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Désaromatisation et Fonctionnalisation de Nitroaromatiques via la Chimie des Nitronates – ARONITRO

Towards innovative functionalisations of nitroarenes

Re-evaluation of the synthetic potential of nitroarenes: Fast access to complex polysubstituted aminocompounds of high added value.

Development of an original chemistry to enhance the synthetic potential of nitroarenes

This project aims at re-evaluating the synthetic potential of nitroarenes. We proposed to develop new dearomatisation reactions via cycloadditions involving electron rich reagents (such as dienes , alkenes , dipoles) in order to access amino compounds having tetrasubstituted carbon centers at the ring junction, in a simple and efficient way. The complex structures thus formed are difficult to synthesize by other methods, and have many common points with biologically active compounds or ligands for catalysis.<br />In some cases, the proposed reactions lead to the formation of nitronate intermediates we intended to isolate, to assess their reactivity and develop different functionalizations for these species.<br />We also proposed to develop a stereoselective version of the reactions involved in these transformations.

This project is divided into three main parts:
Part 1: Study of the reactivity of nitroarenes - dearomatisation of nitroarenes
Study of the reactivity of nitroarenes was proposed, especially with nitrobenzenes, involving mainly dearomatizing cycloaddition reactions under high pressure.
Part 2: Nitronate chemistry
The reactivity of the cyclic nitronates obtained by [4 +2] cycloaddition on nitroarenes was examined.
Part 3: Study of a stereoselective version of these transformations was envisaged by involvement of chiral organocatalysts.

Part 1: Study of the reactivity of nitroarenes - dearomatisation of nitroarenes
Several interesting results were obtained:
- The tandem [4 +2]/[3+2] cycloaddition reactions proposed have been achieved with nitrobenzenic derivatives, under hyperbaric activation;
- Dearomatizing [3+2] Cycloaddition reactions were developed on nitrobenzene derivatives, dinitropyridine or tetraesterified benzene in the presence non stabilized azomethine ylides ;
- A new type of reactivity of enamines with nitroarene derivatives such as dinitrobenzene, was observed and examplified, leading to the formation of amino polycycles.
Part 2: Nitronate chemistry
Whatever the operating conditions, isolation of the nitronate proved difficult because of its instability under the conditions of its formation. In contrast, enamines were shown to react with nitroindole to lead to the formation of an ene adduct. Functionalization of the latter, after protection, was investigated.
Part 3: Study of a stereoselective version
Organocatalysts such as thioureas, sulfonamides and chiral squaramides were synthesized and evaluated in different cycloaddition reactions. The best results have led to an encouraging 30 % enantiomeric excess. Some catalysts have also been shown to be efficient in other enantioselective cyclization reaction studied by Michael Paolis.

The results obtained show that the reactions that allow dearomatization of nitrobenzene derivatives all involve polar cycloadditions reactions.
It would thus be interesting to chech the reactivity of such species in dearomatizing nucleophilic additions, which often lead, in the bibliography, to complex mixtures and inefficient processes. Based on the results obtained in this study, we can now envisage to perform these reactions in a very efficient manner.
The compounds obtained in this project bear original features and their biological activities will soon be evaluated.

A first article, published in Chem. Eur. J., early 2013, describes the reactivity of various nitroarenes in [3 +2] cycloadditions involving azomethine ylide as dipole.
A second article, published in J. Org. Chem., 2013 mid-year, focuses on the mechanisms involved in tandem [4+2]/[3+2] cycloadditions.
Several articles, including the report of the reactivity of nitroarenes in the presence of enamines or the description of organocatalyzed transformations are in preparation.

This project aims at re-evaluating the synthetic potential of nitroarenes compounds. Most of these compounds are easily accessible and produced on large scales by a classical aromatic electrophilic nitration reaction. However, up to now, their synthetic use is, up to now, essentially devoted to their reduction into aromatic amines. Our goals are thus to develop the chemistry of nitroarenes and enlarge the panel of applicable transformations to increase their synthetic potential in view of accessing aminated compounds of high added value. We propose to develop new reactions involving the dearomatization of nitrobenzenes, via [4+2] cycloaddition reactions. In this inverse electron demand process, we expect the nitroarene to behave as an electron-poor heterodiene (C=C-N=O) by involving one of its aromatic C=C bonds in a cycloaddition with electron-rich dienophiles. Our experience in the field of dearomatizing cycloadditions will be helpful to tackle this substantial challenge. This [4+2] dearomatizing cycloaddition would lead to a cyclic nitronate that could be subsequently functionalized. The chemistry of cyclic nitronates is a challenging field but offers a large panel of possible C-C bond formation. If the basic principles of their reactivity as nucleophiles are known on 'classical' negatively charged nitronate anions, generated by deprotonation of nitroalkanes, (Henry, Michael reactions) the chemistry of neutral nitronates remains unknown. Activation of the nucleophilic properties of the nitronate may thus be required to get reactive species. In this context, the "umpolung" type reactivity of the structurally related nitrones, which has been described when using samarium diiodide, will probably reveal pivotal. An enantioselective version of this process, catalyzed by chiral acids, or chiral organocatalysts will be envisaged in the course of this study. This approach would be particularly appealing since to date no example of an enantioselective [4+2] heterocycloaddition process involving nitro alkenes as dienes has been described. Alternatively, a diastereoselective approach using chiral enol ethers will be envisaged. Reductive cleavage of the N-O bonds of the compounds thereby produced would then lead to aminated compounds bearing a quaternary center adjacent to the nitrogen atom. Such structural motifs are of difficult access by other synthetic methods. In particular, the direct Csp3-H bond activation adjacent to nitrogen followed by C-C bond formation has been reported in the literature, but remains limited so far. Our method thus bears the advantage of involving trivial starting materials to lead, in two or three synthetic steps only, to dearomatized aminated polycycles featuring a quaternary center at ring junction. The structural analogies of the target polyfunctionalized compounds with many alkaloids make these derivatives potential candidates for biological screening. In addition, the rigid diamino moiety of these scaffolds make them attractive for the design and preparation of novel catalysts in the context of asymmetric synthesis.

Project coordinator

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


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