Enantioselective Desymmetrization of Trifluoromethylated Tertiary Benzhydrols via Hydrogen-Acceptor-Free Ir-Catalyzed Dehydrogenative C-H Silylation: Decisive Role of the Trifluoromethyl Group.

Although the trifluoromethyl (CF3) group is one of the most important fluorinated groups owing to its significant ability to modulate pharmacological properties, constructing trifluoromethylated stereogenic centers in an enantioselective manner has been a formidable challenge. Herein, we report the development of the enantioselective desymmetrization of trifluoromethylated benzhydrols via intramolecular dehydrogenative silylation using Ir catalysts with chiral pyridine-oxazoline (PyOX) ligands. The produced benzoxasilol was transformed into several unsymmetrical benzhydrols via iododesilylation and subsequent transition-metal-catalyzed cross-coupling reactions. Moreover, the same Ir catalyst system was used for the kinetic resolution of unsymmetrical trifluoromethylated benzhydrols.

Trifluoromethylated Oxidopyridinium Betaines: Unique (5+2) Cycloaddition Selectivity Imposed by 2- or 6-Trifluoromethyl Groups.

Despite the significant advances in trifluoromethylation methods, the synthesis of complex trifluoromethylated molecules, bearing a natural-product-like three-dimensional framework, remains as a formidable challenge. Therefore, the cycloaddition of unprecedented CF3 -substituted oxidopyridinium betaines was investigated. After the methylation of trifluoromethylated pyridin-3-ols with methyl triflate, pyridinium ions generated in-situ were treated with triethylamine in the presence of N-methylmaleimide to produce trifluoromethylated 8-azabicyclo[3.2.1]octane derivatives via (5+2) cycloaddition of the corresponding oxidopyridinium betaines. Exo/endo-selectivity varied depending on the positions of the CF3 substituents; endo-products were preferred in the reactions of oxidopyridinium betaines with the CF3 group at the 2- or 6-positions, whereas the 5-CF3 -substituted betaine exclusively produced an exo-product. Moreover, unique regio- and stereoselectivities have been observed in the reactions of 2- or 6-CF3 -substituted oxidopyridinium betaines with vinyl sulfones and trans-1,2-disubstituted alkenes. To gain insight into the reactivity of trifluoromethylated oxidopyridinium betaines, computational investigations were also conducted.

Combined Computational and Experimental Study on [5 + 2] Cycloaddition of 2-Trifluoromethylated Oxidopyrylium Species Leading to 1-(Trifluoromethyl)-8-oxabicyclo[3.2.1]oct-3-en-2-ones.

Trifluoromethylation of furfural using the Ruppert-Prakash reagent (TMSCF3) and subsequent photo-Achmatowicz reaction afforded 6-hydroxy-2-(trifluoromethyl)-2H-pyran-3(6H)-one. After acetylation, the resultant 6-acetoxy-2-(trifluoromethyl)-2H-pyran-3(6H)-one was transformed into various 1-(trifluoromethyl)-8-oxabicyclo[3.2.1]oct-3-en-2-one derivatives through a base-mediated oxidopyrylium [5 + 2] cycloaddition. The reactivity and selectivity of the 2-trifluoromethylated oxidopyrylium species toward [5 + 2] cycloaddition were analyzed using density functional theory calculations.