Arene Difunctionalisations: Complementary Dearomatization Strategies – ArDCo

The methodologies employed to carry out this project are based on the difunctionalization of the C2=C3 bond of indole compounds in three ways:
1) by reacting electron-rich species (R-) onto electrophilic indoles, properly functionalized, with electron-withdrawing groups ;
2) by reacting of radical species (R.) on the indole compound;
3) by oxidizing the indole and trapping the intermediate.

As a notable result, we have developed several innovative methodologies for the de-aromatization of indole compounds, according to the three routes mentioned above (electrophilic, radical, nucleophilic), under eco-compatible conditions. Thus, formal cycloadditions allowed to obtain original tricyclic indolines. A spiro-functionalization was also developed, showing the diversity of compounds accessible by the studied methods. Post-functionalization reactions have also shown the synthetic potential of the molecular platforms thereby obtained.

This project has resulted in 14 publications in internationally recognized journals such as «Angewandte« or «Chemistry, a European Journal«. The consortium has been invited to publish an article on its work in the «Actualité Chimique«. Finally, oral or poster communications, within the framework of congresses or seminars also made it possible to expose the various results obtained.

This project has resulted in 14 publications in internationally recognized journals such as «Angewandte« or «Chemistry, a European Journal«. The consortium has been invited to publish an article on its work in the «Actualité Chimique«. Finally, oral or poster communications, within the framework of congresses or seminars also made it possible to expose the various results obtained.

This project aims at developing innovative dearomatization strategies through the asymmetric difunctionalisation of substituted aromatic double bonds. Arenes are large tonnages easily accessible compounds but their synthetic utility remains underused. We propose new dearomatization methodologies via difunctionalisation reactions which allow an efficient and rapid access to chiral functionalized (poly)cyclic architectures of high added value with two contiguous tri- and tetra-substituted centers. Thanks to the features they present, these units will be derivatized to yield a large number of compounds of original tridimensionnal structures.

Three complementary dearomatization strategies are considered in this project, involving either the aromatic compound as a 2p-partner in cycloaddition/annulation reactions or "umpolung" of an aromatic double bond in ionic or radical reactions.

The selective addition of activated dipolar nucleophiles on substituted electron-depleted aromatics furnishes a carbanion that we plan to trap intramolecularly to generate efficiently dearomatized formal cycloadducts. Enantioselectivity will be achieved thanks to bifunctional organocatalysis. Depending on the nature of the dipole involved, the polycyclic compounds thereby obtained will bear different derivatizable functions.

Selective addition of radicals on electron-rich aromatics such as indoles will furnish dearomatized polycyclic derivatives of high added value bearing derivatizable functions of a complementary nature. In this case, additions of chiral carbon centered radicals (through enamine and NHC catalyses) or of nitrogenated amidyl radicals will initiate these new radical dearomative cascades.

Umpolung of electron-rich indoles and other azoles through unusual C2-additions of different electrophiles will complete these strategies, allowing the formation of C3-centered carbocations and their trapping, intra- or intermolecularly. Umpolung activation of the aromatic C2=C3 bond toward different types of electrophiles will be triggered by amidine/proton donor and/or N-Ac/FeCl3 systems.

These innovative dearomatization sequences will enlarge the panel of applicable transformations to increase the synthetic potential of aromatic compounds in view of accessing high added value 3D-compounds bearing diversified structures. Our different and complementary expertise in the field of dearomatizing reactions will be helpful to tackle these substantial challenges.