Benzofuroxans reactions

H. Acyl- and Carboxy-Substituted Benzofuroxans Reactions of the Heterocyclic Ring... 

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. 

In spite of the usefulness of the Beirut reaction, mechanistically it is not well understood. It has been suggested that the first step involves the nucleophilic attack by the enolate or the enamine at N-3 of the benzofuroxan to yield an intermediate iV-oxide (Scheme 50) which subsequently undergoes tautomerism to an hydroxylamino derivative. This intermediate then cyclizes to the dihydroquinoxaline 1,4-dioxide. This suggestion has not been proven, and indeed there is evidence that benzofuroxan is in equilibrium with 1,2-dinitrosobenzene... 

Scheme 51), so it has been suggested that the initial reaction involves the dinitrosobenzene. It does seem, however, that this may be an over-simplification, as there are documented cases where mono-iV-oxides rather than the di-iV-oxides are formed for instance, the reaction of benzofuran-3(2//)-ones with benzofuroxan yields 3-(o-hydroxyphenyI)quinoxa-line 1-oxide (Scheme 52). Other mechanistic possibilities may also be put forward but it seems probable that more than one pathway may be operating, particularly in view of the more recent findings on the reactions of benzofuroxans (81AHC(29)251). 

The most reliable method of preparing benzofuroxans is by decomposition of o-nitrophenyl azides. Decomposition can be achieved by irradiation, or more usually by pyrolysis temperatures between 100° and 1.50° are commonly used. Refluxing in glacial acetic acid is the recommended procedure for 4- or 5-sub-stituted 2-nitrophenyl azides, but with 3- or 6-substituted compounds higher boiling solvents are usually necessary. Quantitative studies on the reaction rate have been made, and a cyclic transition state invoked, an argument which has been used to account for the greater difficulty of decomposition of the 6-substituted 2-nitrophenyl azides. Substituent effects on the reaction rate have also been correlated with Hammett a constants, ... 

A table listing the benzofuroxans Imown to the authors, from the literature or otherwise, with their melting points, appears in Section X, at the end of this chapter. The present section presents a brief summary of the presently available types of substituent groups on the benzene nucleus, and of the reactions they undergo. 

Nitration proceeds readily in benzofuroxan, giving first the 4-nitro, then the 4,6-dinitro compound. 6-Nitrobenzofuroxan, according to Drost, is nitrated further in the adjacent 6-position. Bailey and Case reported that the major product is the 4,6-dinitro compound, but they did succeed in isolating a small amount of the 6,6-dinitro derivative from the reaction. 

Reduction of benzofuroxans is usually the most convenient route to benzofurazans and o-quinone dioximes (see Section VI, C). Reduction of 4-nitrobenzofuroxan would seem to be a method of synthesis of 1,2,3-triaminobenzene, while the haloalkoxy-substitution reaction (Section VTT,B) and the rearrangements of Section VIII provide compounds accessible only with difficulty by other methods. Apart from these reactions, the benzofuroxans appear to be of limited synthetic utility. 

Benzofuroxan 79 can be generated from 2-nitrophenyl azide 80 (Scheme 49). Neighboring-group assistance within the pyrolysis leads to a one-step mechanism with an activation barrier of 24.6 kcal/mol at the CCSD(T)/6-31 lG(2d,p) level [99JPC(A)9086]. This value closely resembles the experimental one of 25.5 kcal/mol. Based on the ab initio results for this reaction, rate constants were computed using variational transition state theory. 

Intermediates involved in the tautomerization of furoxans gave rise to speculations about their structure. Systematic calculations on possible intermediates being involved in the reaction of furoxan [92JCC177] and benzofuroxan 79 showed that dinitrosoethylene and dinitrosobenzene 81 are the most likely ones (Scheme 50) [94JOC6431, 94JPC12933]. 

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxan(e) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-V-oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

Furoxans and benzofuroxans undergo thermal and photochemical ring cleavage, reactions with nucleophiles, Boulton-Katritzky rearrangement, reduction and deoxygenation, ring transformation, etc. (see also Section 5.05.6.2). 

The formation of quinoxaline heterocyclic systems is a well-known transformation of benzofuroxanes, which occurs in the presence of /3-dicarbonyl compounds <2001RJ0891, 2003BMC2149, 2003EJM791, 2005JME2019>. For example, the synthesis of quinoxaline 1,4-di-jV-oxides was carried out by reaction of the appropriate benzofuroxane 69 with the corresponding /3-ketoester, using triethylamine as the catalyst (Scheme 15) <2005JME2019>. 

A series of quinoxaline oxides 70 and 72 was obtained by the classical Beimt reaction of the substituted benzofuroxanes 71 and the 1,3-diketones, /3-ketoesters, amides, or l-(alkyl/phenyl) 4,4,4-trifluoromethyl-/3-diace-tones (Scheme 16) <1999CHE459, 2004BMC3711>. 

Quinoxalines 76 and 78 can be synthesized by the reaction of benzofuroxanes 77 with 4-cyclohexenylmorpholine <2001SC2329> or styrene <2001RJ0892>, respectively (Scheme 18). 

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