Chiral counteranion synergistic organocatalysis under high temperature: Efficient construction of optically pure spiro[cyclohexanone-oxindole] backbone

Article abstract of DOI:10.1021/ol201943g

The combination of a cinchona-based chiral primary amine and a BINOL-phosphoric acid has been demonstrated as a powerful and synergistic catalyst system for the double Michael addition of isatylidene malononitriles with α,β-unsaturated ketones, to provide

Full text of DOI:10.1021/ol201943g

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4866–4869
Chiral Counteranion Synergistic
Organocatalysis under High Temperature:
Efficient Construction of Optically Pure
Spiro[cyclohexanone-oxindole] Backbone
Yu-Bao Lan,† Hua Zhao,† Zhao-Min Liu,‡ Guo-Gui Liu,‡ Jing-Chao Tao,*,† and
Xing-Wang Wang*,‡
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow (Suzhou) University,
Suzhou 215123, P. R. China, and Department of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China.
jctao@zzu.edu.cn; wangxw@suda.edu.cn
Received July 20, 2011
ABSTRACT
The combination of a cinchona-based chiral primary amine and a BINOL-phosphoric acid has been demonstrated as a powerful and synergistic
catalyst system for the double Michael addition of isatylidene malononitriles with R,β-unsaturated ketones, to provide the novel chiral spiro
[cyclohexane-1,30-indoline]-20,3-diones in high yields (88ꢀ99%) with excellent diastereo- and enantioselectivities (94:6ꢀ99:1 dr’s, 95ꢀ99% ee’s).
The spirooxindole alkaloids represent a great family of
natural products and pharmaceutically relevant com-
pounds with remarkable structural complexity and inter-
esting biological activities.1 Consequently, various syn-
thetic protocols have been developed over the past decades
for the construction of the multistereogenic spirocyclic
oxindoles.2 Among these procedures, several types of
organo-catalyzed domino transformations that have
emerged very recently in the literature are especially at-
tractive by virtue of features such as highly efficient multi-
stereogenic formation, operational simplicity, and excel-
lent stereoselective control in the synthetic reactions.3
Specifically, the spirocyclic oxindole family with a chiral
spiro[cyclohexanone-1,30-indoline] core, an intriguing
combination of multistereogenic cyclohexanone and oxi-
ndole motifs, is a promising subset with potential
† Zhengzhou University.
‡ Soochow (Suzhou) University.
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r
10.1021/ol201943g
Published on Web 08/23/2011
2011 American Chemical Society

bioactivity.4 The asymmetric synthesis of this class of
compounds involves the stereocontrolled installation of a
spiro-quaternary chiral carbon center, which has been a
challenging goal for synthetic chemists. In 2009, Melchiorre
and co-workers reported the first example of a one-step
synthesis of multistereogenic spiro[cyclohexane-1,30-in-
doline]-20,4-diones via a tandem iminium and enamine
catalytic sequence (Figure 1).5 Shortly after, Gong’s group
disclosed a highly enantioselective synthesis via the reaction
between methyleneindolinones and Nazarov reagents cata-
lyzed by Brønsted acid-Lewis base bifunctional organocata-
lysts.6 Very recently, Wang et al. reported a highly enantio-
selective procedure to the similar types of spirocyclic
oxindoles by using a primary amine-catalyzed double
Michael reaction of 3-nonsubstituted oxindoles with die-
nones (Figure 1).7 However, to the best of our knowledge, so
far no results have been reported in the literature for the
enantioselective synthesis of spiro[cyclohexane-1,30-in-
doline]-20,3-diones (Figure 1). Herein, we disclosed that
optically pure spiro[cyclohexane-1,30-indoline]-20,3-diones
could be efficiently synthesized in high yields with excellent
diastereo- and enantioselectivities through the cascade
Michael additions of isatylidene malononitriles 18 with R,β-
unsaturated ketones 2via the catalysis of a cinchona alkaloid-
derived primary amine together with an acidic additive.
Figure 2. Screened catalysts.
achiral protic acid9 can act as powerful catalyst in asym-
metric enamine and iminium ion transformation,10 we
began the investigation by testing the model reaction
between 1a and 2a with 20 mol % quinidine-derived
primary amine I or its pseudoenantiomer II as the catalyst
and 40 mol % protic acids A1ꢀA6 (Figure 2) as the
additives. After an initial screening of additives for the
reactions performed at room temperature (Table S1, Sup-
porting Information), it was found that the combination of
amine catalyst I and BINOL-derived chiral phosphoric
acid11 A5 was optimal in terms of both diastereo- and
enantioselectivities, affording the corresponding spiro-
[cyclohexane-1,30-indoline]-20,3-dione 3ain90% yield with
excellent optical purity (98:2 dr, 98% ee). However, in this
case the reaction was found to be somewhat sluggish, which
took several days to completion. Therefore, the reaction
conditions were further optimized by examination of the
effects of temperature and solvent, as well as the potential
matched/mismatched combinations10 of catalysts I or II with
chiral A1ꢀA6, and the results were shown in Table 1.
Gratifyingly, the I/A5 catalyzed reaction in 1,2-dichlor-
oethane (DCE) proceeded much faster with the elevation
of temperature from rt to 80 °C, to furnish the product 3a in
nearly quantitative yields without sacrificing of either diaster-
eoselectivities or enantioselectivities (entries 1ꢀ8). Further
screening of the other catalyst/additive pairs reveals that I/A5
was the matched combination, affording the product in
Figure 1. Spiro[cyclohexanone-oxindole] backbones.
Inspiredbythe establishedfactthatthe combination ofa
cinchona alkaloid-derived primary amine with a chiral or
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Candeias, N. R.; Barbas, C. F., III Nat. Chem. 2011, 3, 473.
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(10) For limited reviews and publications on aminocatalysis, see: (a)
List, B. Acc. Chem. Res. 2004, 37, 548. (b) List, B. Chem. Commun. 2006,
819. (c) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
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(g) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008,
130, 8134. (h) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.;
Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (i) Xu, L.-W.; Luo, J.; Lu,
Y. Chem. Commum. 2010, 45, 1807.
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Yokota, K.; Fuchibe, K. Angew. Chem., Int.Ed. 2004, 43, 1566. (b)
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Org. Lett., Vol. 13, No. 18, 2011
4867

