Ultrasonication-Assisted Synthesis of a d-Glucosamine-Based β-CD Inclusion Complex and Its Application as an Aqueous Heterogeneous Organocatalytic System

Article abstract of DOI:10.1021/acs.joc.0c00420

For the first time, an inclusion complex has been crafted between a carbohydrate-based molecule and a β-cyclodextrin (CD) hydrophobic cavity for asymmetric catalytic applications. This novel d-glucosamine-based inclusion compound has been synthesized in h

Full text of DOI:10.1021/acs.joc.0c00420

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Article
Ultra-sonication Assisted Synthesis of D-Glucosamine
Based #-CD Inclusion complex and Its Application as
an Aqueous Heterogeneous Organocatalytic System
Dhiraj Rani, Aaftaab Sethi, Khushwinder Kaur, and Jyoti Agarwal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00420 • Publication Date (Web): 16 Jul 2020
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Page 1 of 11
The Journal of Organic Chemistry
Ultra-sonication Assisted Synthesis of D-Glucosamine Based β-CD Inclusion complex and Its
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Application as an Aqueous Heterogeneous Organocatalytic System
Dhiraj Rani, Aaftaab Sethi, Khushwinder Kaur* and Jyoti Agarwal*
Department of Chemistry and Center of Advanced Studies, Panjab University, Chandigarh-160014, INDIA
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Graphical Abstract:
O
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Selectivity
syn
O
O
O
N
H
H
IC-5 (Catalyst)
O
O
R2
HO
OMe
NH2
NH2 OMe
O
In
Water
HO
R1
O
H
H
+
OH2
H
H
O
O
HO
N
O
H
O
OH
HO
H
OH
HO
O
OH
HO
UP200St
O
OH
HO
O
OH
O
H
H1
H2
H4
O
O
H3
H5
H6
OH
O
OH
In
Water
HO
-CD

R
OH
O
OH
O
OH
OH
OHO
O
O
OH
O
OH
yield up to >99 %
ee up to 99%
H
Aqueous Asymmetric
Heterogeneous Organocatalytic System
R
HO
O
OH
Abstract:
For the first time, inclusion has been crafted between a carbohydrate based molecule and β-CD hydrophobic cavity for the
asymmetric catalytic applications. This novel D-glucosamine based inclusion compound has been synthesized in high yields
using innovative and proficient acoustic cavitation technology and well characterized by using various techniques, such as IR,
NMR, UV, TGA, SEM and other spectroscopic techniques. It was observed that the inclusion of D-glucosamine derivative in
hydrophobic cavity of β-CD increased its surface area and thermal stability. This catalytic system worked well in water for the
direct aldol reaction to afford the products in excellent yields with high diastereo- and enantio-selectivities.
Introduction
Though various reports are available in which catalytic sites
were attached on β-cyclodextrin bucket through conjugate
immobilization,26-33 only 2-3 reports are found in which
chiral organocatalytic moiety was inserted inside the β-
cyclodextrin cavity via non-covalent interactions.34,35 Those
too lack appropriate characterization of the chiral inclusion
complexes. Moreover, no extensive study is available to
understand the effect of inclusion on the other properties of
catalytic system (except enhancing solubility in water) such
as surface area, thermal stability etc.
Despite of many striking features, organocatalysts are
seldom used in industry due to their high catalyst loading,
difficult separation and non-recyclability etc.1-9 Even for the
reduction of global chemical waste, these factors are
imperative and need to be addressed rigorously.10-13
However, catalyst immobilization can be marked as an
efficient technology to produce easily separable, reusable
and aqueous catalytic system with high level of
stereoselectivity.14
In recent years, several carbohydrate molecules have been
developed as independent bifunctional organocatalysts.36
Though, to achieve high selectivity, their structures are
modified by introducing new groups but at the cost of their
reduced solubility in water. Peddinti group had developed D-
glucosamine derived methyl-2-amino-4,6-benzylidene-2-
Immobilization through conjugate addition requires tedious
synthetic
strategies,
allowing
possible
structural
perturbations to the parent organocatalyst and increases
effective cost.15-17 However, non-covalent immobilization
approach is a straightforward, trouble-free; and can be easily
achieved through non-covalent interactions like ionic,
hydrophobic, ion-pair, van der Waals and π-π interactions.17
Among various known immobilizing solid supports,
cyclodextrins (CDs) are the famous macrocyclic
oligosaccharides known for their capability to immobilize
various molecules.18-22 They possess hydrophilic exterior and
a hydrophobic cavity that accommodates hydrophobic guest
molecules inside the cavity via non-covalent interactions in
aqueous medium. The hydrophobic cavity of CDs mimics
the hydrophobic pockets of enzymes, thus exhibiting its
significance for the exploration of biomimetic catalysis.23-25
deoxy-α-D-glucopyranoside
as
bifunctional
chiral
organcatalyst for aldol reaction, though it required either
organic solvent or excess of one of the reactant to provide
good results.37 Therefore, for such molecules, there is a need
to establish novel strategies for producing aqueous
organocatalytic system.
This paper delineates the easy and trouble-free synthesis of
D-glycopyrasonide based inclusion complex (IC) with β-CD
using ultrasonic frequencies and an investigation to
understand the effect of inclusion on the various properties
of D-glycopyrasonide 4. Then its catalytic applications have
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Page 2 of 11
been explored as heterogeneous catalyst towards a green
efficiency by providing the more catalytic sites to the
substrates.
