Highly enantioselective and organocatalytic α-amination of 2-Oxindoles

Article abstract of DOI:10.1021/ol901405r

Figur Presented An effective method for the asymmetric synthesis of 3-amino-2-oxindoles was developed. The tetrasubstituted chiral carbon center was generated by asymmetric amination of N-unprotected 2-oxindoles with azodicarboxylate catalyzed by commercial biscinchona alkaloids in good to excellent yields with high enantioselectivities.

Full text of DOI:10.1021/ol901405r

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3874-3877
Highly Enantioselective and
Organocatalytic r-Amination of
2-Oxindoles
Liang Cheng,† Li Liu,*,† Dong Wang,† and Yong-Jun Chen*,†
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, and Graduate School of Chinese Academy of
Sciences, Beijing 100049, China
lliu@iccas.ac.cn; yjchen@iccas.ac.cn
Received June 21, 2009
ABSTRACT
An effective method for the asymmetric synthesis of 3-amino-2-oxindoles was developed. The tetrasubstituted chiral carbon center was generated
by asymmetric amination of N-unprotected 2-oxindoles with azodicarboxylate catalyzed by commercial biscinchona alkaloids in good to excellent
yields with high enantioselectivities.
As important substructures, chiral 3,3-disubstituted 2-oxin-
doles constitute a ubiquitous class of heterocycles found in
numerous natural products, marketed drugs, and drug can-
didates.1 Among them, 3-amino-2-oxindole compounds bear-
ing a chiral quaternary carbon center have been investigated
extensively and recognized as core structures in a variety of
biologically active compounds, which exhibit significant
pharmaceutical properties (Figure 1),2 and challenging targets
for medicinal chemistry and synthetic organic chemistry.
Figure 1. Bioactive disubstituted 3-amino-2-oxindoles.
A plethora of different procedures have been developed
to accomplish the synthesis of tetrasubstituted 3-amino-2-
oxindoles, including cyclization of o-chlorinated anilines,3
alkylation or addition of 2-oxindoles,4 and other miscel-
laneous sequences.5 However, these methods showed a lack
of generality and gave variable yields, and most of them were
hard to perform in a catalytic asymmetric manner.3c,4a,e
† Institute of Chemistry, Chinese Academy of Sciences.
(1) Brown, R. T. In The Chemistry of Heterocyclic Compounds, Part 4.
Indoles: The Monoterpenoid Indole Alkaloids; Saxton, J. E., Eds.; John
Wiley and Sons: New York, 1983; Vol. 25.
(4) For selected examples, see: (a) Emura, T.; Esaki, T.; Tachibana, K.;
Shimizu, M. J. Org. Chem. 2006, 71, 8559. (b) Sun, C.; Lin, X.; Weinreb,
S. M. J. Org. Chem. 2006, 71, 3159. (c) Magnus, P.; Turnbull, R. Org.
Lett. 2006, 8, 3497. (d) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org.
Chem. 2005, 70, 3324. (e) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti,
A.; Silvani, A. J. Org. Chem. 2009, 74, 4537.
(2) (a) Ochi, M.; Kawasaki, Y.; Kataoka, H.; Uchio, Y. Biochem.
Biophys. Res. Commun. 2001, 283, 1118. (b) Bernard, K.; Bogliolo, S.;
Ehrenfeld, J. Br. J. Pharmacol. 2005, 144, 1037. (c) Chen, L.; Yang, S.;
Zhang, J.; Zhang, Z. U. S. Patent 81810 A1, 2008.
(3) (a) Marsden, S. P.; Watson, E. L.; Sraw, S. A. Org. Lett. 2008, 10,
2905. (b) Watson, E. L.; Marsden, S. P.; Raw, S. A. Tetrahedron Lett.
2009, 50, 3318. (c) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden,
S. P.; Ku¨ndig, E. P. Chem. Commun. 2008, 4040.
(5) For selected examples, see: (a) Bella, A. F.; Slawin, A. M. Z.;
Walton, J. C. J. Org. Chem. 2004, 69, 5926. (b) O’Connor, S. J.; Liu, Z.
Synlett 2003, 14, 2135.
10.1021/ol901405r CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

