Enantioselective organocatalytic aldol reaction of unactivated ketones with isatins

Article abstract of DOI:10.1016/j.tetlet.2011.05.013

Enantioselective organocatalytic direct aldol reaction of unactivated ketones with various isatin derivatives was developed using cinchonine based urea ligand employing a noncovalent catalysis mechanism. Using this protocol we can access functionalized 3-

Full text of DOI:10.1016/j.tetlet.2011.05.013

Tetrahedron Letters 52 (2011) 4080–4083
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Tetrahedron Letters
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Enantioselective organocatalytic aldol reaction of unactivated ketones
with isatins
Suresh Allu a, Nagaraju Molleti b, Ramachandrarao Panem a, Vinod K. Singh a,b,
⇑
a Department of Chemistry, Indian Institute of Technology, Kanpur, UP 208 016, India
b Department of Chemistry, Indian Institute of Science Education and Research, 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:
Enantioselective organocatalytic direct aldol reaction of unactivated ketones with various isatin deriva-
tives was developed using cinchonine based urea ligand employing a noncovalent catalysis mechanism.
Using this protocol we can access functionalized 3-alkyl-3-hydroxyindolin-2-ones in high yields with
good to excellent enantioselectivities.
Received 21 March 2011
Revised 2 May 2011
Accepted 3 May 2011
Available online 11 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
This paper is dedicated respectfully to
Professor Yashwant D. Vankar on the
occasion of his 60th birthday
Keywords:
Organocatalysis
Thiourea
Isatin
Enamine mechanism
3-Alkyl-3-hydroxyindolin-2-ones
Organocatalytic direct aldol reactions of activated carbonyl
compounds via preformed enamine pathway are currently one of
the most promising areas of research.1 This method provides a use-
ful route to access chiral b-hydroxy carbonyl compounds which are
versatile synthetic motifs for biologically and pharmaceutically
important intermediates.2 The efficiency of these processes relies
mainly on the formation of a highly reactive enamine intermediate
which is derived from activated ketones. Enamines, obtained from
unactivated ketones such as aromatic ones, are less reactive due to
the low orbital overlap between the enamine double bond and the
nitrogen lone pair3 which, inturn, results in very slow and incom-
plete reaction. To the best of our knowledge, there are very few
organocatalysts reported so far based on enolization-driven mech-
anism using base catalysis for the effective aldol reaction of unac-
tivated ketones3,4 and while our work was in progress, a report has
recently been disclosed by Zhao et al.5 using isatin as an acceptor.6
Intensive efforts have been devoted to the development of
asymmetric transformations using isatin as an electrophile7 as
they provide powerful tools for the rapid and efficient construction
of 2-oxindole containing chiral quaternary carbon center at its 3-
position.8 The product, 3-alkyl-3-hydroxyindolin-2-one9 consti-
tutes a key structural feature of vast majority of important and
complex natural products10 as well as pharmaceutically active
compounds.11 Hence, the synthesis of enantiomerically pure
3-alkyl-3-hydroxyindolin-2-ones via catalytic enantioselective
process has emerged as an area of active research.10,12
Chiral bifunctional compounds have become powerful catalysts
for inducing asymmetric induction in various reactions.13 During
the last few years, several enantioselective processes have been
reported using these catalysts for asymmetric C–C bond-forming
reactions.14 Isatins are relatively stronger and directional H-bond
acceptors in comparison to normal ketones-a property which
makes them one of the best substrates for H-bond catalysis.15
We envisioned that the tertiary amine part of a chiral bifunctional
catalyst 1 (Fig. 1) would assist in the formation of an enolate and
thus effectively catalyze aldol reaction of isatins with unactivated
carbonyls. Further, we anticipated that the aldol reaction of aro-
matic ketones with isatin would work better via a soft enolate16
mechanism in the presence of bifunctional catalysts. Based on this
idea, we herein report cinchonine based urea catalyst for direct
aldol reaction of unactivated ketones as well as activated ones with
a variety of isatins. In addition, we have also shown that the rever-
sal of enantioselectivity was observed using chinchonidine based
primary amine catalysts.
At the outset, the reaction of acetophenone with isatin was ini-
tially examined under enamine catalysis using 10 mol % of
diamines 1a–1e17 in combination with equimolar acid additives.
⇑
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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.013