1
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3
4
5
6
7
process for asymmetric aldol reaction. Since aldol
condensation is of utmost importance in organic chemistry,38-
44
the substrate scope has been extended towards the
synthesis of oxindole derivatives by using isatin as acceptor
along with a variety of arylaldehydes and different ketones
as donors.
8
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Results and Discussions
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(b)
(a)
Initially, glucosamine derivative methyl-2-amino-4,6-
benzylidene-2-deoxy-α-D-glucopyranoside
(4)
was
synthesized as shown in Scheme 1.37 Then, the solution of
compound 4 in ethanol and β-CD in water were mixed and
sonicated for 15 minutes followed by lyophilisation to obtain
IC-5 as white solid. To synthesize inclusion complex, ultra
sonication method was chosen over the conventional
methods due to its various benefits such as higher yields, low
reaction time and ease of operation.18 Moreover it utilises the
eco-friendly ultrasonic frequencies rather than conventional
heating to perform the reaction. Then, the inclusion complex
IC-5 was characterized by using various techniques like UV-
visible, IR, 1H NMR, powder XRD (PXRD), scanning
electron microscopy (SEM), thermogravimetric analysis
(TGA) and Differential scanning colorimetry (DSC) and the
effect of encapsulation on the various properties of
compound 4 was investigated. Preliminary investigation was
done with UV-visible and FT-IR (Supporting information).
(c)
(d)
Figure 1: SEM images of a) β-CD, b) 4, c) IC-5 and d) PM.
To further confirm the formation of IC-5 and to understand
the interactions between host and guest molecules, the H
NMR spectra of 4, β-CD and IC-5 (DMSO-d6, 500 MHz)
were compared (fig 2). H NMR spectra were measured in
DMSO-d6, as all three compounds were soluble in this
solvent. The H chemical shifts of glucosamine derivative 4
1
1
1
and β-CD were found to be in agreement with the
literature.36,45 In case of IC-5, signals appeared in region of δ
3.0 - 4.0 ppm were overlapping and appeared as multiplets,
therefore these signals could not be resolved and compared
with the signals of pure compound 4 and β-CD. But, on the
comparison of other protons’ signals, significant chemical
shifts could be observed, which confirmed the insertion of
Ph ring of glucosamine derivative 4 inside the hydrophobic
moiety of β-CD. For example, H1, OH2, OH3 and OH6
protons on monomeric unit of β-CD showed the downfield
chemical shift of ∆δ 0.021, 0.065, 0.056 and 0.077 ppm,
respectively. Similarly, phenyl ring protons of compound 4
also exhibited upfield chemical shift of ∆δ 0.011 and 0.008
ppm. H7' proton showed upfield chemical shift of ∆δ 0.014
and confirmed its presence inside the cavity (Table 1).
Though H1' & H6' showed minimal chemical shift of ∆δ 0.004
ppm, which clearly indicated that this moiety of compound 4
(other than phenyl ring) was existing outside the β-CD
cavity.
OH
OH
amberlyst
IRN 120 H+
O
O
HO
HO
HO
HO
MeOH, 10 h
AcHN OH
AcHN OMe
1
2
O
Ph
PhCH(OMe)2
p-TsOH
O
KOH/EtOH
reflux, 5 h
O
HO
AcHN
DMF, 70 o
2.5 h
C
OMe
3
O
O
O
-CD
UP200St
sonication
Ph
O
O
O
HO
HO
NH2 OMe
H2N
OMe
IC-5
4
Scheme 1: Synthesis of Inclusion complex IC-5.
To further visualise the structural morphology of prepared
IC-5, SEM images were recorded and compared with β-CD,
4 and physical mixture (PM) (Figure 1). The images clearly
depicted that β-CD crystallized in polyhedral form (Fig. 1a),
whereas 4 materialized as irregular shaped aggregated crystal
particles with large dimensions (Fig. 1b). However, IC-5
appeared as homogeneously curled structure particles that
were different in shape as well as size from both β-CD and 4
because of non-covalent interactions (Fig 1c). The physical
mixture (PM) can be clearly seen having the particles of both
β-CD and 4 separately (Fig 1d). This not only confirmed the
inclusion compound formation, but also confirmed that IC-5
is not merely a physical mixture of both β-CD and 4. These
SEM images also indicated the increased surface area of IC-
5 in comparison to 4, which may enhance its catalytic
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H
1
Figure 2: H NMR spectra (DMSO-d6, 500 MHz) showing
OMe
O
1
2
3
4
5
6
7
the expanded region between δ 4.0-6.0 ppm for compound 4,
inclusion complex IC-5 and β-CD.
H
NH2
H
H
H
H6'
H
H7'
7'
O
OH6
HO
H6'
H
H
4
H
6
3
O
H
H
6'
5
O
O
H1
H2
H4
2
H3
O
O
O
4'
O
H3O
2'
5'
H1'
1
H5
H6
H
HO
OH2
1'
3'
H1
H
NH2
H
OMe
H
4
IC-5
D-Glucosamine derivative (
)
Monomeric unit of -CD
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Table 1: Comparison of δ values of various proton of β-CD, compound 4 and IC-5.
