Organocatalyzed direct asymmetric aldol reaction of isatins in water: Low catalyst loading in command

Article abstract of DOI:10.1016/j.tet.2013.04.044

Simple primary-tertiary diamines easily derived from natural primary amino acids have been used to catalyze the aldol reactions in water. The 1 mol % of diamine catalyst is sufficient to catalyze the aldol reaction of cyclohexanone/acetone to isatins prov

Full text of DOI:10.1016/j.tet.2013.04.044

Tetrahedron 69 (2013) 5197e5204
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalyzed direct asymmetric aldol reaction of isatins in
water: low catalyst loading in command
*
Akshay Kumar, Swapandeep Singh Chimni
Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 March 2013
Received in revised form 9 April 2013
Accepted 12 April 2013
Available online 25 April 2013
Simple primaryetertiary diamines easily derived from natural primary amino acids have been used to
catalyze the aldol reactions in water. The 1 mol % of diamine catalyst is sufficient to catalyze the aldol
reaction of cyclohexanone/acetone to isatins provided 3-substituted-3-hydroxy-2-oxindole in good yield
and good enantioselectivity. The methodology highlights the importance of low catalyst loading in
achieving high enantioselectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Low catalyst loading
Organocatalysis
3-Hydroxy oxindoles
Aldol reaction
Water
1. Introduction
generally required high catalyst loading due to poor reactivity and
greater steric hindrance of ketones as electrophilic species.7
3-Substituted-3-hydroxy-2-oxindole is one of the key structural
units found in a large variety of natural products and drug candi-
dates, having wide spectrum of biological activities.1 Among them,
3-alkyl-3-hydroxy-2-oxindole entities are of immense importance
in the field of medicinal chemistry due to their anticonvulsant
properties. Owing to the significance of this structural motif, the
development of asymmetric organocatalytic methods for their
synthesis has attracted the attention of synthetic chemist.2 The aldol
Therefore, this requires activation of both aldol donor and accep-
tor by bifunctional organocatalyst. Recently, we have developed
primaryetertiary-Brønsted acid conjugates as a bifunctional orga-
nocatalysts for direct asymmetric aldol reaction.8 Considering pri-
mary amine as an excellent catalyst for intramolecular ketone
aldolization,9 we planned to explore the applicability of pri-
maryetertiary-Brønsted acid conjugate organocatalysts10 for in-
termolecular ketone aldolization of cyclohexanone and isatins to
procure 3-cycloalkane-3-hydroxy-2-oxindole, which is of immense
importance in the field of medicinal chemistry due to their anti-
convulsant properties.11
On the other hand, the use of water in organocatalytic reactions
is of great current interest due to its unique properties as compared
to commonly employed organic solvents.12 Our research group
have successfully explored organocatalytic asymmetric ketone-
aldehyde cross aldolization using water as a solvent.13 Here we
disclose our finding of intermolecular ketone aldolization in water
catalyzed by 1 mol % of chiral primaryetertiary-Brønsted acid
conjugate organocatalysts (Fig. 1).
addition of carbonyl compounds, containing a-hydrogen to isatins
via enamine-organocatalysis is a straightforward approach to this
end. Tomasini et al.3 reported the first aldol addition of acetone to
isatin catalyzed by using 10 mol % of dipeptide containing secondary
amine at N-terminus, whereas, Singh et al.4 developed the aldol
addition of cyclohexanone and acetophenone to isatins using pri-
mary amine based organocatalysts. After these reports some other
groups had also reported the aldol addition of acetone and cyclo-
hexanone to isatins using 5e20 mol % of primary as well as sec-
ondary amine based organocatalyst.5 But, the major limitation of
enamine catalysis with primary amine is the requirement of high
catalyst loading in comparison with secondary amine based orga-
nocatalyst due to the low nucleophilicity of enamine intermediate
derived from primary amine.6 In addition, aldolization of ketones
2. Results and discussion
Initially, the aldol reaction of cyclohexanone (3) with isatin (2a)
was performed using 10 mol % of catalyst 1a and 2,4-dinitrophenol
(DNP) as an additive in water (Scheme 1). The aldol addition
product 4a was isolated in 90% yield with diastereomeric ratio of
* Corresponding author. Fax: þ91 183 2258820; e-mail addresses: sschimni@
yahoo.com, sschimni.chem@gndu.ac.in (S.S. Chimni).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.044

5198
A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
Table 2
Catalyst and additive screening for enantioselective aldol reaction of cyclohexanone
N
N
N
N
N
(3) with isatin (2a)a
NH2
1b
NH2
1d
NH2
1a
O
NH2
1c
Entry Catalyst Additive
Time Yieldb drc (syn/anti) eed (%)
(h)
(%)
(syn)
N
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
DNP
DNP
DNP
DNP
DNP
DNP
DNP
DNP
24
24
24
28
28
36
24
24
24
96
20
93
92
94
90
89
85
90
92
91
82
94
95
93:7
91:9
92:8
90:10
91:9
86:14
94:6
92:8
82
79
80
70
71
65
81
79
80
10
78
82
NH2
1e
NH2
1f
N
N
N
N
H
NH2
1i
O
NH2
1g
O
NH2
1h
O
NH2
1j
9
DNP
DNP
91:9
Fig. 1. Structure of organocatalysts.
10
11
12
1j
1a
1a
70:30
90:10
90:10
Benzoic acid
2-Chlorobenzoic 22
acid
82:18 (syn/anti) but with a very low enantioselectivity of 10% of syn
isomer (Table 1, entry 1). Although the results were not encour-
aging, but inspired by the reaction reported in the literature14 we
thought of studying the effects of catalyst loading on the enantio-
selectivity of the reaction. The aldol reaction performed with cat-
alyst loading of 5 mol % gave the product 4a with an enhanced ee of
27% (dr of 86:14) (Table 1, entry 2). Encouraged by this result we
further lowered the catalyst loading to 2.5 mol %, which yielded 4a
in 45% ee (dr of 90:10) (Table 1, entry 3). On performing the reaction
at 1 mol % of catalyst loading, 4a was obtained in comparably high
enantioselectivity of 82% ee and diastereomeric ratio of 93:7 (Table
1, entry 4). Further, reducing the catalyst loading to 0.5 mol % had
no effect on enantioselectivity of the product but resulted in lower
yield (Table 1, entry 5). Therefore, catalyst loading of 1 mol % was
found to be optimal and was used in all further optimizations.
13
1a
4-Nitrobenzoic
22
91
91:9
82
acid
TFA
TfOH
d
14
15
16
1a
1a
1a
40
40
24
81
78
82
91:9
82:18
84:16
79
78
71
a
Reaction condition: 0.5 mmol of isatin, 5 mmol of cyclohexanone, 0.5 mL of
water, 1 mol % diamine catalyst, 1 mol % acid additive, temperature 25 ꢀC.
b
Isolated yield determined after chromatographic purification.
Diastereoselectivity determined from HPLC spectra of crude reaction mixture.
Enantiomeric excess determined from HPLC using chiralpak columns.
c
d
catalyst structure was performed by varying the hydrophobic group
and keeping the tertiary amine component (morpholinyl) constant.
Thus, the catalytic potential of diamines (1gei) synthesized
from L-leucine, L-valine and L-phenylalanine were studied. These
catalyst provided aldol adduct 4a in 90%, 92% and 91% yield, dr of
94:6, 92:8, 91:9 (syn/anti) and enantioselectivity of 81% ee, 79% ee
and 80% ee, respectively (Table 2, entries 7e9). Other chiral diamine
catalyst, such as primary-secondary (1j) was also tested on this
reaction, which gave the aldol product 4a in very low enantiose-
lectivity (10% ee) after 96 h (Table 2, entry 10). This result high-
lighted the importance of primaryetertiary diamine skeleton for
effective aldol catalysis. The catalyst 1a turned out to be the best
organocatalyst and was used in all further optimization study.
