Highly efficient and stereocontrolled construction of 3,3′- pyrrolidonyl spirooxindoles via organocatalytic domino Michael/cyclization reaction

Article abstract of DOI:10.1021/ol400183k

A wide range of structurally diverse 3,3′-thiopyrrolidonyl spirooxindoles bearing three contiguous stereogenic centers can be smoothly obtained via a domino Michael/cyclization reaction between 3-isothiocyanato oxindoles and 3-methyl-4-nitro-5-alkenyl-isoxazoles with commercially available quinine as the catalyst under mild conditions. The protocol is significantly characterized by high reactivity, a low catalyst loading (1 mol %), and an excellent diastereo- and enantioselectivity (up to >99:1 dr and 98% ee).

Full text of DOI:10.1021/ol400183k

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1246–1249
Highly Efficient and Stereocontrolled
Construction of 3,30-Pyrrolidonyl
Spirooxindoles via Organocatalytic
Domino Michael/Cyclization Reaction
Xiong-Li Liu,†,‡ Wen-Yong Han,†,‡ Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China, and University of
Chinese Academy of Sciences, Beijing, 100049, China
yuanwc@cioc.ac.cn
Received January 21, 2013
ABSTRACT
A wide range of structurally diverse 3,30-thiopyrrolidonyl spirooxindoles bearing three contiguous stereogenic centers can be smoothly obtained
via a domino Michael/cyclization reaction between 3-isothiocyanato oxindoles and 3-methyl-4-nitro-5-alkenyl-isoxazoles with commercially
available quinine as the catalyst under mild conditions. The protocol is significantly characterized by high reactivity, a low catalyst loading
(1 mol %), and an excellent diastereo- and enantioselectivity (up to >99:1 dr and 98% ee).
Highly efficient, diastereoselective, and enantioselective
reactions generating complex chiral heterocyclic com-
pounds in one step are unusually valuable and remain a
challenging goalin organicsynthesis. Spirocyclic oxindoles
in particular have emerged as attractive synthetic targets
because of their prevalence in numerous natural products
and significant biological activity.1 Intense efforts have
been made on the development of various elegant methods
to access the structurally diverse family of spirocyclic
oxindoles.2 Undoubtedly, any of the known strategies
should result in a different class of spirocycle oxindoles
that may show promise as biologically active compounds.
In this context, searching for creative procedures that
could achieve high reactivity and stereoselectivity for the
construction of structurally diverse spirocycle oxindoles
is still challenging and interesting, because it might be
practically applied not only to natural products synthesis
but also to library synthesis in medicinal chemistry.1,2a,3
A family of potentially promising spirocyclic oxindole
frameworks common to many bioactive molecules are the
3,30-pyrrolidonyl spirooxindoles (Figure 1),3,4 which are
an intriguing fusion of two privileged motifs, the pyrroli-
done and 2-indolinone substructures. The frameworks
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ University of Chinese Academy of Sciences.
(1) For leading reviews on the spirooxindole core as a “privileged
structure” in synthetic and medicinal chemistry, see: (a) Zhou, F.; Liu,
Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. (b) Rios, R. Chem.
Soc. Rev. 2012, 41, 1060. (c) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012,
112, 6104. (d) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol.
Chem. 2012, 10, 5165.
(2) For recent examples on asymmetric synthesis of spirocyclic
oxindoles, see: (a) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella,
€
M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H.
Nat. Chem. 2010, 2, 735. (b) Liu, T.-L.; Xue, Z.-Y.; Tao, H.-Y.; Wang,
C.-J. Org. Biomol. Chem. 2011, 9, 1980. (c) Tan, B.; Candeias, N. R.;
Barbas, C. F., III. Nat. Chem. 2011, 3, 473. (d) Tan, B.; Candeias, N. R.;
Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 4672. (e) Zhong, F.; Han,
X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (f) Cao, Y.;
Jing, X.; Liu, L.; Shen, F.; Zhang, F.; Wang, R. Angew. Chem., Int. Ed.
