has been claimed to give a mixture of products analogous to those obtained from its reaction with sodium methoxide (688). 2-Amino-5-chloromethyl-3-cyanopyrazine with... 

Amino-5-bromomethyl-3-cyanopyrazine with the sodium salt of diethyl malonate in tetrahydrofuran at room temperature gave 2-amino-3-cyano-5-(2, 2 -diethoxycarbonylethyl)pyrazine together with a little dialkylated product (1031). Similar reactions were observed with the sodium salts of ethyl acetoacetate and ethyl 7-ethoxyacetoacetate, but methyl cyanoacetate gave only dialkylated product (1031). 2-Amino-5-chloromethyl-3-cyanopyrazine and 1-pyrroIidino-l-cyclohexene in tetrahydrofuran have been shown to give 2-amino-3-cyano-5-(2 -oxocyclohexyl-methyOpyrazine (542). 

Amino-5-chloromethyl-3-cyanopyrazine on treatment with potassium acetate in propan-2-ol at 80-90° gave 5-acetoxymethyl-2-amino-3-cyanopyrazine(542),and 2-amino-6-chIoro-5-chloromethyl-3-cyanopyrazine with anhydrous sodium acetate in dimethylformamide gave 2-acetoxymethyl-5-amino-3-chloro-6-cyanopyrazine (874). 

Chloromethylpyrazine with sodium azide in refluxing aqueous acetonitrile gave 2-azidomethylpyrazine (690), and 2-amino-5-bromomethyl-3-cyanopyrazine with sodium cyanide in dimethyl sulfoxide at 40° gave 2-amino-3-cyano-5-cyano-methylpy razine (1031). 

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-5-chloromethyl-3-cyanopyrazine 1-oxide at reflux in methanol gave... 

Condensation of 2-amino-5-bromomethyl-3-cyanopyrazine 1-oxides with the appropriate substituted amine afforded a series of 2-amino-5-([(aryl and aralkyl)-amino]methyl -3-cyanopyrazine 1-oxides (1040), and with p-chlorophenol and arylthiols gave 2-amino-5-[(p-chlorophenoxy)methyl]-3-cyanopyrazine 1-oxide and 2-amino-5[(arylthio)methyl]-3-cyanopyrazine 1-oxides (1041). 

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)]. 

Diisobutyl-3miethoxypyrazine 1,4-dioxide (107) with phosphorus trichloride in ethyl acetate at 40° gave 2,5-diisobutyl-3-methoxypyrazine (980). 2-Amino-5-[(/7-chlorophenoxy)methyl]-3-cyanopyrazine 1-oxide was deoxygenated with triethyl phosphite in dimethylformamide at 120° (1041). 

Amino-3-cyanopyrazine 1,4-dioxide was selectively monodeoxygenated with phosphorus trichloride in tetrahydrofuran at 25° to 3-amino-2-cyanopyrazine 1 -oxide (538). 

C-imino-C-methylthiomethyl)pyrazine refluxed in N hydrochloric acid gave 2-amino-3-(methylthio)carbonylpyrazine (1075) and 2-methoxy-6-(C-imino-C-methoxymethyOpyrazine (from 2sodium methoxide) acidified with hydrochloric acid gave 2-methoxy-6-methoxycarbonylpyrazine (986). 

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