Highly efficient and stereoselective construction of dispiro-[oxazolidine- 2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles

Article abstract of DOI:10.1021/ol203081x

An efficient and stereoselective reaction between 3-isothiocyanato oxindoles and isatins/isatinimines has been developed to afford structurally diverse dispiro[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2- thione]bisoxindoles in excellent results under mild conditions. The potential of asymmetric induction by means of a chiral auxiliary was explored. The isomers are separable, and products could be isolated as single diastereomers by column chromatography. Further synthetic transformations of the reaction product were also successfully realized.

Full text of DOI:10.1021/ol203081x

ORGANIC
LETTERS
2012
Vol. 14, No. 2
490–493
Highly Efficient and Stereoselective
Construction of Dispiro-[oxazolidine-
2-thione]bisoxindoles and Dispiro
[imidazolidine-2-thione]bisoxindoles
Yan-Yan Han,†,§ Wen-Bing Chen,†,§ Wen-Yong Han,†,§ Zhi-Jun Wu,‡ 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, Chengdu Institute of
Biology, Chinese Academy of Sciences, Chengdu 610041, China, and Graduate School of
Chinese Academy of Sciences, Beijing, 100049, China
yuanwc@cioc.ac.cn
Received November 17, 2011
ABSTRACT
An efficient and stereoselective reaction between 3-isothiocyanato oxindoles and isatins/isatinimines has been developed to afford structurally
diverse dispiro[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles in excellent results under mild conditions. The
potential of asymmetric induction by means of a chiral auxiliary was explored. The isomers are separable, and products could be isolated as single
diastereomers by column chromatography. Further synthetic transformations of the reaction product were also successfully realized.
The development of efficient methods to construct spiro
compounds has been a topic of great relevance in organic
synthesis due to the pronounced biological activities of this
class of compounds.1 In particular, the spirocyclic oxi-
ndoles have emerged as attractive synthetic targets because
of their prevalence in numerous natural and unnatural
products.2 A variety of synthetic strategies have been
developed to access analogous compounds possessing the
spirocyclic oxindole skeleton.2,3 Notably, these diverse
spirocyclic oxindoles are characterized by a spiro ring
fusion at the C3 position of the oxindole core with varied
heterocycle motifs (Figure 1). In addition, a report has it
that sharing of the oxindole C3 atom in the construction of
(3) For selected examples, see: (a) Jia, Z.; Jiang, H.; Li, J.; Gschwend,
B.; Li, Q.; Yin, X.; Grouleff, J.; Chen, Y.; Jørgensen, K. A. J. Am. Chem.
Soc. 2011, 133, 5053. (b) Tan, B.; Candeias, R. N.; Barbas, C. F., III.
J. Am. Chem. Soc. 2011, 133, 4672. (c) Tan, B.; Candeias, R. N.; Barbas,
C. F., III. Nat. Chem. 2011, 3, 473. (d) Zhong, F.; Han, X.; Wang, Y.; Lu,
Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (e) Peng, J.; Huang, X.; Jiang,
L.; Cui, H.; Chen, Y. Org. Lett. 2011, 13, 4584. (f) Shen, L.; Shao, P.; Ye,
S. Adv. Synth. Catal. 2011, 353, 1943. (g) Duce, S.; Pesciaioli, F.;
Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.; Bartoli, G.;
Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860. (h) Lu, C.; Xiao, Q.;
Floreancig, P. E. Org. Lett. 2010, 12, 5112. (i) Jiang, K.; Jia, Z.-J.; Chen,
S.; Wu, L.; Chen, Y.-C. Chem.;Eur. J. 2010, 16, 2852. (j) Jiang, K.; Jia,
Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 2766. (k) Wei, Q.;
Gong, L.-Z. Org. Lett. 2010, 12, 1008. (l) Westermann, B.; Ayaz, M.; van
Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49, 846. (m) Chen, X.-H.; Wei,
Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131,
13819. (n) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.;
Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2009, 48, 7200.
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
§ Graduate School of Chinese Academy of Sciences.
‡ Chengdu Institute of Biology, Chinese Academy of Sciences.
