Organocatalytic Michael addition of unprotected 3-substituted oxindoles to nitroolefins

Article abstract of DOI:10.1039/c004037a

Quinidine was found to catalyze the Michael addition of unprotected 3-substituted oxindoles to nitroolefins in excellent yield and moderate to good diastereoselectivity. Bifunctional quinidine derived thiourea catalyst 10 could catalyze this reaction to a

Full text of DOI:10.1039/c004037a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic Michael addition of unprotected 3-substituted oxindoles
to nitroolefins†
Miao Ding, Feng Zhou, Zi-Qing Qian and Jian Zhou*
Received 9th March 2010, Accepted 4th May 2010
First published as an Advance Article on the web 17th May 2010
DOI: 10.1039/c004037a
Quinidine was found to catalyze the Michael addition of un-
protected 3-substituted oxindoles to nitroolefins in excellent
yield and moderate to good diastereoselectivity. Bifunctional
quinidine derived thiourea catalyst 10 could catalyze this
reaction to afford the major diastereomer in up to 85% ee.
The catalytic asymmetric synthesis of oxindoles bearing a tetra-
substituted carbon stereocenter at the 3-position has received
much attention, because 3,3-disubstituted oxindole structural mo-
Scheme 1 The synthesis of N-Boc 3-substituted oxindole 2.
tif is widely presented in natural products, drugs and pharmaceuti-
cally active compounds.1 Among the synthetic strategies developed
As part of a program directed at the synthesis of 3,3-
to date,2 the catalytic asymmetric direct functionalization of 3-
disubstituted oxindoles for biological evaluation, we have de-
substituted oxindoles is probably the most versatile method to
veloped a highly enantioselective amination of unprotected 3-
substituted oxindoles 1.8b We also focused on the Michael addition
construct all-carbon or heteroatom-containing tetrasubstituted
carbon stereocenter at the C3 position, via alkylation,3 Mannich,4
fluorination,5 hydroxylation,6 aldol,7 amination8 and Michael
addition reaction.9 However, N-protected 3-substituted oxindoles
were used in most of these protocols, and only very limited
examples were based on the use of unprotected 3-substituted
oxindoles 1.4b,7a–b,8a–b,9b
of unprotected oxindole derivative 1 to nitroolefins,12 because the
desired adducts are very useful in organic synthesis. During our
investigation, Barbas III9c and Shibasaki9d independently reported
the highly enantioselective Michael addition of N-Boc protected 3-
alkylsubstituted oxindole 2 to nitroolefins, respectively. Maruoka
reported chiral PTC-catalyzed base-free Michael addition of
N-Boc protected 3-arylsubstituted oxindole 2 to nitroolefins.9e
Later, Luo and Cheng reported the Michael addition of
N-phenyl 3-substituted oxindole to nitroolefins.9g To the best of
our knowledge, the Michael addition of unprotected 3-substituted
oxindole to nitroolefins has not been reported. Here we wish to
report our preliminary results in this communication.
The difficulty in the direct functionalization of unprotected 3-
substituted oxindoles 1 was possibly due to the high pKa value
of C–H bond at the C3 position, considering the pKa value
of oxindole is 18.2.10 To facilitate the deprotonative activation,
the introduction of electron-withdrawing protecting group to the
nitrogen moiety might lower down the pKa value, for example,
N-acetyl oxindole has a pKa value of 13.0, much lower than that of
oxindole.10 Accordingly, N-Boc protected 3-substituted oxindole
2 is most commonly used for reaction design, allowing easier
deprotonative activation and better enantiofacial control owing to
the bulky shielding group. However, it took three steps to obtain
N-Boc protected oxindole 2 from isatins 4, with the sacrifice of one
more equivalent of (Boc)2O (Scheme 1).11 The direct protection
of 3-substituted oxindole 1 with Boc group was reported to be
problematic due to the competitive O- and N-reactivity. Even
using the new method recently introduced by Trost et al,11 the
yield of the N-Boc 3-substituted oxindole is still moderate. Since
the oxindole moiety in most of the natural products, drugs and
bioactive compounds is without protecting groups, it is more
atom economical and convenient to use unprotected 3-substituted
oxindole 1 for reaction development.
We began reaction development by optimizing reaction pa-
rameters for the Michael addition of 3-phenyloxindole 1b with
nitroolefin 7a. The solvent effect was first evaluated by treating
compound 1b and nitroolefin 7a in the presence of 10 mol%
of CD at 0 ◦C. As shown in Table 1, the reaction proceeded
well in all the screened solvents except cyclohexane (entries 1–
7), possibly due to poor solubility of oxindole 1b in cyclohexane.