(3) For selected examples, see: (a) Tomita, D.; Yamatsugu, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946. (b) Bergonzini, G.;
Melchiorre, P. Angew, Chem., Int. Ed. 2012, 51, 971. (c) Guo, C.; Song, J.;
Huang, J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed.
2012, 51, 1046.
ꢀ
2011, 50, 9124. (g) Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III.
(4) For selected examples, see: (a) Bella, M.; Kobbelgaard, S.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 3670. (b) Trost, B. M.; Brennan, M. K.
Org. Lett. 2006, 8, 2027. (c) Kobbelgaard, S.; Bella, M.; Jørgensen, K. A.
J. Org. Chem. 2006, 71, 4980. (d)Sen, S.;Potti, V. R.;Surakanti, R.;Murthy,
Y. L. N.; Pallepoguc, R. Org. Biomol. Chem. 2011, 9, 358.
J. Am. Chem. Soc. 2011, 133, 12354. (h) Liu, Y.; Nappi, M.; Arceo, E.;
Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (i) Tan,
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r
10.1021/ol400183k
Published on Web 03/01/2013
2013 American Chemical Society

from the reactions between 3-isothiocyanato oxindoles and
3-methyl-4-nitro-5-alkenyl-isoxazoles9 with excellent diaste-
reo- and enantioselectivity in very high yields in the presence
of very low loadings of an organocatalyst. Herein, we wish to
report our preliminary results on this subject.
Figure 1. Diversely structured 3,30-pyrrolidonyl spirooxindoles.
Scheme 1. Strategy for the Reaciton of 3-Isothiocyanato
Oxindoles and Appropriate Electron-Deficient Olefins via a
Domino Michael Addition/Cyclization Sequence
are characterized by a spiro ring fusion at the C3-position
of the oxindole core with more substitution variants
(Figure 1). Although many exquisite approaches to var-
ious spirocyclic oxindoles have been developed, to the best
of our knowledge, the examples that can efficiently pro-
duce structurally diverse 3,30-pyrrolidonyl spirooxindoles
in a catalytic asymmetric manner are still limited.2f,i,4 Thus,
the development of novel asymmetric methods for the
synthesis of various stereoenriched 3,30-pyrrolidonyl spir-
ooxindole derivatives is of paramount importance.
Recently, we have synthesized a series of 3-isothiocyanato
oxindoles and employed them as attractive reactants to per-
form some domino reactions for the construction of various
spirocyclic oxindoles.5,6 The successes of the domino tactics
lead us to speculate the possibility of a catalytic asymmetric
domino process regarding a Michael addition/cyclization
reaction between 3-isothiocyanato oxindoles and somewhat
appropriate electron-deficient olefins (Scheme 1).7 If this idea
is viable, we can imagine that a library of chiral 3,30-thiopyr-
rolidonyl spirooxindoles will be formed via a domino Michael
addition/cyclization sequence under the elegant stereocontrol
of chiral catalysts. Surely, the 3,30-thiopyrrolidonyl spiroox-
indoles are liable to be transformed into corresponding 3,30-
pyrrolidonyl spirooxindoles by oxidizing (Scheme 1). There-
fore, as part of our ongoing effort to develop new strategies
for the construction of diversely structured oxindoles bearing
a tetrasubstituted stereogenic center at C3,5,8 we have found
that a wide range of 3,30-thiopyrrolidonyl spirooxindoles
bearing three contiguous stereogenic centers can be obtained
Our initial studies started with the reaction of N-methyl-
3-isothiocyanato oxindole 1a and (E)-3-methyl-4-nitro-5-
styrylisoxazole (2a)10 in dichloromethane for the optimi-