(1) For selected examples, see: (a) Nicholas, G. M.; Eckman, L. L.;
Newton, G. L. Bioorg. Med. Chem. 2003, 11, 601. (b) Suenaga, K.;
Araki, K.; Sengoku, T. Org. Lett. 2001, 3, 527. (c) Winfred, G. B.;
Rutger, M.; Fieseler, F. J. Org. Chem. 2000, 65, 8317. (d) Patrizia,
C.; Carmela, D.; Ernesto, F. J. Nat. Prod. 1999, 62, 590. (e) Metwally,
K. A.; Dukat, M. J. Med. Chem. 1998, 41, 5084. (f) Barbara, C. M.;
Potts, D.; John, F. J. Am. Chem. Soc. 1991, 113, 6321.
(2) For selected reviews, see: (a) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 3003. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209.
r
10.1021/ol203081x
Published on Web 01/11/2012
2012 American Chemical Society

Scheme 1. Our Strategy for the Construction of Two New
Classes of Spirocyclic Oxindoles
Figure 1. Fusing the oxindole core with different heterocycle
motifs for the construction of spirocyclic oxindoles.
of new methodologies for the construction of diverse 3,
30-disubstituted oxindole derivatives,6,8 we were further in-
trigued by the reactions of 3-isothiocyanato oxindoles with
isatins and isatinimines (Scheme 1). As illustrated in
Scheme 1, the reactions will afford dispiro[oxazolidine-2-
thione]bisoxindoles and dispiro[imidazolidine-2-thione]-
bisoxindoles, which are two new classes of spirocyclic
oxindoles. It is noteworthy that the significant structural
features of these spirocyclic oxindole products include
pentacyclic ring skeleton, bis-spirocyclic oxindole frame-
work, and complex molecular architecture. Undoubtedly,
these spirocyclic oxindole compounds may provide pro-
mising candidates for chemical biology and drug discov-
ery, due to the fact that some spirocyclic bisindoles have
recently emerged as promising scaffolds for anticancer
activity.9 Herein, we wish to report our preliminary efforts
on the subject regarding the development of an efficient
method for the construction of two classes of novel
spirocyclic oxindoles.
Initially, the reaction of 3-isothiocyanato oxindole 1a
and istain (2a) in dichloromethane (DCM)10 at rt was
selected as the model reaction (Table 1). The blank reac-
tion of the model reaction afforded the desired product 4aa
in 80% yield in 99:1 dr after 240 min (Table 1, entry 1).
From this reaction, we were aware that the reaction easily
took place and showed high reactivity. Despite this, we
further examined several bases to further improve the
reaction. We were pleased to find that the reaction rapidly
went tocompletion with20 mol % Et3N to give4aa in 91%
yield with 99:1 dr only in 2 min (Table 1, entry 3). Based on
the reactivity and diastereoselectivity, the catalysis of Et3N
was significantly better than that of DABCO, Na2CO3,
DIPEA, and DIPA (Table 1, entry 2 vs 4ꢀ6). Subse-
quently, with Et3N as the catalyst, the different catalyst
loadings were surveyed (Table 1, entries 7ꢀ9). Finally, it
was observed that the reaction was able to proceed to
completion in 2 min even with 1 mol % Et3N and afford
product 4aa in 90% yield with 92:8 dr (Table 1, entry 9).
Under the optimized conditions the reactions of 3-
isothiocyanato oxindoles and isatins were investigated. As
spirocyclic oxindole compounds can enhance biological
activity.4 Thus, the fusion of oxindole motifs with different
heterocycles for the formation of structurally diverse
spirocyclic oxindoles has attracted significant attention
from organic chemists.2,5 More importantly, these fused-
heterocycle compounds seem to be promising candidates
for biological responses since they incorporate both oxi-
ndoles and other heterocyclic moieties simultaneously.
However, a careful survey of the relevant literature re-
veals that only we and Wang et al. independently re-
ported different methods for fusing an oxazolidine-2-
thione motif (Figure 1) into the oxindole C3 position to
deliver spiro[oxazolidine-2-thione-oxindoles].6,7 Neverthe-
less, the realization of employing an imidazolidine-2-
thione (Figure 1) moiety for generating the corresponding
spiro[imidazolidine-2-thione-oxindoles] remains elusive.
We recently synthesized a series of 3-isothiocyanato
oxindoles and successfully used them as nucleophiles for
asymmetric synthesis of a range of enantioenriched spiro-
cyclic oxindoles bearing two highly congested contiguous
tetrasubstituted carbon stereocenters.6 Based on this
achievement and our recent successes in the development
(4) (a) Zhu, S.-L.; Ji, S.-J.; Yong, Z. Tetrahedron 2007, 63, 9365.
(b) Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; El-Bady, S. M.
