Catalytic asymmetric sulfenylation of unprotected 3-substituted oxindoles

Article abstract of DOI:10.1021/ol3009446

Catalytic asymmetric sulfenylation of unprotected 3-substituted oxindoles has been developed via cooperative catalysis of a chiral N,N′-dioxide- Sc(OTf)₃ complex and a Bronsted base. Utilizing readily available N-(phenylthio)phthalimide as the sulfur source, a wide range of optically active 3-phenylthiooxindoles were obtained in excellent yields with excellent enantioselectivities under mild reaction conditions.

Full text of DOI:10.1021/ol3009446

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2726–2729
Catalytic Asymmetric Sulfenylation of
Unprotected 3-Substituted Oxindoles
Yunfei Cai, Jun Li, Weiliang Chen, Mingsheng Xie, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
xmfeng@scu.edu.cn
Received April 11, 2012
ABSTRACT
Catalytic asymmetric sulfenylation of unprotected 3-substituted oxindoles has been developed via cooperative catalysis of a chiral N,N0-
dioxideꢀSc(OTf)3 complex and a Brønsted base. Utilizing readily available N-(phenylthio)phthalimide as the sulfur source, a wide range of
optically active 3-phenylthiooxindoles were obtained in excellent yields with excellent enantioselectivities under mild reaction conditions.
Oxindoles bearing a chiral quaternary stereogenic center
at the 3-position constitute an important structural motif
in the library of natural products and biologically active
drugs.1 In view of the importance of chiral 3-heteroatom
substituted oxindoles in medicinal chemistry,2ꢀ5 enantio-
selective syntheses of 3-heteroatom substituted oxindoles,
such as 3-fluorooxindoles,2 3-chlorooxindoles,3 3-amino-
oxindoles,4 and 3-hydroxyoxindoles,5 have been established
in recent years.
(1) For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res.
2003, 36, 127. (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945. (c) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
(d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (e)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(f) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003. (g) Zhou, F.; Liu,
Y. L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. (h) Shen, K.; Liu,
X. H.; Lin, L. L.; Feng, X. M. Chem. Sci 2012, 3, 327.
(2) For catalytic asymmetric synthesis of 3-fluorooxindoles, see: (a)
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M.
J. Am. Chem. Soc. 2005, 127, 10164. (b) Shibata, N.; Kohno, J.; Takai,
K.; Nakamura, S.; Toru, T.; Kagemasa, S. Angew. Chem., Int. Ed. 2005,
44, 4204. (c) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.;
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47,
4157. (d) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Chem.;Eur. J. 2011,
17, 14922. (e) Wu, L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden, A.;
Cavallo, L.; Dorta, R. Angew. Chem., Int. Ed. 2012, 51, 2870.
(3) For catalytic asymmetric synthesis of 3-chlorooxindoles, see: (a)
Zheng, W. H.; Zhang, Z. H.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem.
Soc. 2011, 133, 3339. (b) Zhao, M.-X.; Zhang, Z.-W.; Chen, M.-X.;
Tang, W.-H.; Shi, M. Eur. J. Org. Chem. 2011, 3001.
(4) For catalytic asymmetric synthesis of 3-aminooxindoles, see: (a)
Bui, T.; Borregan, M.; Barbas, C. F., III J. Org. Chem. 2009, 74, 8935. (b)
Cheng, L.; Liu, L.; Wang, D.; Chen, Y. J. Org. Lett. 2009, 11, 3874. (c)
Qian, Z. Q.; Zhou, F.; Du, T. P.; Wang, B. L.; Zhou, J. Chem. Commun.
2009, 6753. (d) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. (e)
Yang, Z. G.; Wang, Z.; Bai, S.; Shen, K.; Chen, D. H.; Liu, X. H.; Lin,
L. L.; Feng, X. M. Chem.;Eur. J. 2010, 16, 6632. (f) Shen, K.; Liu,
X. H.; Wang, G.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2011,
50, 4684.