zation of the catalyst. We were pleased to find that the
commercially available quinine was the most powerful
catalyst.11 Subsequently, to further find the optimal con-
ditions for the reaction, a screening was performed using
different solvents, temperatures, substrate concentrations,
and additives (Table 1). Firstly, we decided to screen a
number of solvents to examine the effect on the yield
and selectivity of this process. The reaction proceeded
at ꢀ40 °C and was complete after only 30 min in each
solvent (Table 1, entries 1ꢀ6), but mesitylene appeared
optimal in terms of yield and diastereo- and enantioselec-
tivity (Table 1, entry 6). Perfoming the reaction in mesity-
lene at different temperatures (Table 1, entries 6ꢀ10)
revealed that the process gave full conversion into 3a in
97% yield with 96:4 dr and 92% ee only after 10 min at
30 °C (Table 1, entry 9). Afterward, among the substrate
concentrations probed (Table 1, entries 9, 11ꢀ13), it was
observed that a lower concentration was beneficial to the
enantioselectivity and without sacrificing the yield and
diastereoselectivity with a slight extension of reaction time
(20 min, Table 1, entry 13). Additionally, it was noted that
adding different types of molecular sieve (MS) into the
reaction system was favorable to obtain a slightly higher ee
(Table 1, entries 14ꢀ16). As a result, these studies provided
the optimal reaction conditions: addition of 1a (0.1 mmol)
and 2a (0.13 mmol) in 8.0 mL of mesitylene in the presence
(5) (a) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Org. Lett. 2011, 13, 2472. (b) Han, Y.-Y.; Chen, W.-B.; Han, W.-Y.;
Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2012, 14, 490.
(6) For selected examples, see: (a) Li, L.; Ganesh, M.; Seidel, D. J. Am.
Chem. Soc. 2009, 131, 11648. (b) Yoshino, T.; Morimoto, H.; Lu, G.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17082. (c) Jiang,
X.; Zhang, G.; Fu, D.; Cao, Y.; Shen, F.; Wang, R. Org. Lett. 2010, 12, 1544.
(d) Vecchione, M. K.; Li, L.; Seidel, D. Chem. Commun. 2010, 46, 4604. (e)
Chen, X.; Zhu, Y.; Qiao, Z.; Xie, M.; Lin, L.; Liu, X.; Feng, X. Chem.;Eur.
J. 2010, 16, 10124. (f) Chen, X.-H.; Dong, S.-X.; Qiao, Z.; Zhu, Y.; Xie, M.-
S.;Lin, L.-L.;Liu, X.-H.;Feng, X.-M.Chem.;Eur. J. 2011, 17, 2583. (g) Lu,
G.; Yoshino, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2011, 50, 4382. (h) Liu, L.; Zhong, Y.; Zhang, P.; Jiang,
X.; Wang, R. J. Org. Chem. 2012, 77, 10228.
˚
of 10 mol % quinine and 50 mg of 5 A MS at 30 °C for
20 min (Table 1, entry 16).
(9) For leading references on the Michael addition reactions of 3-methyl-
4-nitro-5-alkenylisoxazoles with various nucleophiles, see: (a) Baschieri, A.;
Bernardi, L.; Ricci, A.; Suresh, S.; Adamo, M. F. A. Angew. Chem., Int. Ed.
2009, 48, 9342. (b) Fini, F.; Nagabelli, M.; Adamo, M. F. A. Adv. Synth.
Catal. 2010, 352, 3163. (c) Sun, H.-W.; Liao, Y.-H.; Wu, Z.-J.; Wang, H.-Y.;
Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2011, 67, 3991. (d) Pei, Q.-L.;
Sun, H.-W.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. J. Org.
Chem. 2011, 76, 7849.
(10) (a) Adamo, M. F. A.; Duffy, E. F.; Konda, V. R.; Murphy, F.
Heterocycles 2007, 71, 1173. (b) Adamo, M. F. A.; Donati, D.; Duffy, E. F.;
Sarti-Fantoni, P. Tetrahedron 2007, 63, 2047.
(11) For details about the optimization of the catalyst, see the
Supporting Information.
