Highly enantioselective organocatalytic sulfenylation of 3-aryloxindoles

Article abstract of DOI:10.1021/ol3021176

An organocatalytic asymmetric sulfenylation of 3-aryloxindoles with N-(sulfanyl)succinimides has been developed by using commercially available (DHQD)₂PHAL as catalyst. Various chiral 3-benzylthio-, alkylthio-, and arylthio-substituted oxindole

Full text of DOI:10.1021/ol3021176

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4670–4673
Highly Enantioselective Organocatalytic
Sulfenylation of 3‑Aryloxindoles
Zhiqiang Han,† Wenchao Chen,† Sheng Dong,§ Caiyun Yang,† Hongjun Liu,‡
Yuanhuang Pan,‡ Lin Yan,† and Zhiyong Jiang*,†,‡
Institute of Chemical Biology and Key Laboratory of Natural Medicine and
Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan,
People’s Republic of China 475004, and Department of Chemistry,
National University of Singapore, 3 Science Drive 3, Singapore 117543
chmjzy@henu.edu.cn
Received July 31, 2012
ABSTRACT
An organocatalytic asymmetric sulfenylation of 3-aryloxindoles with N-(sulfanyl)succinimides has been developed by using commercially
available (DHQD)2PHAL as catalyst. Various chiral 3-benzylthio-, alkylthio-, and arylthio-substituted oxindoles, containing 3,3-disubstituted
quarternary carbon stereocenters, could be obtained in high enantioselectivities (85ꢀ97% ee). Furthermore, the opposite enantiomers of the
sulfenylated products were readily accessible with equal excellent enantioselectivities (86ꢀ95% ee) by replacing the catalyst with (DHQ)2PHAL.
Enantioselective construction of quaternary stereogenic
centers is of fundamental and practical significance but is
often challenging.1 In particular, the enantioselective con-
struction of 3,3-disubstituted oxindoles has attracted special
attention of organic chemists since the oxindole framework
bearing a quaternary carbon stereocenter at the 3-position is
a privileged heterocyclic motif, which is a core backbone of
many natural products and pharmaceutical molecules.2 The
established methods include nucleophilic additions to isa-
tins and miscellaneous reactions of 3-substituted oxindoles,3
affording various 3,3-full carbons4 and 3-heteroatoms, in-
cluding 3-fluoro-,5 3-chloro-,6 3-amino-7 and 3-hydroxy8-
substituted oxindoles. Due to the important role of
† Institute of Chemical Biology, Henan University.
§ Department of Chemistry, National University of Singapore.
(5) (a) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Chem.;Eur. J. 2011,
17, 14922. (b) Wu, L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden, A.;
Cavallo, L.; Dorta, R. Angew. Chem., Int. Ed. 2012, 51, 2870.
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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.
‡ Key Laboratory of Natural Medicine and Immuno-Engineering of Henan
Province.
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r
10.1021/ol3021176
Published on Web 08/24/2012
2012 American Chemical Society

3-thio-substituted oxindoles in medicinal chemistry,9 the
specific incorporation of sulfur into the 3-position of
oxindoles in a stereoselective manner has become a highly
pivotal consideration. In 2012, Feng and co-workers pre-
sented the first asymmetric synthesis of 3-phenylthio-
substituted oxindoles from an enantioselective sulfenylation
of 3-substituted oxindoles with N-(phenylthio)phthalimide
via cooperative catalysis of a chiral N,N0-dioxide-Sc(OTf)3
complex and an achiral Brønsted base.10 Very recently,
Enders and co-workers described the first organocatalytic
enantioselective sulfenylation of N-Boc-protected oxindoles
by using N-(sulfanyl)phthalimides as the sulfenylating
agents catalyzed by Cinchona alkaloid-derived squaramide,
affording a variety of 3-arylthio-substituted oxindoles with
excellent enantioselectivities.11 Notably, the highly stereo-
selective construction of 3-benzylthio- and alkylthio-sub-
stituted oxindoles has never been reported and remains
highly in demand for their facile modification. As part of
our ongoing investigation on the organocatalytic syntheses
of chiral sulfur-substituted R-stereogenic amides12 and 3,3-
disubstituted oxindoles,4g we thus became interested in
developing an efficient organocatalytic sulfenylation of
3-substituted oxindoles to allow easy access to alkylthio-,
benzylthio-, and arylthio-substituted oxindoles.
