Facile creation of 2-substituted indolin-3-ones by using primary-secondary diamine catalysts

Article abstract of DOI:10.1002/chem.201100144

Indolin-3-ones with a chiral center at the 2-position are encountered in a large variety of natural products and can be used in the total synthesis of biologically active alkaloids such as (+)-austamide, (-)-brevianamideB, (+)-aristotelone, isatisineA, an

Full text of DOI:10.1002/chem.201100144

DOI: 10.1002/chem.201100144
Facile Creation of 2-Substituted Indolin-3-ones by Using Primary–Secondary
Diamine Catalysts
Wangsheng Sun,[a] Liang Hong,[a] and Rui Wang*[a, b]
Indolin-3-ones with a chiral center at the 2-position are
encountered in a large variety of natural products and can
be used in the total synthesis of biologically active alkaloids
such as (+)-austamide, (À)-brevianamideB, (+)-aristote-
lone, isatisineA, and hinckdentineA.[1] Consequently, these
structures have been the target of considerable synthetic
effort and a variety of preparative methods have already
been developed.[2] Among these common methods, the Mi-
chael addition[3] has been the most fascinating and powerful
reaction.[4] However, the enantioselective versions of this re-
action are still surprisingly rare and less exploited.[5] Thus,
the development of asymmetric catalytic methods for the
construction of chiral indolin-3-ones is particularly appeal-
ing.
catalysis, the use of chiral secondary amines has proven to
be an extremely powerful approach and has dominated the
field of amino catalysis.[6] In contrast, less progress has been
made in the development of chiral primary amine catalysts.
Recently, primary–tertiary diamine catalysts derived from
cinchona alkaloids (type I) or 1,2-diamino-cyclohexane
(type II) have emerged as readily available, highly versatile,
and extremely powerful catalysts in asymmetric synthesis.[7]
Although these catalysts often avoid the need for multiple
screening of new catalysts to determine the optimal reaction
conditions, they may not always be the best candidates to
solve some specific and challenging reactions. Therefore, it
is necessary to develop some new chiral amine catalysts.
Three facts must be taken into account when preparing
these catalysts: 1) the starting material should be commer-
cially available and cheap; 2) the synthesis should be amena-
ble to fine-tuning of the substituents at the nitrogen atoms;
and most importantly, 3) the framework can be easily modi-
fied. We envisioned that natural a-amino acids would be the
starting material of choice.[8] Herein, we describe the use of
primary–secondary diamine catalysts derived from natural
a-amino acids (type III) in the construction of 2-substituted
indolin-3-ones.
On the other hand, organocatalysis has been one of the
most rapidly growing and fruitful research areas in synthetic
organic chemistry during the last decade. In modern organo-
[a] W. Sun, L. Hong, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs
of Gansu Province
Recently, significant progress has been made in the con-
struction of chiral indole motifs by using oxygenated indoles
as starting materials (Scheme 1).[9] However, they are more
generally focused upon modifications of isatin[10] or oxin-
State Key Laboratory of Applied Organic Chemistry
and Institute of Biochemistry and Molecular Biology
Lanzhou University, Lanzhou, 730000 (P.R. China)
Fax : (+86)931-891-2567
E-mail: wangrui@lzu.edu.cn
[b] Prof. Dr. R. Wang
State Key Laboratory of Chiroscience
and Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Kowloon (Hong Kong)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100144.
Scheme 1. Oxygenated indoles. R=H, alkyl, or aryl.
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dole[11] at the 3-position; research in transformations of in-
dolin-3-one at the 2-position still remains elusive. Our group
have also developed very simple primary–secondary diamine
catalysts based on natural amino acids for the asymmetric
reactions of a,b-enones. In connection with our interest in
developing efficient organocatalytic-constructing chiral
indole motifs,[12] we anticipated that this tactic might be ap-
plied in the construction of chiral indolin-3-ones catalyzed
by a primary–secondary diamine catalyst.
conditions defined through our model studies. In general,
the reaction proceeded smoothly with a wide range of
enones. For enones with aromatic substituents, almost opti-
cally pure products could be obtained in high yields and ex-
cellent diastereo- and enantioselectivities, irrespective of the
electronic nature or positions of the substituents on the
phenyl ring (Table 2, entries 1–12). Significantly, alterations
of the heteroaryl substituents did not impact negatively on
In the exploratory study, we carried out the model reac-
tion of indolin-3-one 1 with enone 2a to evaluate the cata-
lysts of type III (Table 1). When catalyst 3a (with two pri-
mary amino groups derived from l-phenylalanine) was used,
Table 2. Scope of the reaction.[a]
Table 1. Reaction conditions optimization.[a]
Entry
R1
R2
4
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
Ph
2-FPh
Me, 2a
Me, 2b
Me, 2c
Me, 2d
Me, 2e
Me, 2 f
Me, 2g
Me, 2h
Me, 2i
Me, 2j
Me, 2k
Me, 2l
Me, 2m
Me, 2n
