C-F activation involving lanthanides: new concepts and applications – ACTIV-CF-LAN

Reactions involving metallic lanthanides are conducted under inert atmosphere using glovebox and Schlenk techniques. Lanthanides are freshly filed before use.
The organic products and organometallic intermediates are characterised by multi-nuclear NMR spectroscopy, esp. 1H, 13C and 19F NMR, as well as by ESI-MS and X-ray diffraction studies. In addition, DFT calculations are performed in collaboration in order to better understand reaction mechanisms. When the organometallic intermediates cannot be isolated trapping experiments are undertaken.

The first part of this project concerns the selective C-F activation in CF3 groups attached to fulvene or diene systems using lanthanide metals. We have achieved significant progress concerning the scope, the mechanism and the applications of this new C-F activation in the case of trifluoromethylated benzofulvenes. These substrates can be transformed regioselectively and in many cases stereoselectively in either 1,1 or 1,3 disubstituted difluorovinylindenes with a large range of aldehydes and ketones. It was found that the selectivity mainly depends on the lanthanide metal, the Lewis acid, the steric and electronic properties of the electrophile, the temperature and the substituents on the benzofulvene.
In order to gain better insights into the reaction mechanism of this new transformation, 19F NMR spectroscopy studies and electro-spray mass spectrometric studies were performed on various reaction intermediates. The structure of two final difluorovinylindene products could also be obtained by single crystal X-ray diffraction studies.
Finally, the new 1,1-disubstituted products were transformed to unprecedented fluorinated spiro-indanes.
The second part of the project aims at the selective C-F activation in polyfluorinated arenes using lanthanide metals. In a preliminary report, only ytterbium metal had been successfully employed to activate selectively the para-C-F bond in pentafluorobenzene. We have now shown that europium is also capable to undergo this reaction. Initial attempts to trap reaction intermediates using esters are promising but still need to be optimized.

Future work for the first part will consist in
a) extending the new C-F activation methodology to other CF3-containing fulvenes and dienes and widening the scope of electrophiles beyond aldehydes and ketones
b) obtaining a library of new spirocyclic compounds for biological testing.
c) the synthesis of ferrocene-type molecules for biological testing, based on the new difluorovinylindenes

Futur work for the second part will consist in
a) further investigating the metal and substrate scope
b) extending the trapping experiments to CO2 and other electrophiles
c) developing new applications in organic chemistry

A first article on the C-F activation in CF3-dienes in Chem. Eur. J. (2017, p. 16460) was selected as « Hot paper » by the editors. A second article describing the use of lanthanide metals appeared as videopublication in JoVe (2018, e57948). An invited review on selective single C-F activation in CF3 groups was published in Chem. Eur. J. (2018, p. 14572). Further publications are in preparation.

Fluorine-containing organic molecules play a major role in medicinal chemistry, asymmetric synthesis, crop sciences and material sciences. The selective removal of one fluorine atom from a polyfluorinated functional group by C–F activation is a powerful tool for the synthesis of new fluorinated molecules. This proposal is based on the recent discovery of two unprecedented C–F activation processes involving lanthanide metals: (i) the transformation of trifluoromethylated benzofulvenes into difluorovinylindenes and (ii) the selective formation of 1,2,4,5-tetrafluorobenzene from the reaction of ytterbium with pentafluorobenzene. The aim is the understanding of the aforementioned reactions and the screening of their potential for future applications in organic and organometallic chemistry, with a special interest in the synthesis of biologically active compounds. The outcomes should have an important impact on the understanding and use of lanthanide metals in C–F activation processes.