S. Allu et al. / Tetrahedron Letters 52 (2011) 4080–4083
4081
Table 2
Optimization of aldol reaction using 1f–1la
N
H
H
N
H
N
H2N
H2N
N
Ph
HO
O
H
acetophenone (3a),
1f-1l (10 mol%),
solvent, 5 °C
O
R
R
Me
H2N
Me
N
O
O
Ph
N
N
H
1a
1d: R = H
H
1b: R = H
2a
4a
1e: R = OMe
1c: R = OMe
eeb (%)
Ar
Entry
Catalyst
Solvent
Time (d)
Yield (%)
46c
82
83
68
56
66
66
45
62
81
91
70
84
71
21
90
91f
HN
X
H
1
2
3
4
5
6
7
8
1f
1f
1f
1f
1f
1f
1f
1f
1f
1g
1h
1i
1j
1k
1l
1h
1h
THF
THF
Dioxane
Et2O
CHCl3
2
5
4
4
5
5
5
3
3
4
6
4
6
4
8
5
4
85
82
93
70
86
79
85
60
65
91
89
93
85
90
75
92
92
N
H
H
N
H
N
H
N
N
Ar
HN
HN
HN
Ar
R
N
H
H
BnO
S
X
H
R
DCM
N
Toluene
CH3CN
Water
N
1f: R = H, X = S;
1i: R = OMe, X = S
1j: R = OMe, X = O
1k: R = H, X = S
1l
9
1g: R = OMe, X = S;
1h: R = H, X = O.
10
11
12d
13d
14d
15
16e
17
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
1f-1l; Ar = 3,5-(CF3)2C6H3
Figure 1. Vicinal diamines based chiral catalysts.
Table 1
Optimization of aldol reaction using 1a–1ea
a
Reactions were carried out on a 0.1 mmol of 2a with 0.5 mmol of 3a in 100 lL of
Ph
solvent, unless stated otherwise.
O
1a-1e (10 mol%),
b
Determined by HPLC using chiral column.
Reaction was carried out at rt.
S-Enantiomer was obtained.
4 Å MS were used.
O
HO
10 mol% additive,
solvent, rt, 10 d
c
O
D
O
O
e
Me
Ph
N
H
N
f
20 mol % of catalyst (1 h) was used.
H
(3a)
(2a)
(4a)
Entry
Diamine
Additive
Solvent
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
CF3COOH
CH3COOH
CF3SO3H
HCOOH
PhCOOH
P-TSA
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
Water
Water
Water
Water
Water
Water
THF
51
40
53
48
35
38
42
58
42
58
58
55
59
60
74
26
67
63
45
10
52
63
20 °C makes the reaction very sluggish. Thus, it was decided to per-
form rest of the reactions at 5 °C.
Among all solvents screened (Table 1, entries 3–9), dioxane
proved to be the optimum choice for this reaction (entry 3) in
terms of both rate of the reaction as well as enantioselectivity. At
5 °C using dioxane as a solvent, various bifunctional thiourea and
urea catalysts (1f–1l) were screened. It was found that catalysts
1f and 1g provided enantioselectivities in the range of 81–83% with
very good to excellent yields (Table 2, entries 1–10). Poor enanti-
oselectivity with catalyst 1l (entry 15), emphasizes the significance
of the relative orientation and positions, respectively, of acidic and
basic functional groups in the chiral scaffold. Among all the cata-
lysts screened, urea derived catalyst 1h proved to be the best in
the direct aldol reaction (up to 91% ee, entry 11) at 5 °C with
10 mol % catalyst loading.19 Addition of molecular sieves to the
reaction did not make any difference in the enantioselectivity (en-
try 16). Increasing the catalyst loading to 20 mol % shortened the
reaction time to four days without affecting the enantioselectivity
(entry 11 vs 17). Thus it was decided to use 20 mol % of the catalyst
for further substrate scope (Table 3).
Aldol reaction of isatin with a wide range of aromatic ketones
was studied using the catalyst 1h under standard conditions. In
all the cases, the enantioselectivities obtained were good to very
high (Table 3). A number of C-acetyl heterocyclic compounds, on
reaction with isatins, gave a series of 3-hydroxy-3-substituted
oxindoles (entries 11, 12 and 14). Interestingly, the product 4k,
formed from the reaction of 2-acetylthiophene 3h and isatin, is ac-
tive at 100 mg/kg in the maximal electroshock seizure test, and
could also be obtained in 84% ee with 98% of yield (entry 11).20
Further, we were interested in using activated carbonyl com-
pounds such as acetone and acetaldehyde as a donor in the aldol
DMF
DCM
49
81
Brine
Brine
Brine
Brine
Brine
À80c
À75c
90
89
a
Unless otherwise stated, all the reactions were carried out on 0.25 mmol scale
using 5.0 mmol of acetophenone in 250 L of solvent.
l
b
Determined by HPLC using chiral column.
Opposite enantiomers were obtained.
c
Under optimized conditions, in the presence of 10 mol % of TFA, a
maximum of 81% ee was observed with a moderate yield of 58%
when 1a–1c were used (Table 1, entries 10–12). Increased enanti-
oselectivities were observed (up to 90% ee) using 1d and 1e in the
presence of 10 mol % of TFA (entries 13 and 14) in brine.18 As it is
obvious, the ligands 1b and 1c provided aldol products with oppo-
site stereochemistry. In these cases, the reaction proceeded
through an enamine mechanism. The longer reaction time (10
days) is a limitation.
In contrast, the bifunctional thiourea 1f catalyzed the aldol
reaction of isatin with acetophneone more efficiently but in poor
ee (Table 2, entry 1). To our delight, a remarkable increase in the
enantioselectivity on decreasing the reaction temperature to 5 °C
was observed (entry 2). Further decrease in the temperature to
reaction. To our delight,
a high level of enantioselectivities