Recently, the catalytic asymmetric nucleophilic addition
reaction of 2-oxindole has attracted considerable attention.6,7
Since significant advances have been achieved in the metal-
catalyzed or organocatalytic asymmetric R-amination of
carbonyl compounds with azodicarboxylates,8 we envisioned
that the enantioselective electrophilic amination of 2-oxindole
with azodicarboxylates would be a direct method for the
synthesis of 3-amino-2-oxindole alkaloid compounds. How-
ever, to the best of our knowledge, the use of oxindoles as
simple R-aryl amides has never been reported.
Herein we report the first enantioselective synthesis of the
title compounds through the amination of various 2-oxindoles
with azodicarboxylate catalyzed by commercial biscinchona
alkaloids.9,10 This appealing methodology, using readily
available N-unprotected 3-monosubstituted 2-oxindoles as
starting materials,11 will undoubtedly provide effective
method for the enantioselective synthesis of functionalized
and complex 3,3′-disubstituted 3-amino-2-oxindole alkaloids.
Initially, the enantioselective amination reaction of 2-oxindole
1a with 1.0 equiv of diethyl azodicarboxylate (DEAD, 2a) in
dichloromethane in the presence of natural cinchona alkaloids
4a-d (10 mol %) (Figure 2) was carried out (Scheme 1).
Table 1. Catalyst Screening for Enantioselective R-Amination of
2-Oxindoles 1a with 2a
entry
2
catalystb
products
yieldc (%)
ee of 3d (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2c
2d
4a
4b
4c
4d
4e
4f
4e
4e
4e
3a
3a
3a
3a
3a
3a
3b
3c
3d
45
63
50
69
47
48
quant
85
58
7
5
1
7
33
-31
57
39
<10
a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), CH2Cl2 (0.2 mL),
room temperature. b Catalyst loading: 10 mol %. c Isolated yields. d Determined
by chiral HPLC analysis.
reaction (Figure 2).12,13 While the catalysts 4g,h were not
suitable for the enantioselective amination of 1a with 2a
(yields 13-17%, ee 1-40%), by using (DHQD)2PHAL 4e
and (DHQ)2PHAL 4f as catalysts, the adduct 3a was
produced in 47-48% yield with moderate enantioselectivities
(ee 31-33%) (Table 1, entries 5 and 6). Catalysts 4e and 4f
showed nearly equal reactivity and enantioselectivity with
opposite configuration.
Next, we assessed the influence of the alkyl group R3 at
the azodicarboxylate. To our great delight, the enantio-
selectivity was dramatically improved to 57% ee when 2b
(DIAD, R3 ) i-Pr) was used as an amination reagent (Table
1, entry 7). Interestingly, when more steric hindered 2c
(DTAD, R3 ) t-Bu) was applied, the ee value of the product
3c decreased to 39% (entry 8), while 2d (DBAD, R3 ) Bn)
afforded a product mixture with very poor enatioselectivity
(entry 9).
The influence of solvents was extensively studied. Interest-
ingly, though the reaction of 1a and 1b with 2a could
proceeded to completion in a wide range of solvents, a large
variation of enantioinduction was observed (Table 2).13
The reaction performed in Et2O, a high dielectric constant
oxygenated solvent, which was utilized in the highly enan-
Figure 2. Catalysts for screening.
(6) Aldol and Mannich reactions of oxindoles: (a) Ogawa, S.; Shibata,
N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiri, M. Angew. Chem., Int. Ed.
2007, 46, 8666. (b) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org.
Lett. 2008, 10, 3583. (c) He, R.; Ding, C.; Maruoka, K. Angew. Chem., Int.
Ed. 2009, 48, 4559. (d) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J.
J. Org. Chem. 2009, 74, 4650. Michael addition: (e) Galzerano, P.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem.sEur. J. [Online early access]. DOI:
10.1002/chem.200802466. Published Online: Jan 29, 2009. (f) Bui, T.; Syed,
S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131, 8758. (g) Kato, Y.;
Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 9168, and ref 6c Allylation: (h) Trost, B. M.;
Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308. (i) Trost, B. M.;
Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (j) Trost, B. M.; Zhang, Y.
J. Am. Chem. Soc. 2007, 129, 14548. (k) Jiang, K.; Peng, J.; Cui, H.-L.;
Although 1a was smoothly converted to the adduct 3a in
moderate yields (45-69%), unfortunately, very poor enan-
tioselectivities of the product were obtained (Table 1, entries
1-4). Various biscinchona alkaloids were screened for this
Scheme 1
Chen, Y.-C. Chem. Commun. 2009, 3955
.
(7) For recent examples of fluorination and hydroxylation of 2-oxindoles,
see: (a) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura,
S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157. (b) Sano,
D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593
(8) (a) Genet, J.-P.; Creck, C.; Lavergne, D. In Modern Amination
Methods; Ricci, A., Eds.; Wiley-VCH: Weinheim, 2000; Chapter 3. (b)
.
Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292
.
Org. Lett., Vol. 11, No. 17, 2009
3875