Next, in order to study the effect of acid additive, we performed
the model aldol reaction in the presence of different acids using
catalyst 1a. The aldol reaction performed in the presence of acid
additive, such as benzoic acid, 2-chlorobenzoic acid and 4-
nitrobenzoic acid afforded aldol adduct 4a within a close range of
enantioselectivity (78e82% ee) with almost similar diastereomeric
ratio (Table 2, entries 11e13). Use of strong acid additive results in
slight decrease in yield without much change in the enantiose-
lectivity and diastereomeric ratio (Table 2, entries 14 and 15). The
aldol reaction performed in the absence of acid additive yielded the
aldol product 4a in moderate enantioselectivity of 71% ee (Table 2,
entry 16).
O
O
O
∗
HO
diamine
additive
∗
O
+
O
N
water, rt
N
H
H
4a
2a
3
Scheme 1. Diamine catalyzed aldol reaction of cyclohexanone with isatin.
Table 1
Effect of catalyst concentration on the enantioselectivitya
Entry Catalyst loading 1a-DNP (1:1) Yieldb (%) drc (syn/anti) eed (%) (syn)
1
2
3
4
5
1a-DNP (10 mol %)
1a-DNP (5 mol %)
1a-DNP (2.5 mol %)
1a-DNP (1 mol %)
1a-DNP (0.5 mol %)
90
92
95
93
80
82:18
86:14
90:10
93:7
10
27
45
82
80
89:11
a
Reaction condition: 0.5 mmol of isatin, 5 mmol of cyclohexanone, 0.5 mL of
water, x mol % catalyst 1a, x mol % DNP, temperature 25 ꢀC.
b
Isolated yield determined after chromatographic purification.
c
Diastereoselectivity determined from HPLC spectra of crude reaction mixture.
Enantiomeric excess determined from HPLC using chiralpak columns.
d
In order to find the beneficial effect of water as a solvent, we
screened different organic solvents. The reaction proceeded
smoothly using toluene and THF as a solvent in the model aldol
reaction affording product 4a with good enantioselectivity of 81%
ee and 78% ee (Table 3, entries 1 and 2). The polar solvent (DMF,
MeOH) and chlorinated (DCM, DCE) solvent were found to be poor
solvent for this reaction (Table 3, entries 3e6). Acetonitrile (ACN)
gave aldol product 4a with lowest enantioselectivity of 30% ee
(Table 3, entry 7).
Using the optimized conditions, we studied the scope of the
reaction with variety of isatin derivatives (2aem) (Scheme 2). All
aldol adducts (4aem) were isolated in high yield (90e95%) and
with good enantioselectivity (70e95% ee) (Table 4). N-Substitut
ed
isatin derivatives were found to afford good level of enantiose-
In order to find a highly enantioselective catalyst, we screened
different primary amine derived catalyst. L-Isoleucine derived pri-
maryetertiary diamine catalyst having piperidinyl 1b and pyrroli-
dinyl 1c group gave aldol product 4a in high yield (>90%) and
enantioselectivity of 79% ee and 80% ee with similar level of di-
astereomeric ratio (Table 2, entries 2 and 3). Next, the catalytic
potential of primaryetertiary diamines (1d and 1e) having acyclic
tertiary amine was evaluated. The diamine catalyst having diethyl
1d and dibutyl 1e groups gave aldol product 4a in good yield with
moderate enantioselectivity of 70% ee and 71% ee (Table 2, entries 4
and 5). The diamine catalyst having long alkyl chain (N,N-dioctyl)
group 1f provided aldol product 4a with low enantioselectivity of
65% ee (Table 2, entry 6). Therefore, further optimization of the
lectivity as compared to NeH isatin derivatives. The 5-chloroisatin

A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
5199
Table 3
Table 4
Solvent screening for 1a-DNP catalyzed aldol reaction of cyclohexanone (3) with
Substrate scope for 1a-DNP catalyzed asymmetric direct aldol reaction of cyclo-
isatin (2a)a
hexanone (3) with isatin derivatives (2)a
Entry
Solvent
Time (h)
Yieldb (%)
drc (syn/anti)
eed (syn)
Entry
Isatins
(2)
Time
(h)
Product
(4)
Yieldb
(%)
drc
(syn/anti)
eed (%)
(syn)
1
2
3
4
5
6
7
Toluene
THF
DMF
MeOH
CH2Cl2
ClCHCHCl
CH3CN
24
24
52
30
36
36
40
90
93
82
88
86
84
80
94:6
81
78
40
53
56
52
26
88:12
70:30
77:33
86:14
91:9
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
24
24
24
24
22
22
26
26
26
26
26
30
30
4a
4b
4c
4d
4e
4f
4g
4h
4i
93
94
95
90
92
92
90
93
94
94
91
93
94
93:7
94:6
91:9
d
82
79
78
NR
88
NR
77
91
90
90
88
70
95
90:10
d
90:10
96:4
95:5
91:9
89:11
91:9
73:27
90:10
a
Reaction condition: 0.5 mmol of isatin, 5 mmol of cyclohexanone, 0.5 mL of
solvent, 1 mol % catalyst 1a1 mol % of DNP, temperature 25 ꢀC.
9
b
Isolated yield determined after chromatographic purification.
Diastereoselectivity determined from HPLC spectra of crude reaction mixture.
Enantiomeric excess determined from HPLC using chiralpak columns.
10
11
12
13
2j
2k
2l
4j
4k
4l
c
d
2m
4m
a
Reaction condition: 0.5 mmol of isatin derivatives, 5 mmol of cyclohexanone,
(2b) and 5-bromoisatin (2c) gave aldol adduct 4b and 4c in 94% and
95% yield, 94:6 and 91:9 (syn/anti) of dr; and 79% ee and 78% ee,
respectively (Table 4, entries 2 and 3). 5-Nitroisatin (2d) reacted
smoothly with cyclohexanone (3) providing aldol product 4d in 90%
yield (Table 4, entry 4). The aldol product 4d could not be resolved
on HPLC. The N-substituted isatin derivatives (2eem) react with
cyclohexanone (3), yielding aldol adduct (4eem) in high yield and
enantiomeric excess ranging from 77 to 95% (Table 4, entries 5e13).
The 5-bromo-N-methylisatin (2e) provided 4e in 92% yield, 90:10 of
dr and 88% ee (Table 4, entry 5). N-Methylisatin (2f) also reacts
efficiently to give 4f in 92% yield, but the product could not be
resolved on chiral HPLC (Table 4, entry 6). 5-Fluoro-N-allylisatin
(2h), 5-chloro-N-allylisatin (2i), 5-bromo-N-allylisatin (2j) and 5-
iodo-N-allylisatin (2k) gave aldol products (4hek) in 95%, 93%,
94% and 92% yield, 95:5, 91:9, 89:11 and 91:9 (syn/anti) dr and 91%
ee, 90% ee, 90% ee and 88% ee, respectively (Table 4, entries 8e11).
The N-allylisatin (2g) provided 4g in good yield of 90% and good
enantioselectivity of 77% ee (Table 3, entry 7). 5-Bromo-N-benzy-
lisatin (2m) provided aldol adduct 4m in good yield (94%) and high
enantioselectivity (95% ee), while N-benzylisatin (2l) provided al-
dol adduct 4l in good yield (93%) and moderate enantioselectivity
(70% ee) (Table 4, entries 12 and 13).
0.5 mL of water, 1 mol % catalyst 1a, 1 mol % of DNP, temperature 25 ꢀC.
b
Isolated yield determined after chromatographic purification.
Diastereoselectivity determined from HPLC spectra of crude reaction mixture.
