Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.

New quinoxaline 1,4‐dioxide derivatives have been synthesized from novel fluorinated benzofuroxans such as 4‐fluorobenzofuroxan, which is prepared for the first time. Furthermore, the preparation 4,6‐difluorobenzofuroxan has been revisited because we were unable to reproduce the reported synthetic method. Several synthetic pathways have thus been investigated, and the optimal way to prepare this disubstituted benzofuroxan was from the 3,5‐difluoro‐2‐nitroaniline. The various synthetic attempts have allowed the isolation of interesting new compounds such as hydroxybenzotriazole‐like heterocycles or benzoquinone 2‐diazide. In the latter case, our study reveals some interesting features in the mechanism of their formation. The first structural elucidation of benzoquinone 2‐diazide through an X‐ray crystallographic study is also reported. This study has unambiguously shown that benzoquinone 2‐diazide can be involved in Diels–Alder reactions. The first case of a reaction involving a nitro‐substituted benzoquinone 2‐diazide and cyclopentadiene is also reported. To understand better the influence of the fluorine atoms on the reactivity of benzofuroxans and benzofurazans, a wide array of new fluorinated heterocycles were synthesized together with some already known compounds. This has enabled an extensive investigation of their electrophilic behavior to be undertaken through a theoretical and an electrochemical study. From these studies, it could be deduced that the replacement of nitro groups by fluorine atoms results in a significant decrease in the electrophilic character of benzofuroxan. Nevertheless, these compounds could undergo SNAr processes, leading to new functionalized heterocycles. The first examples of aromatic nucleophilic substitution of fluorine with these compounds are also described.

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Benzofuroxans are well known compounds that continue to attract particular attention since the discovery of 4,6‐dinitrobenzofuroxan (DNBF) back in 1899. It has been shown that these compounds possess biological activities that are related to their electronic behaviours and the positioning of substituents borne by the heterocycles. In this paper, we report the first synthesis of 4‐fluoro‐6‐nitrobenzofuroxan and 6‐fluoro‐4‐nitrobenzofuroxan; the altered positions of the substituents enabling us to carry out structural and reactivity comparisons, with DNBF and 4,6‐difluorobenzofuroxan. These compounds have been unambiguously characterized through NMR and radiocrystallographic studies. Two main synthetic pathways involving fluoroanisoles and fluorophenols, cheap and easily available chemicals, have been successfully developed. Finally, benzofurazan analogues have been prepared via deoxygenation of corresponding benzofuroxans with triethylphosphite.

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and Access to Fluorinated Quinoxaline Oxides. -Since the approach to the title compound (III) described in the literature is not reproducible, another way is investigated. The best method is presented in the scheme and some substitution reactions of the fluorine atoms are carried out. The main interest in (III), however, includes the synthesis of substituted quinoxalines such as (VIII), (IX), and (XI) as possible pharmaceutically important components. Monofluorinated benzofuroxan (XV) and some analogues are also prepared. The influence of the fluoro substituents on the reactivity of benzofuroxan and benzofurazan systems is studied and discussed in detail. -(JOVENE, C.; JACQUET, M.; MARROT, J.; BOURDREUX, F.; KLETSKY, M. E.; BUROV, O. N.; GONCALVES, A.-M.; GOUMONT*, R.; Eur. J. Org. Chem. 2014, 29, 6451-6466, http://dx.doi.org/10.1002/ejoc.201402692 ; Inst. Lavoisier Versailles, UMR, Univ. Versailles, F-78035 Versailles, Fr.; Eng.) -Lehmann 13-214

The syntheses of 4‐fluoro‐6‐nitrobenzofuroxan and 6‐fluoro‐4‐nitrobenzofuroxan are achieved from a sulfonate intermediate possessing an electron‐donating group that facilitates the key nitration step.