Table 1. Evaluation of Catalyst/Additive Combination and
Optimization of Reaction Conditionsa
Table 2. Substrate Scope of I/A5-Catalyzed Double Michael
Addition of Isatylidene Malononitriles 1aꢀk with Benzylide-
neacetone 2aa
cat./add.
(mol %)
temp time yield
dr
(%)c
ee
(%)c
entry
solv
(°C)
(h)
(%)b
entry
R
time (h)
yield (%)b dr (%)c
ee (%)c
1
2
3
4
5
6
7
8
9
I (20)/A1(40) DCE
I(20)/A5(40) DCE
I(20)/A5(40) DCE
I(20)/A5(40) DCE
I(20)/A5(40) DCE
I(20)/A6(40) DCE
II(20)/A5(40) DCE
II(20)/A6(40) DCE
I(20)/A2(40) DCE
rt 42
85
90
92
95
16:84
98:2
98:2
98:2
99
98
98
98
98
97
rt 84
40 14
1
H (1a)
1.5
36
3a/99
3b/90
3c/88
3d/99
3e/92
3f/99
3g/92
3h/95
3i/99
3j/96
3k/99
>99:1
99:1
98
98
98
98
97
98
97
97
>99
98
97
2d
3d
4
4-Cl (1b)
4-Br (1c)
5-CH3O (1d)
5-CH3 (1e)
5-F (1f)
60
80
80
80
2.5
36
>99:1
>99:1
98:2
1.5
2.0
1.0
99 >99:1
99 >99:1
2.0
4.7
2.5
5.0
3.5
3.0
4.0
1.5
5
99
99
92
80
97
93:7 ꢀ86
85:15 ꢀ90
6
>99:1
>99:1
99:1
80 30
7
5-Cl (1g)
5-Br (1h)
6-Br (1i)
80
80
80
7.0
17:83
34:66
41:59
90
91
94
98
98
98
95
97
95
94
98
98
8
10 I(20)/A3(40) DCE
11 I(20)/A4(40) DCE
12 I(20)/A5(40) DCM
13 I(20)/A5(40) THF
14 I(20)/A5(40) CHCl3
15 I(20)/A5(40) CH3CN
16 I(20)/A5(40) Toluene
7.0
6.0
9
99:1
10
11
5,6-F2 (1j)
7-CF3 (1k)
>99:1
96:4
40 48
99 >99:1
99 >99:1
99 >99:1
65
60
80
80
6.0
a Reactions were performed with 1aꢀk (0.1 mmol), 2a (0.2 mmol)
and catalyst loading I (20 mol %)/A5 (40 mol %), in DCE (1.0 mL).
b Isolated yields. c Determined by chiral HPLC. d Reactions were per-
formed at 40 °C.
6.5
2.0
1.5
1.0
6.5
95
83:17
94 >99:1
99 >99:1
92 >99:1
94 >99:1
90 >99:1
17 I(20)/A5(40) Toluene 100
18 I(15)/A5(30) DCE
19 I(10)/A5 (20) DCE
20 I (5)/A5(10) DCE
80
80 10
80 26
1c, the -Cl or -F substitutent at the 4-position of the oxindole
backbones seems to have a detrimental effect on both the
diastereo- and enantioselectivities at the relatively higher
reaction temperature of 80 °C. Nevertheless, the corre-
sponding products 3b and 3c could still be obtained in high
yields and excellent diastereo-and enantioselectivities when
the reactions were carried out at 40 °C, albeit at the cost of
some losses in reactivity in these cases (entries 2 and 3).
We found that the combination I/A5 is also an excellent
catalytic system with respect to the double Michael addi-
tion of 1a with various R,β-unsaturated ketones 2bꢀp. The
reactions were carried out in DCE in the presence of 20mol
% catalyst I at 80 °C, and the results are shown in Table 3.
For the enone substrates 2bꢀm bearing either electron-
donating or electron- withdrawing substituents on the
β-phenyl group, the adducts 3lꢀw were obtained in 90ꢀ99%