Enantiomeric excess of syn diastereomer determined from HPLC using chiralpak
c
d
columns; NR¼not resolved on chiral HPLC.
Fig. 2. ORTEP diagram of 4a.
with acetone (5) to afford respective aldol adducts in good yield
(85e88%) and with moderate to good level of enantioselectivity
(62e80% ee) (Table 5, entries 4e8). The reaction of acetone (5) with
N-methylisatin derivatives (2e and 2f) provide corresponding aldol
adducts (6e and 6f) in 88% and 86% yield; and 69% ee and 80% ee,
respectively (Table 5, entries 4 and 5). The N-allylisatin derivatives
(2h and 2j) react with acetone (5) to provide the respective aldol
adducts (6h and 6j) in 89% and 87% yield; and 69% ee and 62% ee,
respectively (Table 5, entries 6 and 7). The N-benzylisatins de-
rivatives 2l react with acetone (5) to provide 6l in 87% and enan-
tioselectivity of 80% ee (Table 5, entry 8).
O
O
Catalyst 1a (1 mol%)
HO
O
R1
R1
DNP (1 mol%)
O
O
+
Water, rt
N
N
R2
4a-o
R2
3
2a-o
(2a) R1 = H, R2 = H;
(2c) R1 = Br, R2 = H;
(2e) R1 = Br, R2 = -CH3;
(2b) R1 = Cl, R2 = H;
(2d) R1 = NO2, R2 = H;
(2f) R1 = H, R2 = -CH3;
(2g) R1 = H, R2 = -CH2CH=CH2; (2h) R1 = F, R2 = -CH2CH=CH2;
(2i) R1 = Cl, R2 = -CH2CH=CH2;
(2k) R1 = I, R2 = -CH2CH=CH2
(2m) R1 = Br, R2 = -C6H5
(2j) R1 = Br, R2 = -CH2CH=CH2;
(2l) R1 = H, R2 = -C6H5;
Scheme 2. Aldol reaction of cyclohexanone with isatins.
O
The absolute configuration of aldol adduct 4a was assigned as
(R,S) on the basis of the single crystal X-ray structure analysis.15 The
single crystal was obtained by crystallization from 2-propanol
(Fig. 2).
O
Catalyst 1a (1 mol%)
HO
R1
R1
DNP 1 mol%
O
O
O
+
Water, rt
N
N
R2
R2
5
2a-o
6a-o
Further, in order to extend the scope of catalyst 1a to acyclic
ketone, we studied the direct aldol reaction of acetone (5) and
isatin derivatives (2) catalyzed by 1 mol % of 1a in the presence of
DNP (1 mol %) as an additive in water (Scheme 3). The acetone (5)
reacts with isatin (2a) to provide 3-acetonyl-3-hydroxy-2-oxindole
(6a) after 74 h in high yield (90%) and good enantioselectivity (70%
ee) (Table 5, entry 1). Acetone (5) also reacted successfully with 5-
haloisatin derivatives (2b and 2c) to provide aldol adducts (6b and
6c) in 88% and 94% yield; and 67% ee, 71% ee, respectively (Table 5,
entries 2 and 3). The N-alkylated isatins also undergo aldol reaction
(2a) R1 = H, R2 = H;
(2c) R1 = Br, R2 = H;
(2f) R1 = H, R2 = -CH3;
(2b) R1 = Cl, R2 = H;
(2e) R1 = Br, R2 = -CH3;
(2h) R1 = H, R2 = -CH2CH=CH2;
(2j) R1 = Br, R2 = -CH2CH=CH2; (2l) R1 = H, R2 = -C6H5;
Scheme 3. Aldol reaction of acetone with isatins.
A gram scale reaction was performed to demonstrate the prac-
tical utility of this reaction. The reaction of isatin (2a) with cyclo-
hexanone (3) at 10 mmol scale using 1 mol % of 1a-DNP resulted in

5200
A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
Table 5
O
Substrate scope for 1a-DNP catalyzed asymmetric direct aldol reaction of acetone (5)
O
O
with isatin derivatives (2)a
HO
1a-DNP
(1 or 10 mol%)
Yieldb (%)
eec (%)
+
O
Entry
Isatins (2)
Time (h)
Product (6)
O
water, rt
N
1
2
3
4
5
6
7
8
2a
2b
2c
2e
2f
2h
2j
2l
74
76
70
75
70
72
72
72
6a
6b
6c
6e
6f
6h
6j
6l
90
88
89
88
86
89
87
87
70
67
71
69
80
69
62
80
N
H
H
3
2a
4a
a
Reaction condition: 0.5 mmol of isatin, 5 mmol of acetone, 0.5 mL of water,
1 mol % catalyst 1a, 1 mol % DNP, temperature 25 ꢀC.
b
Isolated yield determined after chromatographic purification.
Enantiomeric excess determined from HPLC using chiralpak columns.
c
the formation of 4a in 86% yield after 24 h, 90:10 (syn/anti) dr, and
enantioselectivity of 81% ee.
Further, it was planned to investigate the success of the reaction
of isatin with cyclohexanone at low catalyst loading. A similar ob-
servation has been made by Singh et al.14 in the aldol reaction of
aldehydes with acetone catalyzed by prolinamide, which was
explained by Groger et al.16 by involving the shifting of the reaction
€
Fig. 3. Study of enantioselectivity as a function of time.
from kinetic control to thermodynamic control. Since primary
amine derived organocatalysts along with antibodies and transition
metal catalysts have been known to catalyze the retro-aldol re-
action,17 therefore we envisioned that at high catalyst loading the
retro-aldol would occur at a faster ratedin comparison to secondary
amineddue to the ease of the primary amine to form imineeen-
Table 6
Study of change in enantioselectivity of 4a (dr of 85:15 (syn/anti) and 60% ee) at 10
and 1 mol % of catalyst loading
O
HO
O
HO
O
O
amine intermediate with sterically demanding aldol adduct (b-hy-
1a-DNP (x mol%)
+
O
+
O
droxyl ketone). On account of the faster rate, the reaction reaches
equilibrium quickly and there is possibility of a swing of the reaction
from kinetic control to thermodynamic control. At low catalyst
loading the retro-aldol is very slow and the shifting of the reaction
from kinetic control to thermodynamic control is not possible.
In order to explain our hypothesis we designed some experi-
ments. Initially, the enantioselectivity of ketone aldolization be-
tween cyclohexanone (3) and isatin (2a) was studied as a function
of time at two different catalyst loadings of 1 mol % and 10 mol %
using catalyst 1a and DNP as additive in 1:1 molar ratio. The change
from kinetic to thermodynamic control at high catalyst loading of
10 mol % with the reaction course has been shown in Fig. 2. The
decrease of enantioselectivity from 70% ee (after 5 min) to 10% ee
(after 24 h) at 10 mol % of catalyst loading shows that with in-
creasing reaction time, initially formed kinetic enantiomeric
product changes into a thermodynamic controlled enantiomer,
thus lowering the enantioselectivity of the product. In contrast to
the above results, at low catalyst loading of 1 mol % there was no
change in the enantioselectivity of the aldol product 4a during the
course of the reaction (Fig. 3).