However, the enantioselective synthesis of 3-thiooxin-
doles6 is unavailable. Catalytic asymmetric sulfenylation
(5) For catalytic asymmetric synthesis of 3-hydroxyloxindoles, see:
(a) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45,
3353. (b) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488. (c) Sano, D.; Nagata,
K.; Itoh, T. Org. Lett. 2008, 10, 1593. (d) Itoh, J.; Han, S. B.; Krische,
M. J. Angew. Chem., Int. Ed. 2009, 48, 6313. (e) Tomita, D.; Yamatsugu,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946. (f) Itoh,
T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. (g) Bui, T.;
Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2010, 132, 5574. (h)
Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, C.; Wang, Y.-X.;
Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176. (i) Zhang, Z.; Zheng, W.;
Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135.
(6) For synthsis of racemic thiooxindoles, see: (a) Li, Y.; Shi, Y.;
Huang, Z.; Wu, X.; Xu, P.; Wang, J.; Zhang, Y. Org. Lett. 2011, 13,
1210. (b) England, D. B.; Merey, G.; Padwa, A. Heterocycle 2007, 74,
491.
(7) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jøgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Sobhani, S.; Fielenbach, D.;
Marigo, M.; Wabnitz, T. C.; Jøgensen, K. A. Chem.;Eur. J. 2005, 11,
5689. (b) Jereb, M.; Togni, A. Org. Lett. 2005, 7, 4041. (c) Jereb, M.;
Togni, A. Chem.;Eur. J. 2007, 13, 9384. (d) Sirisailam, S. K.; Togni, A.
Tetrahedron: Asymmetry 2006, 17, 2603–2607. (e) Fang, L.; Lin, A.-J.;
Hu, H.-W.; Zhu, C.-J. Chem.;Eur. J. 2009, 15, 7039. (f) Lin, A.; Fang,
L.; Zhu, X.; Zhu, C.; Cheng, Y. Adv. Synth. Catal. 2011, 353, 545.
r
10.1021/ol3009446
Published on Web 05/15/2012
2012 American Chemical Society

of 3-substituted oxindoles is the most straightforward and
promising method to this functionality. Although the
successful organocatalytic asymmetric sulfenylation of
aliphatic aldehydes and β-keto esters has been realized,7
the relatively higher pKa value of R-proton of oxindoles,
especially N-protecting-group-free oxindoles, makes them
sluggish carbon nucleophiles.8 In addition, when employ-
ing a Lewis acid as a catalyst, the introduction of sulfur-
based substituents might cause the problem of the unde-
sired association of sulfur with a central metal. Thus, the
development of asymmetric sulfenylation of oxindoles is
still desirable and also a challenge. Herein, we realized the
asymmetric substitution of oxindoles with N-(phenylthio)
phthalimide. The cooperative catalysis9 of a chiral N,
N0-dioxideꢀSc(OTf)3 complex10 and a Brønsted base fur-
nished the optically active 3-phenylthiooxindoles with
excellent outcomes.
was settled by using 1.05 equiv of 2. The formation of
N-adduct 4a was effectively prevented, and the isolated
yield of 3a increased to 98% with 97% ee (Table 1, entry 13).
It should be noted that the catalytic amount of base was
effective in promoting the reaction with similar results by
prolonging the reaction time (Table 1, entry 14).
Table 1. Optimization of the Reaction Conditionsa
Initially, we probed the optimal reaction conditions
using unprotected 3-(4-methoxybenzyl)-2-oxindole (1a)
as the model substrate11 and stable and commercially
available N-(phenylthio)phthalimide 2 as the sulfenylat-
ing agent. When N,N0-dioxideꢀSc(OTf)3 was used exclu-
sively as the Lewis acid catalyst, no reaction was observed
(Table 1, entry 1). Then, Brønsted bases were investigated
to initiate the reaction. Inspiringly, we found that Na2CO3
could promote the reaction to afford the desired 3-phe-
nylthiooxindole derivative 3a in 46% yield (Table 1,
entry 2). In the presence of Na2CO3, the catalytic and
stereoselective ability of the chiral N,N0-dioxideꢀSc(OTf)3
catalystwas investigatedtorealize thecatalytic asymmetric
version of this reaction (Table 1, entries 3ꢀ6). Excitingly,
(S)-pipecolic acid derived N,N0-dioxide L4 with sterically
hindered diisopropyl substituents on the phenyl ring af-
forded 3a in 87% yield with 94% ee (Table 1, entry 6).