(7) For recent examples concerning the Michael cyclization with
3-isothiocyanato oxindoles, see: (a) Cao, Y.-M.; Shen, F.-F.; Zhang,
F.-T.; Wang, R. Chem.;Eur. J. 2013, 19, 1184. (b) Wu, H.; Zhang,
L.-L.; Tian, Z.-Q.; Huang, Y.-D.; Wang, Y.-M. Chem.;Eur. J. 2013,
19, 1747. (c) Chen, Q.; Liang, J.; Wang, S.; Wang, D.; Wang, R. Chem.
Commun. 2013, 49, 1657.
(8) (a) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2010, 12, 3132. (b) Han, Y.-Y.; Wu, Z.-J.; Chen,
W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 5064. (c)
Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C.
Chem.;Eur. J. 2012, 18, 6679. (d) Liao, Y.-H.; Wu, Z.-J.; Han, W.-Y.;
Zhang, X.-M.; Yuan, W.-C. Chem.;Eur. J. 2012, 18, 8916. (e) Zuo, J.;
Liao, Y.-H.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2012, 77, 11325.
Org. Lett., Vol. 15, No. 6, 2013
1247

Table 1. Optimization of Various Reaction Conditionsa
Table 2. Scope of the Reaction between 1 and 2 with 10 mol %
Quininea
temp
time
yield
(%)b
ee
(%)d
entry
solvent
(°C)
(min)
drc
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
THF
CH3CN
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
0
18
30
60
30
30
30
30
30
30
30
30
10
10
10
10
10
20
20
20
20
94
91
89
90
95
96
94
94
97
97
96
94
95
92
94
96
73:27
89:11
77:23
64:36
94:6
94:6
97:3
96:4
96:4
94:6
95:5
97:3
96:4
94:6
94:6
>99:1
59
64
42
7
82
84
86
89
yield
(%)b
ee
entry
1
2
3
drc
(%)d
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
1c
1e
1f
2a
2a
2g
2a
2b
2c
2d
2e
2f
2g
2j
2k
2l
2b
2a
2b
2g
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
92
93
95
93
94
97
92
92
95
97
96
95
92
93
94
95
94
92
91
>99:1
96:4
99:1
95:5
94:6
97:3
94:6
95:5
97:3
96:4
>99:1
92:8
97:3
98:2
99:1
99:1
>99:1
97:3
95:5
93:7
96
96
95
95
93e
96
95
94
94
94
96
96
93
95
96
98
95
97
96
92
toluene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
9
92
90
10
11
12
13
14
15
16
89e
93f
94g
95g,h
95g,i
96g,j
30
30
30
30
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
30
3m
3n
3o
3p
3q
3r
3s
3t
a Unless noted, the reactions were carried out with 1a (0.1 mmol),
2a (0.13 mmol), and quinine (0.01 mmol) in 2.0 mL of solvent. b Yield
of isolated product as a mixture of diastereoisomers. c Determined by
chiral HPLC analysis. d Ee of major diastereomer as determined by
chiral HPLC analysis. e Run in 1.0 mL of mesitylene. f Run in 6.0 mL of
1f
1d
1d
1d
mesitylene. g Run in 8.0 mL of mesitylene. h 50 mg of 3 A MS were used.
˚
i
j
50 mg of 4 A MS were used. 50 mg of 5 A MS were used.
˚
˚
a The reactions were carried out with 1 (0.1 mmol), 2 (0.13 mmol),
˚
quinine (0.01 mmol), and 5 A MS (50 mg) in 8.0 mL of mesitylene at
30 °C for 20 min. b Yield of isolated product as a mixture of diastereoi-
somers. c Determined by chiral HPLC analysis. d Ee of major diastereo-
mer as determined by chiral HPLC analysis. e The absolute configuration
of 3e was assigned (C7R,C8S,C9S).12 The absolute configurations of remain-
ing products shown in this work were tentatively proposed by analogy.
