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.
Keywords: DFT calculation; cycloaddition; fluorine; heterocycle; oxidopyridinium.
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