Further survey of other bases (Table 1, entries 7ꢀ10)
showed that K2CO3 could accelerate the generation of
the product 3a in 88% yield with maintained ee within 2 h
(Table 1, entry 8). Thus, the L4ꢀSc(OTf)3/K2CO3 system
was chosen to assess other reaction parameters (see the
yield
(%)b
ee
entry
ligand
base
time (h)
(%)c
1
2d
L1ꢀL4
ꢀ
ꢀ
20
20
20
20
20
20
20
2
0
ꢀ
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Li2CO3
K2CO3
Cs2CO3
Lud
46(20)
45(21)
71(19)
86(12)
87(11)
65(15)
88(12)
89(8)
ꢀ
3
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
0
4
46
76
94
94
94
90
94
98
97
97
98
5
6
7
8
9
1
10
20
6
86(9)
11e
12e,f
13e,f,g
14e,g,h
K2CO3
K2CO3
K2CO3
K2CO3
88(10)
87(11)
98(<2)
92(5)
10
10
36
a Unless otherwise noted, all reactions were performed with LꢀSc-
(OTf)3 (1:1, 10 mol %), base (0.1 mmol), 1a (0.1 mmol, PMB = p-
methoxybenzyl), N-(phenylthio)phthalimide 2 (0.12 mmol) in CH2Cl2
(0.5 mL) under N2 at 35 °C for the indicated time. Lud = 2,6-
dimethylpyridine. b Yield of isolated product 3a. Data in parentheses
were the isolated yield of 4a. c Determined by HPLC analysis on a chiral
stationary phase using a Chiralcel OD-H column. d Without Lewis acid
e
L-Sc(OTf)3. 4 A MS (25.0 mg), K2CO3 (200 mol %) were added in
˚
CH2Cl2 (2.0 mL). f Using 3 mol % of L4-Sc(OTf)3. g 1.05 equiv of 2 was
Supporting Information for details).12 The use of 4 A
˚
used. h Using 10 mol % of K2CO3 instead of 200 mol % of K2CO3.
molecular sieves (M.S.) and low reaction concentration
improved the enantioselectivity to 98% ee (Table 1,
entry 11). Reducing the catalyst loading to 3 mol % had
little influence on the yield and ee value (Table 1, entry 12).
Although complete conversion could be achieved, the
desired product 3a suffered somewhat from the N-sulfe-
nylation process to generate the byproduct 4a. This matter
Withthe optimized reactionconditionsin hand (Table 1,
entry 13), the substrate scope was investigated as shown in
Tables 2 and 3. The reactions performed well with a series
of 3-benzyl substituted oxindoles, giving the correspond-
ing thiofunctionalized products in 91ꢀ98% yield with
92ꢀ97% ee, regardless of the electronic nature or the
position of the substituents on the phenyl ring (Table 2,
entries 1ꢀ13). Variation of the C3-substituent to naphthyl-
methyl or thienylmethyl was also satisfied to deliver
the desired products in 85ꢀ98% yield with 94ꢀ98% ee
(Table2, entries14ꢀ16). Notably, with Na2CO3 (200mol%)
or K2CO3 (15 mol %) employed as a Brønsted base
cocatalyst, oxindoles with aliphatic substituents at the C3
(8) The pKa value of 3-substituted oxindoles can be expected to be
substantially higher, considering the pKa value of oxindole (pKa∼18),
compared with β-keto esters (pKa∼13).
(9) For selected reviews on cooperative catalysis, see: (a) Shibasaki,
M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (b) Yamamoto, H.;
Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (c) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (d) Kumagai, N.;
Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4760.
(10) For reviews, see: (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc.
ꢀ
ꢁ
Chem. Res. 2011, 44, 574. (b) Malkov, A. V.; Kocovsky, P. Eur. J. Org.
Chem. 2007, 29.
(11) 3-Benzyl-2-oxindole was not used as the model substrate, for it
was hard to separate the substrate and the product via TLC or silica gel.
(12) Using other sulfenylating agents like N-(benzylthio)phthalimide,
BnSSBn or PhSSPh, no desired products were observed.
