Highly enantioselective Michael addition of 2-oxindoles to vinyl selenone in RTILs catalyzed by a Cinchona alkaloid-based thiourea

Article abstract of DOI:10.1039/c1cc10880h

A highly enantioselective Michael addition of 2-oxindoles (1) to vinyl selenone (2) in RTILs catalyzed by a Cinchona alkaloid-based thiourea has been developed in high yields (80-91%) with excellent enantioselectivities (up to 95% ee).

Full text of DOI:10.1039/c1cc10880h

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COMMUNICATION
Highly enantioselective Michael addition of 2-oxindoles to vinyl selenone
in RTILs catalyzed by a Cinchona alkaloid-based thioureaw
Tao Zhang,ab Liang Cheng,a Shahid Hameed,ac Li Liu,*a Dong Wanga and Yong-Jun Chen*a
Received 15th February 2011, Accepted 14th March 2011
DOI: 10.1039/c1cc10880h
A highly enantioselective Michael addition of 2-oxindoles (1) to
vinyl selenone (2) in RTILs catalyzed by a Cinchona alkaloid-
based thiourea has been developed in high yields (80–91%) with
excellent enantioselectivities (up to 95% ee).
drug candidates.6 The asymmetric Michael reaction of
2-oxindoles is a straightforward approach to the biological motif.7
Compared with sulfur analogues, selenones are well recognized
as precursors in organic synthesis, because the selenonyl group
is considered as a good leaving group, offering an opportunity
to accomplish further derivatizations for the synthesis of
biologically active compounds.8 However, to the best of our
knowledge, only one example of enantioselective Michael
addition employing the a,b-unsaturated selenone as the
acceptor was reported.9
Recently, the applications of room-temperature ionic liquids
(RTILs) as green and alternative media1 and organocatalytic
enantioselective reactions for organic synthesis2 have attracted
considerable attention. The organocatalysts employed in the
RTIL-mediated enantioselective reaction, highly interesting
and promising in organic synthesis, were only focused on
proline and its derivatives under the covalent catalysis through
an enamine intermediate.3 However, very few examples were
reported on the RTIL-mediated enantioselective reaction
catalyzed by Cinchona alkaloid-type catalysts. As a chiral
phase-transfer catalyst, a quaternary ammonium salt derived
from quinine was used in the asymmetric Michael reaction and
epoxidation of chalcones in RTILs, but relatively low
enantioselectivities (42–68% ee) were obtained.4 The relatively
low enantioselectivity was attributed to a different catalytic
mode, non-covalent organocatalysis.2a During the course of the
reaction the generated chiral ion-pair intermediate might be
interfered by achiral anions of the ionic liquid via ion exchange.5
To obtain high enantioselectivities in ionic liquids via the mode of
non-covalent catalysis is still a great challenge. In order to
achieve high enantioselectivity, it is necessary to enhance the
non-covalent interaction between chiral catalysts and substrates
to generate a tighter chiral ion-pair intermediate and restrain ion
exchange with the achiral anion of the ionic liquid used.
Herein, we would like to report an enantioselective Michael
addition of 2-oxindoles to vinyl selenone in RTILs catalyzed
by a Cinchona alkaloid-based thiourea in high yields with
excellent enantioselectivities.
Initially, the reaction of 2-oxindole 1a with vinylselenone 2
was carried out in RTIL [bpy][BF4] in the presence of
Cinchona alkaloid catalysts (3a–e) (10 mol%) (Fig. 1) at room
temperature. The stereointroduction via only a single hydrogen
bonding donor either at C9 (3a and 3e) or C60 (3b)10 gave the
product 4a in low yields with poor enantioselectivities
(Table 1, entries 1, 2 and 5). The enantioselectivity could not
be improved by increasing the hindrance at C9 (3c and 3d)
(entries 3 and 4). When Takemoto’s catalyst 3f,11 bearing
Oxindoles bearing a quaternary carbon stereocenter at the
3-position of the indole ring constitute a ubiquitous structural
motif in a variety of natural products and biologically active
a Beijing National Laboratory for Molecular Sciences (BNLMS),
CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China. E-mail: lliu@iccas.ac.cn;
Fax: +8610 62554449; Tel: +8610 62554614
b Graduate School of Chinese Academy of Sciences, Beijing 100049,
China
c Department of Chemistry, Quaid-i-Azam University,
Islamabad 45320, Pakistan
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and chiral chromatographic analysis
for all new compounds. CCDC 802111. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc10880h
Fig. 1 Catalysts for the Michael addition of oxindoles with vinyl
selenone.
c
6644 Chem. Commun., 2011, 47, 6644–6646
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Table 1 Catalyst screening for the reaction of 1a with 2a
imidazole-type ionic liquids, [bmim][BF4] and [bdmim][BF4],
the reaction offered high enantioselectivities, relatively lower
yields were unsatisfactory (entries 1 and 2). Thus, pyridine-type
ionic liquids were selected as the reaction media. It was found
that [bpy][BF4] provided the best result for the asymmetric
Michael addition of 1a with 2. The anions of ionic liquids
influenced the enantioselectivity of the product strongly.
