Enantioselective organocatalyzed sulfenylation of 3-substituted oxindoles

Article abstract of DOI:10.1021/ol301833f

A highly enantioselective sulfenylation reaction with respect to 3-substituted oxindoles and electrophilic sulfur reagents by a quinidine catalyst was investigated.

Full text of DOI:10.1021/ol301833f

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4374–4377
Enantioselective Organocatalyzed
Sulfenylation of 3‑Substituted Oxindoles
Xin Li,* Cong Liu, Xiao-Song Xue, and Jin-Pei Cheng*
State-key Laboratory of Elementoorganic Chemistry and Department of Chemistry,
Nankai University, Tianjin, 300071, P.R. China
xin_li@nankai.edu.cn; chengjp@most.cn
Received July 4, 2012
ABSTRACT
A highly enantioselective sulfenylation reaction with respect to 3-substituted oxindoles and electrophilic sulfur reagents by a quinidine catalyst
was investigated.
Organocatalysis is described as a powerful, environmen-
tally friendly methodology for the enantioselective construc-
tion of valuable synthetic building blocks and have gained a
prominent position in organic chemistry.1 Although rapid
progress in the development of small molecular catalysis has
been realized, practical and efficient asymmetric approaches
remain in high demand. An aspect of an ideal asymmetric
reaction is performing with an adequately facile catalyst to
yield quantitative, enantiomerically pure products. Thus,
some commercially available and inexpensive natural pro-
ducts, such as Cinchona alkaloids and their derivatives, have
emerged as privileged catalysts in asymmetric synthesis.2
Oxindoles and their derivatives have received extensive
attention, since the structural motif of this type of compound,
which has the construction of a quaternary chiral center, is
a prominent feature in many biologically and pharmaceu-
tically active natural products.3 Thus, various synthetic
approaches, including the aldol reaction,4 Mannich
reaction,5 Henry reaction,6 allylic alkylation,7 and Michael
addition8 with 3-substituted oxindoles as nucleophiles,
have been developed in recent years for the asymmetric
synthesis of this challenging structural core.9 Moreover,
the presence of enolizable CꢀH bonds in 3-substituted
oxindoles also allows the possibility of reactions with
different classes of heteroatom type electrophiles leading
(4) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.;
Shiro, M. Angew. Chem., Int. Ed. 2007, 46, 8666 and references therein.
(5) (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett.
2008, 10, 3583. (b) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y. ꢀJ.
J. Org. Chem. 2009, 74, 4650. (c) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun,
L.-F.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2010, 75, 4872.
(6) Dounay, A. B.; Kodanko, K. J. J.; Oestreich, M.; Overman, L. E.;
Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125, 6261 and
references therein.
(1) (a) Acc. Chem. Res. 2004, 37 (8), special issue on organocatalysis.
(b) Chem. Rev. 2007, 107 (12), special issue on organocatalysis. (c) Proc.
Natl. Acad. Sci. U.S.A. 2010, 107 (48), special feature issue on
organocatalysis.
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(b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548 and
references therein. (c) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem.
Commun. 2009, 3955.
(2) For reviews on cinchona alkaloids catalysts, see: (a) Yeboah,
E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron 2011, 67, 1725.
(b) Song, C. E. In Cinchona Alkaloids in Synthesis and Catalysis: Ligands,
Immobilization and Organocatalysis; Song, C. E., Ed.; Wiley-VCH:
Weinheim, 2009. (c) Tian, S.-K.; Chen, Y. G.; Hang, J. F.; Tang, L.; Mcdaid,
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2003, 103, 2945. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed.
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2007, 46, 8748. For examples, see: (d) Malinakova, H. C.; Liebeskind,
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2002, 4, 4237. (f) Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197.
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J. Org. Biomol. Chem. 2010, 8, 2912. (e) Bui, T.; Syed, S.; Barbas, C. F.,
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Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132.
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r
10.1021/ol301833f
Published on Web 08/17/2012
2012 American Chemical Society

