From Aminopyrazines

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 

1- methyl derivative (poor yield) (832), 2,5-dihydroxy-3,6-dimethylpyrazine [prepared from the diamine and nitrosylsulfuric acid in concentrated sulfuric acid (887) but earlier attempts to prepare this compound from 2-amino-5-hydroxy-3,6-dimethylpyrazine with nitrous acid were unsuccessful (872)], 2-hydroxy-3-methoxy-5-phenylpyrazine (365a), 2 hloro-5-hydroxypyrazine (831), 3-chloro-2-hydroxy-5-methylpyrazine (nitrosylsulfuric acid in concentrated sulfuric acid) (373, 835), 

2- chloro-3-hydroxy-5-methylpyrazine (373), 3-chloro-5-hydroxy-2-methylpyrazine (535), 2-carboxy-3-hydroxypyrazine (423, 818, 836, 1056), 2-carboxy-5-hydroxy-pyrazine (aqueous nitrous acid in 2fV sulfuric acid at 80°) (408), 2-carboxy-3-hydroxy-5-methylpyrazinc (361), 3-carboxy-2-hydroxy-5-phenylpyrazine (nitrosylsulfuric acid) (378), 2-hydroxy-5-methoxycarbonylpyrazine (aqueous nitrous acid and heated at 80°) (1057), 2-alkoxycarbonyl-3-hydroxypyrazines (890), 5-bromo-2-hydroxy-3-methoxycarbonylpyrazine (sodium nitrite and concentrated sulfuric 

2-Hydroxy-, 2-hydroxy-3-methyl-, 2diydroxy-3,6-dimethyl-(3diydroxy-2,5-di-methyl-), and 2-hydroxy-3-ethylpyrazines have been prepared by hydrolysis of the corresponding isodiazotate salts (3) in cold 40% aqueous sulfuric acid in 42-72% 

Demethylation of 5-(2 -hydroxy-2 -methylpropyl)-2-isobutyl-3-methoxypyrazine occurred on refluxing with 10% hydrochloric acid to give 3-hydroxy-5-(2 -hydroxy-2 -methylpropyl)-2-isobutylpyrazine but 2-isobutyl-3-methoxy-5-(2 -methylprop-l -enyl)pyrazine and 3-hydroxy-24sobutyl-5-(2 -methylprop-l -enyl)pyrazine were also produced (113b). 

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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. 

These (substituted-amino)pyrazines and piperazines have proved to be useful intermediates for subsequent cyclizations and other reactions. Their formation from aminopyrazines and a few cyclizations are illustrated in the following examples ... 

Some ureido- and thioureidopyrazines have been prepared from aminopyrazines with phenyl isocyanate in pyridine, potassium thiocyanate in acid solution, and with phenyl or isopropyl isothiocyanate in pyridine. Thus 2-amino-3-carbamoyl(and jV-benzylcarbamoyl)-5,6-diphenylpyrazines refluxed with phenyl isocyanate in... 

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). 

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

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... 

As might be expected from a consideration of electronic effects, an amino substituent activates pyrazines, quinoxalines and phenazines to electrophilic attack, usually at positions ortho and para to the amino group thus, bromination of 2-aminopyrazine with bromine in acetic acid yields 2-amino-3,5-dibromopyrazine (Scheme 29). 

Methyl 3-aminopyrazine-2-carhoxylate [16298-03-6] M 153.1, m 169-172°, 172°. Forms yellow needles from H2O (100 parts using charcoal). If it contains the free acid then dissolve in CH2CI2 wash with saturated aqueous Na2C03, brine, dry over MgS04 filter, evaporate and recrystallise the residue. Th free acid has m 203-204° (dec) [UV Brown and Mason J Chem Soc 3443 7956] and pK <1 and pK2 3.70. The ammonium salt has m 232° (dec) (from aq Me2CO) and the amide has m 239.2° (from H2O) [Ellingson et al. J Am Chem Soc 67 1711 1945 ]. 

Amino-pyrazines and -pyridazines have been shown to exist predominantly in the amino form by infrared spectroscopic studies (cf. Table VI). Ultraviolet spectral data have been interpreted to indicate that 4-aminocinnoline exists predominantly in the imino form 256, but this conclusion, which was based on comparison of its spectrum with those of cinnolin-4-one and 4-ethoxycinnoline, is probably incorrect. Ultraviolet spectroscopic data strongly support the predominance of amino structures for 2-aminopyrazine (257) and 2-aminoquin-oxaline how ever, the former compound was at first erroneously concluded to exist in the imino form from ultraviolet spectral evidence. Isolation of two isomers of 2-amino-8-dimethylamino-3-methylphenazine, assigned the amino and imino structures 258 and 259, respectively, has been claimed, but it is very unlikely that these assignments are correct. 

Unsaturated pyrazino[l,2-tf]pyrimidines were synthesized by formation of two bonds from [3+3] atom fragments. The 3-carbethoxy- and 3-acylamino-pyrazino[l,2-tf]pyrimidin-4-ones 81 and 87 were prepared from the 2-aminopyrazines 78 and 84 as depicted in Schemes 9 and 10, respectively. The mesoionic 95 was prepared as shown in Equation (8). 

In view of the importance in biochemical processes of pteridines such as folic acid, methotrexate, L-biopterin, and leucettidine <1996CHEC-II(7)679>, synthetic routes to fused pteridines continue to occupy considerable attention. Imidazo-fused pteridines have now been prepared from 3-aminopyrazine-2-carboxamides via carbodiimide intermediates. If the amido-nitrogen in the starting compound is further substituted, as in the scheme, the... 

Thiazolo[2,3-3]pteridines such as 133 can be prepared by the reaction between 3-aminopyrazine-2-carboxylic esters and 3,4-dihydrothiazoles (Equation 29) <2001JHC1173>. [l,2,4]Triazolo[3,4-A]pteridin-5-ones, 134, can be prepared from 2-thiocarbonylpteridin-4-ones by reaction with hydrazonoyl halides the proposed mechanism is outlined in Scheme 38 <2002MOL494>. 

This same 3-methoxy-2-aminopyrazine (33.1.36) is synthesized from 3-hydroxypyrazin-... 

Construction of pyrazine rings from a-amino nitriles has been sometimes completed through multistep reactions. For example, 2-aminopyrazine 1-oxide 163 is synthesized via amide intermediate 162 formed by reaction of methyl a-aminocyanoacetate with a-oximino carboxylic acid (Scheme 45) <1994H(38)1581>. 

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