In the past few decades, sulfenylations have been investi-
gated intensively to construct valuable optically active sulfur-
substituted R-stereogenic compounds, which are common
key building blocks in many bioactive compounds,13 and it
is commonplace to employ chiral auxiliaries.14 In 2005,
Jørgensen and co-workers disclosed the first highly enantio-
selective organocatalytic sulfenlyation of aldehydes catalyzed
by chiral pyrrolidine derivatives.15 Meanwhile, they reported
asymmetric sulfenylation of lactones, lactams, and β-dicar-
bonyl compounds with moderate to good enantioselectivities
in the presence of Cinchona alkaloid derivatives as Brønsted
base catalysts.16 Afterward, Zhu and Cheng and co-workers
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
solvent
t (°C) yield (%)b ee (%)c
1
2
cinchonine
cinchonidine
quinine
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
0
56
53
67
63
60
65
77
59
63
95
72
79
87
70
65
30
97
63
65
ꢀ26
ꢀ14
ꢀ10
ꢀ12
5
3
4
quinidine
5
(DHQ)2PYR
(DHQD)2AQN
6
7
(DHQD)2PHAL CH2Cl2
(DHQ)2PHAL CH2Cl2
70
8
ꢀ50
20
9
(DHQD)2PHAL THF
10
11
12
13
14
15
16
17
18d
(DHQD)2PHAL toluene
(DHQD)2PHAL Et2O
92
91
(DHQD)2PHAL p-xylene
(DHQD)2PHAL m-xylene
(DHQD)2PHAL mesitylene
(DHQD)2PHAL m-xylene
(DHQD)2PHAL m-xylene
(DHQD)2PHAL m-xylene
(DHQD)2PHAL m-xylene
93
93
93
82
65
30
30
93
93
a Unless otherwise noted, reactions were performed with 0.02 mmol
of 1a, 0.03 mmol of 2a, and 0.002 mmol of catalyst in 0.2 mL of solvent.
b Yield of isolated product. c Determined by HPLC on a chiral stationary
phase. d 5 mol % catalyst was used.
successively demonstrated the highly enantioselective sulfe-
nylation of β-ketoesters17a and β-keto phosphonates17b cat-
alyzed by R,R-diaryl-L-prolinols. It is worth noting that the
successful example on Brønsted-base-catalyzed sulfenylation
is still rare.11 Herein, we would like to report a highly
enantioselective sulfenylation of 3-aryloxindoles with a vari-
ety of N-(sulfanyl)succinimides catalyzed by commercially
avaliable (DHQD)2PHAL, which leads to the efficient
syntheses of various chiral 3-benzylthio-, alkylthio-, and
arylthio-substituted oxindoles. Furthermore, this methodol-
ogy is applicable to prepare the opposite enantiomers of the
sulfenylated products with equal excellent enantioselectivities
(86ꢀ95% ee) by replacing the catalyst with (DHQ)2PHAL.
In organocatalytic asymmetric transformations, Cinch-
ona alkaloid derivatives have been proven as a kind of
highly effective catalyst and thus have attracted considerable
interest.18 Especially, the commercially available Cinchona
alkaloids are the most favorable for the economical and
practical standpoints. Therefore, we investigated several
commercially available Cinchona alkaloids catalysts in
the model sulfenylation of 3-phenyloxindole 1a and
N-(benzylthio)succinimide 2a in methylene chloride at
25 °C in our initial studies. The results are summarized in
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L.; Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2011, 353, 2624.