Scheme 1. Strategy of Chiral Tertiary-Amine Catalyzed
Asymmetric Sulfenylations of 3-Substituted Oxindoles
Figure 1. Examined catalysts.
to the formation of carbonꢀheteroatom bonds of oxi-
ndoles. A number of asymmetric strategies for the con-
structed heteroquaternary stereocenter of oxindole type
compounds, including fluorination,10 chlorination,11 hydro-
xylation,12 and amination,13 have been successfully estab-
lished. To sum up, enantioselective formation of a variety of
chemical bonds (i.e., CꢀC, CꢀO, CꢀN, CꢀCl, CꢀF) with a
chiral tetrasubstituted stereocenter at the C3-position of
oxindole have been accomplished.
It is well-known that enantiomerically pure sulfur-
containing compounds constitute an important class of chiral
ligands, auxiliaries, and synthetic intermediates in organic
chemistry.14 Moreover, many chiral S-containing mole-
cules also exhibit pharmaceutical activities. As a result, several
groups have successfully accomplished the asymmetric
sulfenylation of aldehydes15 and ketones16 with different
electrophilic sulfur reagents in recent years. On the other
hand, asymmetric conjugated addition reactions, in which
thiols or thioacetic acids were used as donors, were also
studied as a valuable method for the preparation of chiral
S-containing compounds.17 Although impressive advances
have been made in this area, searching for efficient, espe-
cially simple catalysts that could achieve high enantioselec-
tivity and extending the substrate scope are still desirable
and challenging. Very recently, Feng et al. reported a chiral
N,N0-dioxide-Sc(OTf)3 complex and a Brønsted base cata-
lyzed asymmetric sulfenylation of unprotected 3-substituted
oxindoles.18 To our knowledge to date, no organocatalytic
processes are available for the preparation of chiral 3-sub-
stituted 3-sulfenylindol-2-ones, in which the motif is the key
structure of bioactive oxindole type products.19ꢀ21 As part
of our ongoing program on asymmetric organocatalysis,22
we have recently found that various 3-substituted 3-sulfe-
nylindol-2-ones can be obtained in high yield and good to
excellent enantioselectivity with a very simple Cinchona
alkaloids catalyst (Scheme 1). Herein we wish to report
our preliminary results on this subject.
(10) (a) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem.
Soc. 2001, 123, 7001. (b) Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk,
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Barbas, C. F., III. J. Am. Chem. Soc. 2010, 132, 5574.
We envision that the application of enolizable 3-sub-
stituted oxindoles and electrophilic sulfur reagents in the
presence of a chiral tertiary-amine organic catalyst will
generate 3-substituted 3-sulfenylindol-2-ones (Scheme 1).
(18) Cai, Y.; Li, J.; Chen, W.; Xie, M.; Liu, X.; Lin, L.; Feng, X. Org.
Lett. 2012, 14, 2726.
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Chem. Soc. 2010, 132, 1255.
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Enders, D. Chem.;Eur. J. 2012, DOI: 10.1002/chem.201201262
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Constantinou, A.; Hawthorne, M.; Pezzuto, J. M.; Moon, R. C.;
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H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Chem.;Eur. J.
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Org. Lett., Vol. 14, No. 17, 2012
4375

