Aminopyrazines

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... 

In principle, aminopyrazine and 2-aminoquinoxaline are capable of existing in the form of the imino tautomers (81) and (82) however, comparison of the UV spectra of the amino, methylamino and dimethylamino derivatives indicates that in both systems the amino rather than the imino tautomer is favored (60JCS242, 58JCS108). 

Aminopyrazines and 2-aminoquinoxalines, like their pyridine analogs, react with nitrous acid under aqueous conditions to give the 2(l//)-pyrazinones and 2(l//)-quinoxalinones. 2-Aminoquinoxalines are more readily hydrolyzed than typical heterocyclic amines and 2-amino-3-methylquinoxaline, for example, undergoes hydrolysis on heating at 100 °C with dilute sodium hydroxide (59JCS1132). 

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). 

Monooximes of a-diketones have found applicability in the synthesis of 2-aminopyrazine 1-oxides by condensation with a-aminonitriles, and this reaction was used by White and coworkers in an approach to the synthesis of Cypridina etioluciferamine (Scheme 66 R = 3-indoloyl) (73T3761). In this instance, the use of TiCU as a catalyst was essential, since the carbonyl group in 3-acylindoles is normally deactivated and the required amine/carbonyl condensation is impractically slow. Under normal circumstances the carbonyl group in simple alkyl-substituted monoximes of a-diketones is the more reactive site and the reaction is rapid, requiring no catalysis (69LA(726)loo). 

Most syntheses of this type have followed the classical Gould-Jacobs pattern (Section 2.15.5.4.2) in which 2-aminopyrazines bearing a 6-substituent give esters of 8-oxopyrido[2,3-f ]pyrazine-7-carboxylic acids (424) via the usual intermediate ethoxy-methylenemalonate adducts. In some cases the isomeric pyrazino[l,2-a]pyrimidines are formed in addition (e.g. 74CPB1864). 

There is also the possibility of removing the 2-oxo group by ring cleavage and subsequent recyclization. Lumazine can be hydrolyzed by strong alkali to 2-aminopyrazine-3-carboxylic acid (153) which is converted first into the amide (154) and then cyclized by ethyl orthoformate into pteridine-4-one (155 equation 47) (51JCS474). 

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. 

Amino-1,3-propanediol lopamidol 2-Aminopyrazine Sulfalene 2-Aminopyridine Diphenpyramide Methapyrilene HCI Phenyramidol Pyrilamine Sulfadiazine Tripelennamine Zolimidine... 

Coelenteramide and coelenterazine. The structure of AF-350 contains the same aminopyrazine skeleton as in Cypridina etioluciferin and oxyluciferin (Fig. 3.1.8), suggesting that the bioluminescence reaction of aequorin might resemble that of Cypridina luciferin. To investigate such a possibility, we prepared the reaction product of aequorin luminescence by adding Ca2+ to a solution of aequorin. The product solution (blue fluorescent) was made acidic, and extracted with... 

Aldehydeless dark mutants, 35-37 effect of cyanide, 37 Aminopyrazine, 160 Ammodytes, 163 Amphipod, 47 Ampbiura, 163, 337 Amphiura fHiformis, 302, 307, 345 Ampbiura luciferase, 307, 345 Anaerobic condition, 351 Anderson s benzoylation method, 54, 55... 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

MesSiNs 19 (0.34 rtiL, 2.,4 mmol) and of Et2NCOCl (0.32 mL, 2.4 mmol) are added, in this sequence, under argon, to a solution of 3-aminopyrazine-l-oxide 934 (1 mmol) in abs. MeCN (8 mL) and the reaction mixture is heated under reflux for 18 h with exclusion of humidity. After evaporation in vacuo the residue is chromatographed with hexane-ethyl acetate (10 1 to 3 1) on a column of 20 g silica gel to give almost quantitative yield of microcrystalline 2-amino-3-azidopyrazine 935, m.p. 225 °C (dec.) [55] (Scheme 7.56). 

An inhibitor during drilling and servicing of oil and gas wells is a condensate of aminopyrazine and an epoxide compound, such as the glycidyl ether of a mixture of Cn to C14 alkanols [604]. 

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). 

The 2-aminopyrazine 123 with the stable (neopentylimino)propanedienone 125 furnished the 2-(neopentyl)-amino-y//-pyrazino[l,2-tf]pyrimidin 4-one 126 (Equation 14) <2002JOC2619>. 

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>. 

For this purpose, perfluorooctanesulfonyl-tagged benzaldehydes were reacted with 1.1 equivalents of a 2-aminopyridine (or 2-aminopyrazine), 1.2 equivalents of an isonitrile, and a catalytic amount of scandium(III) triflate [Sc(OTf)3] under micro-wave irradiation in a mixture of dichloromethane and methanol (Scheme 7.85). A ramp time of 2 min was employed to achieve the pre-set temperature, and then the reaction mixture was maintained at the final temperature for a further 10 min. The fluorous tag constitutes a multifunctional tool in this reaction, protecting the phenol in the condensation step, being the phase tag for purification, and serving as an acti-... 

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