Asymmetric nitroaldol reactions of nitroalkanes with isatins catalyzed by bifunctional cinchona alkaloid derivatives

Article abstract of DOI:10.1002/ejoc.201100824

The enantioselective nitroaldol reactions of isatins with nitroalkanes were smoothly carried out by organocatalysis. A C6′-OH cinchona alkaloid derivative bearing a C9-OBn group exhibited outstanding catalytic efficiency as an acid-base bifunctional catal

Full text of DOI:10.1002/ejoc.201100824

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100824
Asymmetric Nitroaldol Reactions of Nitroalkanes with Isatins Catalyzed by
Bifunctional Cinchona Alkaloid Derivatives
Mei-Qiu Li,[a] Jin-Xin Zhang,[a] Xiao-Fei Huang,[a] Bin Wu,[a] Zhao-Min Liu,[a]
Jian Chen,[a] Xiang-Dong Li,[a] and Xing-Wang Wang*[a]
Keywords: Enantioselectivity / Aldol reactions / Nitrogen heterocycles / Organocatalysis / Alkaloids
The enantioselective nitroaldol reactions of isatins with nitro-
alkanes were smoothly carried out by organocatalysis. A C6Ј-
OH cinchona alkaloid derivative bearing a C9-OBn group
exhibited outstanding catalytic efficiency as an acid–base bi-
functional catalyst for the nitroaldol reaction of isatins with
nitromethane, providing 3-hydroxy-3-(nitromethyl)indolin-2-
ones in good yields (90–98%) and with good to high enantio-
meric excess values (72–95%). The resultant oxindole deriv-
atives are highly important for the synthesis of related natu-
ral products and pharmaceutically active compounds.
(Scheme 1),[10] asymmetric 1,2-additions,[11] allylation reac-
tions[12] Morita–Baylis–Hillman reactions,[13] Friedel–
Crafts reactions,[14] and hydrogenation,[15] have been devel-
oped to provide optically active 3-substituted-3-hydroxy-2-
oxindoles by using chiral metallic complexes or chiral or-
ganic molecules as catalysts. By comparison, the use of
isatins as acceptors in direct asymmetric aldol reactions has
been extensively explored in recent years, which efficiently
furnishes valuable enantiomerically enriched 3-substituted-
3-hydroxy-2-oxindole derivatives in high yields and excel-
lent enantioselectivities [Scheme 1, Equation (1)].[10–15]
However, there are no reports outlining the use of isatins
and nitroalkanes in the enantioselective nitroaldol reaction,
which is mediated by organic molecular catalysts [Scheme 1,
Equation (2)]. During the preparation of our manuscript,
the enantioselective nitroaldol reaction of isatins with nitro-
alkanes in the presence of cupreine and benzoic acid as
catalysts was reported by Wang and co-workers.[16] In this
paper, we disclose that the nitroaldol reaction of nitro-
alkanes with isatins could be smoothly catalyzed by an
acid–base bifunctional cinchona derived organocatalyst; the
resulting enantiomerically enriched 3-hydroxy-3-(nitrometh-
yl)indolin-2-ones were obtained in high yields (90–98%)
and with good to high enantioselectivities (72–95%ee).
Introduction
With continuing efforts in the development of practical
methods for the asymmetric catalysis of organic reactions,[1]
the nitroaldol (or Henry) reaction has been an important
C–C bond-formation protocol in organic synthesis, which
provides efficient access to valuable functionalized struc-
tural motifs such as 1,2-amino alcohols or amino acids.[2]
To date, both chiral metallic complexes and chiral organo-
catalysts have been developed for the enantioselective cata-
lytic nitroaldol reaction.[3] Among the various chiral Lewis
acids reported, Re (La and Yb), Zn, Cu, Co, and Mg met-
allic complexes are commonly used in asymmetric nitro-
aldol reactions.[4] However, the search for an organo-
catalyzed enantioselective nitroaldol transformation has
attracted considerable attention over the last few years.
Some types of chiral organocatalysts, including quaternary
ammonium salts,[5] guanidine,[6] thiourea,[7] and cinchona
derivatives,[8] have been developed, and many of these sys-
tems have demonstrated powerful efficiency in terms of
their reactivities and enantioselectivities.
Many natural products possessing valuable biological
properties contain the 3-substituted-3-hydroxy-2-oxindole
heterocyclic unit.[2,9] The biological and synthetic impor-
tance of this structural motif has stimulated significant ac-
tivity into its enantioselective variants. Thus, several syn-
thetic methods, such as enantioselective aldol reactions
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and
Materials Science, Soochow University,
Suzhou 215123, P. R. China
Fax: +86-512-65880378
E-mail: wangxw@suda.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100824.
Scheme 1. Organocatalytic aldol and nitroaldol reactions of isatins.
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5237
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X.-W. Wang et al.
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