(13) (a) Brown, M. F.; Reilly, U.; Abramite, J. A.; Arcari, J. T.;
Oliver, R.; Barham, R. A.; Che, Y.; Chen, J. M.; Collantes, E. M.;
Chung, S. W.; Desbonnet, C.; Doty, J.; Doroski, M.; Engtrakul, J. J.;
Harris, T. M.; Huband, M.; Knafels, J. D.; Leach, K. L.; Liu, S.;
Montgomery, A.; Mullins, L.; Noe, M. C.; O’Donnell, J.; Penzien, J.;
Plummer, M. S.; Price, L. M.; Shanmugasundaram, V.; Thoma, C.;
Uccello, D. P.; Warmus, J. S.; Wishika, D. G. J. Med. Chem. 2012, 55,
914. (b) Wang, Y.; Li, Z.-L.; Bai, J.; Zhang, L.-M.; Wu, X.; Zhang, L.;
Pei, Y.-H.; Jing, Y.-K.; Hua, H.-M. Chem. Biodiversity 2012, 9, 385.
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€
1993, 58, 3165. (b) Enders, D.; Schafer, T.; Piva, O.; Zamponi, A.
Tetrahedron 1994, 50, 3349. (c) Chibale, K.; Warren, S. Tetrahedron
€
Lett. 1994, 35, 3991. (d) Enders, D.; Schafer, T.; Mies, W. Tetrahedron
1998, 54, 10239. (e) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael,
ꢀ
F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905.
(15) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
ꢀ
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Franzen, J.; Marigo,
M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 18296.
(16) Sobhani, S.; Fielenbach, D.; Marigo, M.; Wabnitz, T. C.;
Jørgensen, K. A. Chem.;Eur. J. 2005, 11, 5689.
(17) (a) Fang, L.; Lin, A.; Hu, H.; Zhu, C. Chem.;Eur. J. 2009, 15,
7039. (b) Lin, A.; Fang, L.; Zhu, X.; Zhu, C.; Cheng, Y. Adv. Synth.
Catal. 2011, 353, 545.
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Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621.
(b) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560.
Org. Lett., Vol. 14, No. 17, 2012
4671

Table 1. We found that the reaction catalyzed by 10 mol %
of cinchonine gave the desired adduct 3a in 56% yield and
65% ee (entry 1). Better enantioselectivity (70% ee) was
obtained when (DHQD)2PHAL, as the C2-symmetric
(bis)cinchona alkaloid derivative containing a rigid
enzyme-like pocket, was utilized (entry 7). Further opti-
mization of the reaction conditions was carried out by
examining different solvents using (DHQD)2PHAL as
catalyst (entries 9ꢀ14); m-xylene was identified as the
ideal solvent regarding the yield and enantioselectivity
(entry 15). Excellent yield (98%) with the same ee
(94%) was reached when the reaction temperature
was increased to 30 °C (entry 17). When the catalyst
loading was reduced to 5 mol %, the enantioselectivity
of 3a was kept but the yield was decreased to 63%
(entry 18).
Table 3. Sulfenylation of 3-Phenyloxindole 1a to
N-(Sulfanyl)succinimides 2bꢀi Catalyzed by (DHQD)2PHALa
Table 2. Sulfenylation of 3-Aryloxindoles 1aꢀ1o to
N-(Benzylthio)succinimide 2a Catalyzed by (DHQD)2PHALa
a All reactions were performed with 0.10 mmol of 1a, 0.15 mmol of 2,
and 0.01 mmol of (DHQD)2PHAL in 1.0 mL of m-xylene. b Yield of
isolated product. c Determined by HPLC on a chiral stationary phase.
We subsequently evaluated the generality of the reaction
with regard to the variation of N-(sulfanyl)succinimides
(Table 3). Performing the reaction with the N-(ortho-
chlorobenzylthio)succinimide 2b gave 3p in 98% yield and
91% ee (entry 1), while the N-(para-cholorobenzylthio)-
succinimide 2c gave 3q in 92% yield and 92% ee (entry 2).
The bromo substituent at the corresponding positions did
not affect the yield and enantioselectivity (entries 3 and 4).
