Based on above results, the mechanism of Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene can be summarized as Figure 12. The initial reactant A can isomerize to B firstly. After that, the B isomer forms complex C with Cu(OTf)2. With the addition of isoprene, the initial configuration CR1 for the [3+2] cycloaddition is formed. From CR1, the intermediate structure M1 that combined the final product and Cu(OTf)2 catalyst can be formed via a concerted asynchronous mechanism after overcoming a small barrier of 3.2 kcal/mol: the C­C bond forms first and then C­N bond is formed immediately. This process is driven by the electrostatic interactions. After the departure of the Cu(OTf)2 catalyst, we can finally get the [3+2] product CF3­substituted syn­pyrazolidine P1. It is worth to notify that another enantiomer of P1, P5, can also be formed in the similar way via the enantiomer of C, CR1, TS1 and M1 with the same syn conformation. During the reaction process, the Cu(OTf)2 is revealed to play an important role for the diastereoselectivity and accelerating of the reaction process.
Figure 12. The concerted asynchronous mechanism of Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene based on our present computational results.

Conclusions

In this work, we have systematically investigated the underlying mechanism of Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene to synthesis CF3­substituted pyrazolidine using high level density functional theory method. About eight possible initial configurations of the [3+2] reaction is considered and all relevant reactants, transition states and products are optimized. The related IRC paths are also explored in detail. Based on the transition state structures, IRC paths and the wavefunction analysis, we concluded that the Cu(OTf)2 catalyzed [3+2] cycloaddition follow a concerted asynchronous mechanism. The C­N bond forms immediately after the formation of the C­C bond. The lowest energy barrier for the [3+2] reaction that lead to the CF3­substituted syn­pyrazolidine are about 3.2 kcal/mol, which might be the reason of the diastereoselectivity that observed in experiment. To figure out the exact role of the Cu(OTf)2 played in the [3+2] reaction, we have also investigated the reaction processes that without Cu(OTf)2 molecule. The computational results indicate that the energy barriers that form the diastereoisomers are much closer and also larger than the Cu(OTf)2 catalyzed one, i.e. 2.4 kcal/mol vs 3.7 kcal/mol and 8.0 kcal/mol vs 3.2 kcal/mol. Therefore, Cu(OTf)2 catalyst play an important role for the diastereoselectivity of the [3+2] cycloaddition reaction. Our present work not only provides the detail mechanism of the Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene, but also can be helpful for the future designation of Cu(OTf)2 based cycloaddition processes.

Supporting Information Available

Additional figures, tables and all optimized Cartesian coordinates can be found in Supporting Information.

Acknowledgement

This paper was supported by the High Performance Computing Center of Sichuan Normal University, China.
Keywords: Density Functional Theory [3+2] Cycloaddition Concerted Asynchronous Mechanism CF3­substituted Pyrazolidine

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