Preparation of Aminopyrazines

Most methods of preparation of aminopyrazines and their A-oxides have been described in detail in earlier chapters under pyrazine and pyrazine A-oxide ring syntheses, and their reactions. These are discussed only briefly below reference made to the relevant chapter and literature references. 

Few nitro- and phenylazopyrazines are known, and these too are discussed in this chapter. 

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The preparation of aminopyrazines and hydrazinopyrazines from halogenopyrazines has been described in Sections V.5B and V.5C, respectively. 

Preparations of aminopyrazine A oxides from halogenopyrazine 7V-oxides have been described in Sections V.7A(1) and V.7B(3). 

Numerous other methods are available for the preparation of amino derivatives, and these include direct synthesis (see Section 2.14.3.2) and more traditional transformations such as the Hofmann reaction. Aminopyrazine has been prepared from pyrazinamide (60G1807) and 2-aminoquinoxaline from the corresponding carboxamide (71JOC1158). The... 

The preparation of biologically active [l,2,4]triazolo[l,5- ]pyrazines has been reported recently. The reaction routes are shown in Scheme 50. Dowling et al. reported <2005BML4809> the synthesis of aryl-substituted derivatives 411. The first step was the transformation of the 2-aminopyrazine compound 409 to an amidine 410, which was subjected... 

The principal method for preparation of pyrazino[2,3- [l,3]oxazines, as reported in CHEC-II(1996) <1996CHEC-II(7)737> involves cyclization of a 2-aminopyrazine-3-carboxylic acid ester with an aromatic acid chloride. Further applications of this three-step approach have been reported <19948405, 2000BMC2803>, but a one-pot approach has also been developed (Equation 157). This cyclization has also been carried out using acetic anhydride in place of an acid chloride <2005JMT(741)67>. 

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. 

Another method for the preparation of the pyridazino[3,4-d][l,3]oxazine system (151) is the cyclization of the aminopyrazine esters (150) with carboxylic acid chlorides (Equation (19)) <77JHC1099>. 

Note For the preparation of extranuclear primary aminopyrazines only. 

Note Could be used for the preparation of nuclear or extranuclear primary aminopyrazines. 

The primary syntheses of pyrazine JV-oxides from aliphatic components only are described in this chapter. The preparations of pyrazine JV-oxides by oxidation of pyrazines are dealt with under the reactions of the appropriately substituted pyrazines for example, those of pyrazine and alkylpyrazine TV-oxides are described in Chapter IV, and of halogenopyrazine JV-oxides in Chapter V. The cleavage of JV-oxides of pteridines and related systems to aminopyrazine JV-oxides is described in Section VIII.3A(2). 

Marked activation of the chloro substituent by the A-oxide function to nucleophilic replacement by ammonia and amines has been demonstrated by comparison of the reactivities of chloropyrazine and 3-chloropyrazine 1-oxide. The preparation of 2-aminopyrazine in 87% yield from 2-chloropyrazine and aqueous ammonia required at least 16 hours at 140, but when 3-chloropyrazine 1-oxide was heated with an excess of aqueous ammonia at 115-120° for 2.5 hours (547a), 3-aminopyrazine 1-oxide was formed in good yield (921). [3-Chloropyrazine 1-oxide and aqueous ammonia, heated under the more usual amination conditions at 140° for 16 h, gave a mbcture of 2-aminopyrazine and 2,3-diaminopyrazine the latter product was the only one isolated when 3-aminopyrazine 1 -oxide was heated with aqueous ammonia at 140-145° for 16 h. This formation of 2,3-diaminopyrazine may involve an intermediate of the type (90) (921)]. 2-Butylaminopyrazine could not be prepared in reasonable yield by heating 2-chloropyrazine with butylamine under reflux for periods up to 16 hours, but it was prepared in 75% yield by heating the reactants in a sealed vessel at 120° for 8 hours, whereas 3-butylaminopyrazine 1-oxide was readily formed in 60% yield when 3-chloropyrazine 1-oxide was refluxed with an excess of butylamine for 30 minutes (921). 

Diazotization of 2-aminopyrazine with nitrous acid in dilute or concentrated sulfuric acid gave 2 hydroxypyrazine (to 67% yield) (86, 477, 720, 818). Many such conversions have been described, mostly using nitrosylsulfuric acid in concentrated sulfuric acid solution. Preparations of hydroxypyrazines from the aminopyrazines are summarized as follows 2-hydroxy-3-methylpyrazine (sodium nitrite in concentrated sulfuric acid-acetic acid) (681), 2Jiydroxy-3,5-dimethylpyrazine (aqueous nitrous acid, then at 60°) (524), 3-hydroxy-2,5-dimethylpyrazine (477), 2,5-diethyl-3-hydroxypyrazine (aqueous nitrous acid) (478), 2-hydroxy-6-phenyl-pyrazine (365a), 24iydroxy-3,5-diphenylpyrazine (nitrous acid in N hydrochloric acid) (524), 3-hydroxy-2,5-diphenylpyrazine (282), 2-s-butyl-3-hydroxy-5-isobutyl-pyrazine (93), 5TS-butyl-3 hydroxy-2-isobutylpyrazine (92, 536), 2,5-di-s-butyl-3-hydroxypyrazine (89, 720), 3-hydroxy-2-isobutyl-5-isopropylpyrazine (103, 525), 2,3-dihydroxypyrazine (from 2 amino-3-hydroxypyrazine) (757, 1055) and its... 

Preparations of pyrazine A -oxides containing extranuclear hydroxyl groups are also described in Qiapter III as follows Section III.l, 2-aminopyrazine 1-oxides from a-amino nitriles and a-hydroxyimino carbonyl compounds (540, 541) Section III.2, 3-substituted pyrazine 1-oxides from 2-amino-2-deoxy-D-glucose(or mannose) oxime with glyoxal (543, 544) and Section III.5, ring closure of the C-C-N-C-C-N-0 system (553). 

Some primary syntheses of aminopyrazines have already been described under syntheses of pyrazines in Chapter II and are summarized briefly as follows the condensation of various a,(3-dicarbonyl compounds with a,/3-diamino compounds to give monoaminopyrazines has been discussed in Section 11.2 (342, 346, 347, 376-379) and further information (782, 786, 802) relates to the preparation of... 

Aminopyrazines may be prepared from carbamoylpyrazines by the Hofmann degradation. Gabriel and Sonn (397) first prepared 2-aminopyrazine from 23-dicarbamoylpyrazine with potassium hypobromite through 2-amino-3-carboxy-pyrazine, which was decarboxylated when heated above its melting point (or in refluxing nitrobenzene) (397, 477). 2,3-Dicarbamoylpyrazine with 2 mol of... 

The preparation of extranuclear aminopyrazines by the Mannich reaction has been described in Section IV.2C(6) (657, 715, 716). 

Some preparations of extranuclear aminopyrazines from extranuclear halogenopyrazines and amines have been described in Section V.6B (542, 679, 932,1029-1031). 2-Chloromethylpyrazine also reacted with sodium azide and gave 2-azidomethylpyrazine, which was hydrogenated in 95% ethanol over Adams catalyst to 2-aminomethylpyrazine (690). 

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). 

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. 

Some bicyclic heterocyclic 7V-oxides have been prepared from aminopyrazine A -oxides and some of these are listed together with the reagents in Table VIII3 (528-531,533,534,537,539-541,1039-1041,1222). 

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