Pure β-CD
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Pure Compound 4
Selected protons
δ values in Pure compounds
δ values in IC-5
H1
OH2
4.444
4.509
0.065
OH5
5.656
5.712
0.056
OH6
5.687
5.764
0.077
ArH
7.443
7.432
0.011
ArH
H7'
H1'
H6'
4.803
4.824
0.021
7.371
7.363
0.008
5.578
5.564
0.014
4.622
4.618
0.004
4.160
4.164
0.004
∆δ (ppm)
o
After confirming the inclusion complex formation by above
techniques, other analyses were performed for further
confirmation and to study the effect of encapsulation on the
different properties of compound 4. In this direction, powder
XRD analysis (Fig 3(a)) was performed and it was observed
that β–CD exhibited crystalline nature, while compound 4
appeared to be moderately crystalline due to the presence of
mixture of broad and sharp peaks. In contrast, the XRD
pattern of the IC-5 showed a broad diffraction profile and
exhibited no reflections ascribed to either β–CD or 4. This
indicated that the groups responsible for crystalline structure
of 4 got embedded in β–CD cavity. This was a good
indicator for the formation of IC-5. The presence of new
peaks at 2θ values of 12.12°, 17.64°, 18.78° and 30.04°
indicated that the formed IC-5 attained a new solid phase
having amorphous behaviour as evidenced by broader
diffraction peaks with lower intensity.
the peak of the band was shifted by 48 C to a lower
temperature in comparison to that of β-CD. The other
endothermic peak observed at 335 C is associated with the
decomposition of IC-5, which further strengthened the
finding of IC possessing a greater thermal stability than that
of β-CD and 4. Furthermore, the thermogram of IC-5
showed the complete disappearance of the peak of 4, which
indicated molecular encapsulation of this compound within
the cavity of β-CD and not merely a physical mixture (Fig
3b).
o
Thermogravimetric (TG) analysis of 4, β-CD and the IC-5
was carried out at a heating rate of 10 C min-1. Comparing
o
the decomposition behavior, it was observed that while 4
was decomposed in a single step, β-CD, and IC-5 was
decomposed following two step mechanism (Fig. 4 A-C); the
first step being the removal of water in both β-CD and the
IC-5. It was observed that β-CD was decomposed at 360oC
whereas 4 showed decomposition at 330oC. The IC showed
decomposition between 340 to 360oC which could be
attributed to the fact that compound 4 present in the cavity of
β-CD also started decomposing at similar temperatures. The
activation energy for thermal decomposition was calculated
using Coats Redfern method, Madhusudanan–Krishnan–
Ninan method, Wanjun–Yuwen–Hen–Cunxin method, Van
Krevelen method, Horowitz–Metzger method.48-51 The
calculated activation energy (IC-5) came out to be nearly the
same for all the methods (Table 2). All these methods have
been explained in supporting information with relevant
linearization curves.
In TGA and DSC analysis, the effect of thermal stability was
investigated. The DSC profiles of 4 showed a broad
endothermic peak in the range of 118–150 ºC followed by
another broad endothermic peak in the range of 220 – 270 °C
corresponding to melting and decomposition of
4
respectively; shedding light on the amorphous nature of 4 as
concluded by analyzing PXRD profiles. The DSC
thermogram of β-CD showed two endothermic peaks, one
centered at 140°C which was associated with the release of
water from the β-CD cavity46 and the other at 310 oC, which
was attributed to the decomposition of β-CD.47 The
thermogram of IC-5 also showed a broad endothermic peak
centred at 92 oC corresponding to release of water, however,
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1
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4
3500
3000
2500
2000
1500
1000
500
IC-5
IC-5
CD
5
0
5000
6
7
8
9
4
4000
3000
2000
1000
4
0
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8000
-CD
6000
4000
2000
0
60
90
120
150
180
210
240
270
300
330
10
20
30
40
50
60
70
80
Temperature (oC )

(a)
(b)
Figure 3: Comparison of Powder XRD profiles and DSC curves of inclusion complex IC-5 with β-CD and compound 4.
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
(C)
(B)
(A)
-20
-20
0
200 400 600 800 1000
Temperature(oC)
0
75 150 225 300 375 450
Temperature(oC)
0
50 100 150 200 250 300 350 400 450
Temperature(oC)
-11.4
-11.6
-11.8
-12.0
-12.2
-12.4
-15.4
-15.6
-15.8
-16.0
-16.2
-16.4
-17.7
-17.8
-17.9
-18.0
-18.1
(D)
(E)
(F)
0.0045
0.0046
0.0047
-1
1/T(K )
0.0048
0.0049 0.00216 0.00224 0.00232 0.00240 0.00248 0.00256
0.0035
0.0036
0.0037
0.0038
-1
1/T(K )
-1
1/T(K )
Figure 4: TGA graphs for (A) 4, (B) β-CD (C) IC-5; Linearization curves obtained by Coats–Redfern (CR) for (D) 4, (E) β-CD (F) IC-5.
Here we have described the TGA analysis using Coats
Redfern method, which indicated that the stability of 4 was
increased after complexation with β-CD (Figure 4). The
increased thermal stability of the 4 after encapsulation in β-
CD hydrophobic cavity may be beneficial to explore its
catalytic activity for the reactions that require high
temperature to work. The calculated values of activation
energy for β-CD, 4 and IC-5 by Coats-Redfern method were
found to be 11.54, 7.84 and 9.63 kJ mol-1 respectively. Also,
the apparent activation energy and behaviour for thermal
decomposition varied as: Eβ-CD> EIC-5 >E4.