In order to understand the effect of high catalyst loading leading
to low enantioselectivity, we planned further experiments
(Table 6). The aldol product 4a (ee of 60%; dr 85:15 (syn/anti)) and
catalyst 1a was stirred at ambient temperature. Using 10 mol % of
1a, the resulting aldol product 4a was obtained with decreased ee
of 27% and dr of 81:19 (syn/anti) after 12 h, whereas no change in
the ee and minor change in dr of aldol product 4a was observed
using 1 mol % of catalyst 1a (Table 1, entries 1 and 3). After 24 h,
there was further lowering in the enantioselectivity to 10% ee and
dr of 69:31 (syn/anti) with 10 mol % of catalyst loading, whereas no
change in enantioselectivity18 and slight change in diastereomeric
ratio was observed using low catalyst loading of 1 mol % (Table 1,
entries 2 and 4). We therefore reasoned that at high catalyst loading
the retro-aldol reaction occurs rapidly leading to the breakup of
kinetic aldol adduct into its precursor, which recombines to form
thermodynamic aldol adduct and kinetic aldol adduct, thus shifting
O
THF + Water = 1:1
N
N
H
N
H
H
3
2a
4a
4a
ee 60% (syn)
dr 85:15 (syn/anti)
Entry Catalyst loading (mol %) Time (h) dra (syn/anti) eeb (%) Isatinc (%)
1
2
3
4
10
10
1
12
24
12
24
81:19
69:31
84:16
82:18
27
10
60
61
6
7
9
1
10
a
b
c
Diastereoselectivity determined from HPLC spectra of crude reaction mixture.
Enantiomeric excess determined from HPLC using chiralpak columns.
Recovered isatin determined from HPLC.
the reaction from kinetic control to thermodynamic control. But at
low catalyst loading, the retro-aldol is very slow and change from
kinetic to thermodynamic control nearly ceases.
In order to support our hypothesis of fast retro-aldol at high
catalyst loading (10 mol %) contrary to the very slow retro-aldol at
low catalyst loading (ꢁ1 mol %), we further studied the transfer
aldol reaction (Scheme 4). The transfer aldol reaction of racemic 4a
with excess of acetone using 5 mol % of catalyst 1a in water at
O
O
O
HO
HO
HO
O
1a-DNP (5mol%)
+
O
+
O
O
Water, 24h
N
N
N
H
H
H
5
6a
40% yield, 65% ee
( ) 4a
8% ee
Scheme 4. Transfer aldol reaction.
ambient temperature for 24 h provided the transfer aldol adduct 6a
with 65% ee and 40% yield. But, on performing the transfer aldol
reaction using 1 mol % of catalyst 1a, it provided the transfer aldol
adduct 6a after 24 h in traces, thus confirming the occurrence of
retro-aldol at 10 mol % of catalyst loading.

A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
5201
Next, we studied the ketone aldolization of acetone with isatin
3. Conclusions
(2a) in water at two different catalyst loadings of diamine 1a in the
presence of DNP additive (Scheme 5). While on the one hand the
1 mol % of catalyst 1a afforded product 6a in 55% yield with 76% ee
after 24 h, on the other hand the R isomer of aldol product 6a was
isolated in 95% yield and enantiomeric excess of 65% ee after 24 h of
reaction time using 10 mol % of catalyst 1a. This decrease in the
enantioselectivity of 6a at high catalyst loadingdalthough not as
profound as observed in the case of product 4adis understood to
be due to the retro-aldol reaction.
In conclusion, we have developed a highly efficient primary
amine based organocatalysts for ketoneeketone aldolization. Low
catalyst concentration was used to catalyze the direct aldol reaction
between cyclohexanone/acetone and isatin derivatives to procure
biologically relevant 3-substituted-3-hydroxy-2-oxindoles. The
methodology is very simple and environmentally benign and
highly enantioselective. Water as a solvent and low catalyst con-
centration is the important asset of this methodology.
Retro-aldol at high catalyst loading forces the reaction to reach
equilibrium quickly and shift the reaction from kinetic to thermo-
dynamic control. Low catalyst loading leads to slow retro-aldol
reaction and the shift of the reaction from kinetic to thermody-
namic control is nearly nonexistent.
O
O
HO
O
1a-DNP (1:1)
O
O
+
water, 24h
N
H
N
5
H
2a
4. Experimental section
4.1. General remarks
6a
Using 10 mol% of 1a-DNP = 95% yield, 65% ee of 6a
Using 1 mol% of 1a-DNP = 56% yield 76% ee of 6a
Scheme 5. Direct aldol reaction of acetone with isatin.
NMR spectra were obtained at 300 MHz (Jeol AL-300) and
400 MHz (Bruker Avance 400 MHz) using CDCl3 and DMSO-d6 as
solvent with Me4Si in CDCl3 as the internal standard. Chemical
In order to demonstrate the effect of catalyst loading on the
enantioselectivity of 6a, the aldol product 6a (88% ee) was stirred
with 10 mol % of catalyst 1a at ambient temperature, provided the
aldol product 6a with decreased enantioselectivity of 65% ee after
24 h (Table 7, entry 1). On performing the similar reaction using
1 mol % of catalyst 1a the aldol adduct 6a was isolated with almost
same enantioselectivity (87% ee) as of the initial aldol adduct 6a
(Table 7, entry 2). The above results also support our hypothesis
that fast retro-aldol at high catalyst loading leads to decrease in the
enantioselectivity due to the shifting of reaction from kinetic con-
trol to thermodynamic control.
shifts (d) are expressed in parts per million and Hertz downfield
from internal TMS. Spectral patterns are designated as s¼singlet;
d¼doublet; dd¼doublet of doublets; t¼triplet; br¼broad;
m¼multiplet. Optical rotation was determined with JASCO DIP-360
polarimeter at 25 ꢀC. HRMS were recorded on a UPLC-Q-TOF. En-
antiomeric excess was determined by using Shimadzu LC-20AD
using Daicel Chiralpak AD-H, ODH, AS-H and IB column. Column
chromatography was performed on 60e120 mesh silica (Spec-
trochem, India) using mixtures of hexane and ethyl acetate as an
eluents.
Table 7
Study of change in enantioselectivity of 6a (88% ee) at 10 mol % and 1 mol % of
catalyst loading
4.2. General procedure for enantioselective aldol reactions
O
O
O
O
To a stirring mixture of catalyst 1a (0.005 mmol) and cyclo-
HO
HO
1a-DNP (x mol%)
hexanone/acetone (5 mmol) in water (500 mL), additive DNP
+
O
+
O
O
(0.920 mg, 0.005 mmol) was added at 25 ꢀC and the mixture was
allowed to stir for 5 min followed by addition of isatin derivative
(0.5 mmol). The mixture was stirred for 20e96 h and the progress
of the reaction was monitored at regular intervals by TLC. On the
completion of reaction, saturated solution of NH4Cl (5 mL) was
added to it and resulting mixture was extracted with ethyl acetate
(3ꢃ15 mL). The organic layer was separated, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure
to obtain crude aldol product. The column chromatography on
silica gel (60e120 mesh) using hexane/ethyl acetate as an eluent
gave the corresponding aldol adducts as a syn/anti mixture. The
enantiomeric excess of aldol addition products was determined by
chiral HPLC. The diastereoselectivity of product was determined by
HPLC of crude reaction mixture. Racemic standards were prepared
using (ꢂ) 3-methyl-1-morpholinobutan-2-amine catalyst synthe-
sized form (ꢂ) valine.
N
THF + Water = 1:1
N
N
H
H
H
3
2
6a
6a
88% ee
Entry
Catalyst loading (mol %)
Time (h)
eea (%)
Isatinb (%)
1
2
10
1
24
24
65
87
9
11
a
Enantiomeric excess determined from HPLC using chiralpak columns.
Recovered isatin determined from HPLC.
b
Further, in order to provide additional support to our hypothe-
sis, we studied the transfer aldol reaction of racemic 6a (Scheme 6).
The stirring of (ꢂ) 6a with excess cyclohexanone using 10 mol % of
1a in water at ambient temperature for 24 h gave the transfer aldol
adduct 4a in 20% yield with dr of 69:31 (syn/anti) and 47% ee of
major diastereomer. The initial aldol adduct 6a was obtained in 70%
yield and also with the enantio-enrichment of S isomer to 55% ee,
thus confirming our hypothesis.