Results and Discussion
Initially, inspired by the direct aldol reactions of isatins
with carbonyl compounds,[10] we examined several cin-
chona-derived organocatalysts for the catalytic nitroaldol
reaction of nitromethane with isatin 1a in the presence of a
catalyst loading of 10 mol-% in THF (Scheme 2). The re-
sults are summarized in Table 1. Quinine I and cinchon-
idine II were not effective in the enantioselective nitroaldol
reaction, although desired 3a was obtained in 92% and
95% yield, respectively, within 2 h (Table 1, Entries 1 & 2).
Subsequently, cinchona alkaloid derivatives III–VI were in-
vestigated (Table 1, Entries 3–6). Promisingly, when C6Ј-
OH cinchona alkaloid V was employed as the catalyst, the
reaction provided the desired product in 98% yield with
33%ee (Table 1, Entry 5). We immediately shifted our at-
tention to C6Ј-OH cinchona alkaloid derivative VI bearing
a C9-OBn group,[17] which was established by the Deng
Entry Cat.
Solvent
Temp.
[°C]
Time
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
I
THF
THF
THF
THF
THF
THF
DCM
Et2O
EtOAc
dioxane
THF
THF
THF
THF
10
10
10
10
10
10
10
10
10
2
2
2
11
2
3.5
6
6
1
1
12
24
96
96
92
95
96
80
98
98
80
88
75
96
96
94
93
80
0
0
II
III
IV
V
10
21
33
87
3
54
73
65
88
91
93
71
VI
VI
VI
VI
VI
VI
VI
VI
VI
7
8
9
10
11
10
–10
–20
–30
–40
group as a type of acid–base bifunctional catalyst. Pleas- 12
ingly, the reaction proceeded smoothly in the presence of
the catalyst (10 mol-%), which afforded the desired product
13
14
[a] Reactions were performed with 1a (0.2 mmol), 2 (2.0 mmol),
and catalyst I–VI (10 mol-%) in solvent (2.0 mL). [b] Isolated yield.
[c] Determined by chiral HPLC.
in 98% yield with 87%ee (Table 1, Entry 6). Thus, catalyst
VI proved to be the optimal catalyst for the nitroaldol reac-
tion of nitromethane with isatin in terms of enantio-
selectivity.
of 91 and 93%ee, respectively, could be obtained for this
transformation at the cost of reactivity (Table 1, En-
tries 12 & 13). Unexpectedly, when the reaction temperature
was lowered to –40 °C, both the enantioselectivity and the
yield were dramatically reduced in comparison to those ob-
tained at –30 °C (Table 1, Entry 14 vs. 13). In pursuit of the
optimal reaction conditions, the reaction concentration, the
catalyst loading, and the molar ratio of nitromethane were
also investigated, and the results are summarized in the
Supporting Information (Table S1). Finally, we found that
the optimal reaction conditions for this transformation in-
volved the use of THF at –30 °C with nitromethane
(10 equiv.) in the presence of the catalyst (10 mol-%).
With the optimized reaction conditions in hand, the sub-
strate scope and limitations of the reaction were sub-
sequently investigated (Table 2). We found that substitu-
tions on the isatins and their positions had a great impact
Scheme 2. Screened catalysts.
To further improve the enantioselectivities, the solvent on the enantioselectivities of the desired products (Table 2,
and temperature were optimized. As shown in Table 1, we Entries 1–10). For 4-Cl- and 4-Br-substituted isatins 1b and
found that the enantioselectivities were greatly influenced 1c, the reactions provided desired products 3b and 3c in 97
by the reaction media. Dichloromethane was particularly and 96% yield, respectively, with 82 and 78%ee, respec-
unfavorable for this stereoselective transformation, furnish- tively (Table 2, Entries 2 & 3). Pleasingly, 5-Me-substituted
ing the addition product as a nearly racemic mixture isatin 1d gave the product in 92% yield with 95%ee after
(Table 1, Entry 7). The reactions proceeded in the other sol- 5 d (Table 2, Entry 4), whereas 5-halogenated isatins 1e–g
vents, including ethyl ether, ethyl acetate, and dioxane, and furnished the products with the varying level of enantio-
the desired products were obtained in good to excellent selectivities (Table 2, Entries 5–7). Among them, substrate
yields (75–96%) with moderate to good enantioselectivities 1e bearing a 5-F group gave the desired product in 90%
(54–73%ee; Table 1, Entries 8–10). Furthermore, when the yield with 79%ee (Table 2, Entry 5). Apparently, electron-
reaction temperature was dropped to –10 °C, the enantio- donating substituents on the isatins give products with
selectivity slightly increased to 88%, and the yield of the higher enantioselectivity, whereas electron-withdrawing
desired product was invariable even if the reaction time was substituents on the isatins give products with lower enantio-
prolonged to 12 h (Table 1, Entry 11). By decreasing the re- selectivity. Expectedly, for substrates 1g and 1h bearing 5-
action temperature to –20 and –30 °C, enantioselectivities Br and 6-Br substituents, desired products 3g and 3h could
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Eur. J. Org. Chem. 2011, 5237–5241