Methods
Coats-Redfern
E (kJ mol−1)
9.63
R
0.9788
0.9819
0.9856
0.9923
0.9763
Madhusudanan–Krishnan–Ninan
Wanjun–Yuwen–Hen–Cunxin
Van Krevelen
9.06
9.89
9.12
8.89
Horowitz–Metzger
Thus the high surface area, high thermal stability and
hydrophilic exterior of IC-5 marks its potential as aqueous
organocatalytic system for the asymmetric reactions and its
catalytic activity was investigated for the direct aldol
reaction of a variety of ketones (6, 9-13) as nucleophiles with
various arylaldehydes (7a-f) and isatin (14) as acceptors.
Except DMSO, in all the solvents including water, it
Table 2: Calculation of activation energy (E) and regression coefficient
(R) for IC-5 using different methods.
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remained insoluble and worked as heterogeneous yield of 92% but with almost no selectivity (Table 3, entry 8).
1
2
3
4
5
6
7
organocatalytic system. Model reaction was performed with
cyclohexanone (6) and 3-nitrobenzaldehyde (7a) in different
solvents using 5 mol % IC-5 at room temperature (Table 3).
These results have been compared with the results obtained
from the reactions carried out in presence of 20 mol%
compound 4 as catalyst.37
However IC-5 provided the product with syn preference and
with good enantioselectivity for both the diastereoisomers
(Table 3, entry 7). The higher yields of the product 8a using
compound 4 as catalyst than the IC-5 can be attributed to the
higher solubility of 4 in the tested solvents.
Next, reaction was tested in water, and both the catalysts
afforded the product 8a in excellent yields i.e >99% (IC-5)
and 94% (catalyst 4). Here also, IC-5 provided higher
selectivity with 83:17 diastereomeric ratio for syn (30% ee)
and anti (>99% ee) isomers, respectively (Table 3, entry 10).
Compound 4 provided very low diastereomeric ratio of 41:59
for syn (18 ee) and anti (12 ee) isomers, respectively. This
reaction was performed in solvent free condition also and
similar trend was obtained. IC-5 produced quantitative yield
with 71:29 dr. In this case, anti-isomer was achieved with
>99% ee and syn-isomer was obtained as racemic mixture
(Table 3, entry 12). While, compound 4 produced 95% yield
in 3 h, but no diastereoselectivity was obtained and
enantioselectivity was also very low (Table 1, entry 13).
8
9
Table 3: Solvent optimization a
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syn
OH
anti
OH
O
CHO
O
O
IC-5
5 mol%
NO2
+
NO2
+
Sovent, rt
NO2
6
7a
8a
eec (%)
anti
S
No.
Time
(h)
Yieldb
(%)
dr
Solvent
DCM
(syn:anti)
syn
41
1
2d
3
30
48
30
48
30
96
30
72
50
96
58
96
30
90
66
92
70:30
60:40
76:24
60:40
78:22
56:44
79:21
44:56
71
24
75
4
20
68
0
ACN
4d
Thus above results clearly indicated that the encapsulation of
5
39
10
70
0
>99
20
78
2
compound
4 in β-CD hydrophobic cavity i.e. IC-5
DMSO
6d
7
8d
significantly enhanced its catalytic efficiency in terms of
optical yields irrespective of the solvent chosen to perform
the reaction. Though yields were decreased in non-aqueous
solvents, quantitative yields were obtained in water with
slight increment. Next we studied the solvent concentration
effect on the outcome of the reaction using IC-5 as catalyst
(Table 4). When the volume of water was decreased from 0.5
ml to 0.3 ml and 0.1 ml with 5 mol% catalyst, it resulted in
acceleration of reaction rate, but the enantioselectivity (ee)
for syn product was decreased without affecting the ee of
anti-product (Table 4, entries 1-3). With 10 mol% of catalyst
loading, ee for anti-isomers were remained unaffected, but ee
for syn diastereomers was increased (Table 2, entries 4-6). In
MeOH, product yield was increased with decreasing in
solvent volume, but could not reach to completion even after
30 h (Table 4, entries 7-12). Here also, anti-product was
achieved with >99 ee, low to good ee was observed for syn
product (Table 2, entry 12). In case of acetonitrile with 0.5
ml and 0.1 ml of solvent, the ee of syn product was increased
to 68% (75% ee for anti) and 48% (>99ee for anti),
respectively; reactions provided low yield of 58% and 70%,
MeOH
t-BuOH
Water
9
30
30
24
36
3
46
99
91
99
95
90:10
83:17
41:59
71:29
50:50
49
30
18
1
>99
>99
12
10
11d
12
>99
32
Neat
13d
15
a)
Reaction was performed with 3-nitrobenzaldehyde (0.2
mmol) and cyclohexanone (0.4 mmol) in the presence of IC-5 (5 mol%)
and solvent (0.5 ml) at room temperature. b) isolated yields by column
chromatography c) diastereoselectivity and enantioselectivity were
determined by HPLC analysis using chiral columns. d) Reactions were
performed in presence of 20 mol% compound 4 as catalyst in place of 5
mol% IC-5.