Spectral data of compounds 4a,4a 4b,4a 4c,4a 4f,5h 4l,5h 6a,3 6b,5b
6c,3 6e,5b 6f,3 6h5e and 6m3 were in excellent agreement with those
in the literature.
O
O
O
4.2.1. (R)-3-Hydroxy-3-((S)-20-oxocyclohexyl)indolin-2-one4a
O
∗
HO
HO
HO
∗
(4a). White solid; yield¼93%; mp¼176e178 ꢀC (lit.5h mp 159 ꢀC); Rf
1a-DNP (10 mol%)
O
+
O
O
(60% EtOAc/hexane) 0.24; ½a D25
ꢄ
þ65 (c 0.1, MeOH); syn/anti¼82:18;
+
water, 24 h
N
H
N
H
N
H
4a
6a
enantiomeric excess: 82% of syn diastereomer determine by HPLC
3
( ) 6a
20% yield
55% ee
(Diacel chiralpak AS-H, hexane/i-PrOH, 60:40, 1.0 mL/min,
69:31 dr (syn/anti)
47% ee (syn)
l
¼254 nm, tR (syn, major)¼14.2 min, tR (syn, major)¼35.3 min); 1H
11% ee (anti)
NMR (300 MHz, DMSO-d6): d 1.43e1.98 (m, 6H, CH2), 2.25e2.36 (m,
Scheme 6. Transfer aldol reaction.
1H, CH2), 2.53e2.57 (m, 1H, CH2), 3.04e3.10 (m, 1H, CH), 5.8 (s, 1H,

5202
A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
OH), 6.77e6.87 (m, 2H, ArH), 7.13e7.25 (m, 2H, ArH), 10.17 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6):
24.4, 26.6, 26.7, 41.4, 57.3, 73.9,
109.4, 120.8, 124.7, 128.5, 130.8, 143.4, 178.6, 209.1; m/z (TOF):
268.9803 (MþþNa).
excess: 77% of syn diastereomer determined by HPLC (Diacel
d
Chiralpak AS-H; hexane/i-PrOH 93:7; flow rate 1 mL/min;
l
¼254 nm, tR (syn, major)¼33.3 min, tR (syn, minor)¼46.2 min); 1H
NMR (300 MHz, CDCl3): d 1.57e1.68 (m, 4H, CH2), 1.89e2.04 (m, 2H,
CH2), 2.30e2.49 (m, 2H, CH2), 2.97e3.00 (m, 1H, CH), 4.18e4.24 (m,
1H, eCHaHbeCH]CH2), 4.38e4.45 (m, 1H, eCHaHbeCH]CH2),
4.76 (br, 1H, OH), 5.21e5.34 (m, 2H, eCH]CH2), 5.82e5.86 (m, 1H,
eCH]CH2), 6.80e6.83 (d, J¼7.5 Hz, 1H, ArH), 7.02e7.07 (m, 1H,
4.2.2. (R)-5-Chloro-3-hydroxy-3-((S)-20-oxocyclohexyl)indolin-2-
one4a (4b). White solid; yield¼94%; mp¼182e184 ꢀC; Rf (60%
EtOAc/hexane) 0.27; ½a D25
þ62 (c 0.1, MeOH); syn/anti¼94:6; en-
ꢄ
antiomeric excess: 79% of syn diastereomer determined by HPLC
ArH), 7.27e7.35 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
d 24.4,
(Diacel Chiralpak IB; hexane/i-PrOH 80:20; flow rate 0.5 mL/min;
l
25.9, 27.0, 41.9, 42.3, 55.6, 76.7,109.2,117.6,122.7,124.0,128.8,129.7,
131.2, 143.6, 176.5, 211.4; HRMS (ESI) m/z: [MþþNa] calcd for
C17H19NO3 308.1263; found 308.1230.
¼254 nm, tR (syn, major)¼21.0 min, tR (syn, minor)¼28.2 min); 1H
NMR (300 MHz, DMSO-d6):
d 1.50e2.04 (m, 6H, CH2); 2.27e2.54
(m, 2H, CH2), 3.05e3.11 (m, 1H, CH), 5.99 (s, 1H, OH), 6.79 (d,
J¼8.1 Hz, 1H, ArH), 7.17e7.23 (m, 2H, ArH), 10.34 (s, 1H, NH); 13C
4.2.8. (R)-1-Allyl-5-fluoro-3-hydroxy-3-((S)-20-oxocyclohexyl)in-
dolin-2-one (4h). Sticky solid; yield¼93%; Rf (50% EtOAc/hexane)
NMR (75 MHz, DMSO-d6):
d 24.9, 27.1, 41.9, 57.8, 74.4, 111.2, 125.2,
128.7, 133.3, 142.8, 178.8, 209.7; m/z (TOF): 302.0302 (MþþNa).
0.46; ½a 2D5
þ34 (c 0.1, MeOH); syn/anti¼95:5; enantiomeric excess:
ꢄ
91% of syn diastereomer determined by HPLC (Diacel Chiralpak OD-
4.2.3. (R)-5-Bromo-3-hydroxy-3-((S)-20-oxocyclohexyl)indolin-2-
H; hexane/i-PrOH 95:5; flow rate 1 mL/min;
l
¼254 nm, tR (syn,
one4a (4c). White solid; yield¼95%; mp¼187e189 ꢀC; Rf (60%
major)¼19.4 min, tR (syn, minor)¼23.0 min); 1H NMR (300 MHz,
EtOAc/hexane) 0.28; ½a D25
ꢄ
þ71 (c 0.1, MeOH); syn/anti¼91:9; en-
CDCl3): d 1.57e168 (m, 4H, CH2), 1.94e2.14 (m, 2H, CH2),
antiomeric excess: 78% of syn diastereomer determined by HPLC
2.25e2.46 (m, 2H, CH2), 2.97e3.03 (m, 1H, CH), 4.15e4.22 (m,
1H, eCHaHbeCH]CH2), 4.37e4.44 (m, 1H, eCHaHbeCH]CH2), 4.74
(br s, 1H, OH), 5.23e5.34 (m, 2H, eCH]CH2), 5.77e5.90 (m,
1H, eCH]CH2), 6.73e6.77 (m, 1H, ArH), 6.95e7.02 (m, 1H, ArH),
(Diacel Chiralpak AD-H; hexane/i-PrOH 92:8; flow rate 0.8 mL/min;
l
¼254 nm, tR (syn, major)¼71.9 min, tR (syn, minor)¼54.9 min); 1H
NMR (300 MHz, DMSO-d6): d 1.47e2.04 (m, 6H, CH2), 2.26e2.58 (m,
2H, CH2), 3.04e3.11 (m, 1H, CH), 5.98 (s, 1H, OH), 6.74 (d, J¼8.1 Hz,
7.07e7.11 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3):
d 24.4, 26.1, 27.1,
1H, ArH), 7.28e7.42 (m, 2H, ArH), 10.34 (s, 1H, NH); 13C NMR
41.9, 42.5, 55.7, 76.8, 109.9, 112.5, 116.0, 131.0, 139.6, 157.6, 160.8,
176.3, 211.2; HRMS (ESI) m/z: [MþþNa] calcd for C17H18FNNaO3
326.1168; found 326.1264.
(75 MHz, DMSO-d6):
d 24.9, 27.1, 27.2, 41.9, 57.9, 74.4, 111.9, 113.0,
127.9, 131.8, 133.8, 143.3, 178.7, 209.8; m/z (TOF): 347.9740
(MþþNa).
