form. As a matter of fact, the catalytic asymmetric 1,3-
DCR of nitrile imine encounters some difficulties. The
selectivity challenge is to control the regio-, diastereo-, and
enantioselectivity. Usually, the active nitrile imine is gen-
erated in situ by dehydrohalogenation of the correspond-
ing hydrazonyl halidein the presence of anequivalent base,
which causes strong background reaction, as well as the
coordination with Lewis acid catalysts. Moreover, such a
dipole bearing a linear bond and two terminal substituents
makes the asymmetric induction using chiral catalyst
difficult.
Table 1. Optimization of the Reaction Conditionsa
With regard to the dipolarophile variety, 3-alkenyl-
oxindoles reagents have been employed in the construction
of different types of spirooxindoles.7 These densely func-
tionalized core structures represent an attractive synthetic
target due to the biological activity and physical property.
For example, the asymmetric synthesis of spiro-pyrrolidine-
oxindole derivatives was realized via 1,3-dipolar addi-
tions of azomethine ylides by Gong’s, Waldmann’s and
Wang’s groups, respectively.8 We envisioned that the
oxindole skeleton, decorated with a 2-pyrazoline in a spiro
ring form, would be useful for studying structureꢀactivity
relationships of these two privileged units.9 The asym-
metric 1,3-DCR of nitrile imine with 3-alkenyl-oxindole
provides a straightforward route to obtain optically active
spiro-pyrazoline-oxindole. Considering that chiral N,N0-
dioxide-metal complex catalysts developed in our
group could perform excellent and flexible stereoenvi-
ronment,10 we then focused on their application toward
this object.
entry
ligand
metal
t (°C)
yield (%)b
ee (%)c
1
ꢀ
ꢀ
35
35
96
94
0
0
2
L1
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
Ca(OTf)2
3
Sc(OTf)3
35
94
0
4
Mg(OTf)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
35
92
55
65
54
53
89
88
92
89
ꢀ
5
35
86
6
35
75
7
35
88
8
35
86
9
35
88
10
11
12
13
14
35
86
ꢀ20
ꢀ78
60
67
trace
93
96
92
80
72
a Unless specified, all reactions were performed with Lꢀmetal (10 mol %,
1:1.2), 1a (0.10 mmol), 2a (0.12 mmol), i-Pr2NEt (0.12 mmol) at 35 °C for
4 h. b Isolated yield. c Determined by HPLC analysis (Chiralcel IC).
(7) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (b) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 3003. (c) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K.
Org. Biomol. Chem. 2012, 10, 5165. (d) Singh, G. S.; Desta, Z. Y. Chem.
Rev. 2012, 112, 6104. (e) Dalpozzo, R.; Bartoli, G.; Bencivenni, G.
Chem. Soc. Rev. 2012, 41, 7247. For recent examples see: (f) Trost, B. M.;
Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396. (g)
Tan, B.; Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133,
4672. (h) Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 57,
971.
Initially, we selected (E)-1-Boc-3-tert-butylideneindoli-
none 1a as a dipolarophile on account of that the Boc-
group on the nitrogen atom of 1a would reduce its energy
of the lowest unoccupied molecular orbital (LUMO) and
enhance the polarizability.1cꢀe The noncoordinating diiso-
propylethylamine was used to generate the nitrile imine by
dehydrohalogenation of hydrazonyl chloride 2a. Without
a Lewis acid catalyst, the desired racemic spiro-pyrazoline-
oxindole 3a was obtained within 4 h in 96% yield at 35 °C
(Table 1, entry 1). The reaction was regioselective, with the
carbon end of the dipole adding to the β-position of
3-alkenyl-oxindole 1a. Next, we set out to find a compat-
ible chiral Lewis acid catalyst by screening across an array
of chiral ligands and metal ions. Mg(ClO4)2 was proven to
be the best metal salt for the reaction, affording 65% ee,
albeit the yield was slightly reduced (Table 1, entry 5).
Gratifyingly, the introduction of 2,6-diethyl and 4-methyl
groups into the ligand L6 provided the single diastereomer
with 86% yield and 92% ee (Table 1, entry 10).
(8) For asymmetric synthesis of spiro-pyrrolidine-oxindole deriva-
tives with azomethine ylides, see: (a) Chen, X. H.; Wei, Q.; Luo, S. W.;
Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (b)
€
Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann,
M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2,
735. (c) Liu, T.-L.; Xue, Z.-Y.; Tao, H.-Y.; Wang, C.-J. Org. Biomol.
Chem. 2011, 9, 1980.
(9) Mogilaiah, K.; Rao, R. B. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1998, 37B, 139.
(10) For recent examples of N,N0-dioxide-metal complexes, see: (a)
Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, 44, 574. (b)
Huang, S.-X.; Ding, K. L. Angew. Chem., Int. Ed. 2011, 50, 7734. (c)
Feng, X. M.; Liu, X. H. In Scandium: Compounds, Productions and
Applications, Chiral Scandium Complexes in Catalytic Asymmetric Re-
actions; Greene, V. A., Ed.; Nova Science: New York, 2011; p 1. (d) Li, W.;
Liu, X. H.; Hao, X. Y.; Hu, X. L.; Chu, Y. Y.; Cao, W. D.; Qin, S.; Hu,
C. W.; Lin, L. L.; Feng, X. M. J. Am. Chem. Soc. 2011, 133, 15268. (e)
Shen, K.; Liu, X. H.; Wang, G.; Lin, L. L.; Feng, X. M. Angew. Chem.,
Int. Ed. 2011, 50, 4684. (f) Wang, Z.; Yang, Z. G.; Chen, D. H.; Liu,
X. H.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2011, 50, 4928. (g)
Zheng, K.; Yin, C. K.; Liu, X. H.; Lin, L. L.; Feng, X. M. Angew. Chem.,
Int. Ed. 2011, 50, 2573. (h) Zheng, K.; Lin, L. L.; Feng, X. M. Acta Chim.
Sinica 2012, 70, 1785. (i) Li, W.; Liu, X. H.; Hao, X. Y.; Cai, Y. F.; Lin,
L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2012, 51, 8644. (j) Wang, Z.;
Chen, Z. L.; Bai, S.; Li, W.; Liu, X. H.; Lin, L. L.; Feng, X. M. Angew.
Chem., Int. Ed. 2012, 51, 2776. (k) Zhou, L.; Liu, X. H.; Ji, J.; Zhang,
Y. H.; Hu, X. L.; Lin, L. L.; Feng, X. M. J. Am. Chem. Soc. 2012, 134,
17023.
Further attempts to improve the yield and enantioselec-
tivity focused on the reaction temperature. Interestingly, in
this case the enantioselectivity declined as the temperature
decreased, and the reactivity was almost diminished
at ꢀ78 °C (Table 1, entries 11ꢀ12). However, when the
reaction temperature was elevated to 60 °C, both the yield
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