In non-protic solvents such as dichloromethane, acetonitrile
and dimethylsulfoxide, when IC-5 was used as catalyst,
product 8a was achieved with low yields in range of 30-58%,
but with good diastereoselectivity and syn preference (Table
3, entries 1, 3 & 5). In all three cases, ee of anti-isomer was
higher than that of syn isomer. Even, in case of DMSO, anti-
isomer was formed with >99% enantioselectivity. When
compound 4 was used as catalyst in these solvents, reactions
took more time to provide the higher yields, but in all cases,
lower selectivities were obtained (Table 3, entries 2, 4 & 6). In
MeOH also, compound 4 provided product 8a with very high
t
respectively (Table 2, entries 13 & 14). In BuOH, reactions
took 30 h to provide lower yields of 55 and 46% in 0.5 ml
and 0.3 ml of solvent, respectively, with 22% and 49% ee for
syn product. Though in both cases, anti-product was
Table 4: Optimization of reaction parameters.a
syn
anti
O
CHO
O
OH
O
OH
O
O
IC-5
Catalyst
NO2
+
NO2
O
+
HO
Sovent, rt
NH2 OMe
NO2
7a
IC-5
6
8a
S.No.
Solvent
Volume of
Catalyst loading
Time
Yieldb (%)
drc(%)
eec(%)
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solvent (mL)
(mol%)
(h)
syn:anti
syn
anti
1
2
3
4
5
6
7
8
1
2
Water
Water
Water
Water
Water
Water
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
ACN
0.5
5
30
99
99
99
99
99
99
66
72
79
73
84
97
58
70
55
46
99
99
99
97
83:17
30
>99
0.3
0.1
0.5
0.3
0.1
0.5
0.3
0.1
0.5
0.3
0.1
0.5
0.1
0.5
0.1
-
5
5
17
8
86:14
83:17
75:25
76:24
80:20
79:21
83:17
81:19
69:31
83:17
63:37
76:24
83:17
77:23
90:10
89:11
89:11
>99 (syn)
47:53
28
17
44
48
47
70
54
53
-8
>99
>99
>99
>99
>99
78
3
4
10
10
10
5
24
15
12
30
30
30
30
30
24
30
30
30
30
24
24
24
48
5
6
9
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
5
>99
>99
>99
>99
>99
75
9
5
10
11
12
13
14
15
16
17d
18e
19f
20g
10
10
10
5
54
-10
68
48
22
49
18
44
77
1
ACN
5
>99
>99
>99
>99
>99
-
t-BuOH
t-BuOH
Neat
5
5
5
Neat
-
5
Water
Water
0.3
0.5
10
20
4
a)
Reaction was performed with 3-nitrobenzaldehyde (0.2mmol) and cyclohexanone (0.4mmol) in the presence of IC-5 and solvent at room
temperature. b) isolated yields. c) determined by HPLC analysis. d) 0.3 ml cyclohexanone e) 0.5 mL cyclohexanone. f) reaction was performed at 5 oC.
g) reaction was performed in presence of 20 mol% compound 4 as catalyst, at 0 ºC.
achieved with >99 % ee (Table 4, entries 15 & 16). Next,
>99% yields were obtained in neat condition, but low ee for
syn-isomer was obtained (Table 4, entries 17 & 18). Then,
with 96% yield and 28:72 dr for syn (51% ee) and anti (55%
ee) isomers in 30 h, respectively (Table 6, entry 1). Then, the
functionalized ketones 9 and 10 were tested; in both cases
very high yields 89 and 87% of the corresponding products
16 and 17 were afforded with syn preference (Table 6,
entries 2 & 3). It was observed that the functionalization of
ring reversed the diastereoselectivity and in case of 4-tert-
butylcyclohexanone (10), exclusively syn isomer was
achieved. Next the effect of ring size on selectivity of
reaction was investigated. In case of cyclpentanone (11),
product 18 was achieved with 88% yield and 67:33 dr in 48
h. Here also syn selectivity was preferred but with low
enantioselectivity of 12% (Table 6, entry 4). Then reaction
was performed with cycloheptanone (12), it also showed
excellent diastereoselectivity to provide exclusively syn
diastereomer with 11% ee for the product 19 (Table 6, entry
5). In case of acetone (13), excellent 98% yield of product 20
was achieved with low ee of 10% in 32 h (Table 6, entry 6).
o
we performed next reaction at 5 C in water (0.3 ml), it
provided 99% yield in 24 h. This reaction provided excellent
diastereoselectivity with 77% ee of preferred syn-isomer
(Table 4, entry 19). While, in presence of 20 mol%
compound 4, this reaction afforded the product 8a almost as
a racemic mixture with very poor diastereoselectivity (Table
4, entry 20). Thus, based on overall selectivity, the reaction
conditions used for entry 19 in table 4 were chosen as
optimized one for further studies. Subsequently, we shifted
our attention to broaden the substrate scope and reactions of
a variety of aromatic aldehydes 7a-f with cyclohexanone 6
were performed (Table 5). All reactions afforded aldol
adducts 8a-f in excellent yields with moderate dr and good
ee(s) irrespective of electronic nature of substituents.