The use of N-(benzylthio)succinimide with a heteroaro-
matic group, such as furyl (2f), also afforded the desired
product 3t with excellent yield and ee (entry 5). We were
pleased to see that the reaction condition was also applicable
to N-(alkylthio)succinimides (2gꢀ2h), giving excellent en-
antioselectivities as well as good reactivity (entries 6 and 7).
The use of N-(phenylthio)succinimide 2i resulted in excel-
lent yield and good enantioselectivity (entry 8).
entry
R1/R2
H/Ph (1a)
3
yield (%)b
ee (%)c
1
2
3a
3b
3c
3d
3e
3f
97
95
98
91
93
95
85
98
97
94
98
81
97
72
90
93
92
94
93
93
93
92
88
90
94
96
92
96
91
93
5-F/Ph (1b)
3
5-Cl/Ph (1c)
4
5-Br/Ph (1d)
5
5-Me/Ph (1e)
6
5-MeO/Ph (1f)
6-Br/Ph (1g)
7
3g
3h
3i
8
7-F/Ph (1h)
9
H/4-FC6H4 (1i)
H/3-FC6H4 (1j)
H/3-CF3C6H4 (1k)
H/4-MeC6H4 (1l)
H/3-MeC6H4 (1m)
H/4-MeOC6H4 (1n)
H/2-naphthyl (1o)
10
11
12
13
14
15
3j
3k
3l
3m
3n
3o
It is highly desirable to prepare both of the enantiomeric
products with equally high enantioselectivities in an asym-
metric protocol. Using the pseudoenantiomeric pair of
Cinchona alkaloids as catalysts is a unique approach to
achieve this purpose,19 which prompts us to explore the
possibilities of our methodology.
a All reactions were performed with 0.10 mmol of 1, 0.15 mmol of 2a,
and 0.01 mmol of (DHQD)2PHAL in 1.0 mL of m-xylene. b Yield of
isolated product. c Determined by HPLC on a chiral stationary phase.
We then examined the scope of 3-aryloxindoles 1aꢀ1o
reacting with N-(benzylthio)succinimide 2a under the opti-
mized reaction conditions (10 mol % of (DHQD)2PHAL,
m-xylene, 30 °C, Table 2). The reactions were complete
within 12ꢀ24 h and gave products in good to excellent yields
(72ꢀ99%) and with excellent enantioselectivities (88ꢀ
96% ee). The introduction of various substituents on the
5-, 6-, and 7-position of the aromatic ring of 3-phenylox-
indoles (1aꢀ1h) appeared to have a very limited effect on
enantioselectivity (entries 2ꢀ8). It was also found that the
position and electronic properties of the substituents on the
aromatic ring at the C3-position of 3-aryloxindoles (1iꢀ1o)
did not affect the ee (entries 9ꢀ15).
It is interesting to note that ent-3a, as the enantiomer of 3a,
could be obtained with 50% ee when using (DHQ)2PHAL as
catalyst in our screening experiments (Table 1, entry 8).
Therefore, we investigated the sulfenylation of 1a and 2a
catalyzed by 10 mol % of (DHQ)2PHAL under the estab-
lished reaction conditions (m-xylene as solvent, 30 °C). We
observed that the ee of ent-3a was enhanced to 81% (Table 4,
entry 1). The ee could be improved to 88% when toluene was
the solvent (entry 3). The best results were obtained in 96%
yield and 90% ee when the catalyst loading was reduced to
(19) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127,
8948.
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Org. Lett., Vol. 14, No. 17, 2012

Table 4. Reaction Condition Screening on the Synthesis of
ent-3a Catalyzed by (DHQ)2PHALa
Scheme 1. Synthetic Transformation of Adduct 3a and the
ORTEP Structure of the Product 4
entry
equiv of catalyst
solvent
yield (%)b
ee (%)c
1
2
3
4
5
0.1
m-xylene
p-xylene
toluene
toluene
toluene
80
76
98
96
68
81
87
88
90d
84
0.1
products (ent-3) could be obtained in 68ꢀ99% yield and
86ꢀ95% ee (Table 5). On the basis of the experimental
results, we have proposed two tentative transition states for
the sulfenylations using (DHQD)2PHAL and (DHQ)2-
PHAL as catalyst (see Supporting Information).
