Skip to main content
European Commission logo print header

Synthesis and properties of trifluoromethylated Carbo- and Heterocycles

Final Activity Report Summary - TRIFLU (Synthesis and Properties of trifluoromethylated Carbo- and Heterocycles)

Commercial interests in fluorine chemistry emerged in the eighties mainly due to the need to replace industrial chlorofluorocarbons but also because of the increasing use of organofluorine compounds in agrochemical, medicinal and in material science. Rational design exploiting the remarkable properties of F or CF3 containing group or substructures has been successful in the development of new and effective biochemical tools as well as medicinal and therapeutic agents. The trifluorométhyle group (CF3) is therefore an important structural moiety in diverse classes of bioactive organic molecules as its introduction often changes their physical, chemical and physiological properties. Nevertheless, progress is still hampered by the lack of general methodologies to access fluorinated compounds.

We initiated a research programme based on the concept of electrophilic fluorodesilylation for the preparation of organofluorine compounds. The current project was built on our emerging interest in the use of organosilanes as starting materials for the preparation of various novel trifluoromethylated targets. The proposed chemistry is unprecedented and involves both the powerful catalytic Diels-Alder reaction of structurally diverse non fluorinated dienophiles followed by a trifluoromethylation process and an asymmetric Diels-Alder of trifluoromethylated building block.

Firstly, the trifluoromethylation process was tuned with model substrates in order to determinate the optimal conditions of the reaction varying several well-known reagents of trifluoromethylation. This study allowed us to conclude that the silyl enol ether or the allylsilanes under investigation were not amenable to electrophilic trifluoromethyldesilylation using those reagents.

In the light of this preliminary work, we focused our efforts on the preparation of CF3 carbocycles via a Diels-Alder reaction using a trifluoromethylated dienophile. As preliminary study, we explored the racemic series in order to examine the reactivity of the silylated diene with the representative dienophile, namely ethyl trifluorocrotonate. TiCl4 was finally selected as the catalyst of choice for subsequent work.

The asymmetric Diels-Alder reaction was investigated using the chiral dienophile and the various prepared silylated dienes. A significant result from this study is the observation that the introduction of a methyl group on position 4 of the diene gave exclusive exo-selectivity with excellent facial control.

Starting from these corresponding silylated cycloadducts, the protodesilylation was performed in the presence of trifluoroacetic acid and was accomplished in good yield. Although, the cycloaddition and the protodesilylation sequence offer a new preparation of enantiopure trifluoromethylated carbocycles featuring an exo methylene group. The electrophilic fluorination of silylated cycloadducts in the presence of Selectfluor was performed and provides potentially useful, stereoselectively functionalized carbocycles featuring both trifluoromethyl and fluorine substituents.

Novel methods for the preparation of fluorinated molecules based on fluorinated building blocks or C-F bond forming reactions are therefore in great demand. After a large screening of catalysts to carry out the cyclisation of starting a-hydroxy-ynones, we were pleased to find that the reaction did proceed in synthetically useful yield in the presence of 5 mol% of AuCl.

We investigated next the possibility of coupling the 6-endo-dig cyclization with an halogenation of the presumably formed vinyl gold intermediate. The Au(I)-catalyzed alkoxyhalogenation was attempted using N-halogenosuccinimide (NXS) and delivered the corresponding halogenated pyranones. The scarce information available on transition metal catalyzed methods for C-F bond construction prompted us to investigate thoroughly the feasibility of a cascade alkoxylation-fluorination. In conclusion, we have developed a new method for the preparation of 5-iodo, 5-bromo- and 5-fluoro-3,3'-difluorodihydro-pyranones from ?-hydroxy-a,a-difluoro-ynones.

In the light of this first example of oxidative fluorination involving organogold intermediate, we explored the synthetic potential of this oxidative fluorination by use of a gold catalyst in combination with electrophilic fluorinating reagents. Interestingly, upon treatment with Selectfluor, a repeat of the gold catalysed cyclisation of functionalised allenoate esters afforded the dihydroindenofuranone derivatives. This work has revealed that this chemistry is potentially extremely broad in scope having shown that the gold catalysed cyclisation of benzyl substituted allenoate esters can deliver unusual dihydroindenofuranones.