4082
S. Allu et al. / Tetrahedron Letters 52 (2011) 4080–4083
Table 3
Substrate scopes of aldol reactiona
Ar
O
HO
O
1h (20 mol%),
Me
dioxane, 5 °C
O
O
O
N
N
Ar
(3a-3k)
R2
R2
R1
R1
(4a-4o)
2a-2e
Entry
R1
R2
Ar
Time (d)
Product
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H/2a
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
4
4
4
5
4
4
4
6
6
4
4
4
4
7
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
92
88
93
92
98
92
95
83
80
97
98
91
98
85
98
91
84
84
91
90
87
88
89
85
84
84
78
85
91
88
5-F/2b
5-Cl/2c
4,6-DiBr/2d
H/2a
H/2a
H/2a
H/2a
H/2a
H/2a
H/2a
4-FC6H4 (3b)
4-ClC6H4 (3c)
4-BrC6H4 (3d)
4-MeOC6H4 (3e)
4-MeC6H4 (3f)
3-ClC6H4 (3g)
2-Thienyl (3h)
2-Pyridyl (3i)
1-Naphthyl (3j)
H/2a
H/2a
H/2a
H/2e
2-Pyridyl-N-oxide (3k)
Ph (3a)
a
Reactions were carried out by using 0.1 mmol of two with 0.5 mmol of three in 100
lL of dioxane at 5 °C, unless stated otherwise.
b
Determined by HPLC using chiral column and absolute configuration was assigned according to Reference.8a
Table 4
PMP
HO
PMPO
Aldol reaction of activated carbonyls with isatinsa
O
O
m
-CPBA, TFA,
HO
CH2Cl2, rt,12 h
R
N
O
O
O
N
H
N
H
87%
HO
O
1h (20 mol%),
dioxane, 5 °C
O
(4h)
(5)
O
+
O
PMP=
p-OMeC6H4
89% ee
89% ee
Me
R
N
R2
R2
(2a-2f)
R1
R1
Scheme 1. Baeyer–Villiger oxidations of Aldol adduct 4h.
(4p-4x)
(3l-3m)
Entry R1
R2
R
Time
(d)
Product Yield
(%)
eeb
(%)
N
N
CF3
CF3
1
2
3
4
5
H
H
H
H
H
H/2a
Me
(3I)
Me
(3I)
Me
(3I)
Me
(3I)
Me
(3I)
H (3m)
H (3m)
H (3m)
H (3m)
4
5
4
4
5
4p
4q
4r
4s
4t
92
87
88
85
93
89
O
O
H
H
5-Br/2f
5-F/2b
5-Cl/2c
88
89
89
92
F3C
N
H
N
H
F3C
N
H
N
H
NH
NH
O
O
O
6a
O
O
6b
O
Br
CH3
CH3
Br
HN
NH
4,6-DiBr/
2d
H/2a
5-F/2b
5-Cl/2c
67c
72c
63c
78c
Br
disfavored
Attack from Si- face
favored
6
7
8
9
H
H
H
6
4
4
4
4u
4v
4w
4x
68
73
80
71
Br
CH3
O
Me H/2e
a
HO
Unless otherwise stated, all reactions were carried out by using 0.1 mmol of 2
and 1 mmol of 3 in 100 L of dioxane at 5 °C.
Br
Br
O
l
b
Determined by HPLC using chiral column and the absolute configuration was
NH
assigned as per the literature method.8a
c
Yield of corresponding diol after reduction of the aldehydes with NaBH4.
4t
Figure 2. Proposed transition state model.
(88–92% ee) was achieved when the reaction was performed using
acetone with a variety of isatins (Table 4, entries 1–5). Modest
enantioselectivity was also obtained in the case of acetaldehyde.
It was heartening to note that 10 equiv of acetone and acetalde-
hyde gave good result as the large excess of these substrates
usually required in its addition reactions.8b,21
We have transformed an aldol adduct 4h into the corresponding
ester via Baeyer–Villiger oxidation22 (Scheme 1) with no loss of
enantiopurity. The ester obtained in this reaction could be used
as intermediates for several convultamydins synthesis.23
While studying the scope of the reaction, we synthesized (R)-
convolutamydine A 4t in 92% ee and 93% yield (Table 4, entry 5).
A tentative mechanism has been proposed ( Fig. 2) based on
recent literature report,5 where an enolate ion, derived from a