0.1
0.05
0.02
a Unless otherwise noted, reactions were performed with 0.02 mmol
of 1a, 0.03 mmol of 2a, and 0.002 mmol of catalyst in 0.2 mL of solvent.
b Yield of isolated product. c Determined by HPLC on a chiral stationary
phase. d 0.1 mmol scale in 1.0 mL of toluene, yield = 90%, ee = 90%.
Next, by using mCPBA as the oxidant, the sulfenylation
adduct 3a was readily transformed into the corresponding
sulfone20 4 in 5 h with 91% yield and without compromising
the enantiomeric excess (Scheme 1). The absolute config-
urations of the sulfenylation products were assigned based
on X-ray crystallographic analysis of a single crystal of 4.21
In summary, we have developed a highly enantioselec-
tive sulfenylation of 3-aryloxindoles with N-(sulfanyl)-
succinimides. (DHQD)2PHAL, as the commercially avail-
able Cinchona alkaloid derivative, was demonstrated as an
efficient catalyst to promote the reaction. Several chiral
3-benzylthio-, alkylthio-, and arylthio-substituted oxindoles,
containing 3,3-disubstituted quarternary carbon stereo-
centers, could be readily obtained with excellent enantios-
electivities (85ꢀ97% ee). By replacing the catalyst with
(DHQ)2PHAL, this methodology is applicable to prepare
the opposite enantiomers of the sulfenylated products with
equal excellent enantioselectivities (86ꢀ95% ee). This is
the first report on the highly enantioselective construction
of 3-benzylthio- and alkylthio-substituted oxindoles.
Further investigations into the full reaction scope and
mechanism of this catalytic system are still in progress.
Table 5. Sulfenylation of 3-Aryloxindoles 1 to
N-(Sulfanyl)succinimides 2 Catalyzed by (DHQ)2PHALa
entry
R1/Ar/R2 (ent-3)
yield (%)b
ee (%)c
1
2
5-Cl/Ph/Bn (ent-3c)
98
97
70
96
95
97
80
72
81
90
68
91
90
85
91
90
90
95
90
86
88
91
5-Br/Ph/Bn (ent-3d)
3
5-MeO/Ph/Bn (ent-3f)
6-Br/Ph/Bn (ent-3g)
4
5
H/4-FC6H4/Bn (ent-3i)
H/3-FC6H4/Bn (ent-3j)
H/3-MeC6H4/Bn (ent-3m)
H/4-MeOC6H4/Bn (ent-3n)
H/H/2-ClC6H5CH2 (ent-3p)
H/H/4-ClC6H5CH2 (ent-3q)
H/H/cyclohexyl (ent-3u)
6
7
8
9
10
11
Acknowledgment. This work was supported by NSFC
(21072044) and the Program for New Century Excellent
Talents in University of Ministry of Education (NCET-11-
0938).
a All reactions were performed with 0.10 mmol of 1, 0.15 mmol
of 2a, and 0.01 mmol of (DHQD)2PHAL in 1.0 mL of m-xylene. b Yield
of isolated product. c Determined by HPLC on a chiral stationary
phase.
Supporting Information Available. General information,
typical experimental procedures, characterization, HPLC
and NMR spectra of the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
5 mol % (entry 4). However, the lower catalyst loading
(2 mol %) compromised the enantioselectivity (entry 5).
Subsequently, we carried out the sulfenylation of 3-arylox-
indoles 1 with N-(sulfanyl)succinimides 2 using 5 mol % of
(DHQ)2PHAL in toluene at 30 °C. Various sulfenylated
(21) CCDC-889149 (4) 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.
(20) Gutteridge, C. E.; de Laszlo, S. E.; Kamenecka, T. M.; McCauley,
E.; van Riper, G.; Mumford, R. A.; Kidambi, U.; Egger, L. A.; Tong, S.;
Hagmann, W. K. Bioorg. Med. Chem. Lett. 2003, 13, 885.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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