To demonstrate the working hypothesis, we carried out a
model reaction of 3-phenyl-N-Boc oxindole (1a) with
N-(phenylthio)phthalimide (2a) in dichloromethane at
20 °C with a 10 mol % loading of quinine (4a, Figure 1).
A high yield and good enantioselectivity for sulfenylation
product 3a was obtained (Table 1, entry 1). Other Cinch-
ona alkaloids and their derivatives (4bꢀ4h, Figure 1) were
then evaluated (Table 1, entries 2ꢀ8). To our delight, the
examined catalysts exhibited high catalytic activities, and
the sulfenylation products were isolated with very good
yields (97ꢀ99%). However, the enantioselectivities varied
significantly. Among the catalysts tested, quinidine (4b)
was found to givethe optimal enantioselectivity (99% yield
and 82% ee, entry 2 in Table 1). Two other types of amine
catalysts, including R,R-diphenyl-L-prolinol 4i and bifuc-
tional tertiary-amine thiourea 4j, were inferior to 4b in
terms of enantioselectivity (Table 1, entries 9 and 10).
We then focused on the optimization of a 4b catalyzed
sulfenylation of 3-phenyl-N-Boc oxindole to improve the
reaction efficiency. All of the solvents afforded the desired
products in quantitative yield. Moderate stereoselectivities
were obtained for toluene, benzene, ether, and THF (Table 1,
entries 13ꢀ16, 54ꢀ68% ee). It was observed that chloric
solvents were favored for this reaction (Table 1, entries 2,
11ꢀ12, 74ꢀ82% ee). Further studies indicated that lowering
the reaction temperature can promote the enantioselectivity
(Table 1, entry 17). Gratifyingly, diluting the reaction system
also displays an increase in the ee value of sulfenylation
product 3a to 97% ee (Table 1, entry 18). Collectively, the
best result with respect to yield and stereoselectivity was
obtained by performing the reaction with 10 mol % quini-
dine at ꢀ80 °C under a 0.05 M concentration in CH2Cl2.
With the optimal protocol in hand, we then turned our
attention toward the scope of the reaction. We first examined
the reactions of a range of 3-aryl oxindoles 1aꢀ1k with 2a
under the optimized conditions. As shown in Table 2, oxi-
ndoles with 3-aryl groups bearing either an electron-
withdrawing or -donating moiety could be converted into the
desired products with excellent yields (83ꢀ99%) and enantio-
selectivities (90ꢀ99% ee) (Table 2, entries 1ꢀ11). A slightly
lower stereoselectivity was obtained with meta-methoxy-
substituted 3-aryl-N-Boc oxindole 1g (Table 2, entries 7). The
reaction of 5-position substituted oxindole 1iꢀ1k also worked
very well to give the desired sulfenylation products 3iꢀ3k with
91ꢀ99% yield and 94ꢀ97% ee (Table 2, entries 9ꢀ11).
We also investigated the effect of differently substituted
sulfenylation reagents on the currently studied sulfenylation
reaction. When 3-substituted-N-Boc oxindoles 1a and 1d
were chosen as the substrates, sulfur reagents (2aꢀ2e) with
Table 1. Screening of the Reaction Conditions for the
Sulfenylation of 3-Phenyl-N-Boc Oxindole (1a)a
Table 2. Substrate Scope of 3-Aryl Oxindolesa
yieldb
(%)
eec
entry
cat.
solvent
CH2Cl2
(%)
1
4a
4b
4c
4d
4e
4f
99
99
99
99
98
99
98
97
99
99
99
99
99
99
99
99
99
99
ꢀ77f
82
time yieldb
eec
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
entry
R1
1a: H
R2
R3
2a: H
(h)
(%)
(%)
3
53
4
ꢀ46f
ꢀ31f
ꢀ60f
8
1
2
3
4
5
6
7
8
9
H
12
18
12
12
18
24
48
24
36
3a: 99 97
3b: 99 97
5
1b: 4-CH3
1c: 4-nBu
1d: 3,5-2CH3
1e: 4-F
H
H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
6
3c: 99
95
7
4g
4h
4i
H
3d: 99 98
8
48
H
3e: 85
3f: 99
97
99
9
ꢀ44f
1f: 4-CH3O
1g: 3-CH3O
1h: 4-C2H5O
1i: H
H
10
11
12
13
14
15
16
17d
18e
4j
43
H
3g: 99 90
3h: 83 98
4b
4b
4b
4b
4b
4b
4b
4b
81
H
CH2ClCH2Cl
toluene
benzene
ether
74
5-
3i: 99
97
68
CH3O
5-F
54
10
11
12
13
14
15
16
17
1j: H
2a: H
24
24
24
12
12
24
24
24
3j: 91
94
56
1k: H
5-Br 2a: H
3k: 93 94
3l: 99 97
THF
60
1d: 3,5-2CH3
1a: H
H
H
H
H
H
H
2b: 4-F
CH2Cl2
CH2Cl2
94
2c: 4-Cl
3m: 98 95
3n: 98 99
3o: 99 97
3p: 99 95
3q: 95 97
97
1d: 3,5-2CH3
1d: 3,5-2CH3
1a: H
2c: 4-Cl
a The general reaction was carried out on a 0.1 mmol scale in 1 mL of
solvent with 20 min, and the molar ratio of 1a/2a is 1/1.2. b Isolated yield
after chromatography. c Determined by chiral HPLC. d The reaction was
carried out under general conditions at ꢀ80 °C in 12 h. e The reaction
was carried out under general conditions in 2 mL of CH2Cl2 at ꢀ80 °C in
12 h. f The major productis the enantiomer of the one obtained in the rest
of the entries.
2d: 4-CH3
2e: 4-CH3O
2e: 4-CH3O
1d: 3,5-2CH3
a The reaction was carried out on a 0.1 mmol scale in 2 mL of CH2Cl2
at ꢀ80 °C, and the molar ratio of 1/2 is 1/1.2. b Isolated yield after
chromatography. c Determined by chiral HPLC.
4376
Org. Lett., Vol. 14, No. 17, 2012

