Highly enantioselective synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles, potential anticonvulsants

Article abstract of DOI:10.1016/j.tetlet.2010.02.082

Highly enantioselective catalytic synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles was achieved by using primary-tertiary diamine-Br?nsted acid catalyst in both organic medium and aqueous medium. The products, thus obtained act as potential anticonvulsa

Full text of DOI:10.1016/j.tetlet.2010.02.082

Tetrahedron Letters 51 (2010) 2157–2159
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles,
potential anticonvulsants
Monika Raj a, Nagarathanam Veerasamy a, Vinod K. Singh a,b,
*
a Department of Chemistry, Indian Institute of Technology-Kanpur, Kanpur, UP 208 016, India
b Department of Chemistry, Indian Institute of Science Education and Research-Bhopal, ITI (Gas Rahat) Building, Govindpura, Bhopal, MP 462 023, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantioselective catalytic synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles was achieved by
using primary-tertiary diamine-Brønsted acid catalyst in both organic medium and aqueous medium.
The products, thus obtained act as potential anticonvulsants.
Received 11 January 2010
Revised 11 February 2010
Accepted 13 February 2010
Available online 18 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aldol Reaction
Aqueous medium
Organocatalyst
Enantioselective reaction
Anticonvulsants
Oxindoles, having a quaternary stereogenic center at C-3 posi-
tion, are of immense interest in organic synthesis as these struc-
tural moieties exist in large number of natural products1,2 and
pharmaceutically active compounds.3 Among them, 3-cycloalka-
none-3-hydroxy-2-oxindoles are quite promising in the field of
medicinal chemistry.4 It has been reported that these compounds
possess an anticonvulsant activity. For example, compounds A
and B antagonize the maximal electroshock seizures (anti-MES)
R
O
O
O
HO
HO
O
N
H
N
H
C
A: R = H B: R = Me
and
C antagonizes the pentylenetetrazol-induced convulsions
Figure 1. Bioactive 3-cycloalkanone-3-hydroxy-2-oxindoles.
(anti-PTZ) in mice (Fig. 1).4
Since biological activities are sensitive to the absolute configu-
ration of stereogenic center, an efficient catalytic enantioselective
synthesis of these oxindoles is highly desirable. The most obvious
approach to these chiral compounds is via asymmetric direct aldol
reaction of cycloalkanones with isatin and its derivatives. From a
green chemistry perspective, asymmetric organocatalytic aldol
reaction would be the method of choice for synthesizing these
compounds. To the best of our knowledge, enantioselective syn-
thesis of these compounds is not known by any of the methods.
Herein, we report the first asymmetric organocatalytic approach
to 3-cyclohexanone-3-hydroxy-2-oxindoles 1 with excellent dia-
stereoselectivities and enantioselectivities under mild reaction
conditions (Scheme 1).
O
O
O
catalyst,
solvent
HO
X
+
O
X
O
N
H
N
H
1
X = H, Cl, Br
Scheme 1. Asymmetric direct aldol reaction for the synthesis of 3-cyclohexanone-
3-hydroxy-2-oxindoles.
developed in our laboratory and well known for carrying out asym-
metric aldol reactions5 (Fig. 2). Unfortunately, the reaction did not
proceed even after 4 days. Given the success to primary-tertiary
diamine-based catalysts for aldol reaction pioneered by Cheng
and co-workers6 we designed another series of primary-tertiary
diamines 3a–c,7 bearing aromatic groups (Fig. 2). The idea behind
this is that aromatic groups will form a hydrophobic cavity with
At the outset, we carried out the reaction of cyclohexanone with
isatin in the presence of a secondary amine catalyst 2 which was
* Corresponding author. Tel.: +91 512 2597291; fax: +91 512 2597436.
E-mail address: vinodks@iitk.ac.in (V.K. Singh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.082