Generally, the reaction could finish within two days, affording the
desired product 8a in moderate diastereoselectivity. The dr was
1
determined by H NMR analysis of the crude reaction mixture.
Since reaction in acetone afforded the best diastereoselectivity
(entry 3), the evaluation of different bases was carried out using
acetone as the solvent. Not only organic but inorganic bases
could serve as catalyst for this reaction, but the base obviously
influenced the dr of the product. K2CO3 and Cs2CO3 could readily
catalyze this reaction, but afforded the two diastereomers of
product 8a in almost equal amount (entries 8 and 9). Organic bases
such as triethylamine, DBU, i-Pr2NEt and TMEDA all afforded
inferior dr than cinchonidine (entries 10–13). To our delight, QD
could improve the dr to 5.0 : 1.0. We also tried the addition of
molecular sieves or lowering temperature to further improve the
diastereoselectivity, but no obvious improvement was obtained.
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, De-
partment of Chemistry, East China Normal University, 3663 N. Zhongshan
Road, Shanghai 200062, (P. R. China). E-mail: jzhou@chem.ecnu.edu.cn;
Fax: +86-21-62234560; Tel: +86-21-62234560
† Electronic supplementary information (ESI) available: General experi-
mental procedures and spectral data. See DOI: 10.1039/c004037a
2912 | Org. Biomol. Chem., 2010, 8, 2912–2914
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 1 Reaction optimization
1-(2-thienyl)-2-nitroethene afforded the desired products in good
dr and excellent yield (entries 9–10). However, product 8k derived
from 1-(2-furyl)-2-nitroethene was obtained in lower yield and
moderate dr (entry 11). Alkyl nitroolefins were also workable
under the reaction condition, but afforded the product in lower dr
(entries 12 and 13). Less reactive 3-alkyloxindoles were also tried.
For example, 3-benzyloxindole reacted with nitroolefin 7a at room
temperature for two days to afford product 8n in 61% yield with
moderate dr (1.6 : 1.0, entry 14).
The relative configuration of the product 8a was assigned via
conversion to known compound 9.9e By comparing the 1H NMR
data with the literature report, the relative configuration of the
product 8a was finally determined as shown in the eqn (1). It
should be noted that the stereochemistry shown in Table 1, 2
and eqn (1) was referred to relative configuration, not absolute
configuration. Those of other products 8b–8l were tentatively
assigned by analogy.
Entrya
Base
Solvent
Conv.b
Drc
1
2
CD
CD
CH2Cl2
Toluene
Acetone
t-BuOMe
CH3CN
THF
c-Hexane
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Full
Full
Full
Full
Full
Full
<10%
Full
Full
Full
Full
Full
Full
Full
2.1 : 1.0
1.8 : 1.0
2.7 : 1.0
2.1 : 1.0
1.8 : 1.0
2.6 : 1.0
1.7 : 1.0
1.0 : 1.1
1.0 : 1.0
2.0 : 1.0
1.2 : 1.0
2.0 : 1.0
2.3 : 1.0
5.0 : 1.0
3
4
CD
CD
5
6
CD
CD
7
8
9
10
11
12
13
14
CD
K2CO3
Cs2CO3
Et3N
DBU
i-Pr2NEt
TMEDA
QD
a Reaction scale: 0.1 mmol; b Monitored by TLC analysis and confirmed
by 1H NMR analysis of the crude reaction mixture; c Determined by
1H NMR analysis of the crude reaction mixture. d Abbreviations: CD
(cinchonidine), DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), TMEDA (N,
N, N¢,N¢-tetramethylethylenediamine), QD (quinidine).
(1)
We also tried to develop a catalytic asymmetric Michael addition
of unprotected oxindoles 1 to nitroolefins 7. Reaction optimization
revealed that the catalyst structure significantly influenced the
enantioselectivity of the product (see ESI†). Compared with other
quinidine derivatives examined, bifunctional cinchona alkaloid-
based thiourea catalyst 10 turned out to be the most enantiose-
lective catalyst,13 which could promote the reaction of oxindole
1b and nitroolefin 7d to afford product 8h in up to 85% ee for
major diastereomer with moderate dr (2.2 : 1.0), using CH2Cl2 as
the solvent at 0 ◦C. Unfortunately, only the enantiomeric excess of
product 8h could be analyzed by now, since we can not separate
the diastereomers and enantiomers of other Michael adducts (8a–
g and 8i–n) by chiral HPLC.
