A density functional theory study of the stereoselectivity of Cu(OTf)2-catalyzed [3+2] cycloaddition of trifluoromethylated N-acylhydrazones and isoprene: A concerted asynchronous mechanism

Here we employ density functional theory calculations to systematically investigate the underlying mechanism of Cu(OTf)(2)-catalyzed [3+2] cycloaddition reactions in the synthesis of CF3-substituted pyrazolidines. About eight possible initial configurations of the [3+2] reaction is considered, and all relevant reactants, transition states, and products are optimized. Based on these structures, internal reaction coordinate paths, and wavefunction analysis results, we conclude that the Cu(OTf)(2)-catalyzed [3+2] cycloaddition follows a concerted asynchronous mechanism. The C-N bond forms immediately after the formation of the C-C bond. Among the eight reaction paths, the energy barrier for the [3+2] reaction that leads to the CF3-substituted syn-pyrazolidine is the lowest, similar to 5.4 kcal/mol, which might result in the diastereoselectivity that is observed in the experiment. This work not only gives the detailed mechanism of the Cu(OTf)(2)-catalyzed [3+2] cycloaddition but can also be helpful for the future designation of Cu(OTf)(2)-based cycloaddition processes.