Next, we chose to evaluate the catalytic activity of IC-5 for
the synthesis of 3-hydroxy-2-oxindole derivatives through
the direct aldol reaction of isatin (14) as acceptor with
diverse functionalized ketones (Table 6). 3-hydroxy-2-
oxindole derivatives are significant structural motifs for
various natural products and drugs having medicinal
properties and the introduction of asymmetry in these
products bearing isatin like rings is a challenging part.52
When we performed the reaction of isatin 14 with
cyclohexanone (6), it provided the corresponding product 15
Table 5: Substrate scope a
syn
OH
anti
O OH
(10 mol%)
O
O
O
IC-5
Catalyst
+
+
H
Water, 5 
C
R
R
R
6
7a-f
8a-f
ee (%)
syn anti
En
try
Prod
uct
Time
(h)
Yield
(%)b
drc
syn:anti
─R
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The Journal of Organic Chemistry
made inclusion complex an efficient aqueous heterogeneous
organocatalytic system for the asymmetric catalytic
applications. Though in this report, aldol reactions were
chosen for the investigation of its catalytic efficiency and the
best results were obtained at 5oC, its higher thermal stability
may provide a future opportunity to explore its more
applications along with performing the reactions at high
temperatures. In this direction, further exploration of its
catalytic activity as heterogeneous catalytic system for other
organic transformations is under progress in our lab.
1
2
3
4
5
6
3-NO2
2-NO2
4-NO2
2-Cl
8a
8b
8c
8d
8e
8f
24
26
24
52
44
44
99
98
98
89
94
96
>99
77
30
-
1
2
3
4
5
6
7
63:37
57:43
37:63
38:62
54:46
35
26
1
39
>99
48
4-Br
80
26
4-F
10
a)
Reaction was performed with arylaldehydes (0.2 mmol) and
8
9
cyclohexanone (0.4 mmol) in the presence of inclusion complex (10
mol%) and solvent (0.3 ml) at 5 ˚C. b) isolated yields. c) determined by
HPLC analysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6: Substrate scope with isatin (14).a
Experimental Section
O
O
Materials and reagents
O
HO
O
R2
R1
All reagents were purchased from Sigma Aldrich and Avra
synthesis and were used as received, unless otherwise noted.
Reactions were monitored by thin-layer chromatography
(TLC) on aluminium plates coated with silica gel using UV
light as visualizing agent.
NH2 OMe
O
HO
10 mol%
IC-5
O
Catalyst (
Water, 5 
)
+
O
O
N
N
C
R1
6, 9-13
R2
H
H
14
15-20
Instrumentation:
S.
No
.
Yiel
db
(%)
eec (%)
Tim
e (h)
drc
syn: anti
Powder X-ray diffraction (PXRD) was obtained by X'Pert
Pro Diffractometer equipped with x'Celerator solid-state
detector. The radiation used is Cu K-alpha-1, where nickel
metal is used as beta filter. Thermalgravimetric Analysis
(TGA) was performed in Al2O3 crucible at the heating rate of
10ºC/min (TGA SDT-Q-600, TA Instruments New Castle,
DE). Differential Scanning Calorimetry (DSC) was
measured in a hermetic vessel at a ramp rate of 10ºC min-1.
Scanning Electron Microscopy (SEM) was performed upon
JEOL-JSM-7600F. The 1H-NMR and 13C-NMR spectra were
recorded at 500 MHz on Bruker Avance II FT-NMR
Spectrometer using TMS as internal standard. Chemical
shifts of NMR spectra were given in parts per million (ppm)
with respect to TMS. The abbreviations used to describe the
multiplicities of 1H-NMR spectra were as follows: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad. Reference peak for solvents were set as follows: in
1H-NMR: CDCl3 = 7.26 ppm, DMSO-d6 = 2.50 ppm; in 13C-
NMR: CDCl3 = 77.0 ppm, DMSO-d6 = 35.52 ppm. HPLC
analyses were carried out on Agilent Technologies 1260
Infinity II with UV detector by using Chiralpak AS-H and
Cellulose-1 (equivalent to Chiralpak OD-H), Amylose-1
(equivalent to Chiralpak AD-H), and Cellulose-3 (equivalent
to Chiralpak OJ-H) chiral columns.
Product (s)
syn
anti
O
HO
1
15
16
17
18
19
20
30
60
64
48
48
32
96
89
87
88
98
98
28:72
78:22
51
15
98
12
11
55
O
N
H
O
HO
O
2d
3d
4d
5d
6
17
-
O
N
H
O
HO
O
>99
N
H
O
HO
O
67:33
36
-
O
N
H
HO
>99
(syn)
O
N
H
O
HO
-
10
O
N
H
Preparation of Inclusion Complex (IC): Initially, β -CD
(0.25 g, 0.2 mmol) was dissolved in water (5 mL) at elevated
temperature of 65 °C and compound 4 (0.06 g, 0.2 mmol)
was dissolved in ethanol (5mL). These two solutions were
then added to a glass vial and the mixture was sonicated with
a Hielsher UP200St ultrasonic device for 15 min. Next,
sonicated mixture was lyophilized to obtain the IC-5 as
white solid.
a) Reaction was performed with isatin (0.2 mmol) and cyclic ketones (1
mmol) in the presence of inclusion complex (10 mol%) and water (0.3
ml) at 5˚C. b) isolated yields c) determined by HPLC analysis. d) 5
equivalents of ketones were used.