yields with94:6ꢀ99:1dr’sand 97ꢀ99% ee’s(entries 1ꢀ12).
Moreover, the R,β-unsaturated ketones 2nꢀp containing
heteroaromatic or fused aromatic rings were also suitable
substrates for this reaction, affording the corresponding
products 3xꢀz in 92ꢀ98% yields with 97:3ꢀ99:1 dr’s and
97ꢀ99% ee’s (entries 13ꢀ15).
a Reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol) and
primary amine catalyst loading I and II (5ꢀ20 mol %) and the additives
A1ꢀA6 (10ꢀ40 mol %) in solvent (1.0 mL) under the reaction tempera-
ture of rtꢀ100 °C. b Isolated yields. c Determined by chiral HPLC.
optimal diastereo- and enantioselectivities (entry 5 vs entries
9ꢀ11). Whereafter, several common solvents were examined
for this transformation in the presence of catalyst I/A5, from
which 1,2-dichloroethane and toluene turned out to be the
best choice in terms of both the reactivity and selectivities
(entries 12ꢀ17). Finally, a screening of catalyst loading in the
range of 5ꢀ20 mol % indicates that the diastereo- and
enantioselectivities were almost retained, albeit the re-
activity dropped considerably with the decreased catalyst
loadings (entries 18ꢀ20 vs entry 5).
Encouraged by these promising results, we further ex-
amined the scope of the I/A5-catalyzed double Michael
addition between substituted isatylidene malononitriles
1aꢀk and benzylideneacetone 2a. The reactions were
performed in DCE under the above optimized reaction
conditions, and the results were shown in Table 2. Ex-
cellent diastereo- and enantioselectivities were obtained by
using this catalytic system, irrespective of the variatons in
electronic and steric properties of the substituents attached
to the phenyl rings of the oxindole backbones. Thus, re-
actions of various 2-(2-oxoindolin-3-ylidene) malononitriles
1aꢀk and benzylideneacetone 2a proceeded smoothly to
afford the spiro[cyclohexane-1,30-indoline]-20,3-diones 3aꢀk
in 88ꢀ99% yields with 96:4ꢀ99:1 dr’s and 97ꢀ99% ee’s
(entries 1ꢀ11). For the reactions involving substrates 1b or
Intriguingly, we have also found that this double
Michael addition may proceed smoothly under relatively
high temperature (100 °C) without significant loss of stereo-
selectivities, thus providing an effective way to improve the
efficiency of the catalysis. Several reactions of isatylidene
malononitriles and R,β-unsaturated ketones 2 were rein-
vestigated in the presence of 20 mol % of catalyst I/A5
(1/2 molar ratio) in toluene at 100 °C, and the results are
summarized in Table 4. The desired products 3a, 3d, 3i, 3k, 3n,
4868
Org. Lett., Vol. 13, No. 18, 2011

