Quinoxaline di-A-oxides

Enamines and enolate anions react with benzofuroxan to give quinoxaline di-A -oxides (Scheme 38) (69AHC(10)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275) (76AHC(19)l), and from (276) the intermediate adduct (277) can be isolated (73JA8452). This is one of the few instances in which such primary cycloadducts have been isolated in the oxazole series of mesoionic compounds. 

Protonation of pyrazine A-oxides takes place at the unsubstituted ring nitrogen as revealed by examination of their UV spectra and ionization constants in water. The same holds for unsubstituted quinoxaline A-oxide and the 3-amino derivative. Pyrazine and quinoxaline di-A-oxides are protonated at one A-oxide oxygen atom (74KGS1554). 

The bioreductively-activated, hypoxia-selective DNA-damaging properties found in tirapazamine are not uniqne to this nitrogen heterocycle. Analogous properties have been observed for quinoxaline di-A-oxides snch as 99 and In addi-... 

From Benzofuroxan to Quinoxaline A -Oxides or Quinoxaline Di-A -Oxides (the Beirut Reaction)... 

Cycloaddition reactions of quinoxaline A-oxides and quinoxaline di-A-oxides have been reviewed. ... 

Dimethylquinoxaline 1.4-dioxide (1) condenses with diketones to yield a mixture of mono- and di-A-oxides, e.g. diphenyl diketone (2) gives mono- 3 and di-A-oxidcs 4 in 6 and 14% yield, respectively. Since the A-oxide functions of quinoxaline di-A -oxides may be regarded as the combination of two nitrone groups, methyl protons at positions C2 and C3 show enhanced acidity. 

The NBH reduction of 1,4-quinoxaline di-A -oxide (327) in alcohols has been shown to produce the d5-tetrahydroquinoxalines 328 as the predominant product. The product 328 was identical to that obtained from the reduction of 2,3-dimethylquinoxaline with LAH. ... 

A variety of enamines and enolate anions have been found to react with benzofuroxan, giving quinoxaline di-A-oxides in moderate yields [Eq. (5)]. 

Bis-deoxygenation of 2,3-disubstituted quinoxaline di-A -oxides has been performed under very mild conditions with a variety of reagents, such as hex-achlorodisilane or trifluoroacetic anhydride plus sodium iodide. ... 

Habibi D, Nematollahi D, Meshldnghalam S, Varmaghani E (2014) An unexpected oxidative decarboxylation reaction of 2,3-dihydroxybenzoic acid in the synthesis of new dibenzylte-trahydroquinoxalinediones. Tetrahedron 70 4361-4366. doi 10.1016/j.teL2014.04.077 Haddadin MJ, Issidorides CH (1976) Application of benzolurazan oxide to the synthesis of heteroaromatic A-oxides. Heterocycles 4(4) 767-816. doi 10.3987/R-1976-04-0767 Haddadin MJ, Agopian G, Issidorides CH (1971) Synthesis and photolysis of some substituted quinoxaline di-A-oxides. J Org Chem 36(4) 514-518. doi 10.1021/jo00803a005 Haddadin MJ, Bitar H, Issidorides CH (1979) Synthesis and some reactions of o-nitrosoaniline. 

Ring contraction also occurs in irradiation of quinoxaline di-A-oxide of the type 10, the product of the reaction being a 1,3-disubstituted benzimidazolone 11 (Scheme 6.6) (Jarrer et al. 1976). 

Haddadin MJ, Issidorides CH (1967) Photolysis of a quinoxaline-di-A-oxide. Tetrahedron Lett 8 (8) 753-756. doi 10.1016/S0040 039(00)90589-6 Hakan G, Tuncbilek M, Ayhan G, Altanlar N (1998) Synthesis of some new benzimidazolecar-boxamides and evaluation of their antimicrobial activity. Farmaco 53(6) 415-420. doi 10.1016/ S0014-827X(98)00045-7... 

Perhaps one of the most exciting developments in the chemistry of quinoxalines and phenazines in recent years originates from the American University of Beirut in Lebanon, where Haddadin and Issidorides first made the observation that benzofuroxans undergo reaction with a variety of alkenic substrates to produce quinoxaline di-AT-oxides in a one-pot reaction which has subsequently become known as the Beirut reaction . Many new reactions tend to fall by the wayside by virtue of the fact that they are experimentally complex or require starting materials which are inaccessible however, in this instance the experimental conditions are straightforward and the starting benzofuroxans are conveniently prepared by hypochlorite oxidation of the corresponding o-nitroanilines or by pyrolysis of o-nitrophenyl azides. 

The reaction of isobenzofuroxan (131) with the morpholine enamine of cyclohexanone results in a 1,4 cycloaddition to form quinoxaline-di-N-oxide 132 (777). Quinone dibenzenesulfonimide has been found to undergo... 

