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

Abstract

AbstractDespite 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.