Et, 2o
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
85
87
81
85
78
74
83
80
75
83
72
78
80
80
81
60
61
66
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4.2:1
97
96
95
96
95
95
96
95
95
96
96
97
92
92
95
95
2-ClPh
2-BrPh
2-MePh
2-MeOPh
3-ClPh
3-BrPh
3-MePh
3-MeOPh
4-ClPh
4-BrPh
2-furyl
2-thienyl
Ph
9
10
11
12
13
14
15
16
17[e]
18[e]
Entry
Catalyst
Solvent
Conversion
[%][b]
d.r.[b]
2:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
ee
[%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3 f
3 f
3 f
3 f
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
71
81
91
94
90
90
91
83
77
43
21
88
95
90
92
97
95
96
91
76
6.6:1
6:1
8:1
2:1
-(CH2)3-, 2p
n-C3H7
n-C5H11
Me, 2q
Me, 2r
93/90
94/90
1.1:1
[a] Unless otherwise specified, the reaction was carried out with
1
(0.20 mmol) and 2 (0.30 mmol) in the presence of 3 f (20 mol%) and
TFA in CHCl3 (1.0 mL) at 308C for 72 h. [b] Isolated yield of both diaste-
reoisomers. [c] Determined by 1H NMR analysis of the crude mixture.
[d] For analysis of the ee values of the products, see the Supporting Infor-
mation. [e] 30 mol% 3 f and TFA was used.
9
10
Et2O
CH3OH
[a] Unless otherwise specified, the reaction was carried out with
1
(0.20 mmol) and 2a (0.30 mmol) in the presence of an organocatalyst 3
(0.04 mmol), trifluoroacetic acid (TFA) (0.04 mmol), and solvent
(1.0 mL) for 72 h. [b] Diastereomeric ratio (d.r.) determined by 1H NMR
analysis of the crude mixture. [c] Determined by chiral HPLC on a Chir-
alpak OD column.
the enantioselectivity of the reaction (Table 2, entries 13 and
14). No decrease in yield and enantiomeric excess (ee) value
was observed for the slightly sterically hindered enone 2o,
albeit with slight decrease in diastereoselectivity (Table 2,
entry 15).[13] Notably, cyclic enone 2p also participates well
in this reaction; the products could be obtained in moderate
yields, with excellent diastereo- and enantioselectivities
(Table 2, entry 16). For the less reactive alkyl substituted
enones 2q and 2r, excellent enantioselectivities could be
also obtained, although the corresponding products were ob-
tained with low diastereoselectivities (Table 2, entries 17 and
18).
Finally, the absolute configuration of product 4g was de-
termined by single-crystal X-ray analysis.[14] This result
prompted us to assume a possible mechanism for the asym-
metric Michael addition. We envisioned that catalyst 3 f
would act in a bifunctional fashion (Figure 1). The primary
amine moiety activates the enone 2 via the formation of an
only a low enantioselectivity was achieved (Table 1, entry 1).
Fortunately, its monoalkylated analogues 3b–3e provided
promising results; the length of the alkyl chain influenced
the catalytic activity of 3 and the N-ethylated catalyst 3c
gave the best result (Table 1, entries 2–5). Moreover, chang-
ing the benzyl group of 3c to a 3-indolyl group resulted in
the optimum catalyst 3 f derived from l-tryptophan
(Table 1, entry 6). To further improve the enantioselectivity,
several solvents were screened; CHCl3 proved to be the op-
timal solvent for the reaction (Table 1, entries 6–10). Finally,
optimum results were obtained when using catalyst 3 f in
combination with CF3CO2H in CHCl3 at 308C for 72 h
(Table 1, entry 6).
Encouraged by this promising result, we next investigated
the scope and limitations of the reaction under the optimal
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Figure 1. Proposed transition state. Ac=acetyl.
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intermediate after the addition step.
In summary, we have developed a highly enantioselective
conjugate addition of 1-acetylindolin-3-one to enones. The
reaction is efficiently catalyzed by a readily available pri-
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in good yields, moderate to high diastereoselectivities, and
excellent enantioselectivities. The high enantioselectivity
and broad substrate scope of this transformation make it po-
tentially useful in the synthesis of chiral indolin-3-one deriv-
atives. The synthetic applications of this transformation are
currently ongoing in our laboratory.
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Experimental Section
General procedure: Indolin-3-one 1 (0.20 mmol) was added to a stirred
mixture of enone 2 (0.30 mmol), organocatalyst 3 f (0.04 mmol), and tri-
fluoroacetic acid (TFA, 0.04 mmol) in dry CHCl3 (1.0 mL) at 308C. After
72 h, the reaction mixture was directly purified by silica gel chromatogra-
phy without workup and fractions were collected and concentrated under
vacuum to provide the pure desired product 4.
Acknowledgements
We gratefully acknowledge the financial support from NSFC (20932003,
90813012) and the National S&T Major Project of China (2009ZX09503–
017).
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Keywords: enantioselectivity
· enones · indolin-3-one ·
michael addition · organocatalysis
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2-Substituted Indolin-3-ones by Using Primary–Secondary Diamine Catalysts
COMMUNICATION
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Received: January 14, 2011
Published online: April 18, 2011
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