Table 2 Substrate scope
Entrya
X
R
R11
8c Yieldb(%) Drc
1
2
3
4
5
6
7
8
H
F
Ph
Ph
Ph
Ph
Ph
Ph
8a 96
8b 87
8c 95
8d 92
8e 95
8f 95
8g 92
8h 85
5.0 : 1.0
4.3 : 1.0
4.3 : 1.0
5.0 : 1.0
4.7 : 1.0
2.3 : 1.0
4.5 : 1.0
3.0 : 1.0
4.8 : 1.0
4.3 : 1.0
2.4 : 1.0
1.7 : 1.0
3.0 : 1.0
1.6 : 1.0
Br Ph
H
H
H
H
H
H
H
H
H
H
H
2-Naphthyl
p-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-CF3C6H4
p-ClC6H4
2,4-Cl2C6H3
2-Naphthyl
2-Thienyl
2-Furanyl
n-Bu
9
8i
8j
92
95
8k 75
10
11
12
13
14d
(2)
8l 95
i-Bu
Ph
8m 78
8n 61
a Reaction scale: 0.25 mmol; b Isolated yield; c Determined by 1H NMR
analysis of the crude reaction mixture; d At room temperature.
In conclusion, we developed the first example of Michael
addition of unprotected 3-substituted oxindoles to nitroolefins.
Under the catalysis of quinidine, fourteen examples of 3,3-
disubstituted oxindole derivatives, with two adjacent quaternary-
tertiary carbon centers, were synthesized in excellent yield and
moderate to good diastereoselectivity. The simple and mild
reaction conditions including air-tolerance, together with the
usefulness of the product, make our method very useful. Initial
investigation revealed that alkaloid-based thiourea catalyst was a
highly enantioselective catalyst for this transformation, affording
the desired product in up to 85% ee with moderate diastereose-
lectivity. Based on the evaluation of the different catalysts derived
from cinchona alkaloids, the development of new bifunctional
chiral cinchona alkaloids catalyst might be promising to expand
Based on the above optimization studies, we next examined
the substrate scope of different 3-substituted oxindole 1 and
nitroolefins 7 in acetone at 0 ◦C, using 10 mol% of quinidine
as catalyst (Table 2). All 3-aryloxindoles worked well to afford the
desired product in excellent yield. The substituents on C5 position
of oxindole or different aryl substituents on the C3 position had
small impact on the diastereoselectivity of the reaction, and all
afforded good diastereoselectivity (entries 1–5). The substituent
of nitroolefin 7 influenced the dr of the reaction to some extent.
In the case of substituted nitrostyrenes, the substituent on the
phenyl ring lowered the diastereoselectivity of the reaction, com-
pared with nitroolefin 7a (entries 6–8). Both 1-(2-napthyl)-2- and
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2912–2914 | 2913
©

View Article Online
the substrate scope and to improve the diastereoselectivity and
enantioselectivity, which is now underway in our lab.
The financial support from the Natural Science Foundation of
China (20902025) and East China Normal University are highly
appreciated.
Yasuda, S. Nakamura, T. Toru and M. Shiro, Angew. Chem., Int. Ed.,
2008, 47, 4157.
6 (a) T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura, T. Toru and S.
Kanemasa, J. Am. Chem. Soc., 2006, 128, 16488; (b) D. Sano, K. Nagata
and T. Itoh, Org. Lett., 2008, 10, 1593.
7 (a) S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru and M.
Shiro, Angew. Chem., Int. Ed., 2007, 46, 8666; (b) K. Shen, X. Liu,
K. Zheng, W. Li, X. Hu, L. Lin and X. Feng, Chem.–Eur. J., 2010,
16, 3736; (c) S. Kobayashi, M. Kobubo, K. Kawasumi and T. Nagano,
Chem.–Asian J., 2010, 5, 490.
Notes and references
1 For reviews, see: (a) C. V. Galliford and K. A. Scheidt, Angew. Chem.,
Int. Ed., 2007, 46, 8748; (b) C. Marti and E. M. Carreira, Eur. J. Org.
Chem., 2003, 2209; (c) S. Hibino and T. Choshi, Nat. Prod. Rep., 2001,
18, 66.
8 (a) L. Cheng, L. Liu, D. Wang and Y.-J. Chen, Org. Lett., 2009, 11, 3874;
(b) Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding, X.-L. Zhao
and J. Zhou, Chem. Commun., 2009, 6753; (c) T. Bui, M. Borregan and
C. F. Barbas III, J. Org. Chem., 2009, 74, 8935; (d) S. Mouri, Z. Chen,
H. Mitsunuma, M. Furutachi, S. Matsunaga and M. Shibasaki, J. Am.
Chem. Soc., 2010, 132, 1255.
9 (a) R. He, C. Ding and K. Maruoka, Angew. Chem., Int. Ed., 2009, 48,
4559; (b) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B.
