2-Substituted aminoquinoxalines

Various 3-substituted aminoquinoxaline-2-thiones have been prepared from quinoxaline-2,3-dithione. For example, treatment of the dithione with methylamine yields 3-methylaminoquinoxaline-2-thione, and the corresponding reaction with hydrazine hydrate yields 3-hydrazino-quinoxaline-2-thione. The latter compound is also obtained by treatment of 2,3-dichloroquinoxaline with thiourea and then with hydrazine hydrate. When 2-chloroquinoxaline 1-oxide is heated with thiourea in methanol at room temperature, an unidentified solid m.p. 184-185° is obtained alkaline hydrolysis of methanol-soluble products gives quinoxaline-2-thione in 41% yield. A method of some general applicability is illustrated by the preparation of the thioxo compound 4 from o-anilinoaniline (3). °... 

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. 

This section contains some typical examples (not given elsewhere) of the cyclization reactions of regular aminoquinoxalines or their substituted-amino analogs. 

Ford and co-workers reported regioselective substitutions of 2,3-dichloro-6-amino-quinoxaline 270 with various dialkylamines to study the biological properties of substituted quinoxalines <00TL3197>. For example, 2,3-dichloro-6-aminoquinoxaline 270 reacted with nucleophiles to give the opposite regioisomer to that seen with 2,3-dichloro-6-nitroquinoxalines 267. 

Analysis248 of the UV spectra of the monoprotonated 2-substituted quinoxalines, and the Hammett correlation of the pKa shifts with the substituent constants, give two straight lines, corresponding to two sets of substituents, and so reflecting a change in the position of protonation. Thus, 2-methoxyquinoxaline was found to protonate at N-4, and 2-aminoquinoxaline at N-1. However, the site of protonation of 2-chloro-quinox aline was ambiguous. 

Nitration of different quinoxalinamines may be carried out in concentrated sulfuric acid. The site of electrophilic substitution depends on the position of the amino group,e.g. nitration of 3-aminoquinoxaline-2-carbonitrile affords the 7-nitro derivative (mp > 300"C). ... 

Substituted quinoxalines undergo some interesting reactions when treated with nucleophilic reagents. When 6-bromoquinoxaline is treated with potassium amide in liquid ammonia the main product is benzimidazole. Minor amounts of 2-amino- and 2,3-diaminoquinoxalines are also formed, but none of the expected 5- and 6-aminoquinoxalines are obtained (Scheme ) Similar treatment of 6-chloroquinoxaline gives a mixture of 2-amino-7-chloroquinoxaline and 6-chloro-2,3-diamino-quinoxaline. It has been suggested that the difference in behavior between the 6-bromo and 6-chloro compounds may be explained by the... 

A study of the reaction of 2-halogenoquinoxalines and 3-substituted 2-halogenoquinoxalines with potassium amide in liquid ammonia has shown that, in addition to the expected 2-aminoquinoxalines, benzimidazole may also be formed (Scheme 1). With 2-chloroquinoxaline the main product is... 

Dichloro-6-nitroquinoxaline reacts with aziridine(ethyleneimine) in benzene solution at room temperature, in the presence of triethylamine as acid scavenger, to give the 2-aziridinyl derivative, the 6-nitro group thus selectively activating the 2-chloro substituent. Chlorine activation is also apparent in the substitution reactions of 2-chloroquinoxaline 1-oxide, which is converted into the 2-amino 1-oxide by treatment with aqueous or ethanolic ammonia at 60-80° and thus under much milder conditions than those used for the conversion of 2-chloroquinoxaline into 2-aminoquinoxaline. 

There is evidence that in the acid hydrolysis of the 2,3-dicycloalkyl-aminoquinoxalines to the corresponding substituted quinoxalinones, the ease of hydrolysis is in the order morpholino>piperidino>pyrrolidinyl. Thus 2-morpholino-3-pyrrolidinylquinoxaline (10) can be selectively hydrolyzed to 3-pyrrolidinylquinoxalin-2-one (11). The hydrolysis of 2,3-dicycloaminoquinoxalines proceeds much more readily than is the case with the corresponding 2,4-disubstituted quinazolines, presumably because of the steric hindrance in the quinoxaline derivatives. ... 

An effective approach to condensed heterocyclic systems is the use of intramolecular nucleophilic substitution of hydrogen. The key role of the Sn step has been demonstrated by the synthesis of quinoxalines condensed with five- and six-membered heterocycles starting firom 2-aminoquinoxaline [166] or quinoxaline-2-carbaldehyde [167, 168], correspondingly. Indeed, 2-aminoquinoxaline can be condensed with acetylacetone or other p-dicarbonyl compounds to give after oxidative intramolecular Sn reaction pyrrolo[2,3-i>]quinoxalines in good yields (Scheme 52) [166]. Also condensation of quinoxaline aldehyde with ethyl... 

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