Among various derivatives of pyrazolidine and pyrazoline, one of the important classes are trifluoromethylated substituted compounds. Due to the existence of the trifluoromethyl group, the biological and physicochemical properties of such kind of derivatives are greatly changed. The binding affinity, bioavailability and metabolic stability of the pyrazolidine and pyrazoline can be enhanced significantly. For instance, the CF3­substituted pyrazolines have already been proved to exhibit excellent bioactivity.29–32 However, the investigations concerning about the synthesis of CF3­substituted pyrazolidines and pyrazolines are rather limited. 33–39
Recently, Hu et al. systematically investigated the synthesis of CF3­substituted pyrazolidines.33 They have conducted the [3+2] reactions of trifluoromethylated N­acylhydrazones and isoprene using different Lewis acid as catalyst. Based on their results, they found that using Cu(OTf)2 as catalyst can generate trifluoromethylated pyrazolidines in both good yields and diastereoselectivity and the reaction mechanism can be described by Figure 1. The initial reactant 1 can isomerize to 2 and 3 two isomers, after which the isomer 3 can form the intermediate 4 via combining the Cu(OTf)2 molecule through hydrogen bonding and coordination. Once generating the complex 4, the isoprene can react with 4 to generate another intermediate 6 that combine the final pyrazolidine products and the Cu(OTf)2 catalyst via a concerted transition state 5. With the departure of the catalyst, they finally obtain the expected CF3­substituted pyrazolidine product 7. In their experiments, the diastereoselectivity of the products can be as high as 72:28 (syn:anti).
Figure 1. The mechanism of Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene proposed by previous experimental study. 33
However, whether the mechanism proposed by experiments is correct remains to be verified. Also, there are still some other questions that need to be settled. For example, what is the origin of the diastereoselectivity of Cu(OTf)2 catalyzed [3+2] cycloaddition? How about the detail of the cycloaddition processes? Whether the [3+2] reactions follow a concerted as the experimentalist expected or follow a step­wise reaction mechanism? To answer these important questions, we always need the help of the high level computational calculations, which have be proved to be very useful in elucidating the underlying mechanism of the cycloaddition reactions.21,40–46 To our best knowledge, no computational works have been conducted before to study the mechanism of the Cu(OTf)2 catalyzed [3+2] cycloaddition of trifluoromethylated N­acylhydrazones and isoprene. Therefore, in this work, we have employed high­level DFT calculations to help clarify the underlying mechanism of the Cu(OTf)2 catalyzed [3+2] cycloaddition.

Computational Details