Mechanistically, we envisioned that the construction of
a spiro[cyclohexane-1,30-indoline]-20,3-dione core might
be accomplished with isatylidene malononitriles acting
both as an acceptor and a latent donator in a double Michael
addition sequence. The R,β-unsaturated ketones can be
activated by condensation with the chiral primary amine
catalyst with the assistance of a protic acid (HX), leading to
the formation of a chiral nucleophilic dienamine intermedi-
ate, that will stereoselectively attack the 3-C of the isatylidene
moiety. Herein the regioselectivity would be determined by
the dicyano groups, which are more electron-withdrawing
than the carbonyl group in the isatin moiety. The resulting
Michael adduct would further undergo an iminium catalyzed
intramolecular conjugate addition, thus affording the desired
product in a one-pot fashion. In addition, excellent diastereo-
and enantioselectivities of the present catalytic system indi-
cate that the chiral counteranion provides additional stereo-
discrimination in the transition state (Figure 3).
Table 3. Substrate Scope of I/A5-Catalyzed Double Michael
Addition of Isatylidene Malononitrile 1a with R,β-Unsaturated
Ketones 2bꢀpa
entry
Ar
time (h) yield (%)b dr (%)c ee (%)c
1
2
3
4
5
6
7
8
9
o-MeOC6H4 (2b)
o-FC6H4 (2c)
1.5
3.0
2.0
3.0
2.0
1.5
2.0
3.5
2.5
2.5
3.0
2.0
2.5
3.0
2.0
3l/91
94:6
>99:1
>99:1
98:2
>99
97
3m/99
3n/90
3o/93
3p/99
3q/99
3r/99
3s/95
3t/92
3u/99
3v/95
3w/96
3x/93
3y/98
3z/92
o-ClC6H4 (2d)
m-ClC6H4 (2e)
p-MeOC6H4 (2f)
p-MeC6H4 (2g)
p-iPrC6H4 (2h)
p-FC6H4 (2i)
99
99
99:1
>99
98
>99:1
>99:1
97:3
99
98
p-ClC6H4 (2g)
>99:1
>99:1
>99:1
96:4
>99
97
10 p-BrC6H4 (2k)
11 p-CF3C6H4 (2l)
12 o,p-(MeO)2C6H3 (2m)
13 2-thienyl (n)
99
98
>99:1
97:3
>99
>99
97
14 2-furyl (2o)
15 1-naphthyl (2p)
>99:1
a Reactions were performed with 1a (0.1 mmol), 2bꢀp (0.2 mmol)
and catalyst loading I (20 mol %)/A5 (40 mol %), in DCE (1.0 mL).
b Isolated yields. c Determined by chiral HPLC.
Figure 3. Proposed transition state.
In summary, the combination of a cinchona-based chiral
primary amine and a BINOL-phosphoric acid has been
demonstrated as a powerful and synergistic catalyst system
for the double Michael addition of isatylidene malononitriles
with R,β-unsaturated ketones, to provide the novel chiral
spiro [cyclohexane-1,30-indoline]-20,3-diones in high yields
(88ꢀ99%) with excellent diastereo- and enantioselectivities
(94:6ꢀ99:1 dr’s, 95ꢀ99% ee’s). Salient features of the present
protocol include excellent stereoselective control in the multi-
stereogenic formation, operational simplicity, and highly
efficient one-pot synthesis of the sophisticated spiro oxindole
structures. The dicyano groups in the products provide a
convenient handle for synthetic manipulations; further work
along this line is undergoing in this laboratory.
Table 4. I/A5-Catalyzed Double Michael Addition of Isatyli-
dene Malononitriles 1 with R,β-Unsaturated Ketones 2 in
Toluene at 100 °Ca
time yield
dr
ee
(%)c
entry
R
Ar
(h)
(%)b (%)c
1
2
3
4
5
6
7
H (1a)
C6H5 (2a)
1.0 3a/99 >99:1
1.5 3d/99 99:1
95
95
5-CH3O (1d) C6H5 (2a)
6-Br (1i)
7-CF3 (1k)
H (1a)
C6H5 (2a)
2.0 3i/98
1.5 3k/96 95:5
2.5 3n/97 97:3 >99
99:1 >99
C6H5 (2a)
97
Acknowledgment. We are grateful for financial support
of the National Natural Science Foundation of China
(21072145), Foundation for the Author of National Ex-
cellent Doctoral Dissertation of P.R. China (200931), and
Natural Science Foundation of Jiangsu Province of China
(BK2009115). This project was funded by the Priority
Academic Program Development of Jiangsu Higher Edu-
cation Institutions (PAPD).
o-ClC6H4 (2d)
p-CF3C6H4 (2l)
H (1a)
2.5 3v/95 97:3
97
98
H (1a)
p-MeOC6H4 (2f) 1.4 3p/99 >99:1
a Reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol) and
catalyst loading I (20 mol %)/A5 (40 mol %), in toluene (1.0 mL).
b Isolated yields. c Determined by chiral HPLC.
3v, and3p were obtained in 95ꢀ99% yields within 1.0ꢀ2.5 h,
with95:5ꢀ99:1 dr’s and 95ꢀ99%ee’s(entries1ꢀ7). Finally,
we were fortunate to obtain single crystals of compound 3i,
for which the absolute configuration was unambiguously
established on the basis of the X-ray crystallographic
analysis (see Supporting Information).
Supporting Information Available. Experimental pro-
cedures and characterization data, HPLC data and X-ray
data for 3i (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
4869