demonstrated that both enantiomers could be synthesized
upon the selection of the appropriate cinchona alkaloid.
Encouraged by these results, the generality of this addition
reaction was next examined. As summarized in Table 3,
Table 2. Solvent Effect on the R-Amination of 2-Oxindoles 1a
and 1b with 2ba
entry
1
solvent
products yieldb (%) ee of 3c (%)
1
1a Et2O
1b Et2O
1a toluene
1a hexane
1a DCE
3b
3e
3b
3b
3b
3e
3b
3e
3e
3e
3e
99
83
39
53
55
2d
3
quant
trace
quant
88
quant
99
95
90
99
Table 3. Asymmetric Organocatalytic Addition of 2-Oxindoles
1 with DIAD 2ba
4
5
62
90
78
93
91
6d
7d
8d
9d, e
10d, f
11d, g
1b DCE
1a 1,1,2-TCA
1b 1,1,2-TCA
1b 1,1,2-TCA
1b 1,1,2-TCA
1b 1,1,2-TCA
90
-91
entry
1
X
R
3
yieldb (%) eec (%)
a Reaction conditions (unless otherwise noted): 1 (0.2 mmol), 2b (0.2
mmol), 4e (0.02 mmol, 10 mol %), solvent (0.2 mL), room temperature.
b Isolated yields. c Determined by chiral HPLC analysis. d Solvent (2 mL).
e Catalyst loading: 5 mol %. f Catalyst loading: 2 mol %. g 4f was used as
the catalyst.
1
2
3
4
5
6
7
8
1a
1b
1e
1f
1g
1h
1i
1j
1k
1l
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
CH2Ph
3b
3e
3f
3g
3h
3i
3j
3k
3l
quant
99
78
93
CH2-C6H4-4-Cl
80
96
CH2-C6H4-4-Br
CH2-C6H4-4-OMe
CH2-C6H4-4-Me
CH2-C6H4-2-Br
CH2-C6H4-2-CF3
CH2-C6H4-2-OMe
CH2-C6H4-2-Me
CH2-C6H3-2,6-(Me)2
97
90
80
93
65
97
tioselective aldol-type reaction of oxindoles with ethyl
trifluoropyruvate catalyzed by the same cinchona alkaloid
(DHQD)2PHAL 4e,6a did not give desirable selectivity
(entries 1 and 2). The use of nonpolar solvents, such as
toluene and hexane, did not improve the results either (entries
3 and 4). However, the use of aprotic dipolar chlorinated
alkanes as solvents in the reaction provided facile product
isolation and the corresponding adducts was obtained in
significantly improved enantioselectivities (entries 5-7).
The best solvent for this reaction was found to be 1,1,2-
TCA (1,1,2-trichloroethane), and the enantioselectivity of 3e
was further increased up to 93% by performing the reaction
in a dilute concentration (0.1 M) (entry 8), which required
no additional additives and enabled milder reaction condi-
tions. Lowering the catalyst loading led to a decrease of yield
and enantioselectivity of the product, and a longer reaction
time was required (entries 9-10). Most importantly, the
amination catalyzed by (DHQ)2PHAL 4f also proceeded in
excellent yield and enantioselectivity (entry 11), which
54
96
79
93
9
87
90
10
11
12
13
14
15
16
3m
3n
83
91
1m
1n
1o
quant
90
88
89
CH2-C6H3-3,4-OCH2O 3o
CH2-2-thiophene
3p
3q
3r
3s
quant
71
96
94
88
1p Cl CH2Ph
1q Br Me
1r
85(99)d
63
H
Ph
74
a Reaction conditions: 1 (0.2 mmol), 2b (0.2 mmol), 1,1,2-TCA (2 mL),
(DHQD)2PHAL 4e (10 mol %), room temperature. b Isolated yields.
c Determined by chiral HPLC analysis. d The value in parentheses refer to
the single crystal.
under the optimized reaction conditions, the asymmetric
addition of 2-oxindoles (1e-r) to DIAD 2b catalyzed by
(DHQD)2PHAL 4e was then evaluated, which exhibited a
broad substrate scope and tolerance toward the presence of
various substituents.
Regardless of the electronic or steric nature of the
substituents on the benzylic rings at C-3 position, the
asymmetric R-amination of 2-oxindoles consistently gave
good yields (up to quant) and very high enantioselectivities
(up to 97%) (entries 3-12). This transformation tolerated
significant functionalization in the aromatic rings, both of
electron-donating (OMe, OCH2O, Me) and electron-with-
drawing groups (Cl, Br, CF3), including ortho- or para-
substitutions, can be accommodated.
The variation of the C-3 benzylic substituent to an
heteroaryl group (thiephene) was also possible to give the
expected product 3p in quantitative yield with 94% ee (entry
13). We were pleased to find that the catalytic system was
also effective for the asymmetric amination of 5-halogenated-
2-oxindoles, which gave the adducts with good enantio-
selectivities (entries 14 and 15).
(9) For examples of catalytic asymmetric R-amination using cinchona
alkaloids catalysts, see: (a) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 8120. (b) Pihko, P. M.; Pohjakallio, A. Synlett 2004,
2115. (c) Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 11614. (d) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7,
167. (e) Liu, T.-Y.; Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.;
Chen, Y.-C. Org. Lett. 2007, 9, 3671.
(10) For selected examples of catalytic asymmetric R-amination using
other organocatalysts, see: (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656.
(b) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org. Lett. 2005, 7, 3885.
(c) Franzn, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 18296. (d) Terada, M.; Nakano, M.; Ube, H.
J. Am. Chem. Soc. 2006, 128, 16044. (e) Kim, S. M.; Lee, J. H.; Kim,
D. Y. Synlett 2008, 2659. (f) He, R.; Wang, X.; Hashimoto, T.; Maruoka,
K. Angew. Chem., Int. Ed. 2008, 47, 9466.
(11) For a few reported catalytic asymmetric reaction using N-H
2-oxindoles, see ref 6a,d,e.
(12) For reviews on modified cinchona alkaoids, see: (a) Kacprzak, K.;
Gawron´ski, J. Synthesis 2001, 961. (b) Tian, S.-K.; Chen, Y.; Hang, J.;
Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. For some
pioneering work using biscinchona alkaloids, see: (c) Tian, S.-K.; Deng,
L. J. Am. Chem. Soc. 2001, 123, 6195. (d) McDaid, P.; Chen, Y.; Deng, L.
Angew. Chem., Int. Ed. 2002, 41, 338. (e) Tian, S.-K.; Hong, R.; Deng, L.
J. Am. Chem. Soc. 2003, 125, 9900.
However, 3-phenyl-2-oxindole 1r afforded the product 3s
in acceptable yield with moderate enantioselectivity, which
(13) See the Supporting Information for details.
3876
Org. Lett., Vol. 11, No. 17, 2009