Bioorg. Med. Chem. 2004, 12, 2483. (c) Da-Silva, J. F. M.; Garden, S. J.;
Pinto, A. C. J. Braz. Chem. Soc 2001, 12, 273. (d) Joshi, K. C.; Chand, P.
Pharmazie 1982, 37, 1.
(5) For selected examples, see: (a) Cao, Y.; Jiang, X.; Liu, L.; Shen,
F.; Zhang, F.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124.
(b) Wang, J.; Crane, E. A.; Scheidt, K. A. Org. Lett. 2011, 13, 3086.
(c) Hande, S. M.; Nakajima, M.; Kamisaki, H.; Tsukano, C.; Takemoto,
Y. Org. Lett. 2011, 13, 1828. (d) Badillo, J. J.; Arevalo, G. E.; Fettinger,
J. C.; Franz, A. K. Org. Lett. 2011, 13, 418. (e) Chen, T.; Xu, X.-P.; Ji, S.
J. Comb. Chem. 2010, 12, 659. (f) Chen, H.; Shi, D. J. Comb. Chem. 2010,
12, 571. (g) Li, Y.; Chen, H.; Shi, C.; Shi, D.; Ji, S. J. Comb. Chem. 2010,
12, 231. (h) Shintani, R.; Hayashi, S.-y.; Murakami, M.; Takeda, M.;
Hayashi, T. Org. Lett. 2009, 11, 3754. (i) Zhang, Y.; Panek, J. S. Org.
Lett. 2009, 11, 3366.
(6) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Org. Lett. 2011, 13, 2472.
(7) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am.
Chem. Soc. 2010, 132, 15328.
(8) For selected reports from our research group, see: (a) Han, Y.-Y.;
Wu, Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org.
Lett. 2011, 13, 5064. (b) Liu, X.-L.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron Lett. 2011, 52, 903. (c) Liu, X.-L.; Wu, Z.-J.; Du, X.-L.;
Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2011, 76, 4008. (d) Liu,
X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
J. Org. Chem. 2010, 75, 4872. (e) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun,
L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896. (f) Chen,
W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org.
Lett. 2010, 12, 3132. (g) Chen, W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron 2010, 66, 1441. (h) Chen, W.-B.; Liao, Y.-H.; Du,
X.-L.; Zhang, X.-M.; Yuan, W.-C. Green Chem. 2009, 11, 1465.
(9) For selected examples, see: (a) Ji, X.; Liu, X.; Li, K.; Chen, R.;
Wang, L. Biomed. Environ. Sci. 1991, 4, 332. (b) Liu, X. M.; Wang, L. G.;
Li, H. Y.; Ji, X. J. Biochem. Pharmacol. 1996, 51, 545. (c) Wee, X. K.;
Yeo, W. K.; Zhang, B.; Tan, V. B. C.; Lim, K. M.; Tay, T. E.; Go, M.-L.
Bioorg. Med. Chem. 2009, 17, 7562.
(10) Allowing for the solubility of the substrates and the convenience
of operation, dichloromethane was screened out from THF, DMSO,
DMF, H2O, and toluene as the perfect solvent in this work.
Org. Lett., Vol. 14, No. 2, 2012
491

Table 1. Optimization of the Reaction of 3-Isothiocyanato
Oxindole 1a and 2aa
Table 2. Substrate Scope Studies for the Reaction of 3-Isothio-
cyanato Oxindoles and Isatinsa
entry
cat.
x
time
drb
yield (%)c
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
240 min
90 min
2 min
99:1
91:9
99:1
99:1
92:8
75:25
94:6
92:8
92:8
80
93
91
92
93
94
90
92
90
DABCO
Et3N
20
20
20
20
20
10
5
entry
1
2
4
time
drb
yield (%)c
Na2CO3
DIPEA
DIPA
240 min
2 min
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
2b
2c
2d
2e
2f
4ab
4ac
4ad
4ae
4af
120 min
60 min
10 min
20 min
20 min
35 min
40 min
40 min
40 min
20 min
5 min
50:50
99:1
99:1
92:8
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
84
87
93
92
87
80
91
97
95
92
95
92
91
84d
2 min
2
Et3N
2 min
3
Et3N
2 min
4
Et3N
1
2 min
5
a The reactions were carried out with 1a (0.04 mmol) and 2a (0.04 mmol)
with specified catalyst loading in DCM (1.0 mL) at rt. b Determined by 1H
NMR analysis of the product after purification via flash chromatography.
c Isolated yield. DABCO = 1,4-diazabicyclo-[2.2.2]octane, DIPEA = diiso-
propylethylamine, DIPA = diisopropylamine.