4.2.9. (R)-1-Allyl-5-chloro-3-hydroxy-3-((S)-20-oxocyclohexyl)in-
4.2.4. (R)-3-Hydroxy-5-nitro-3-((S)-20-oxocyclohexyl)indolin-2-one
dolin-2-one (4i). White solid; yield¼94%; mp¼149e151 ꢀC; Rf (50%
(4d). White solid; yield¼90%; mp¼198e200 ꢀC; Rf (50% EtOAc/
EtOAc/hexane) 0.41; ½a D25
þ41 (c 0.1, MeOH); syn/anti¼91:9; en-
ꢄ
hexane) 0.21; ½a D25
ꢄ
þ65 (c 0.1, MeOH); 1H NMR (400 MHz, DMSO-
antiomeric excess: 90% of syn diastereomer determined by HPLC
d6):
d
1.60e1.93 (m, 3H, CH2); 2.01e2.40 (m, 4H, CH2), 2.75e2.79
(Diacel Chiralpak AD-H; hexane/i-PrOH 95:5; flow rate 1 mL/min;
(m, 1H, CH2), 3.22e3.30 (m, 1H, CH), 6.20 (s, 1H, OH), 6.93e7.01 (m,
l
¼254 nm, tR (syn, major)¼39.5 min, tR (syn, minor)¼47.3 min); 1H
1H, ArH), 8.06e8.22 (m, 2H, ArH), 10.81 (s, 1H, NH); 13C NMR
NMR (300 MHz, CDCl3): 1.56e1.77 (m, 4H, CH2), 1.93e2.13 (m, 2H,
CH2), 2.25e2.47 (m, 2H, CH2), 2.97e3.03 (m, 1H, CH), 4.15e4.22 (m,
1H, eNeCHaHbeCH]CH2), 4.37e4.44 (m, 1H, eNeCHaHbeCH]
CH2), 4.67 (s, 1H, OH), 5.22e5.33 (m, 2H, eCH]CH2), 5.77e5.88 (m,
1H, eCH]CH2), 6.73e6.76 (m, 1H, ArH), 7.24e7.32 (m, 2H, ArH);
(100 MHz, DMSO-d6): d 209.3, 179.4, 150.1, 141.8, 131.5, 125.9, 120.3,
109.4, 73.8, 57.8, 41.6, 27.7, 26.9, 24.8; m/z (TOF): 313.0865
(MþþNa).
4.2.5. (R)-5-Bromo-3-hydroxy-1-methyl-3-((S)-20-oxocyclohexy)in-
13C NMR (75 MHz, CDCl3):
d 24.5, 25.3, 27.2, 41.9, 42.5, 55.7, 76.5,
dolin-2-one (4e). White solid; yield¼92%; mp¼164e166 ꢀC; Rf (50%
110.8, 115.4, 118.9, 128.4, 131.8, 133.4, 142.7, 176.0, 211.5; HRMS (ESI)
EtOAc/hexane) 0.42; ½a D25
ꢄ
þ45 (c 0.1, MeOH); syn/anti¼90:10; en-
m/z: [MþþNa] calcd for C17H18ClNNaO3 342.0873; found 342.0874.
antiomeric excess: 88% of syn diastereomer determined by HPLC
(Diacel Chiralpak OD-H; hexane/i-PrOH 97.5:2.5; flow rate 1 mL/
4.2.10. (R)-1-Allyl-5-bromo-3-hydroxy-3-((S)-20-oxocyclohexyl)in-
min;
l
¼254 nm, tR (syn, major)¼54.7 min, tR (syn, minor)¼
dolin-2-one (4j). White solid; yield¼94%; Rf (50% EtOAc/hexane)
68.5 min); 1H NMR (300 MHz, CDCl3):
d
1.63e1.59 (m, 4H, CH2),
0.49; mp¼158e160 ꢀC; ½a D25
þ40 (c 0.1, MeOH); syn/anti¼89:11;
ꢄ
2.14e1.92 (m, 3H, CH2), 2.44e2.28 (m, 1H, CH2), 2.97e3.01 (m, 1H,
CH), 3.16 (s, 3H, NCH3), 4.70 (br s, 1H, OH), 6.71 (d, J¼8.7 Hz, 1H,
enantiomeric excess: 90% of syn diastereomer determined by HPLC
(Diacel Chiralpak OD-H; hexane/i-PrOH 95:5; flow rate 1 mL/min;
ArH), 7.43e7.45 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
d
24.4,
l
¼254 nm, tR (syn, major)¼19.6 min, tR (syn, minor)¼27.0 min); 1H
26.0, 26.2, 27.0, 42.0, 55.7, 76.5, 109.7, 115.4, 127.4, 130.8, 132.6,
NMR (300 MHz, CDCl3): d 1.52e1.87 (m, 4H, CH2), 1.89e2.18 (m, 2H,
143.5, 176.2, 211.2; m/z (TOF): 360.0315 (MþþNa).
CH2), 2.22e2.46 (m, 2H, CH2), 4.21e4.23 (m, 1H, NeCHaHbeCH]
CH2), 4.37e4.44 (m, 1H, NeCHaHbeCH]CH2), 4.75 (s, 1H, OH),
5.22e5.33 (m, 2H, eCH]CH2), 5.72e5.83 (m, 1H, eCH]CH2),
6.68e6.72 (m, 1H, ArH), 7.39e7.59 (m, 2H, ArH); 13C NMR (75 MHz,
4.2.6. (R)-3-Hydroxy-1-methyl-3-((S)-20-oxocyclohex-10-yl)indolin-
2-one5h (4f). White solid; yield¼92%; mp¼144e146 ꢀC; Rf (50%
EtOAc/hexane) 0.40; ½a D25
ꢄ
þ35 (c 0.1, MeOH); 1H NMR (400 MHz,
CDCl3): d 24.5, 25.2, 27.1, 41.9, 42.4, 55.9, 76.4, 110.8, 115.4, 117.9,
CDCl3):
d
1.55e1.75 (m, 4H, CH2), 1.88e2.07 (m, 2H, CH2), 2.25e2.47
127.4, 130.8, 132.4, 142.7, 176.0, 211.0; HRMS (ESI) m/z:
(m, 2H, CH2), 2.91e3.01 (m, 1H, CH), 3.19 (s, 3H, NCH3), 4.86 (br s,
1H, OH), 6.82 (d, J¼5.7 Hz, 1H, ArH), 7.04e7.08 (m, 1H, ArH),
[MþþNaþ2H] calcd. for C17H18BrNO3 388.0524; found 388.0512.
7.27e7.35 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d
24.5, 26.0,
4.2.11. (R)-1-Allyl-5-iodo-3-hydroxy-3-((S)-20-oxocyclohexyl)in-
26.1, 27.1, 42.1, 55.5, 76.7, 108.3, 122.8, 123.9, 128.8, 129.9, 144.4,
dolin-2-one (4k). White solid; yield¼91%; mp¼135e137 ꢀC; Rf (50%
176.6, 211.7; m/z (ESI): 256.2 (MþþH).
EtOAc/hexane) 0.51; ½a D25
þ43 (c 0.1, MeOH); syn/anti¼91:9; en-
ꢄ
antiomeric excess: 88% of syn diastereomer determined by HPLC
4.2.7. (R)-1-Allyl–3-hydroxy-3-((S)-20-oxocyclohexyl)indolin-2-one
(4g). White solid; yield¼90%; mp¼109e111 ꢀC; Rf (50% EtOAc/
(Diacel Chiralpak OD-H; hexane/i-PrOH 93:7; flow rate 1 mL/min;
l
¼254 nm, tR (syn, major)¼19.8 min, tR (syn, minor)¼37.9 min); 1H
hexane) 0.45; ½a D25
ꢄ
þ37 (c 0.1, MeOH); syn/anti¼96:4; enantiomeric
NMR (300 MHz, CDCl3): d 1.60e1.80 (m, 4H, CH2); 1.92e2.14 (m, 2H,

A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
5203
CH2), 2.25e2.45 (m, 2H, CH2), 2.97e3.03 (m, 1H, CH), 4.14e4.21 (m,
1H, eCHaHbeCH]CH2), 4.35e4.44 (m, 1H, eCHaHbeCH]CH2),
4.71 (br s, 1H, OH), 5.22e5.33 (m, 2H, eCH]CH2), 5.74e5.88 (m,
1H, eCH]CH2), 6.58e6.62 (m, 1H, ArH), 7.58e7.75 (m, 2H, ArH);
1H, CH2), 6.07 (s, 1H, OH), 6.73 (d, J¼8.1 Hz, 1H, ArH), 7.32e7.44 (m,
2H, ArH), 10.34 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6):
d 30.3,
50.0, 72.6, 111.5, 112.9, 126.7, 131.6, 134.2, 142.1, 177.8, 205.4.