[bpy][NO3] gave a very poor enantioselectivity (9% ee) despite
giving a good yield (87%) of 4a (entry 3). Furthermore, when
[bpy][OTf] was employed, no reaction was observed (entry 4).
The relatively loose anion–cation interaction of ILs may be
more prone to interference with the chiral ion-pair inter-
mediate.5b When [c6py][BF4] and [c8py][BF4] bearing a longer
alkyl chain were used (entries 5 and 6) and when the catalyst
loading and concentration of substrates in [bpy][BF4] were
varied (entries 7–10), the enantioselectivity of the reaction was
not improved noticeably.
Entry
Catalyst
Reaction time/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
48
48
48
48
48
4
4
4
4
19
35
13
56
25
65
77
86
88
22
12
0
46
ꢀ2d
68
ꢀ91d
ꢀ91d
ꢀ95d
a
Reaction conditions: 0.2 mmol 1a with 1 equiv. of 2, using 10 mol%
Under the optimum conditions various 2-oxindoles
(Table 3) with 3-alkyl substituents including methyl, ethyl,
n-propyl, naphthylmethyl and benzyl groups were employed
in the asymmetric Michael addition reaction catalyzed by
3i in [bpy][BF4], affording the corresponding adducts 4a–f in
84–91% yields with up to 95% ee (entries 1–6). All 3-benzyl-2-
oxindoles bearing the functional group either at ortho-, meta- or
para-position on the aromatic ring of the benzyl group gave
the corresponding products (4g–k) in high to excellent yields
and enantioselectivities (entries 7–11).
b
of catalyst 3 in 0.5 mL [bpy][BF4]. Isolated yield. Determined by
d
chiral HPLC analysis. The opposite enantiomer was obtained.
c
a thiourea moiety possessing two hydrogen bonding donors,
was used, only moderate yield and enantioseletivity were
obtained (entry 6). The combination of the Cinchona alkaloid
moiety with the thiourea unit formed catalysts 3g–i,12 which
could enhance the hydrogen-bonding interaction and the steric
effect with substrates, leading to high enantioselectivities. To
our delight, the yield and enantioselectivity of the product 4a
were increased noticeably under the catalysis of Cinchona
alkaloid-based thioureas (entries 7–9). With the decrease of
the hindrance at C60, the catalyst 3i provided the highest yield
and enantioselectivity (entry 9, yield 88%, ee 95%).
The absolute configuration of the main enantiomer of 4a
was deduced as (R) by X-ray single-crystal analysis of 4a (see
ESIw). Based on the results listed above, a possible model of
dual activation of the nucleophile and the electrophile was
proposed (Fig. 2). Catalyst 3i serves as the bifunctional chiral
organocatalyst: the thiourea moiety activates selenone 2 by
double hydrogen bonding, while the quinuclidine moiety
deprotonates the C3 methine proton leading to the generation
Subsequently, various ionic liquids were used as reaction
media in the reaction of 1a with 2 (Table 2). Although in the
Table 2 RTIL screening for the reaction of 1a with 2a
Table 3 Organocatalytic Michael reactions of oxindoles with 2 in
RTIL
Entry
RTIL
Yieldb (%)
eec (%)
Entrya
R
R0
H
Products Yieldb (%) eec (%)
1
2
3
4
5
6
[bmim][BF4]
[bdmim][BF4]
[bpy][NO3]
[bpy][OTf]
[c6py][BF4]
[c8py][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
[bpy][BF4]
80
77
87
nrd
87
78
77
28
86
88
92
95
9
1
2
3
4
5
6
7
8
Me
Me
Et
n-Pr
4a
88
84
86
86
91
86
86
90
86
80
80
95
91
94
88
88
88
91
91
85
90
90
Me 4b
H
H
H
H
H
H
H
H
H
4c
4d
4e
4f
91
90
93
93
92
90
Bn
7e
8f
9g
10h
1-Naphthylmethyl
2-MeC6H4CH2
3-MeC6H4CH2
4-MeC6H4CH2
2-MeOC6H4CH2
3-MeOC6H4CH2
4g
4h
4i
4j
4k
9
10
11
a
Reaction performed at a 0.2 mmol scale 1a with 1 equiv. of 2,
10 mol% of catalyst 3i in the indicated solvent (0.5 mL) for 4 h.
b
c
Isolated yield after FC. Determined by chiral HPLC analysis. No
d
a
Reaction conditions: 0.2 mmol 1 with 1 equiv. of 2, 10 mol% catalyst
b
3i in [bpy][BF4] (0.5 mL) at room temperature for 4 h. Isolated
e
f
g
reaction. 5 mol% cat. 1 mol% cat., reaction time: 4 d. 2 mL IL
h
was used. 0.2 ml IL was used.
c
yield. Determined by chiral HPLC analysis.
c
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and 2010CB833305) and the Chinese Academy of Sciences
for the financial support. The post doctoral fellowship to
Dr Shahid Hameed by Higher Education Commission of
Pakistan is also greatly acknowledged.