might be due to its high activity toward electrophiles (entry
16). Thus, we have developed an efficient enantioselective
R-amination of N-unsubstituted 2-oxindoles with broad
generality, which is operationally convenient and could be
performed without exclusion of air or moisture.
It should be indicated that the N-H subunit of oxindole is
necessary for the reaction of 2-oxindole with azodicarboxy-
lates.11,14 Low conversions and poor enantioselectivities were
observed in the direct amination of N-protected oxindoles
(1c, R2 ) Me and 1d, R2 ) Boc) with 2b.13
The absolute configuration of the newly created chiral
quaternary carbon center in the reaction adducts was deduced
as (S) by X-ray single-crystal analysis of 3r after recrystal-
lization.13
Cinchona alkaloid derivatives are conformationally flexible
in solution;15a,c however, in the present state, the transition
state for the formation of (S)-3-amino-2-oxindoles under the
catalysis of (DHQD)2PHAL 4e was presumably through an
open conformation, in which the deprotonated enolated
2-oxindole was supposed to be locked in the open U-shaped
cleft where the aromatic PHAL ring formed the bottom while
two quinoline rings from DHQD alkaloids formed the walls
(Figure 3).6a,15
The enolated 2-oxindole was deprotonated by the quinu-
clidine nitrogen of one alkaloid and then stabilized by
potential π-π stacking with the other alkaloid. The NdN
double bond in azodicarboxylate, which was activated by
hydrogen bonding through protonated quinuclidine nitrogen,
was attacked preferably from the uncovered Si-face of
oxindole, while the (S)-enantiomers were generated pre-
dominately. Nevertheless, further studies should be required
to elucidate the mechanism.
In conclusion, the first organocatalytic enantioselective
amination reaction of N-unprotected 2-oxindoles was devel-
oped by using dialkyl azodicarboxylate as an amination
reagent in the presence of biscinchona alkaloid catalysts. The
catalytic system was applied to the formation of (S)-3-amino-
2-oxindoles in excellent yields and enantioselectivities.
Application of the present method for the synthesis of natural
and bioactive compounds is currently under investigation.
Acknowledgment. We thank the National Natural Science
Foundation of China, Ministry of Science and Technology
(Nos. 2009ZX09501-006 and 2010CB833305) and the
Chinese Academy of Sciences for the financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, chiral chromatographic analy-
sis for all new compounds, and single-crystal structure data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
OL901405R
(14) For recent examples in which the N-H of indole plays a crucial
role, see: (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576. (b) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang,
C.-M.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46, 5565.
(15) (a) Dijkstra, G. D. H.; Kellog, R. M.; Wynberg, H.; Svendsen, J. S.;
Marko´, I.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069. (b) Corey,
E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579. (c) Corey, E. J.;
Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038. (d) Marko, I. E.; Svendsen,
J. S. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg, 2000; Chapter
20.
Figure 3
. Proposed transition state for the enantioselective ami-
nation of 2-oxindoles to give (S)-enantiomers.
Org. Lett., Vol. 11, No. 17, 2009
3877