Fluorinated functional groups are often introduced into drugs and agrochemicals, as they allow increasing metabolic stability and improving the physical properties of the compounds. The trifluoromethyl group is especially frequently encountered, and numerous synthetic methods have been developed for its introduction, either as a nucleophile or as an electrophile (e. g. using Togni’s reagents). Furthermore, the strong electron-withdrawing character of the trifluoromethyl group also has a profound influence on the reactivity of organic molecules. This property can be exploited to develop new reactions. Herein, two examples of transformations enabled by trifluoromethyl groups will be presented: A) Ethynylbenziodoxolone (EBX) reagents have been highly successful for the transfer of alkyne groups in metal-catalyzed reactions. Nevertheless, standard reagents derived from iodobenzoic acid could not be used in challenging domino processes for the synthesis of heterocycles. Replacing the carboxy group by a hexafluoroisopropanol unit allowed to slightly diminish the reactivity of the reagent and enabled its use in domino processes involving gold or platinum catalysts for the synthesis of furans, indoles, benzofurans and benzothiophenes. B) The regio- and stereo-selective functionalization of non-activated olefins is a challenging task, which can be addressed by the use of tethers. Nevertheless, tethering approaches are inherently inefficient, as they are based on multi-step procedures. The use of highly electrophilic derivatives of trifluoroacetaldehyde in their stable hemiacetal or hemiaminal form allowed easy in situ tether formation from allyl amines, followed by a palladium-catalyzed functionalization of the double bond with simultaneous C-O/N and C-C bond formation. Mild deprotection under acidic conditions then gave vicinal amino alcohols and diamines with complete regioselectivity, high yield and good stereoselectivity.

Modulating the reactivity of hypervalent iodine reagents and carbonyl tethers with the trifluoromethyl group

253rd National Meeting (2017)

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