6
2g
2h
2i
4ag
4ah
4ai
7
8
9
2j
4aj
10
11
12
13
14
2k
2a
2a
2a
2a
4ak
4ba
4ca
4da
4aa
summarized in Table 2, it was found that 3-isothiocyanato
oxindoles 1aꢀd reacted smoothly with a variety of isatins
2aꢀk to generate the structurally diverse dispiro-
[oxazolidine-2-thione]bisoxindoles 4abꢀda only in the pre-
sence of 1 mol % Et3N. In all cases, high yields ranging
from 80 to 97% were achieved under the optimized con-
ditions, and the rate of the reactions were very fast. Of
particularinterest was thatexcellent diastereoselectivity, as
high as 99:1, could be obtained for most of the cases except
4ab and 4ae (Table 2, entries 1 and 4). It was observed that
product 4ab could be obtained in 84% yield only with
50:50 dr; this may be attributed to the steric hindrance
of the 4-chloro-substituted isatin 2b (Table 2, entry 1).
N-Methyl-3-isothiocyanato oxindole 1b reacting with isatin
2a needs only 5 min for full conversion and affords 95% of
product 4ba with 99:1 dr (Table 2, entry 11). Additionally,
X-ray crystal structure analysis of the major diastereo-
isomer of product 4af confirmed the exact structure and
the relative stereochemistry as the trans configuration.11
Furthermore, a large scale experiment was performed to
test the potential practicality of this process (Table 2, entry
14). In the presence of 1 mol % Et3N for only 60 min,
product 4aa was isolated in 84% yield with 99:1 dr.
60 min
50 min
60 min
a All reactions were performed with 1 (0.11 mmol) and 2 (0.11 mmol)
in the presence of 1 mol % Et3N in DCM (3.0 mL) at rt. b Determined by
1H NMR analysis of the product after purification via flash chromato-
graphy. c Isolated yield. d Large scale experiment: 1a (2.9 mmol, 0.8 g), 2a
(2.9 mmol, 0.42 g) with 1 mol % Et3N in DCM (80 mL) at rt for 60 min.
(57:43ꢀ99:1) and high yield (84ꢀ97%). Notably, a class
of novel structural dispiro[imidazolidine-2-thione]bisox-
indoles 5aaꢀda could be readily constructed for the first
timewiththisprotocol. Itwas noteworthythatproduct5ag
could be obtained in 97% yield with 99:1 dr only after 2 min
(Table 3, entry 7). Nevertheless, we also found that a variety
of functional groups at different positions of isatinimines
(5-, 6-, and N-1 positions) were tolerated well under the
conditions. The structure and relative stereochemistry
(trans-fused) for the major diastereoisomer were fortunately
determined by using the X-ray crystallography of 5aa.11
Prompted by the above results, we attempted to further
employ isatinimines 6a and 6b, containing an O-TBDMS
(R)-phenylglycinol chiral auxiliary, as substrates for ex-
ploringthepotential ofasymmetricinduction(Table4). To
our delight, we found that the reaction generally exhibited
high efficiency. The starting materials were smoothly con-
sumed after 3 h in the presence of 1 mol % Et3N at rt, and
the desired more complex spirocyclic oxindole products,
containing three stereogenic centers, were abletobe readily
obtainedinhighly combinedyields (Table 4). Interestingly,
in the cases for the generation of 7db, 7ca, and 7da, any one
of the diastereomers formed in the reaction could be easily
obtainedby column chromatography, thusgivingaccess to
the corresponding optically active isomeric products
(Table 4, entries 2ꢀ4). Meanwhile, during the preparation
Having established a general scope with respect to the
reaction between 3-isothiocyanato oxindoles and isatins
(Table 2), we next investigated a similar reaction with various
isatinimines 3aꢀi in place of isatins. As shown in Table 3,
under the optimized reaction conditions from Table 1, the
reactionsbetween 3-isothiocyanato oxindoles and anarray
of N-PMP isatinimines occurred smoothly to provide the
corresponding spirocyclic oxindoles with high reactivity
(2ꢀ44 min), in moderate to excellent diastereoselectivity
(11) See Supporting Information for the CIF files of 4af and 5aa.