A subsequent experiment began to define the substrate
scope of this reaction. As shown in Table 2, the domino
Michael addition/cyclization sequence with the optimal
reaction conditions can be extended to a wide variety of
3-isothiocyanato oxindoles 1aꢀf and 3-methyl-4-nitro-5-
alkenyl-isoxazoles 2aꢀl to give diversely structured 3,30-
thiopyrrolidonyl spirooxindoles 3aꢀt in 91ꢀ97% yield
3-methyl-4-nitro-5-alkenyl-isoxazole combinations and ob-
tained satisfactory results similar to those from the above-
mentioned studies (Table 2, entries 14, 18ꢀ20).
ꢀ
with 92:8 >99:1 dr and 92ꢀ98% ee. Importantly, in all
cases, the reaction showed very high reactivity and reached
completion only within 20 min. Various N-protecting groups
of the 3-isothiocyanato oxindoles having different steric
parameters were well tolerated (Table 2, entries 1ꢀ4). A
variety of aromatic 3-methyl-4-nitro-5-alkenyl-isoxazoles un-
derwent reaction with N-methyl-3-isothiocyanato oxindole
1a in high to excellent yields and diastereo- and enantioselec-
tivity regardless of their electronic properties (Table 2, entries
5ꢀ10). Notably, the 2- and 1-naphthyl-based 3-methyl-4-
nitro-5-alkenyl-isoxazoles (2j and 2k) also gave rise to the
corresponding products (3k and 3l) in very high yields and ee
values (Table 2, entries 11ꢀ12). Additionally, the thiophene
derived reactant 2l also reacted smoothly with 1a and
delivered product 3m in 95% yield with 97:3 dr and 93% ee
(Table 2, entry 13). Nevertheless, the substitution, whether
electron-withdrawing or -donating, on the 3-isothiocyanato
oxindole aromatic ring did not affect the reactivity and
selectivity of the reaction (Table 2, entries 15ꢀ17). Finally,
we also surveyed some other 3-isothiocyanato oxindole/
Encouraged by the gratifying results summarized in
Table 2, we attempted to examine our protocol with a
lower catalyst loading considering the remarkably high
reactivity of the reactions illustrated in Table 2. Decreasing
the quinine loading from 10 to 5 mol % had hardly any
effect on the properties of the reaction (Table 3, entry 1).
Surprisingly, when we further lowered the catalyst loading
to 1 mol % for the same reaction, similar results to those
with 5 mol % catalyst also could be obtained smoothly just
with an extended reaction time to 2 h (Table 3, entry 2).
Subsequently, in the presence of 1 mol % catalyst, we per-
formed a series of reactions with different 3-isothiocyanato
oxindole/3-methyl-4-nitro-5-alkenyl-isoxazole combinations
in 4.0 mL of mesitylene at 30 °C (Table 3, entries 3ꢀ13).
Gratifyingly, the desired 3,30-thiopyrrolidonyl spirooxindole
products were also able to be well obtained in very high yields
(90ꢀ96%) with excellent diastereoselectivities ranging from
92:8 to 99:1 and very high enantioselectivities ranging from
1248
Org. Lett., Vol. 15, No. 6, 2013

The synthetic utility of the current reaction was illustrated
by the versatile conversion of the 3,30-thiopyrrolidonyl
spirooxindole 3a into other 3,30-spirocyclic oxindoles
(Scheme 3).13 The treatment of 3a with 30% aqueous
hydrogen peroxide and formic acid in CH2Cl2 readily
accomplished an oxidation reaction to give 3,30-pyrrolido-
nyl spirooxindole 4 by transforming the thiolactam moiety
intolactam. Then, 4 was treated witha NaOH solution of a
solvent mixture of THF and water at reflux for 15 h,
resulting in the elimination of the isoxazole moiety, in turn
generating the 3,30-pyrrolidonyl spirooxindole 5 in 91%
yield without loss of diastereo- and enantioselectivity.