13C NMR (75 MHz, CDCl3):
d
24.9, 26.4, 27.5, 42.4, 42.8, 56.1, 76.9,
4.2.17. (R)-5-Bromo-3-hydroxy-1-methyl-3-(20-oxopropyl)indolin-2-
85.7, 111.8, 118.4, 131.2, 133.4, 134.5, 138.9, 143.8, 176.2, 211.6; HRMS
(ESI) m/z: [MþþNa] calcd for C17H18INNaO3 434.0229; found
434.0213.
one (6e). White solid; yield¼88%; mp¼102e104 ꢀC; Rf (50% EtOAc/
hexane) 0.33; ½a D25
þ35 (c 0.1, MeOH); enantiomeric excess: 69%
ꢄ
determined by HPLC (Diacel Chiralpak OD-H; hexane/i-PrOH 90:10;
flow rate 1.0 mL/min;
l
¼254 nm, tR (major)¼19.0 min, tR (minor)¼
4.2.12. (R)-1-Benzyl-3-hydroxy-3-((S)-20-oxocyclohexyl)indolin-2-
28.7 min); 1H NMR (300 MHz, CDCl3):
d
2.17 (s, 3H, CH3), 3.01 (d,
one5h (4l). White solid; yield¼93%; mp¼180e182 ꢀC; Rf (50%
J¼17.4 Hz, 1H, CH2), 3.18 (s, 3H, CH3), 3.22 (d, J¼17.4 Hz, 1H, CH2),
4.57 (s, 1H, OH), 6.72 (d, J¼8.4 Hz, 1H, ArH), 7.43e7.48 (m, 2H, ArH);
EtOAc/hexane) 0.54; ½a D25
þ51 (c 0.1, MeOH); syn/anti¼73:27; en-
ꢄ
antiomeric excess: 70% of syn diastereomer determined by HPLC
13C NMR (75 MHz, CDCl3):
d 26.4, 31.1, 49.0, 73.9, 110.1, 115.7, 127.2,
(Diacel Chiralpak OD-H; hexane/i-PrOH 95:5; flow rate 1 mL/min;
l
131.7, 132.7, 142.7, 175.8, 206.9.
¼254 nm, tR (syn, major)¼25.7 min, tR (syn, minor)¼42.8 min); 1H
NMR (300 MHz, CDCl3):
d
1.58e2.02 (m, 6H, CH2) 2.32e2.52 (m, 2H,
4.2.18. (R)-3-Hydroxy-1-methyl-3-(20-oxopropyl)indolin-2-one3
CH2), 2.97e3.06 (m, 1H, CH) 3.26e3.32 (m, 1H, CH), 4.79e4.85 (m,
1H, CHaHbPh), 4.92e5.01 (m, 1H, CHaHbPh), 6.67e6.72 (m, 1H, ArH),
6.99e7.04 (m, 1H, ArH), 7.17e7.46 (m, 7H, ArH); 13C NMR (75 MHz,
(6f). White solid; yield¼86%; mp¼139e141 ꢀC (lit.5b mp
153e155 ꢀC); Rf (50% EtOAc/hexane) 0.22; ½a 2D5
þ36 (c 0.1, MeOH);
ꢄ
enantiomeric excess: 80% determined by HPLC (Diacel Chiralpak IB;
CDCl3):
d
24.5, 26.0, 27.2, 42.0, 43.9, 55.4, 76.5, 109.5, 122.9, 124.0,
hexane/i-PrOH 93:7; flow rate 1.0 mL/min;
l
¼254 nm, tR (major)¼
125.4, 127.3, 127.5, 128.7, 128.8, 128.9, 129.8, 135.6, 143.6, 176.8,
26.7 min, tR (minor)¼30.3 min); 1H NMR (300 MHz, CDCl3):
d 2.18 (s,
211.7; m/z (TOF) 358.1531 (MþþNa).
3H, CH3), 2.94 (d, J¼17.1 Hz,1H, CH2), 3.18 (d, J¼17.1 Hz,1H, CH2), 3.21
(s, 3H, CH3), 4.38 (s,1H, OH), 6.84 (d, J¼8.1 Hz,1H, ArH), 7.04e7.09 (m,
4.2.13. (R)-1-Benzyl-5-bromo-3-hydroxy-3-((S)-20-oxocyclohexyl)in-
1H, ArH), 7.30e7.38 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
d 26.2,
dolin-2-one (4m). White solid; yield¼94%; mp¼193e195 ꢀC; Rf
31.3, 48.8, 74.1, 108.5, 123.1, 123.7, 129.9, 137.9, 143.5, 176.3, 207.3.
(40% EtOAc/hexane) 0.57; ½a D25
þ57 (c 0.1, MeOH); syn/anti¼90:10;
ꢄ
enantiomeric excess: 95% of syn diastereomer determined by HPLC
4.2.19. (R)-1-Allyl-3-hydroxy-3-(20-oxopropyl)indolin-2-one5e
(Diacel Chiralpak OD-H; hexane/i-PrOH 97:3; flow rate 1 mL/min;
(6h). White solid; yield¼89%; mp¼110e112 ꢀC; ½a D25
þ31 (c 0.1,
ꢄ
l
¼254 nm, tR (syn, major)¼18.4 min, tR (syn, minor)¼29.3 min); 1H
MeOH); enantiomeric excess: 69% determined by HPLC (Diacel
NMR (300 MHz, CDCl3):
d
1.58e2.19 (m, 6H, CH2), 2.29e2.47 (m, 2H,
Chiralpak AD-H; hexane/i-PrOH 90:10; flow rate 1.0 mL/min;
CH2), 3.05e3.08 (m, 1H, CH), 4.75e4.96 (m, 3H, CH2 and OH),
6.51e6.57 (m, 1H, ArH), 7.25e7.31 (m, 6H, ArH), 7.43e7.58 (m, 1H,
l
¼254 nm, tR (major)¼13.29 min, tR (minor)¼14.58 min); 1H NMR
(300 MHz, CDCl3):
d
2.17 (s, 1H, CH3), 3.03 (d, J¼17.4 Hz, 1H, CH2),
ArH); 13C NMR (75 MHz, CDCl3):
d
24.4, 26.1, 27.1, 41.9, 43.9, 55.8,
3.24 (d, J¼17.1 Hz, 1H, CH2), 4.22e4.43 (m, 3H, CH2 and OH),
5.23e5.34 (m, 2H, CH2), 5.79e5.92 (m, 1H, CH2), 6.84 (d, 1H, ArH),
7.03e7.26 (m, 1H, ArH), 7.26e7.38 (m, 2H, ArH); 13C NMR (75 MHz,
76.5, 110.9, 115.4, 127.1, 127.4, 127.6, 128.7, 128.8, 130.9, 132.4, 135.0,
142.7, 176.5, 211.0; m/z (TOF): 435.5583 (MþþNa).
