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.

Oxidopyridinium Cycloadditions Revisited: A Combined Computational and Experimental Study on the Reactivity of 1-(2-Pyrimidyl)-3-oxidopyridinium Betaine.

To investigate the effect of N-substituents on their reactivity and selectivity of oxidopyridinium betaines, we performed density functional theory (DFT) calculations of model cycloadditions with N-methylmaleimide and acenaphthylene. The theoretically expected results were compared with the experimental results. Subsequently, we demonstrated that 1-(2-pyrimidyl)-3-oxidopyridinium can be used for (5 + 2) cycloadditions with various electron-deficient alkenes, dimethyl acetylenedicarboxylate, acenaphthylene, and styrene. In addition, a DFT analysis of the cycloaddition of 1-(2-pyrimidyl)-3-oxidopyridinium with 6,6-dimethylpentafulvene suggested the possibility of pathway bifurcations involving a (5 + 4)/(5 + 6) ambimodal transition state, although only (5 + 6) cycloadducts were experimentally observed. A related (5 + 4) cycloaddition was observed in the reaction of 1-(2-pyrimidyl)-3-oxidopyridinium with 2,3-dimethylbut-1,3-diene.