Halogen ‘dance’ reaction in the ferrocene series to access rare although promising polysubstituted scaffolds – Ferrodance

The breakthrough discovery of ferrocene in 1951 has paved the way of metallocenes chemistry, a family of compounds in which two aromatics rings surround a metallic cation, here an iron ion. Prototypical compound of this family, ferrocene exhibits a high stability in various conditions and can even be stored at air without any notable decomposition. Cheapest of the metallocenes, ferrocene is therefore the most employed for various applications in sensing, catalysis, material and medicinal chemistry. A key parameter of this success lies in the planar chirality of ferrocene when two different substituents are on the same ring. However, these developments are limited to derivatives which are monosubstituted (one substituent on one cycle), 1,1’-disubstituted (one substituent on each cycle) and 1,2-disubstituted (two adjacent substituents on the same cycle). In sharp contrast, ferrocene featuring on original substitution pattern (1,3-disubstituted or 1,2,4-trisubstituted) or bearing 4 or 5 substituents on the same ring have been scarcely studied. However, they have specific properties resulting from the large angle between two substituents or from the fine tuning of steric and electronic properties for specific applications.

The lack of general synthesis of such derivative, combined with purification troubles upon the successive introduction of substituents, explain why they do not benefit from more applications. Furthermore, the limited number of described examples combined with the absence of ferrocene-dedicated database does not allow properties predictions.

The goal of the Ferrodance project is to fill that void with the development of a synthetic approach towards these compounds. Therefore, we will functionalize ferrocenic C-H bonds using strong bases for introducing a halogen atom on a remote position, especially in an enantioselective way. Post-functionalization reactions will afford polysubstituted ferrocene derivatives bearing up to five different substituents on the same ring. The electrochemical study of the various compounds made will allow the development of an easy amenable purification process able to solve the longstanding problem of ferrocene derivatives purification. Finally, we will benefit from the structural diversity accessible through Ferrodance to initiate the development of a ferrocene-dedicated database. In the future, its exploration will allow the establishment of structure-property relationships and will help the rational choice of a ferrocene compound for specific applications.