5- Aminoquinoxaline

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. 

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... 

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). 

Finally the preformed 2-formyl-3-aminoquinoxaline (448) gave the pyrido[2,3-f ]quin-oxalin-2-one (449) with activated esters/sodium alkoxide (79ZC422). 

A novel synthesis of 2-aminoquinoxalin-3-one 1-oxide has been effected by the hydrogenation of o-nitro-l-cyanoformanilide in ethanol in the presence of Adam s catalyst.- ... 

Aminoquinoxaline 1-methiodide (65) is slowly formed when 2-aminoquinoxaline is treated with excess of methyl iodide in methanol at room temperature. Decomposition of the 1-methiodide with cold aqueous sodium hydroxide solution gives l-methylquinoxalin-2 one-imine (66) and this on hydrolysis yields l-methylquinoxalin-2-one. ... 

Treatment of 2-aminoquinoxaline with methyl toluene-p-sulfonate at G. W. H. Cheeseman, unpublished work. 

Aminoquinoxaline exists predominantly as such rather than in the tautomeric imino form. This is indicated by a comparison of the basic strength of the 2-amino compound (pKo 3.90) and those of its fixed methylated tautomers, 2-dimethylaminoquinoxaline pKa 3.72) and l-methylquinoxalin-2-oneimine (pfCn 8.70). The ultraviolet spectrum of the neutral molecule of 2-dimethylaminoquinoxaline shows the expected bathochromic shifts compared to that of 2-aminoquinoxaline these spectra differ from the ultraviolet spectrum of the neutral molecule of l-methylquinoxalin-2-oneimine (Fig. 1). The mono-cations (68) and (69) derived from 2-aminoquinoxaline and l-methylquinoxalin-2-oneimine have a similar chromophoric system and show almost identical ultraviolet absorption (Fig. 2). 

Treatment of an alkaline solution of quinoxalin-2-one or quinoxa-line-2,3-dione with an alkyl iodide or sulfate results in A-methylation. Thus methylation of 3-aminoquinoxalin-2-one (74) with methyl sulfate and alkali gives 3-amino-l-methylquinoxalin-2-one (75) and not as previously reported the isomeric 0-methyl derivative. ... 

This section covers primary, secondary, tertiary, and quaternary aminoquinoxalines, both nuclear and extranuclear, but not hydrazino- or azidoquinoxahnes, which are discussed separately in later sections. 

Of the many synthetic routes to aminoquinoxalines, those discussed already are indicated in the following list that includes the potential scope of each procedure. 

The remaining recently used routes to aminoquinoxalines are illustrated by the following classified examples. 

Note For nuclear primary, secondary, or tertiary aminoquinoxalines irrespective of the reagent used, the position of amination is clearly affected by any passenger groups present. 

Note For nuclear primary, secondary, or tertiary aminoquinoxalines but seldom used. 

Note Such deacylations have been done by acidic or alkaline hydrolysis to give primary or secondary aminoquinoxalines, both nuclear and extranuclear. Treatment with hydrazine should also achieve deacylation, but there appear to be no recent examples. 

Note. Hydrolysis can give nuclear or extranuclear primary aminoquinoxalines (no recent examples) reduction can give secondary aminoquinoxalines. 

Note Such conversions of carboxylic acid derivatives into nuclear or extra-nuclear primary aminoquinoxalines appear to be almost unrepresented in recent literature, apart from one partial Curtins procedure. 

Note For the preparation of nuclear or extranuclear secondary or tertiary aminoquinoxalines but rarely used recently. 

Note The replacement of one amino group by another can be used to make nuclear or extranuclear primary, secondary, or tertiary aminoquinoxalines, but the criteria for success are still obscure. 

Note Instances of the formation of extranuclear primary, secondary, or tertiary aminoquinoxalines by introduction of the amino entity as a passenger group will be found in most chapters. Only a couple of random examples are given here. 

Reactions of aminoquinoxalines that have been covered already include the conversion of primary amino- into halogenoquinoxalines (Section 3.1.3),... 

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