2-Amino-3-cyanopyrazines

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

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... 

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

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). 

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)]. 

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

Carbamoylpyrazines with various dehydrating agents afford cyanopyrazines. Ellingson et al. (1175) first dehydrated 2-amino-3-carbamoylpyrazine with phosphorus pentoxide in refluxing pyridine to 2-amino-3-cyanopyrazine this... 

Iminoethers were also prepared from 2-amino-3-cyanopyrazine with ethanolic hydrogen chloride (792, 1218) [the product with guanidine and sodium methoxide in methanol formed 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878, 1218)] from 2,6-diamino-3-chloro-5-cyanopyrazine with ethanolic hydrogen chloride at 0 (the product heated with ethanol gave 2,6-diamino-3-chloro-5-triethoxymethyl-pyrazine) (1432) from 2-amino-5-chloro-3-cyanopyrazine the product with... 

Amino-5-bromomethyl-3-cyanopyrazine with ethyl acetoacetate and sodium hydride in tetrahydrofuran gave 5-[(2 -acetyl-2 -ethoxycarbonyl)ethyl]-2-amino-3-cyanopyrazine (1031) [which with sodium chloride in aqueous dimethyl sulfoxide at 155-170° for 6 hours gave 5-(2 -acetylethyl)-2-amino-3-cyanopyrazine] and a similar reaction with ethyl y-ethoxyacetoacetate gave 2-amino-3-cyano-5-[(2 -ethoxycarbonyl-2 -ethoxymethylcarbonyl)ethyl]pyrazine [which with sodium chloride in aqueous dimethyl sulfoxide at 155-170° for 6 hours gave 2-amino-3-cyano-5-(2 -ethoxymethylcarbonyl)ethylpyrazine] (1031). 

Cyanopyrazine A -oxides have been prepared from a-amino nitriles and a-hydroxyimino carbonyl compounds as summarized in Section III. 1 (528-530, 532-534, 537, 540, 542). Oxidation of 2-cyanopyrazine with perhydrol gave 3-cyanopyrazine 1-oxide (575), 2-cyano-5-ethoxy-3,6-dimethylpyrazine with 30% hydrogen peroxide in acetic acid at 55° gave 2-cyano-5-ethoxy-3,6-dimethylpyrazine iV-oxide (288), and the oxidations of 2-amino-3-cyanopyrazine 1-oxide (538) and... 

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). 

Amine substitution of activated halogeno or other groups on pyrazines and quinoxalines has been described (Section 6.03.5.4.2). It is noteworthy that a variety of 2-amino-3-cyanopyrazines are produced by reaction of 2-cyano-3-phenylsulfonylpyrazine with the corresponding amines (Equation (6)). 

However, some ring systems have posed difficulties. 4-Aminopteridine could not be obtained from 2-amino-3-cyanopyrazine (see 9), and 2-amino-... 

Other ortho esters are usually less reactive than orthoformates,148 but triethyl orthoacetate reacted well with 4-amino-5-cyanoimidazole.147 2-Amino-3-cyanopyrazine, after conversion to its 2-amidoxime (—NCHNOH) gave an excellent yield of 4-aminopteridine N-oxide with triethyl orthoformate.149... 

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