Asymmetric Nitroaldol Reactions of Nitroalkanes with Isatins
be obtained in 94 and 91% yield, respectively, with 91 and the enolate. The isatins could be activated and orientated
88%ee, respectively, which are distinctly better than those through hydrogen bonding between the isatin carbonyl
obtained with substrates 1e and 1f bearing 5-F and 5-Cl groups and the 6Ј-OH group and the protonated N–H
substituents (Table 2, Entries 7 and 8 vs. 5 and 6). On the group in the quinuclidine rings. Attack at the Re face of the
other hand, the use of N–Me and N–Bn protected isatins isatin by the nitro enolate results in the observed major R
1i and 1j afforded corresponding products 3i and 3j in excel- enantiomer for 3g and 3h, whereas the steric hindrance be-
lent yields, but with moderate enantioselectivities (Table 2, tween the phenyl ring of the isatin and the nitro enolate
Entries 9 and 10).
leads to the disfavored S enantiomer as the minor isomer.
Table 2. Substrates scope in the reaction.[a]
Entry
Product (R1, R2)
Time [d] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
3a (H, H)
3b (4-Cl, H)
3c (4-Br, H)
3d (5-CH3, H)
3e (5-F, H)
3f (5-Cl, H)
3g (5-Br, H)
3h (6-Br, H)
3i (H, CH3)
3j (H, CH2C6H5)
4
4
4
5
4
5
5
4
4
4
94
97
96
92
90
96
94
91
96
98
93
82
78
95
79
81
91
88
72
73
Figure 2. The X-ray crystal structure of 3h.
[a] Reactions were performed with 1a–j (0.2 mmol), 2 (2.0 mmol),
and catalyst VI (10 mol-%) in solvent (2.0 mL). [b] Isolated yield.
[c] Determined by chiral HPLC.
Fortunately, single crystals of compounds 3g and 3h were
obtained by recrystallization from hexane/acetone, and the
absolute configurations of 3g and 3h were determined by
X-ray analyses (Figures 1 and 2). On the basis of the corre-
lation of the spatial configuration of catalyst VI and the
absolute configurations of adducts 3g and 3h, and also in-
spired by Deng’s rational analyses of a gauche-open active
conformer for C6Ј-OH cinchona alkaloids (Scheme 3)
Scheme 3. Proposed stereochemical model for the VI-catalyzed
Henry reaction of nitromethane with isatins.
[17a,17b]
we envision that nitromethane is deprotonated by
the tertiary amine in the quinuclidine backbone to form
Conclusions
In conclusion, we have demonstrated the feasibility of
the enantioselective Henry reaction of isatins with nitro-
alkanes catalyzed by C6Ј-OH cinchona alkaloid derivative
VI. This reaction provides a convenient and effective cata-
lytic approach for the synthesis of enantiomerically en-
riched 3-hydroxy-3-(nitromethyl)indolin-2-ones in good
yields (90–98%) and with good to high enantioselectivities
(72–95%ee). The catalyst screening results and X-ray crys-
tallographic analysis suggest that both the C6Ј-OH group
and the quinuclidine are responsible for stereogenic induc-
tion into the nitroaldol products. Further mechanistic stud-
ies and synthetic utilities are underway in our laboratory.
Experimental Section
General Procedure for the Enantioselective Henry Reaction of Nitro-
alkane with Isatins: To a solution of 1 (0.2 mmol) and catalyst VI
(10 mol-%) in THF (2 mL) was added 2 (2.0 mmol, 10 equiv.). The
reaction mixture was kept at –30 °C for 4–5 d. The reaction mixture
Figure 1. The X-ray crystal structure of 3g.
Eur. J. Org. Chem. 2011, 5237–5241
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5239

X.-W. Wang et al.
SHORT COMMUNICATION
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Published Online: August 10, 2011
Eur. J. Org. Chem. 2011, 5237–5241
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