2- -6-substituted aminopyrazines

Amine-imine tautomerism in 3-acyl-substituted aminopyrazines has been examined by H, C, and N spectral analysis as well as X-ray crystallography <2005JST67>. In the same way as the parent aminopyrazine, those aminopyrazines have been shown to exist in the amino form 11 (R = H, Me, Ph) (Scheme 2) in contrast to an expectation that the electron-withdrawing acyl groups adjacent to the amino substituent would stabilize the imino tautomers 12 and 13. Thus, all NMR spectra showed only existence of the amino tautomer 11, and additionally the... 

Pyrazino[2,3-6][ 1,4]thiazin-3-ones (232) have been obtained by cyclization of highly substituted aminopyrazines (231) using NaOEt—EtOH (Equation (33)) (75KGS66). 

A series of 2-cyano-6-substituted aminopyrazines (and imidoesters) refluxed with hydroxylamine in methanol gave 2-(C-amino-C-hydroxyiminomethyl)-6-(substituted amino)pyrazines (943, 1424), and 2-cyano(or thiocarbamoyl)-6-ethylthiopyrazine refluxed with hydroxylamine in aqueous methanol gave 2-(C-amino-C-hydroxyiminomethyl)-6-ethylthiopyrazine (992). 

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. 

The parent compound is a moderately weak base (pK 3.59), comparable with substituted aminopyrazines. The 2,3-dihydro compound 5, however, is very much stronger (pK 9.32). The base-weakening effect of the nitrogen in the 7-position is clearly demonstrated by comparison with the dihydroimidazopyridine (7). The latter compound has a pKa of 12.51 units. Similar effects are found in the imidazopyridazine and imidazo-pyrimidine series. No evidence has been found for covalent hydration in any of the triazaindenes studied. ... 

The major methods for the preparation of this ring system involve formation of the imidazo ring, either by cyclization of appropriately substituted aminopyrazines or by the reaction of aminopyrazines with bifunctional reagents. 

The known preparative methods for the synthesis of imidazo[l,2-a]pyrazines prior to 1983 have been reviewed extensively <84CHEC-1(5)607>. This section will review new methods of syntheses published since 1983. The most common syntheses of this ring system involve closure of the imidazole ring by cyclization of an appropriately substituted aminopyrazine using a variety of reagents, or by the reaction of bifunctional agents (such as a-ketoacids, a-ketoaldehydes, a-halo-carbonyl compounds), with 2-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. 

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). 

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]. 

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... 

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... 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

Two examples were reported for the synthesis of the pyrido[2,3-, ]pyrazine moiety using pyrazine precursors. Thus, amidation of methyl 2-aminopyrazine-3-carboxylate 670 with a substituted acetyl chloride followed by heterocycliza-tion of the formed amide 671 gave 6,8-dihydroxy pyridopyrazine 672 <2004W02004056825>. 

Pyrazines (see Sections II, V,B,2, and D). Both 2-amino- and 2-methylpyrazine react with Mel to give isomers. The observed isomer ratios are very close to those predicted by considering relative reactivities of the appropriately 2- and 3-substituted pyridines.62 The observation159 that 2-aminopyrazine undergoes quaternization... 

Regioselectivity in the chlorination of pyrazine /V-oxides with phosphoryl chloride depends upon the substituent on the C-3 carbon. Thus, 3-aminopyrazine 1-oxide is chlorinated with loss of the /V-oxide oxygen to give 2-amino-3-chloropyrazine as the sole product whereas 3-methoxy and 3-chloropyrazine 1-oxides form approximately equal amounts of 3-chloro- and 6-chloro-2-substituted pyrazines along with a trace of the 5-chloro derivatives. 

Very few imidazo[4,5-b] pyrazines have been reported in the literature1-3 and no good general method has been available for preparing compounds in this most interesting heterocyclic class. We have found that the Curtius reaction of a 3-aminopyrazine-2-carboxylic acid azide (Scheme I) proceeds with intramolecular cyclization to provide, in good yield, a wide variety of the subject compounds. We will report here only the 6-substituted 5-chloro-l, 3-dihydro-2tf-... 

This section covers primary, secondary, tertiary, and quaternary aminopyrazines (both nuclear and extranuclear) but not (functionally substituted amino)pyrazines such as hydrazino-, hydroxyamino-, or azidopyrazines. General discussions have appeared on the spectra of 2-pyrazinamine,255 257 991 the proton-sponge properties of 2,3,5,6-tetra(pyridin-2-yl)pyrazine in relation to its fine structure,925 the fluorescene properties of 3,6-diamino-2,5-pyrazinedicarboxylic acid derivatives in relation to their fine structures,1646,1659 the basic properties of aminopyrazines and other such azines in relation to their electronic structures,412,928 and the fine structures of 3-amino-2-pyrazinecarboxylic acid1340 and l,4-diacetyl-2,3-diphenylpiperazine.559... 

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 ... 

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