Initial nucleophilic attack and ring opening are involved in the conversion of benzofuroxans into quinoxaline di-N-oxides by treatment with imines, enamines, carbonyl compounds, and active methylene compounds (the Beirut reaction, also see Section 3.4.1.10.1) a representative example is shown in Scheme 197 <2003EJM791, 2005H(65) 1589, CHEC-III(8.03.10)313>. 

The infrared spectra of quinoxaline mono- and di-A -oxides 3-quin-oxalinone 1-oxides, and 1-hydroxyquinoxaline 2,3-diones have been reported, and the ring stretching vibrations and C=0 and N—O stretching frequencies were assigned.2 2 2-Methyl-6-amino- and 2-methyl-6-nitro-l,2,3,4-tetrahydro-3-quinoxalinones have been examined... 

Fuchs, T., Gates, K.S., Kwang, J.T., and Greenberg, M.M., 1999, Photosensitization of guanine specific DNA damage by a cyano-substituted quinoxaline di-V-oxide, Chem. Res. Toxicol. 12, 1190-1194. 

The conversion of benzofuroxans into quinoxaline di-JV-oxides (Section V,C,3) provides a quick and easy route to this class of compound, and considerable effort has been expended in the search for a medicinally valuable product. The dioxides show strong antibacterial activity, but it appears that, in the range of compounds investigated so far, the margin between effectiveness toward bacteria and toxicity toward mammals is too small to allow their use in human medicine. However, 2-(acetoxyethoxycarbonyl)-3-methylquinoxaline dioxide506,507 and the methoxycarbonylhydrazone of... 

This method of quinoxaline di-JV-oxide formation is known as the Beirut reaction and is extremely useful, particularly in view of the limitations of direct oxidative procedures for preparing di-N-oxides. Probably several hundred quinoxaline di-iV-oxides have been prepared in this way. Only a selection of those exemplified in the patent literature are included in the table at the end of this chapter. Valuable reviews on the conversion of benzofuroxans into quinoxaline di-JV-oxides have been written by Haddadin and Issidorides and by Ley and Seng. ... 

The first report of the preparation of quinoxaline di-N-oxides from benzofuroxans was by reaction with enamines. Benzofuroxans are themselves conveniently prepared by oxidation of the appropriate o-nitroanilines with hypochlorite or by pyrolysis of the corresponding nitrophenyl azides. A variety of enamines react satisfactorily, but the less reactive morpholine enamines give higher yields and more easily isolata-ble products (Scheme 5). " ... 

The reaction between o-benzoquinone dioxime and a-diketones and a-hydroxyketones yields quinoxaline di-N-oxides, though in relatively low yields (Scheme 9). ... 

Quinoxaline di-N-oxide formation (e.g., 24) has also been achieved by reaction of the dioxime with a, 8-unsaturated ketones A further extension of this reaction is the preparation of l-hydroxyquinoxalin-2-one... 

Several examples of the successful lithium aluminum hydride reduction of l,2,3,4-tetrahydro-2-oxoquinoxalines to the corresponding tetrahydroquinoxalines have been recorded in the literature. " A moderate yield of 1,2,3,4-tetrahydroquinoxaline is obtained by reduction of 1,2,3,4-tetrahydro-2,3-dioxoquinoxaline with lithium aluminum hydride in N-ethylmorpholine. The anils 19 give the tetrahydroquinoxalines 20 on treatment with sodium borohydride. This reagent has also been used to reduce a number of 2,3-disubstituted quinoxaline di-iV-oxides to the corresponding cis-tetrahydro derivatives. The trans isomers can be prepared by first reducing the N-oxides with sodium dithionite to the parent quinoxalines, and then the further reduction of the quinoxalines so formed with sodium and ethanol. ... 

Suter W, Rosselet A, Knusel F, Mode of action of quindoxin and substituted quinoxaline-di-N-oxides on Escherichia coli, Antimicrob. Agents Chemother. 1978 13 770-783. 

Barea C, Pabon A, Perez-Silanes S, Galiano S, Gonzalez G, Monge A, Deharo E, Aldana I (2013) New amide derivatives of quinoxaline 1,4-di-A-oxide with leishmanicidal and antiplasmodial activities. Moleeules 18(4) 4718-4727. doi 10.3390/moleculesl8044718... 

Cyanogen-di-A -oxide appeared to be a convenient reagent for the synthesis of quinoxaline substimted ( , )-dioxime with a dioxadithiadiazamacrobicycle 14 when interacting with the 2,3-diaminobenzene attached to the mixed-donor-macrobicycle 15 (Scheme 5.3) (Kantekin et al. 2002). 

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