(13) For these substrates, when using 200 mol % K2CO3, the
products were obtained with lower ee (such as, for 1q: 75% ee; for 5a:
87% ee) due to the excess of K2CO3 promoted background reaction.
Org. Lett., Vol. 14, No. 11, 2012
2727

position were tolerated well for this reaction (88ꢀ95%
yield, 86ꢀ98% ee; Table 2, entries 17ꢀ24), among which
sterically hindered substituted ones gave higher ee value.13
Oxindoles with a 3-allyl or 3-CH2CO2Me substituent
underwent the reaction with good results (85ꢀ98% yield,
95ꢀ96% ee; Table 2, entries 25 and 26).
Table 3. Substrate Scope of 3-Aryl Substituted Oxindolesa
Table 2. Substrate Scope of 3-Alkyl Substituted Oxindolesa
entry
1d
R2
R3
prod.
time
(h)
yield
(%)b
ee
(%)c
Ph
H
48
(24)
72
48
48
48
48
48
48
48
48
48
48
48
48
72
6a
95
(93)
92
93
94
97
91
90
91
92
90
97
93
92
93
88
99
(97)
>99
99
99
98
97
98
99
97
99
98
97
95
94
93
2
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-MeOC6H4
1-Naphthyl
2-Naphthyl
Ph
H
H
H
H
H
H
H
H
6b
6c
6d
6e
6f
3
4
5
6
7
6g
6h
6i
8
9
10
11
12
13
14
15
5-Me
5-MeO
5-F
6j
Ph
6k
6l
Ph
Ph
5-Cl
6-Br
7-F
6m
6n
6o
Ph
Ph
a Unless specified, the reactions were performed with 5 (0.1 mmol),
˚
L4ꢀSc(III) complex (1:1, 5 mol %) and 4 A MS (25.0 mg), Na2CO3 (0.12
mmol), N-(phenylthio)phthalimide 2 (0.105 mmol) in CH2Cl2 (2.0 mL)
at 35 °C for the indicated time. b Isolated yield of the product 6.
c Determined by HPLC analysis (see Supporting Information). d Data
in parentheses were the results using 15 mol % of K2CO3 instead of 120
mol % of Na2CO3.
entries 1ꢀ7 and 10ꢀ15). 3-Naphthyl substituted ones also
delivered the desired products in 91ꢀ92% yield with
97ꢀ99% ee.
Additionally, the absolute configuration of the product
3p was unambiguously determined to be R by X-ray
crystallography.14 A comparison with the Cotton effect
in the CD spectra of 3p showed that the absolute config-
uration of other 3-phenylthiooxindoles 3 was R (see Sup-
porting Information for details).
To show the synthetic utility of the catalyst system,
sulfenylation of oxindole 1a was expanded to a gram scale,
and the desired 3-phenylthiooxindole 3a was accomplished
in 94% yield with 97% ee. After a single recrystallization of
the product, an 82% yield with 99% ee was obtained
(Scheme 1a). In addition, deprotection of byproduct 4a to
3a with NaBH4 also had little infulence on ee (Scheme 1b).
Control experiments were carried out to elucidate the
reaction process (see Supporting Information). When the
amount of sulfenylating reagent 2 changed from 2.0 to 1.05
equiv, the yield of the C3-product 3a increased from 12%
to 98% with the decreased yield of N-adduct 4a. Mean-
while, upon treatment with K2CO3, 3a could react with
a Unless specified, the reactions were performed with 1 (0.1 mmol),
˚
L4ꢀSc(III) complex (1:1, 3 mol %) and 4 A MS (25.0 mg), K2CO3 (0.2
mmol), N-(phenylthio)phthalimide 2 (0.105 mmol) in CH2Cl2 (2.0 mL) at
35 °C for the indicated time. b Isolated yield of the product 3. c Determined
by HPLC analysis (see Supporting Information). d Using 5.0 mol % of
L4ꢀSc(III) complex and 200 mol % of Na2CO3. e Data in parentheses were
the results using 5.0 mol % of L4ꢀSc(III) complex and 15 mol % of K2CO3.