492
Org. Lett., Vol. 14, No. 2, 2012

Table 3. Substrate Scope Studies for the Reaction of 3-Isothio-
cyanato Oxindoles and Isatiniminesa
Table 4. Exploration for the Potential of Asymmetric Inductiona
entry
1
6
7
drb
yield (%)c
1
2
3
4
1a
1d
1c
1d
6a
6b
6a
6a
7aa
7db
7ca
7da
23:4:73:0
67:33:0:0
50:50:0:0
75:6:19:0
25dþ67 = 92
60þ30 = 90
46þ46 = 92
67þ6þ17 = 90
entry
1
3
5
time
drb
yield (%)c
a Unless otherwise specified, the reactions were carried out with 1 (0.11
mmol) and 6 (0.11 mmol) in the presence of 1 mol % Et3N in DCM (3.0 mL)
at rt. b Based on isolated yield. c Isolated yield. d Isolated yield for the mixture
of two diastereomers. TBDMS = tert-butyldimethylsilyl.
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1d
2a
2b
2c
2d
2e
2f
5aa
5ab
5ac
5ad
5ae
5af
20 min
26 min
20 min
35 min
30 min
44 min
2 min
86:14
80:20
57:43
91:9
87
84
95
91
95
90
97
90
90
91
87
2
3
4
5
83:17
83:17
99:1
6
7
2g
2h
2i
5ag
5ah
5ai
8
30 min
20 min
12 min
20 min
99:1
Scheme 2. Transformations of the Product 4aa to Other Oxi-
ndole Derivatives
9
94:6
10
11
2a
2a
5ba
5da
99:1
99:1
a All reactions were performed with 1 (0.11 mmol) and 3 (0.11 mmol)
in the presence of 1 mol % Et3N in DCM (3.0 mL) at rt. b Determined by
1H NMR analysis of the product after purification via flash chromato-
graphy. c Isolated yield. PMP = p-methoxyphenyl.
of 7aa, we separated two products: one was an optically
active isomer in 67% yield, and the other was a mixture of two
diastereomers in 25% yield with 23:4 dr (Table 4, entry 1).
Finally, versatile transformations of 4aa into other
structurally diverse oxindole derivatives 8ꢀ10 were suc-
cessfully realized.12 As shown in Scheme 2, product 4aa
could be readily transformed to compound 8 by reacting
with iodomethane in acetone at rt in 96% yield and 99:1 dr.
In addition, protection of the two NH groups was carried
out by treatment of 4aa with tert-butyloxycarbonyl anhy-
dride in the presence of 5 mol % 4-dimethylamiopryidine
(DMAP) in CH2Cl2, and then, the reaction mixture was
directly subjected to an oxidation reaction with a solution
of 30% aqueouos H2O2 and 88% aqueouos formic acid in
CH2Cl2, giving compound 9 with 99:1 dr in 87% yield
in two steps. Significantly, the hydrolysis of 9 with LiOH in
the mixture of dioxane and THF smoothly afforded
product 10 in 90% yield with 99:1 dr.
features of these spirocyclic oxindole products include a
pentacyclic ring skeleton, bis-spirocyclic oxindole frame-
work, and complex molecular architecture. Moreover, by
means of a chiral auxiliary for exploring the potential of
asymmetric induction, it was found that the isomers are
separable and products could be easily isolated as single
diastereomers by column chromatography. Finally, syn-
thetic transformations of the reaction product were also
successfully realized. Biological evaluation and efforts to
make the reaction enantioselective are ongoing.
In conclusion, we have developed a method for highly
efficient and diastereoselective construction of structurally
diverse dispiro[oxazolidine-2-thione]bisoxindoles and
dispiro[imidazolidine-2-thione]bisoxindoles by the reac-
tion of 3-isothiocyanato oxindoles with isatins and isatini-
mines. The reactions occurred readily only in the presence
of 1 mol % Et3N under mild reaction conditions, affording
the desired products in excellent yields (up to 97%) and
diastereoselectivities (up to 99:1). Particularly valuable
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(No. 20802074), the National Basic Research Program of
China (973 Program) (2010CB833300), and Sichuan
Youth Science and Technology Foundation.
Supporting Information Available. Experimental details,
characterization data for new compounds, X-ray crystal
structure, and the CIF files of 4af and 5aa. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Details of the transformation procedures are provided in the
Supporting Information.
Org. Lett., Vol. 14, No. 2, 2012
493