Giannichi, L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur. J.,
2009, 15, 7846; (c) T. Bui, S. Syed and C. F. Barbas III, J. Am.
Chem. Soc., 2009, 131, 8758; (d) Y. Kato, M. Furutachi, Z. Chen, H.
Mitsunuma, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009,
131, 9168; (e) R. He, S. Shirakawa and K. Maruoka, J. Am. Chem.
Soc., 2009, 131, 16620; (f) X. Li, Z.-G. Xi, S. Luo and J.-P. Cheng, Org.
Biomol. Chem., 2010, 8, 77; (g) X. Li, B. Zhang, Z.-G. Xi, S. Luo and
J.-P. Cheng, Adv. Synth. Catal., 2010, 352, 416.
2 For a review, see: (a) B. M. Trost and M. K. Brennan, Synthesis, 2009,
3303; (b) for intramolecular coupling reactions, see: T. Matsuura, L. E.
Overman and D. J. Poon, J. Am. Chem. Soc., 1998, 120, 6500; (c) A. B.
Dounay, K. Hatanaka, J. J. Kodanko, M. Oestreich, L. E. Overman,
L. A. Pfeifer and M. M. Weiss, J. Am. Chem. Soc., 2003, 125, 6261;
(d) C. A. Busacca, D. Grossbach, R. C. So, E. M. O’Brien and E. M.
Spinelli, Org. Lett., 2003, 5, 595; (e) A. Pinto, Y. Jia, L. Neuville and J.
Zhu, Chem.–Eur. J., 2007, 13, 961; (f) S. Lee and J. F. Hartwig, J. Org.
Chem., 2001, 66, 3402; (g) E. P. Ku¨ndig, T. M. Seidel, Y. Jia and G.
Bernardinelli, Angew. Chem., Int. Ed., 2007, 46, 8484; (h) Y.-X. Jia,
J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Ku¨ndig, Chem.
Commun., 2008, 4040; (i) Y. Yasui, H. Kamisaki and Y. Takemoto, Org.
Lett., 2008, 10, 3303; (j) for nucleophilic additions to isatins, see: R.
Shintani, M. Inoue and T. Hayashi, Angew. Chem., Int. Ed., 2006, 45,
3353; (k) D. Tomita, K. Yamatsugu, M. Kanai and M. Shibasaki, J. Am.
Chem. Soc., 2009, 131, 6946; (l) J. Itoh, S. B. Han and M. J. Krische,
Angew. Chem., Int. Ed., 2009, 48, 6313; (m) G. Luppi, P. G. Cozzi, M.
Monari, B. Kaptein, Q. B. Broxterman and C. Tomasini, J. Org. Chem.,
2005, 70, 7418; (n) S. Nakamura, N. Hara, H. Nakashima, K. Kubo,
N. Shibata and T. Toru, Chem.–Eur. J., 2008, 14, 8079; (o) T. Itoh,
H. Ishikawa and Y. Hayashi, Org. Lett., 2009, 11, 3854; (p) F. Xue, S.
Zhang, L. Liu, W. Duan and W. Wang, Chem.–Asian J., 2009, 4, 1664;
(q) N. V. Hanhan, A. H. Sahin, T. W. Chang, J. C. Fettinger and A. K.
Franz, Angew. Chem., Int. Ed., 2010, 49, 744; (r) for other methods,
see: I. D. Hills and G. C. Fu, Angew. Chem., Int. Ed., 2003, 42, 3921;
(s) T. A. Duffey, S. A. Shaw and E. Vedejs, J. Am. Chem. Soc., 2009,
131, 14; (t) E. C. Linton and M. C. Kozlowski, J. Am. Chem. Soc., 2008,
130, 16162; (u) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli and P. Melchiorre, Angew. Chem.,
Int. Ed., 2009, 48, 7200; (v) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao
and L.-Z. Gong, J. Am. Chem. Soc., 2009, 131, 13819; (w) S. Ma, X.
Han, S. Krishnan, S. C. Virgil and B. M. Stoltz, Angew. Chem., Int.
Ed., 2009, 48, 8037; (x) B. M. Trost, N. Cramer and S. M. Silverman,
J. Am. Chem. Soc., 2007, 129, 12396.
10 F. G. Bordwell and H. E. Fried, J. Org. Chem., 1991, 56, 4218.
11 Please see the surpporting information of ref. 5a, also see: B. M. Trost,
Y. Zhang and T. Zhang, J. Org. Chem., 2009, 74, 5115.
12 For reviews on the application of nitroolefins in asymmetric Michael
addition, see: (a) O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org.
