Benzofuroxans quinoxaline oxides from

The second class of benzo-fused heterocycles accessible from benzofuroxans are benzimidazole oxides. In this case only one carbon from the co-reactant is incorporated in the product. With primary nitroalkanes 2-substituted l-hydroxybenzimidazole-3-oxides (46) are formed via displacement of nitrite, and / -sulfones behave similarly. The nitrile group of a-cyanoacetamides is likewise eliminated to alford 2-amide derivatives (46 R = CONRjX and the corresponding esters are formed in addition to the expected quinoxaline dioxides from acetoacetate esters. Under similar conditions secondary nitroalkyl compounds afford 2,2-disubstituted 2//-benzimidazole-1,3-dioxides (47). Benzimidazoles can also result from reaction of benzofuroxans with phosphorus ylides <86T3631>, nitrones (85H(23)1625>, and diazo compounds <75TL3577>. 

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). " ... 

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. 

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. 

The generation from furoxans of other heterocyclic systems, some of which show useful biological activity (see Section 4.22.5), has been the subject of intensive investigation. The following subsections summarize the conversion of benzofuroxans into quinoxaline and benzimidazole oxides, the rearrangement of 4-substituted benzofuroxans, and the transformation of monocyclic furoxans into isoxazoles and isoxazolines, furazans, and pyrazolines. More detailed discussion is to be found in recent comprehensive reviews (75S415, 76H(4)767, 81AHC(29)251>. 

Quinoxaline and phenazine bis-jV-oxides, synthesis from benzofuroxan M. J. Haddadin and C. H. Issidorides, Heterocycles 4, 767-816 (1976). 

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

Benzofuroxan (5) reacts under mild conditions with an enamine or with an aldehyde or ketone in the presence of ammonia or an amine to form mono- or disubstituted quinoxaline dioxides (151). Dark red dihydro-quinoxaline dioxides (e.g., 152) may be formed when an enamine is used which does not possess an a-hydrogen atom for elimination.381 2-Amino-substituted quinoxaline dioxides have been produced using (a) an ynamine [providing tertiary amines (153)],382 (b) chloroacetaldehyde and a primary amine [producing secondary amines (154)],9 and (c) some nitriles, e.g., malononitrile (to give the primary amine 155).382 The last reaction, however, is by no means a general one, since benzimidazoles are also produced from these substrates (see below). l-Hydroxyquinoxalin-2-one 4-oxides (156) can also be formed in several ways using (a) an a-substituted /1-ketoester (157)... 

The formation of unsubstituted quinoxaline 1,4-dioxide in the Beirut reaction has been observed using a number of substrates benzoylacetalde-hyde and its enamines,395 vinyl acetate (Et2NH),396 acetylene (NEt3)397,398 propargyl alcohol, propiolic acid, and phenylacetylene (various amines).398 Some of these are unexceptional, but the apparent dephenylation in the case of the phenylacetylene is surprising. However, recently the reaction of benzofuroxan with diethylamine was reinvestigated399 (see Section V,E), and quinoxaline dioxide was found to be one of the major products from a complex sequence of oxidation and reduction reactions. It seems probable with phenylacetylene, and possible in other cases too, that the amines play more than a catalytic role in quinoxaline dioxide production. The amino-quinoxalinone 175 was reported, using vinyl acetate and morpholine.396... 

This reaction was first reported by Haddadin and Issodorides in 1965. It is the preparation of quinoxaline-1,4-dioxides from the cycloaddition between benzofuroxan (i.e., benzofu-razan A -oxide) and dienes, a.y -unsaturated ketones, enamines, or enolates. Unfortunately, this reaction is not named after the authors who discovered it instead it is known as the Beirut reaction after the city in which the inventors carried out is the initial work. In most cases, ketones," /3-diketones, j8-ketoesters, )8-ketonitrile, LS-dinitrile, and/8-ketoamides all are suitable for this reaction, and the corresponding enolates can be easily prepared in the presence of a weak base such as triethylamine. In addition, even phenolic enolates from phenol, resorcinol, hydroquinone, or benzoquinone undergo a similar dehydrative condensation with benzofuroxan under mild conditions (e.g., Na0H/H20, H2O, MeOH/RNH2, Si02/MeCN at room temperature), to give phenazine iV,iV -dioxide derivatives. ... 

Ferfra S, Ahabchane NH, Essassi EM, Bellan J, Pierrot M (2005) Synthesis and complexation of new macrocycles derived from quinoxaline-2,3-dione. J Mar Chim Heterocycl 4 49-58 Forster HI, Niclas HI, Lukyanenko NG (1985) Umsetzungen von benzofuroxan-kronenethem darstellung kronenetheranellierter heterocyclischer /V-oxide. Zeit Chem 25(3) 102-103. doi 10. 1002/zfch. 19850250315... 

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