2158
M. Raj et al. / Tetrahedron Letters 51 (2010) 2157–2159
(10 mol % catalyst, 2 equiv of ketone, TFA as a Brønsted acid and
DMF as a solvent), different catalysts 3b–c were screened for this
reaction. The catalyst 3b gave product with 97:3 de and 98% ee (Ta-
ble 1, entry 7). The catalyst 3c gave similar results (Table 1, entry 8,
98:2 de, 99% ee). As expected, the catalyst 3b gave product with
opposite configuration (Table 1, entries 1–6 and 8 vs entry 7). Thus,
we were able to synthesize both the enantiomeric forms of the
compound 1a.
The absolute configuration of the product with two newly
formed stereogenic centers was determined by single-X-ray dif-
fraction analysis of the crystal 1a, obtained by slow evaporation
of ethyl acetate solution. The X-ray analysis of crystal 1a showed
that the absolute configuration of the stereocenters was (S) and
(R) (Fig. 3).
Among these organocatalysts, the 3a was chosen for further
screening of the reaction with regard to both cycloalkanones8
and substituted isatins. We focused our attention on the reaction
of cyclohexanone with substituted isatins under identical condi-
tions as mentioned above. It was found that 5-bromo isatin in
DMF gave product 1b with high diastereoselectivity of 97:3 and
enantioselectivity of 99% (Table 2, entry 1). Furthermore, a similar
reaction with 5-chloro isatin in DMF gave product 1c with 93:7 de
and 87% ee (Table 2, entry 4). The reaction of 5-bromo isatin and 5-
chloro isatin with cyclohexanone in the presence of water or brine
gave products with moderate to good diastereoselectivities and
enantioselectivities (Table 2, entries 2–3 and 5–6).
It is to be emphasized that the product derived from isatin and
cyclohexanone was active in the maximal electroshock seizure test
(MES) whereas, the products derived from substituted isatins and
cyclohexanone were inactive. In contrast, the product derived from
5-bromo isatin was active in the pentylenetetrazol seizure thresh-
old test (PTZ), thus acts as a potential anticonvulsant.4
O
1
2
Ph
Ph
H2N
N Me
N
H
2'
N
H
OH
R
2
3a-(1S,2S,2'S): R = Ph
3b-(1R,2R,2'R): R = Naphthyl
3c-(1S,2S,2'R): R = Naphthyl
Figure 2. Series of organocatalysts.
O
HO
N
X
N
HN
R2
HN
O
H
H
O
Ph
Ph
E-enamine
N
R1
H
1
Favored
Scheme 2. General mechanism of the reaction catalyzed by organocatalysts 3a–c.
Table 1
Optimization of the reaction conditions
O
O
O
3/TFA (10 mol%),
HO
rt, 6-48 h
O
O
N
H
N
H
1a
Entry Catalyst Solvent Ketone (equiv) Yielda (%) syn:antib eec (%)
1
3a
3a
3a
3a
3a
3a
3b
3c
Water
Water
Water
Brine
DMF
DMF
DMF
DMF
4
2
2
2
4
2
2
2
90
90
85
84
93
92
91
92
97:3
96:4
96:4
95:5
98:2
99:1
97:3
98:2
97
98
92
2
In summary, we have developed the first direct catalytic asym-
metric approach to 3-cyclohexanone-3-hydroxy-2-oxindoles in
3d
4
90
5
>99
>99
98
6
7e
8
99
a
b
c
Isolated yields.
Determined by 1H NMR.
Determined by HPLC using chiral column.
3a/TFA (5 mol %).
d
e
Opposite enantiomer.
reactants in an aqueous medium. High reactivity and enantioselec-
tivity would be expected from such systems as shown in Scheme 2.
With a great hope, cyclohexanone was allowed to react with isatin
in the presence of primary-tertiary diamine-Brønsted acid catalyst
3a/TFA (10 mol %) using water as a medium. Gratifyingly, the aldol
product 1a was obtained in high diastereoselectivity (97:3) and
enantioselectivity (Table 1, entry 1, 97% ee). On reducing the ke-
tone equivalents from four to two with respect to aldehyde, diaste-
reoselectivity and enantioselectivity of the reaction remained
almost constant (Table 1, entry 2, 96:4 de, 98% ee). When the reac-
tion was carried out at a lower catalyst loading of 5 mol %, enanti-
oselectivity of the reaction decreased to 92% (Table 1, entry 3).
Surprisingly, the use of brine as a reaction medium decreased the
enantioselectivity of the product (Table 1, entry 4, 90% ee).
At this point, it was thought that polar aprotic solvent such as
DMF might give better results as it would make the reaction mix-
ture homogeneous. It was indeed the case. The reaction of cyclo-
hexanone and isatin in the presence of 10 mol % of the catalyst
3a and TFA in DMF was completed in 6 h, providing a product 1a
with very high chemical yield, excellent diastereoselectivity and
enantioselectivity (Table 1, entries 5 and 6, 98:2 de, >99% ee and
99:1 de, >99% ee, respectively). Under the optimized conditions
Figure 3. X-ray structure of crystal 1a.
Table 2
Scope of the reaction
O
O
O
HO
X
3a/TFA (10 mol%),
X
rt, 6-48 h
O
O
1b-c
N
H
N
H
Entry
X
Solvent
Yielda (%)
syn:antib
eec (%)
1
2
3
4
5
6
Br
Br
Br
Cl
Cl
Cl
DMF
1b/92
1b/87
1b/83
1c/90
1c/85
1c/84
97:3
99:1
92:8
93:7
98:2
95:5
99
65
60
87
85
80
Water
Brine
DMF
Water
Brine
a
b
c
Isolated yields.
Determined by 1H NMR.
Determined by HPLC using chiral columns.

M. Raj et al. / Tetrahedron Letters 51 (2010) 2157–2159
2159
high yields, excellent diastereoselectivities and enantioselectivities
References and notes
by carrying out aldol reaction of cyclohexanone with isatin and its
derivatives in the presence of new organocatalysts. The products
can be synthesized in both the enantiomeric forms. The reaction
is operationally simple and environmentally benign in that an
organocatalyst is employed and water is used as the reaction med-
ium. The products obtained are active in maximal electroshock sei-
zure test (MES) and pentylenetetrazol seizure threshold test (PTZ)
thus, act as potential anticonvulsants.4
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Acknowledgments
V.K.S. thanks Department of Science & Technology, Govt. of
India, for a research grant through J.C. Bose fellowship. M.R. thanks
Council of Scientific & Industrial Research, Govt. of India, for a
Senior Research Fellowship.
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Supplementary data
5. (a) Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097; (b) Maya,
V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593; (c) Raj, M.; Singh, V. K. Chem.
Commun. 2009, 6687.
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7. Raj, M.; Parashari, G. S.; Singh, V. K. Adv. Synth. Catal. 2009, 351, 1284.
8. The reaction with cyclopentanone and isatin using 3a/TFA (20 mol %) in DMF
gave product with low yield (55%), diastereoselectivity (73:27) and
enantioselectivity (30%). For details see Supplementary data.
Supplementary data (CCDC 715937 and 715938 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.02.082.