Nevertheless, the structural diversity of the products also
could be further demonstrated by the sequential transfor-
mations of 3aintoother spirooxindoles 6 and 7.13 Notably,
when 6 was subjected to the same reaction conditions
as those for the transformation of 3a into 4, 5 could be
smoothly obtained.
Table 3. Scope of the Reaction between 1 and 2 with 1 mol %
Quininea
time
(h)
yield
(%)b
ee
(%)d
entry
1
2
3
drc
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1d
1a
1a
1a
1a
1c
1f
2a
2a
2a
2a
2g
2a
2b
2g
2k
2l
0.5
2
4
4
2
4
4
4
4
4
2
4
4
3a
3a
3a
3b
3c
3d
3e
3j
94
95
92
93
90
90
96
95
94
96
92
95
95
97:3
95:5
96:4
96:4
98:2
93:7
96:4
95:5
92:8
99:1
98:2
95:5
99:1
95e
94f
96
95
92
91
95
94
96
93
90
97
93
9
3l
10
11
12
13
3m
3n
3p
3q
2b
2b
2g
Scheme 3. Transformation of Cycloadduct 3a into other
3,30-Spirocyclic Oxindoles
1f
a Unless noted, the reactions were carried out with 1 (0.1 mmol), 2
˚
(0.13 mmol), quinine (0.001 mmol), and 5 A MS (30 mg) in 4.0 mL of
mesitylene at 30 °C. b Yield of isolated product as a mixture of diaster-
eoisomers. c Determined by chiral HPLC analysis. d Ee of major diaster-
eomer as determined by chiral HPLC analysis. e The reactions were
carried out with 1 (0.1 mmol), 2 (0.13 mmol), quinine (0.005 mmol), and
5 A MS (50 mg) in 8.0 mL of mesitylene at 30 °C. f The reactions was
˚
carried out with 1 (0.1 mmol), 2 (0.13 mmol), quinine (0.001 mmol), and
˚
5 A MS (50 mg) in 8.0 mL of mesitylene at 30 °C.
Scheme 2. Reaction of 1a and 2a on Gram Scale
In conclusion, we have developed a highly efficient, stereo-
controlled method for the construction of enantioenriched
3,30-pyrrolidonyl spirooxindole derivatives with commercially
available quinine as the catalyst under mild reaction condi-
tions. The reactions are accomplished via a domino Michael
addition/cyclization reaction between 3-isothiocyanato oxi-
ndoles and 3-methyl-4-nitro-5-alkenyl-isoxazoles to deliver a
wide range of structurally diverse 3,30-thiopyrrolidonyl spiro-
oxindoles bearing three contiguous stereogenic centers. Most
importantly, the process is significantly characterized by high
reactivity, a low catalyst loading (1 mol %), and an excellent
diastereo- and enantioselectivity (up to 97% yield, >99:1 dr
and 98% ee). The utilities of the protocol have been demon-
strated by the gram scale reaction and the versatile conversion
of the cycloadduct into other 3,30-spirocyclic oxindoles.
90% to 97% (Table 3, entries 3ꢀ13). It is noteworthy that
various functional groups were also well-tolerated when the
reaction time is slightly prolonged to 2ꢀ4 h.
To examine the utility of the catalytic system, gram scale
quantities of 1a and 2a were carried out with 1 mol %
quinine as the catalyst in 100 mL of mesitylene at 30 °C.
The reaction proceeded to completion within 4 h and the
corresponding product 3a also could be obtained in 94%
yield, 96:4 dr, and 94% ee (Scheme 2). Surely, when compar-
ing the gram scale reaction with the milligram scale reaction,
in the presence of the same loading of catalyst, the product
was able to be obtained almost without any loss of yield or
diastereo- or enantioselectivity (Scheme 2 vs Table 3, entry 3).
Acknowledgment. We are grateful for financial support
from the 973 Program (2010CB833300).
Supporting Information Available. Experimental de-
tails, characterization data for new compounds, and
X-ray crystal structure of 3e. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) CCDC-869022 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) See the Supporting Information for more details.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1249