3-Aryl oxindoles were also suitable substrates in this
catalyst system in the presence of Na2CO3 (120 mol %) or
K2CO3 (15 mol %).13 As shown in Table 3, the electronic
natureorthe position ofsubstituentson the C3-phenyl ring
orthe benzo moiety of the oxindole core had little influence
on the yields and ee’s (88ꢀ97% yield, 93ꢀ99% ee; Table 2,
(14) CCDC 869058 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambrige Crystallographic Data Centere via www.ccdc.cam.ac.uk/
data_request/cif.
2728
Org. Lett., Vol. 14, No. 11, 2012

sulfenylating agent 2 smoothly and convertto4acomplete-
ly after 20 h. This implied that a substituted reaction
occurred prior to the C3-position of oxindole, followed by
N-addition with an excess amount of 2.
formation of an enolate anion via a Brønsted base pro-
moted deprotonation of 3-substituted-2-oxindole. HRMS
experiments were performed to shed light on the reaction
mechanism. The spectrum of the sample obtained from the
mixture of L4ꢀSc(OTf)3 and oxindole 1a revealed an
ion at m/z 1094.4995, which corresponded to the inter-
mediate [Sc3þ þ 1a þ (L4ꢀH)ꢀ þ TfOꢀ]þ. Upon addition
ofK2CO3, a new signal appeared at m/z 944.4796related to
[Sc3þ þ (1aꢀH)ꢀ þ (L4ꢀH)ꢀ]þ. It was conceivable that
the base enabled the generation of an enolate ion which
was caught by the oxophilic scandium catalyst15 (see
Supporting Information).
Scheme 1. Synthetic Utility
A linear effect16 between the ee values of the ligand L4
and the product 3a indicated a monomeric catalyst as the
main catalytic active species. In light of the X-ray struc-
tures of the product 3p14 and the N,N0-dioxideꢀSc(III)
complex,17 a proposed catalytic cycle and the catalytic
activation model T2 were provided to explain the observed
sense of asymmetric induction (Figure 1). In the presence
of the chiral scandium catalyst, the racemic products
generated from the achiral Brønsted base catalyzed back-
ground reaction was effectively slowed down and the base-
assisted Lewis acid catalyzed asymmetric sulfenylation
reaction dominated the reaction process via cooperative
catalysis to afford the optically active product. In the
catalytic model T2, the oxygen atoms of N-oxide and the
amide moieties of the ligand L4, oxindoles, and sulfenyla-
tion reagent 2 were coordinated together with the scan-
dium center. The Si face of oxindole was shielded by the
neighboring 2,6-diisopropylphenyl group. Therefore, the
Re-face attacking the sulfur of 2 yielded the corresponding
R-configured product which was in accordance with the
observed experimental result.
In summary, we have developed a highly efficient
enantioselective sulfenylation of unprotected oxindoles
via cooperative catalysis of a N,N0-dioxideꢀSc(OTf)3
complex and a Brønsted base. With readily available
N-(phenylthio)phthalimide as the sulfur source, this
method provides the first access to optically active
3-phenylthio-substituted oxindole derivatives in excel-
lent yields (82ꢀ98% yield) with excellent enantioselec-
tivities (up to 99% ee) under mild reaction conditions.
Further realization of other catalytic asymmetric func-
tionizations of 3-substituted unprotected oxindoles is
underway in our laboratory.
Acknowledgment. Weappreciate the National Natural
Science Foundation of China (Nos. 21021001 and
21172151), and National Basic Research Program of
China (973 Program: No. 2010CB833300) for financial
support.
Figure 1. Proposed catalytic cycle.
Knowing that the reaction did not occur in the absence
of a base, we assume that the reaction is initiated by the
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.;Eur. J. 2004,
10, 484. (b) Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int.
Ed. 2002, 41, 3554.
(16) For a review on nonlinear effects, see: Satyanarayana, T.; Abraham,
S.; Kagan, H. B. Angew. Chem., Int. Ed. 2009, 48, 456.
(17) Liu, Y. L.; Shang, D. J.; Zhou, X.; Liu, X. H.; Feng, X. M.
Chem.;Eur. J. 2009, 15, 2055.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2729