S. Allu et al. / Tetrahedron Letters 52 (2011) 4080–4083
4083
Chem. Asian J. 2009, 4, 1664; (c) Ricci, R.; Bernardi, L.; Gioia, C.; Ierucci, S.;
Robitzer, M.; Quignard, F. Chem. Commun. 2010, 46, 6288.
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Hayashi, Y. Org. Lett. 2009, 11, 3854; (c) Hara, N.; Nakamura, S.; Shibita, N.;
Toru, T. Adv. Synth. Catal. 2010, 352, 1621.
ketone, attacks the isatin which is activated by the H-bonding inter-
action with the urea moiety of the catalyst. It is clear from the tran-
sition state that attack of the enolate from Re-face of isatin is not
preferred because of the possible steric repulsions between the aro-
matic part of the isatin and the quinuclidine ring, thus leading to the
favorable Si-face attack.
9. (a) Raj, M.; Veerasamy, N.; Singh, V. K. Tetrahedron Lett. 2010, 51, 2157; For
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Vishnumaya,
; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097; (c)
In conclusion, we have developed a mild and facile soft enolate
approach, which is complementary to enamine catalysis for direct
aldol reaction of isatin with various unactivated and activated
carbonyl compounds, catalyzed by cinchona alkaloid-based urea
ligand. Employing our methodology, we have also synthesized
(R)-convolutamydine A by an operationally simple procedure. Fur-
ther studies in this direction are still under progress and will be re-
ported in due course.
Vishnumaya, ; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593; (d) Gandhi, S.;
Singh, V. K. J. Org. Chem. 2008, 27, 9411.
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Acknowledgments
13. For reviews on thiourea catalysis, see: (a) Schreiner, P. R. Chem. Soc. Rev. 2003,
32, 289; (b) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103,
2985; (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
14. Some important work on cinchona alkaloid-derived thiourea catalysts, see: (a)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367; (b) Wang, Y.-
Q.; Song, J.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156; (c) Wang, J.; Li,
H.; Zu, L. Z.; Xie, H. X.; Duan, W. H.; Wang, W. J. Am. Chem. Soc. 2006, 128,
V.K.S. thanks the Department of Science and Technology, India
for a research grant through J.C. Bose fellowship. S.A., N.M. and
R.P. thank the Council of Scientific and Industrial Research, New
Delhi for research fellowships.
´
´
12652; (d) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967;
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Supplementary data
Supplementary data (general experimental procedures, charac-
terization data including 1H NMR spectra, 13C NMR spectra for all
new compounds and HPLC chromatograms for aldol adducts as
sociated) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.05.013.
15. Tian, S. –K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res.
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