In conclusion, we have reported an efficient synthesis of
inclusion complex of D-glucosamine derivative (4) with β-CD
using proficient acoustic cavitation technology and studied the
effect of encapsulation on its various properties such as
structural morphology, surface area, crystallinity, and thermal
stability etc. by using different techniques. It was observed
that immobilization of 4 with β-CD increased its surface area
and thermal stability along with its hydrophilic nature, which
General Procedure for the enantioselective aldol
reaction: IC-5 (28 mg, 0.02 mmol, 10 mol%) in water was
stirred at rt or 5 ˚C, then arylaldehyde/isatin (0.2 mmol) and
cycloalkanone/acetone (0.4 mmol) were added. The reaction
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was monitored by TLC at regular intervals. After completion 500 MHz):δ 8.26-8.16 (m, 2 H), 7.53-7.43 (m, 2 H), 5.47 (d,
1
2
3
4
5
6
7
8
of the reaction, 1 ml of water was added and the product was
extracted with DCM, the organic layers were collected, dried
with Na2SO4, filtered and evaporated. Then the crude
product was subjected to column chromatography on silica
gel by using ethyl acetate and hexane as the eluting solvents
to afford the pure aldol products. The HPLC analysis of the
aldol product was performed on a chiral stationary phase
using hexane–isopropanol as eluting solvents.37, 44
J = 2.0 Hz, 0.58 Hsyn), 4.89 (d, J = 8.5, 0.42 Hanti), 2.65-2.54
(m, 1 H), 2.53-2.44 (m ,1 H), 2.43-2.31 (m, 1 H), 2.14-2.06
(m, 1 H), 1.88-1.78 (m ,1 H), 1.74-1.50 (m, 3.5 H), 1.42-1.35
(m, 0.57 H), ppm. 13C{1H} NMR (CDCl3, 125 MHz):δ
214.8, 214.1, 149.3, 148.5, 147.7, 147.2, 142.3, 140.1, 132.6,
130.8, 128.0, 126.7, 123.7, 123.6, 74.1, 70.2, 57.3, 56.9,
42.8, 42.7, 30.9, 27.9, 27.8, 26.0, 24.9, 24.8 ppm. HPLC
(Amylose-1, n-hexane/i-PrOH: 95/5, 1.0 mL/min, λ = 254
nm), tRsyn = 26.75 (major), tRsyn = 34.84 (minor), tRanti= 38.47
(minor), tRanti = 52.64 (major).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Then one reaction was tested at 1 mmol scale and similar
results were obtained. This reaction involved the stirring of 1
mmol of 2-nitrobenzaldehyde (7b) with 2 mmol of
cyclohexanone (6) and 10 mol% IC-5 in water at 5 ºC for 32
h. The corresponding product 8b was obtained in 98% (241.5
mg) yields with 32% ee for syn and 59% ee for anti isomers,
respectively.
2-[Hydroxy(2-chlorophenyl)methyl]cyclohexanone (8d)37:
Yield: 42.6 mg, 89%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3510, 2927, 2856, 1688, 1589, 1488, 1293,
1187, 1128, 1086, 1013, 826, 800, 760, 547 cm-1. 1H
NMR(CDCl3, 500 MHz):δ 7.34-7.29 (m, 2 H), 7.27-7.22
(m, 2H), 5.35 (d, J = 2.5 Hz, 0.46 Hsyn), 4.76 (d, J = 9.0 Hz,
0.54 Hanti), 3.45-2.85 (br s, 1H, OH), 2.60-2.52 (m, 1H),
2.50-2.43 (m, 1H), 2.41-2.31 (m, 1H), 2.12-2.05 (m, 1H),
1.88-1.77 (m, 1H), 1.73-1.63 (m, 2H), 1.59-1.52 (m, 1H),
1.35-1.26 (m, 1H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):δ
215.3, 214.7, 140.0, 139.5, 133.6, 132.7, 131.5, 128.8, 128.6,
128.4, 128.3, 127.2, 77.3, 74.2, 70.1, 57.4, 57.0, 42.7, 30.8,
28.0, 27.7, 26.0, 24.9, 24.7 ppm. HPLC (Cellulose-1, n-
hexane/i-PrOH: 95/5, 1.0 mL/min, λ = 220 nm), tRsyn = 7.79
Characterization data for aldol products 8a-f, 15-20:
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (8a)37:
Yield: 49.2 mg, 99%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3387, 2929, 2856, 1687, 1523, 1349, 1130,
1096, 1068, 1042, 807, 734, 698 cm-1. 1H NMR (CDCl3, 500
MHz): δ 8.26-8.08 (m, 2 H), 7.66 (d, J = 5.0 Hz, 1 H), 7.55-
7.48 (m, 1 H), 5.47 (s, 0.47 Hsyn), 4.89 (d, J =10.0 Hz, 0.54
Hanti), 4.12 (br s, 0.56 H, OHanti), 3.20 (br s, 0.45 H, OHsyn),
2.68-2.58 (m, 1 H), 2.52-2.46 (m, 1 H), 2.43-2.33 (m ,1 H),
2.15-2.07 (m, 1 H), 1.90-1.80 (m,1 H), 1.70-1.54 (m, 3 H),
1.45-1.33 (m, 0.72 H), 0.90-0.80 (m, 0.28 H) ppm. 13C{1H}
NMR(CDCl3, 125 MHz): δ 214.9, 214.2, 148.4, 143.9,
143.4, 133.3, 132.1, 129.4, 129.3, 123.0, 122.2, 122.2, 121.0,
74.2, 70.0, 57.3, 56.9, 42.8, 42.7, 30.9, 28.0, 27.8, 26.0, 24.9,
24.8 ppm. HPLC (Amylose-1, n-hexane/i-PrOH: 95/5, 1.0
mL/min, λ = 254 nm), tRsyn = 19.1 (minor), tRsyn = 22.2
(major), tRanti = 29.3 (major), tRanti = 30.9 (minor).
