2-Bromo-5-aminopyrazine

Coupling of 2-bromo-5-aminopyrazine (64) with 2-methoxy-4-pyridyl boronic acid... 

The 6-position in the oxide becomes less activated than the 3- and 5-positions with the result that mixtures of 3-bromo (3-8%) and 3,5-dibromo (56 R = H) (20-30%) products are formed (cf. bromination of 2-aminopyrazine). A sterically demanding substituent such as 2-morpholino gave rise to the 5-bromo derivative exclusively (83JOC1064) (Scheme 48). Annular bromination of 2,3-dimethylpyrazine 1,4-dioxide could not be achieved (72CHE1153). 

Comparison of the ultraviolet absorption and ionization constants of aminopyrazine, methylaminopyrazine, and dimethylaminopyra-zine indicates that aminopyrazine exists as such and not in the tautomeric imino form.147 Aminopyrazines, like their pyridine analogs, form diazonium salts, which readily decompose to the corresponding pyrazinones. For example, nitrous acid treatment of aminopyrazine318 and 2-aminopyrazine-5-carboxylic acid210 gives the corresponding pyrazinones in 30 and 59% yield, respectively. The diazonium salt from aminopyrazine cannot be converted into bromo-pyrazine under the conditions of the Sandmeyer reaction. 

Bromo-2-pyrazinamine (156) gave 5-benzylthio-2-pyrazinamine (157) [PhCH2SNa (made in situ), Me2NCHO, 20°C, 48 h 93%] 1565 the same substrate (156) gave bis(5-aminopyrazin-2-yl) sulfide (NaHS, Me2NCHO, reflux, 24 h 40%).1565... 

Aminopyrazine with bromine in acetic acid gave 2-amino-3,5-dibromopyrazine (804, 810, 811), also obtained from bromination of 2-amino-3-bromopyrazine in aqueous hydrobromic acid (806, 807), and 5-amino-2,3-dimethylpyrazine with bromine in acetic acid gave 2-amino-3-bromo-5,6-dimethylpyrazine (812). 2-Amino-5-phenylpyrazine with bromine and pyridine in chloroform at 20 gave 2-amino-3-bromo-5-phenylpyrazine (365a), and 2-amino-3-chloropyrazine with 20% hydrobromic acid and bromine gave 2-amino-5-bromo-3-chloropyrazine (806,807). 

Bromopyrazine and anhydrous ammonia in ethanol gave 2-aminopyrazine (939), and 5-bromo-23-diphenylpyrazine with ethanolamine at 125° gave 5-(2 -hydroxyethyl)amino-2,3-diphenylpyrazine (834). 

Bromo-3-methoxycarbonylpyrazine with 2,3-dimethylaniline in refluxing toluene gave 2-(2, 3 -dimethylphenyl)amino-3-methoxycarbonylpyrazine (950) [hydrolysis of this product with sodium hydroxide in ethanol gave 2-carboxy-3-(2, 3 -dimethylphenyl)aminopyrazine, which was also obtained by treatment of l-(2, 3 -dimethylphenyl)lumazine with sodium hydroxide in refluxing ethanol (950)]. 3-Bromo-2-hydroxy-5-phenylpyrazine with ammonium hydroxide and copper at 150° gave 3-amino-2-hydroxy-5-phenylpyrazine (365a). Replacement of the iodo substituent from 2-amino-5-iodo-3,6-dimethylpyrazine has been effected with ammonium hydroxide (887). 

Dipole moments (D) of some aminopyrazines have been determined as follows 2-amino-6-methoxy (3.08, benzene 3.42, dioxane) 2-amino-5-bromo-3-methoxy (2.94, benzene) 2-amino-3-chloro (1.86, benzene 2.26, dioxane) 2-amino-5-bromo-3-mercapto (2.22, dioxane) and 3-amino/l-oxide (3.43, dioxane) (749). 

The diazotization of aminopyrazines has been described in earlier sections. Section V.IH records the preparation of 2-fluoropyrazine from 2-aminopyrazine in fluoroboric acid containing copper powder with sodium nitrite (882, 884) and Section V.ll the preparation of iodopyrazines from some aminopyrazines via isodiazotate salts (30) (887). These salts were assigned the isodiazotate structure, on the basis of their inability to couple with 0-naphthol in alkaline solution (887) and they were characterized by hydrolysis in cold 40% aqueous sulfuric acid to the hydroxypyrazine (887). Section V.I K describes the conversion of aminopyrazines to bromopyrazines (798, 800, 807, 890-892) for example, 2-amino-3-methoxy-carbonylpyrazine with hydrobromic acid, bromine, and sodium nitrite in water gave 2-bromo-3-methoxycarbonylpyrazine (798, 890). The diazotization of aminopyrazines to hydroxypyrazines has been described in Section VI. 1C, to alkoxy-pyrazines in Section V1.3C, and to oxopyrazines in Section V1.9A(5). 2-Amino-pyrazine with isopentyl nitrite in benzene gave 2-phenylpyrazine (45%) and some 2-isopentoxypyrazine and 2,2 -dipyrazinyl amino isomers (1211). 

Aminopyrazine was oxidized by hydrogen peroxide in acetic acid at 20° to 3-aminopyrazine 1 -oxide and at 50° for 15 hours to 2-aininopyrazine 1,4-dioxide (51%) (also obtained by similar oxidation of 3-aminopyrazine 1-oxide) (1189). m-Chloroperoxybenzoic acid was also used for the oxidation of 2-aminopyrazine to its 1-oxide (1258). The following aminopyrazine TV-oxides have been prepared by oxidation (reagent and conditions) 2-amino-3-methoxycarbonylpyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (880, 1222) 2-amino-5-chloro-3-methoxycarbonyl(and methylcarbamoyl)pyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (1222) 2-amino-5-bromo-3-methoxycarbonylpyrazine 1-oxide (wperoxyacetic acid) (906) 2-amino-3-bromo-5,6-dimethylpyrazine 1-oxide (peroxyacetic acid) (907) and 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide (hydrogen peroxide in sulfuric acid at room temperature) (754). 

Miesel (1976) obtained active analogues of diilubenzuron by repladng the /K hloroaniline moiety by substituted aminopyrazines. As an extension of their earlier work DeMilo et al. (1978) have synthesised and tested a series of new analogues where the aniline portion of the diilubenzuron molecule has been exchanged for various substituted heterocycles such as isoxazoles, thiazoles, thiadiazoles, pyridines, pyrimidines, 5-triazines and bicyclic heterocycles. The most active derivatives were the 4-bromo- (112) and 4-chloro-2-pyridinyl analogues (113) but none was as active as diilubenzuron. 

---