Chem., 2002, 1877; (b) A. Alexakis and C. Benhaim, Eur. J. Org. Chem.,
2002, 3221; (c) D. Almasi, D. A. Alonso and C. Na´jera, Tetrahedron:
Asymmetry, 2007, 18, 299; (d) J. L. Vicario, D. Bad´ıa and L. Carrillo,
Synthesis, 2007, 2065; (e) S. Mukhrjee, J. W. Yang, S. Hoffmann and B.
List, Chem. Rev., 2007, 107, 5471; (f) T. Jerphagnon, M. G. Pizzuti, A. J.
Minnaard and B. L. Feringa, Chem. Soc. Rev., 2009, 38, 1039; (g) for
some selected examples, see: Y. Sui, L. Liu, J.-L. Zhao, D Wang and
Y.-J. Chen, Tetrahedron, 2007, 63, 5173; (h) B. M. Trost and C. Mu¨ller,
J. Am. Chem. Soc., 2008, 130, 2438; (i) R. P. Herrera, V. Sgarzani, L.
Bernardi and A. Ricci, Angew. Chem., Int. Ed., 2005, 44, 6576; (j) Y.-X.
Jia, S.-F. Zhu, Y. Yang and Q.-L. Zhou, J. Org. Chem., 2006, 71, 75;
(k) T.-Y. Liu, H.-L. Cui, Q. Chai, J. Long, B.-J. Li, Y. Wu, L.-S. Ding
and Y.-C. Chen, Chem. Commun., 2007, 2228; (l) C.-L. Cao, M.-C. Ye,
X.-L. Sun and Y. Tang, Org. Lett., 2006, 8, 2901; (m) M. Nielsen, W.
Zhuang and K. A. Jørgensen, Tetrahedron, 2007, 63, 5849; (n) J. Wu,
D. M. Mampreian and A. H. Hoveyda, J. Am. Chem. Soc., 2005, 127,
4584; (o) L. Bernardi, F. Fini, M. Fochi and A. Ricci, Synlett, 2008,
1857; (p) N. J. A. Martin, X. Cheng and B. List, J. Am. Chem. Soc.,
2008, 130, 13862; (q) P. Garc´ıa-Garc´ıa, A. Lade´peˆche, R. Halder and
B. List, Angew. Chem., Int. Ed., 2008, 47, 4719; (r) Y.-F. Sheng, Q. Gu,
A.-J. Zhang and S.-L. You, J. Org. Chem., 2009, 74, 6899; (s) H. Liu,
S.-F. Lu, J. Xu and D.-M. Du, Chem.–Asian J., 2008, 3, 1111; (t) C.-L.
Cao, Y.-Y. Zhou, J. Zhou, X.-L. Sun, Y. Tang, Y.-X. Li, C.-Y. Li and J.
Sun, Chem. Eur. J., 2009, 15, 11384.
3 (a) T. B. K. Lee and G. S. K. Wong, J. Org. Chem., 1991, 56, 872;
(b) B. M. Trost and M. U. Frederiksen, Angew. Chem., Int. Ed., 2005,
44, 308; (c) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2006, 128,
4590; (d) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2007, 129,
14548; (e) B. M. Trost and Y. Zhang, Chem.–Eur. J., 2010, 16, 296;
(f) K. Jiang, J. Peng, H.-L. Cui and Y.-C. Chen, Chem. Commun., 2009,
3955.
4 (a) X. Tian, K. Jiang, J. Peng, W. Du and Y.-C. Chen, Org. Lett., 2008,
10, 3583; (b) L. Cheng, L. Liu, H. Jia, D. Wang and Y.-J. Chen, J. Org.
Chem., 2009, 74, 4650.
5 (a) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura and M. Sodeoka,
J. Am. Chem. Soc., 2005, 127, 10164; (b) N. Shibata, J. Kohno, K. Takai,
T. Ishimaru, S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem.,
Int. Ed., 2005, 44, 4204; (c) T. Ishimaru, N. Shibata, T. Horikawa, N.
13 For a review about catalyst 10, see: (a) S. J. Connon, Chem. Commun.,
2008, 2499; (b) For pioneer work on this catalyst, see: B.-J. Li, L. Jiang,
M. Liu, Y.-C. Chen, L.-S. Ding and Y. Wu, Synlett, 2005, 603; (c) B.
Vakulya, S. Varga, A. Csa´mpai and T. Soo´s, Org. Lett., 2005, 7, 1967;
(d) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
44, 6367; (e) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005,
4481.
2914 | Org. Biomol. Chem., 2010, 8, 2912–2914
This journal is
The Royal Society of Chemistry 2010
©