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