CDCl3): d 31.3, 42.4, 49.1, 74.0, 109.6, 117.8, 123.1, 123.8, 129.7, 129.9,
131.0, 142.8, 176.0, 207.1.
4.2.14. (R)-3-Hydroxy-3-(20-oxopropyl)indolin-2-one3 (6a). White
solid; yield¼90%; mp¼180e181 ꢀC (lit.5b mp 166e168 ꢀC); Rf (60%
EtOAc/hexane) 0.22; ½a D25
ꢄ
þ23 (c 0.1, MeOH); enantiomeric excess:
4.2.20. (R)-1-Allyl-5-bromo-3-hydroxy-3-(20-oxopropyl)indolin-2-
70% determined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH
one (6k). White solid, yield¼87%; mp¼120e122 ꢀC; ½a D25
þ41 (c 0.1,
ꢄ
70:30; flow rate 1 mL/min;
l
¼254 nm, tR (major)¼7.8 min, tR
MeOH); enantiomeric excess: 62% determined by HPLC (Diacel
(minor)¼6.4 min); 1H NMR (300 MHz, DMSO-d6):
d
2.00 (s, 3H,
Chiralpak AD-H; hexane/i-PrOH 93:7; flow rate 1.0 mL/min;
CH3), 3.04 (d, J¼17.4 Hz, 1H, CH2), 3.36 (d, J¼17.4 Hz, 1H, CH2), 6.07
l
¼254 nm, tR (major)¼19.6 min, tR (minor)¼21.6 min); 1H NMR
(s, 1H, OH), 6.75e6.84 (m, 2H, ArH), 7.10e7.21 (m, 2H, ArH),10.33 (s,
(300 MHz, CDCl3):
d
2.17 (s, 1H, CH3), 3.04 (d, J¼17.4 Hz, 1H, CH2),
1H, NH); 13C NMR (75 MHz, DMSO-d6):
d
30.5, 50.2, 72.3, 109.3,
3.24 (d, J¼17.4 Hz, 1H, CH2), 4.24e4.35 (m, 3H, CH2 and OH),
121.1, 123.6, 128.9, 131.5, 142.4, 178.1, 205.1.
5.22e5.32 (m, 2H, CH2), 5.77e5.83 (m, 1H, CH), 6.71 (d, J¼8.4 Hz,
1H, ArH), 7.38e7.47 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
d 30.9,
4.2.15. (R)-5-Chloro-3-hydroxy-3-(20-oxopropyl)indolin-2-one5b
42.5, 49.2, 73.7, 111.1, 115.7, 118.0, 127.1, 130.6, 131.7, 132.6, 141.9,
175.6, 206.6.
(6b). White solid; yield¼88%; mp¼196e198 ꢀC (lit.5b mp
158e159 ꢀC); Rf (60% EtOAc/hexane) 0.24; ½a 2D5
þ24 (c 0.1, MeOH);
ꢄ
enantiomeric excess: 67% determined by HPLC (Diacel Chiralpak
4.2.21. (R)-1-Benzyl-3-hydroxy-3-(20-oxopropyl)indolin-2-one3
AS-H; hexane/i-PrOH 70:30; flow rate 1 mL/min;
l¼254 nm, tR
(6m). White solid, yield¼87%; mp¼132e134 ꢀC (lit.5b mp
(major)¼7.7 min, tR (minor)¼5.9 min); 1H NMR (300 MHz, DMSO-
178e179 ꢀC); ½a 2D5
þ45 (c 0.1, MeOH); enantiomeric excess: 80%
ꢄ
d6):
d
2.00 (s, 3H, CH3), 3.05 (d, J¼17.4 Hz, 1H, CH2), 3.37 (d,
determined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH 90:10;
J¼17.4 Hz, 1H, CH2), 6.08 (s, 1H, OH), 6.77 (m, 1H, ArH), 7.20 (dd,
flow rate 1.0 mL/min;
l
¼254 nm, tR (major)¼38.0 min, tR (minor)¼
J¼8.4, 2.1 Hz, 1H, ArH), 7.30 (d, J¼2.1 Hz, 1H, ArH), 10.33 (s, 1H, NH);
28.8 min); 1H NMR (300 MHz, CDCl3):
d
2.16 (s, 1H, CH3), 3.06 (d,
13C NMR (75 MHz, DMSO-d6):
d
30.3, 50.0, 72.6, 110.9, 124.0, 125.2,
J¼17.1 Hz, 1H, CH2), 3.27 (d, J¼17.1 Hz, 1H, CH2), 4.56 (s, 1H, OH),
4.80e4.98 (m, 2H, CH2), 6.69 (d, J¼7.8 Hz, 1H, ArH), 7.02e7.37 (m,
128.7, 133.8, 141.6, 177.9, 205.4.
8H, ArH); 13C NMR (75 MHz, CDCl3):
d 31.2, 43.8, 49.1, 74.0, 109.6,
4.2.16. (R)-5-Bromo-3-hydroxy-3-(20-oxopropyl)indolin-2-one3
123.1, 123.7, 127.2, 127.6, 128.7, 129.6, 129.8, 135.3, 142.7, 176.6,
206.9.
(6c). White solid; yield¼89%; mp¼201e203 ꢀC (lit.5b mp
145e147 ꢀC); Rf (60% EtOAc/hexane) 0.25; ½a 2D5
þ31 (c 0.1, MeOH);
ꢄ
enantiomeric excess: 71% determined by HPLC (Diacel Chiralpak AS-
Acknowledgements
H; hexane/i-PrOH 70:30; flow rate 1 mL/min;
l
¼254 nm, tR
(major)¼10.6 min, tR (minor)¼8.7 min); 1H NMR (300 MHz, DMSO-
We are thankful to CSIR for SRF fellowship to A.K.. Our research
work was supported by the research project (02(0009)/11/EMR-II)
d6):
d
2.00 (s, 3H, CH3), 3.05 (d, J¼17.2 Hz,1H, CH2), 3.38 (d, J¼17.2 Hz,

5204
A. Kumar, S.S. Chimni / Tetrahedron 69 (2013) 5197e5204
2006, 62, 12017; (k) Chen, G.; Wang, Y.; He, H.-P.; Gao, S.; Yang, X.-S.; Hao, X.-J.
Heterocycles 2006, 68, 2327 Also reference cited in 2.
6. Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41,
sanctioned to S.S.C. by the CSIR, India. The financial support to
Department of Chemistry by the Department of Science and
Technology (DST), India under FIST program and UGC, India, under
CAS-I is gratefully acknowledged. We thank Professor M. S. Hundal
for recording of X-crystallographic data of crystal 4a.
2406.
7. For selected example see: (a) Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang, Q.-C.; Xu,
X.-Y.; Wang, L.-X. Chem. Commun. 2010, 8064; (b) Chen, L. J.; Luo, S. Z.; Li, J. Y.; Li,
X.; Cheng, J. P. Org. Biomol. Chem. 2010, 8, 2627; (c) Li, P.; Zhao, J.; Li, F.; Chan, A.
S. C.; Kwong, F. Y. Org. Lett. 2010, 12, 5616.
8. Kumar, A.; Singh, S.; Kumar, V.; Chimni, S. S. Org. Biomol. Chem. 2011, 9, 2731.
9. (a) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47, 7656
Also see Ref. 7a.
Supplementary data
Information about the chemicals used, experimental details and
Copies of 1H NMR, 13C NMR, HPLC chromatogram for all compounds
have been provided. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2013.04.044.
10. For primaryetertiary amine based organocatalysts, see: (a) Luo, S.; Xu, H.; Li, J.;
Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074; (b) Luo, S.; Xu, H.;
Zhang,
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Cheng, J.-P. Org. Lett. 2008, 10, 1775; (d) Peng, F.-Z.; Shao, Z.-H.; Pu, X.-W.;
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