an electron-rich or -deficient group on the aromatic ring
can afford the optically active 3,30-disubstituted sulfeny-
lated oxindoles (3lꢀ3q) with excellent yields (95ꢀ99%) and
enantioselectivities (95ꢀ99% ee) (Table 2, entries 12ꢀ17).
3-Alkyl-N-Boc oxindoles were also applied as nucleo-
philes (Table 3). Compared with 3-aryl-N-Boc oxindoles, a
longer reaction time and higher concentration of the
system were indispensable to accelerate the asymmetric
sulfenylation. As a result, the examined 3-alkyl oxindoles
5aꢀ5d can smoothly react with 2a (or 2c) to afford the
corresponding sulfenylated products 6aꢀ6e with very
good yields (93ꢀ99%) and variable enantioselectivities
(72ꢀ94% ee).
Figure 2. X-ray crystal structure of 3k.
Table 3. Substrate Scope of 3-Alkyl Oxindolesa
Figure 3. Effects of different N-substituted oxindoles.
time
(h)
yieldb
(%)
eec
R-product. The multi-H-bonding interaction between the
catalyst and substrates, described in Scheme S1, would
contribute to the stability of the proposed transition state.
To investigate the synthetic potential of the current sulfe-
nylation strategy, the preparation of 3m, 3o, and 6b at a
1 mmol scale were attempted under the optimal condi-
tions. To our delight, corresponding products were
obtained without any loss in yields and enantioselec-
tivities (Scheme S2).
entry
R4
R5
macR6
2a: H
(%)
1
2
3
4
5
5a: CH3
5b: C2H5
5c: Bn
H
H
H
60
48
48
60
96
6a: 91
6b: 99
6d: 93
6e: 99
6f: 96
94
91
72
91
79
2a: H
2a: H
5d: CH3
5b: C2H5
4-CH3O 2a: H
2c: 4-CH3
H
a The reaction was carried out on a 0.1 mmol scale in 1 mL of CH2Cl2
at ꢀ80 °C, and the molar ratio of 1/2 is 1/1.2. b Isolated yield after
chromatography. c Determined by chiral HPLC.
In summary, we have described the sulfenylation reac-
tion of 3-substituted oxindoles with electrophilic sulfur re-
agents by Cinchona alkaloid type catalysts. Remarkably, in
the presence of a very facile simple natural product, quini-
dine, a wide range of 3-aryl or 3-alkyl substituted oxind-
oles and substituted N-(arylthio)phthalimides underwent
the reaction smoothly, providing chiral sulfur containing
oxindole compounds with a quaternary stereocenter
in excellent yields (up to 99%) and enantioselectivities
(up to 99% ee).
The absolute configuration of adducts 3 was determined
by X-ray crystallographic analysis of 3k (Figure 2; for
details see Supporting Information).23 Absolute config-
urations of other products can therefore be determined by
analogy.
Furthermore, three different 3-methyl N-substituted
oxindoles (7aꢀ7c) were also included in the examina-
tion. As expected, the result was not positive, affording
the corresponding adducts 8aꢀ8c in very low enantios-
electivities (Figure 3). When unprotected 3-phenyl oxi-
ndole was used as a nucleophile, the sulfenylation
product 8d was obtained in 57% yield and with only a
6% ee (Figure 3).
Acknowledgment. The project was supported by NSFC
(20902091, 21172112, and 21172118) and the National Basic
Research Program of China (973 Program, 2010CB833300
and 2012CB821600).
A plausible transition state model was proposed to
account for the observed stereoselectivity (Scheme S1).
In the favored TS model, the sulfenylation reagent attacks
on the Re face of oxindole, giving the observed major
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) CCDC 838460 contains the supplementary crystallographic
data for 3k. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_
request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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