Notes and references
1 (a) V. I. Parvulescu and C. Hardacre, Chem. Rev., 2007, 107, 2615;
(b) C. D. Hubbard, P. Illner and R. V. Eldik, Chem. Soc. Rev.,
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ionic liquids, in Green Solvents Ionic Liquids, ed. P. Wasserscheid
and A. Stark, Wiley-VCH, Weiheim, 2010, vol. 6; (d) M. A.
P. Martins, C. P. Frizzo, D. N. Moreira, N. Zanatta and
H. G. Bonacorso, Chem. Rev., 2008, 108, 2015.
Fig. 2 Proposed transition state of the Michael reaction of 2-oxindole
with vinyl selenone promoted by catalyst 3i.
2 (a) A. Berkessel and H. Groger, Asymmetric Organo-
catalysis—From Biomimetic Concepts to Applications in
Asymmetric Synthesis, Wiley-VCH, Weinheim, 2004; (b) B. List,
Chem. Commun., 2006, 819; (c) M. S. Taylor and E. N. Jacobsen,
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(d) L. E. Overman and D. V. Paone, J. Am. Chem. Soc., 2001,
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7 Selected examples, see: (a) X. Li, S. Luo and J.-P. Cheng,
Chem.–Eur. J., 2010, 16, 14290; (b) Q. Zhu and Y. Lu, Angew.
Chem., Int. Ed., 2010, 49, 7753; (c) R. J. He, C. H. Ding and
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(e) R. He, S. Shirakawa and K. Maruoka, J. Am. Chem. Soc., 2009,
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S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009,
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8 For selected examples, see: (a) F. Marini, S. Sternativo, F. Del
Verme, L. Testaferri and M. Tiecco, Adv. Synth. Catal., 2009,
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L. Bagnoli, F. Marini and C. Santi, Org. Biomol. Chem., 2007,
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46, 6882.
Scheme 1 Applications of the methodology.
of the enolate-anion intermediate of the 2-oxindole.13 The
approach of an activated a,b-unsaturated selenone to the
enolate anion from the Re-face resulted in the formation of
a R-selective product.
The products
4 could readily undergo nucleophilic
substitution reaction with NaN3 and NaI. For example, starting
from (ꢀ)-4a (95% ee), the substitution products 5a and 5b
were obtained in 83% and 86% overall yields both with 93%
ee, respectively (Scheme 1). Followed by reduction and
cyclization, (+)-5b was further transformed to pyrroloindoline
(+)-6 in overall yield 73% with 96% ee. It is noteworthy that
many optically active compounds with a pyrroloindoline unit
(7), such as (ꢀ)-physostigmine, show wide biological activities
and have been clinically used as medicines.14
9 F. Marini, S. Sternativo, F. D. Verme, L. Testaferri and M. Tiecco,
Adv. Synth. Catal., 2009, 351, 103.
10 For the pioneering work catalyzed by C60–OH Cinchona alkaloids,
see: H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc.,
2004, 126, 9906.
11 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003,
125, 12672.
12 For the pioneering work of Cinchona alkaloid-based thioureas, see:
(a) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
44, 6367; (b) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org.
Lett., 2005, 7, 1967; (c) J. Ye, D. J. Dixon and P. S. Hynes, Chem.
Commun., 2005, 4481.
13 For a comprehensive mechanistic study on bifunctional catalysis of
Cinchona alkaloids in 1,4-addition, see: H. Hiemstra and
H. Wynberg, J. Am. Chem. Soc., 1981, 103, 417.
14 (a) P. R. Sanchis, S. A. Savina, F. Albericio and M. Alvarez,
Chem.–Eur. J., 2011, 17, 1388; (b) T. Matsuura, L. E. Overman and
D. J. Poon, J. Am. Chem. Soc., 1998, 120, 6500; (c) K. Asakawa,
N. Noguchi, S. Takashima and M. Nakada, Tetrahedron:
Asymmetry, 2008, 19, 2304.
In summary, we have developed a novel organocatalytic
enantioselective Michael addition of 2-oxindoles to vinyl
selenone, which was promoted by a Cinchona alkaloid-based
thiourea in RTILs. High to excellent yields and enantio-
selectivities were obtained. The developed approach could
readily access chiral pyrroloindoline-type compounds. The
investigation of the Michael addition to other nucleophiles
in RTILs is underway in our lab.
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology (nos 2009ZX09501-006
c
6646 Chem. Commun., 2011, 47, 6644–6646
This journal is The Royal Society of Chemistry 2011