Quinoxalines N-oxidation

In the preparation of quinoxaline N-oxides, it is advantageous to use peracetic acid rather than aqueous hydrogen peroxide as the... 

Some aspects of the deoxidative C-substitution of quinoxaline N-oxides (see Section 4.6.2.2 for cross-references) and the photoinduced rearrangement of quinoxaline dioxides into quinoxalinediones (see Section 4.5.1) have been discussed already. The remaining reactions of quinoxaline A -oxides are covered in the following subsections. 

These major routes to quinoxalmecarbonitriles have been covered already by primary synthesis (Chapter 1), by cyanalysis of halogenoquinoxalines (Section 3.2.5), by deoxidative cyanation of quinoxaline N-oxides (Section 4.6.2.2), by cyanolysis of nitroquinoxalines (Section 6.1.2.2), from primary quinoxalina-mines by a Sandmeyer-type reaction (Section 6.3.2.3), from quaternary ammonio-quinoxalines with cyanide ion (Section 6.3.2.4), and by dehydration of quinoxalinecarboxamides (Section 7.4.2). Those remaining preparative routes that have been used recently are illustrated in the following examples. 

Several recent general papers on the properties of quinoxaline N-oxides have reported studies on the crystal structures of quinoxaline 1,4-dioxide,380 its 2,3-dimethyl derivative,380 ethyl 7-chloro-3-methyl-2-quinoxalinecarboxylate 1,4-dioxide,40 and N-(2-hydroxyethyl)-3-methyl-2-quinoxalinecarboxamide 1,4-dioxide 931 the NMR spectral data of quinoxaline 1,4-dioxide for comparison with those of related dioxides 348 the NMR data for biologically active quinoxalinecarboxamide dioxides 381 thermochemical data for several quinoxaline dioxides 183 and polaro-graphic or cyclic voltammetric data for 2,3-disubstituted quinoxaline dioxides.239 894... 

Quinoxaline N-oxides substituted in the 2,3-position undergo facile nucleophilic displacement. Numerous reactions have been investigated in the search to prepare derivatives which are active... 

Studies of the reactions of quinoxaline N-oxides under Reissert reaction conditions have led to some very interesting and unusual results. Thus, treatment of quinoxaline IV-oxide with PhCOCl/KCN in methanol or water under standard Reissert conditions gave 6-chloroquinoxaline as the major product (ca. 45%), and only small amounts of the desired 2-cyanoquinoxaline. Use of 3 equivalents of TMSCN in place of KCN and dichloromethane as solvent, however, gave 2-cyanoquinoxaline in 72% yield. When 2,3-diphenylquinoxaline iV-oxide was treated with 1 equivalent of PhCOCl in the presence of 3 equivalents of either KCN or TMSCN a mixture of products was always obtained irrespective of the solvent used. The most interesting of these products was the ring cleaved compound 1. 

Isoquinoline is more reactive at the 1-position than quinoline is at the 2-position by approximately the same factor by which the 1-position of naphthalene is more reactive than the 2-position this is true also for the N-oxides. Comparison of the rate data for quinoline and quinoxaline (11.15), and the data in 11.59, suggests that replacement of =CH— by =N— accelerates the exchange at the 2- and 3-positions by factors of 135 and 20, respectively. The low reactivity of quinoxaline N-oxide seems anomalous and may be in error. 

Pyrazine and quinoxaline N-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine N-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine AT-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

Certain quinoxaline N-oxides (191), too, are converted into l-acetyl-3-aroylbenz-imidazolinones (193) when they are heated in acetic anhydride. The reaction proceeds by an initial acetylation at N-3, and this is succeeded by formation and rearrangement of an intermediate oxaziridine (192 Scheme 111). Apart from their involvement in other reactions discussed earlier, such intermediates have also been invoked to explain the formation of 1,3-dibenzoylbenzimidazolinone (70%) when quinoxaline 1,3-dioxide is exposed to sunlight (74CRV279). 

The authentic quinoxaline N-oxide (108) is prepared from quinoxaline 1,4-dioxide by the following route56 ... 

The synthesis of quinoxaline N-oxides from benzofurazan 1-oxides, and by N-oxidation of the corresponding substituted quinoxaline derivatives, has already been discussed (Sections II,D and III,C, respectively). 

The preparation of quinoxaline N-oxides from o-nitroanilines was first reported by Tennant,and work on similar lines has also been carried out by Italian and Pakistani workers The method is illustrated in... 

A related synthesis of a quinoxaline N-oxide is illustrated by the reductive cyclization of the cyanoformyl derivative of o-nitroaniline (Scheme 4). °... 

The longest ultraviolet absorption maximum for quinoxaline N-oxides is shifted to shorter wavelengths in solvents of increasing polarity, and this is attributed to hydrogen bonding. ... 

Many of the reactions of quinoxaline N-oxides are typical of those of heteroaromatic N-oxides in general. Thus the N-oxide function is readily reduced, nuclear substitution products are obtained on treatment with... 

An earlier report stated that quinoxaline N-oxide is unchanged when heated with acetic anhydride. 

Other lH-2,3-dihydro 2-oxo compounds have been prepared by more specialized routes. Reaction of quinoxaline N-oxide (61) with phenyl isocyanate gives a mixture of anilinoquinoxaline 62 and the (presumably) derived diphenyl oxo compound 63. Recently it has been shown that the alloxazine derivative (64) on treatment with di-n-butylamine undergoes a Lossen rearrangement to give the 2-oxo compound 65. Alkali treatment of compound 65 gives the 1,3-unsubstituted product 59. 

Elaboration of quinoxaline N-oxides carrying carbonyl functionality has led to a series of pyridoquinoxaline N-oxides, some of which have been shown to have antitrichomonal and antibacterial activity. For example, compounds of type (231) and (232) have been made. 

The enaminones 660 were refluxed with sodium hydroxide to give the quinoxaline N-oxides 662 in excellent yields. Since a-acyl aromatic-jV-oxides are readily hydrolyzed under basic conditions, the N-oxide 661 was suggested as the intermediate. Scheme 183 (81S60). 

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