(minor), tRsyn = 9.47 (major), tRanti = 11.77 (major), tRanti
15.24 (minor).
=
2-[Hydroxy(4-bromophenyl)methyl]cyclohexanone (8e)37:
Yield: 53.2 mg, 94%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3440, 2920, 2861, 1689, 1484, 1447, 1396,
1311, 1187, 1117, 1065, 1009, 985, 826, 794, 665, 538 cm-1.
1H NMR (CDCl3, 500 MHz):δ 7.48-7.43 (m, 2 H), 7.21-
7.16 (m, 2 H), 5.33 (d, J1 = 2.5 Hz, 0.39 Hsyn), 4.75 (d, J =
9.0 Hz, 0.61 Hanti), 3.05-3.55 (bs, 1 H, OH), 2.59-2.52 (m, 1
H), 2.50-2.42 (m, 1 H), 2.40-2.31 (m, 1 H), 2.12-2.06 (m, 1
H), 1.88-1.76 (m, 1 H), 1.72-1.62 (m, 2 H), 1.58-1.52 (m, 1
H), 1.33-1.26 (m, 1 H) ppm. 13C{1H} NMR (CDCl3, 125
MHz):δ 215.4, 214.7, 140.6, 140.2, 131.6, 131.4, 128.9,
127.7, 121.9, 120.9, 74.3, 70.3, 57.5, 57.1, 42.8, 30.9, 28.1,
27.9, 25.0, 24.8 ppm. HPLC (Amylose-1, n-hexane/i-PrOH:
2-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone (8b)37:
Yield: 48.9 mg, 98%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3497, 2937, 2859, 1697, 1523, 1446, 1344,
1265, 1127, 1034, 858, 784, 733 cm-1. 1H NMR (CDCl3,
500 MHz): δ 7.99 (dd, J = 1.5, 8.0 Hz, 0. 33 H), 7.86-7.81
(m, 1 H), 7.76 (dd, J = 1.0, 7.5 Hz, 0.67 H), 7.66-7.60 (m, 1
H), 7.42 (td, J = 8.5, 1.0 Hz), 5.95 (d, J = 2.0, 0. 35 Hsyn),
5.44 (d, 0.65 Hanti), 3.10-3.44 (br s, 1 H, OH), 2.90-2.85 (m,
0. 36 H), 2.78-2.72 (m, 0.64 H), 2.48-2.41 (m, 1.3 H), 2.36-
2.30 (m, 0.72 H), 2.13-2.06 (m, 1 H), 1.88-1.82 (m ,1 H),
1.78-1.56 (m, 4 H) ppm. 13C{1H} NMR (CDCl3, 125
MHz):δ 214.9, 214.0, 148.7, 147.1, 137.0, 136.6, 133.1,
133.0, 129.6, 129.0, 128.4, 128.0, 124.7, 124.1, 69.8, 66.6,
57.3, 54.8, 42.6, 42.4, 31.1, 27.9, 27.8, 26.5 24.9, 24.8 ppm.
HPLC (Amylose-1, n-hexane/i-PrOH: 95/5, 1.0 mL/min, λ =
95/5, 0.3 mL/min, λ = 222 nm), tRsyn = 25.38 (minor), tRsyn
=
30.16 (major), tRanti = 38.59 (minor), tRanti = 46.11 (major).
2-[Hydroxy(4-fluorophenyl)methyl]cyclohexanone (8f)37:
Yield: 42.7 mg, 96%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3497, 2950, 2868, 1694, 1603, 1508, 1450,
1426, 1295, 1222, 1157, 1129, 1042, 1015, 834, 821, 534
1
cm-1. H NMR (CDCl3, 500 MHz):δ 7.24-7.32 (m, 2 H),
7.00-7.06 (m, 2 H), 5.36 (d, J = 2.5 Hz, 0.47 Hsyn), 4.78 (d, J
= 8.5 Hz, 0.53 Hanti), 2.60-2.54 (m, 1 H), 2.51-2.43 (m, 1 H),
2.41-2.32 (m, 1 H), 2.13-2.06 (m, 1 H), 1.89-1.77 (m, 1 H),
1.74-1.62 (m, 2 H), 1.58-1.52 (m, 1 H), 1.33-1.23 (m, 1 H)
ppm. 13C{1H} NMR (CDCl3, 125 MHz):δ215.6, 214.9,
162.5 (d, J = 244.8 Hz), 162.0 (d, J = 243.1 Hz),137.8,
136.9, 128.8 (d, J = 8.2 Hz), 127.5 (d, J = 7.9 Hz), 115.4 (d,
J = 21.0 Hz), 115.1 (d, J = 20.9 Hz), 74.3, 70.3, 57.6, 57.3,
42.8, 30.9, 29.4, 28.1, 27.9, 26.2, 25.0, 24.9 ppm. HPLC
254 nm), tRsyn= 18.56 (minor), tRsyn = 19.57 (major), tRanti
31.94 (major), tRanti = 34.62 (minor).
=
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (8c)37:
Yield: 49.0 mg, 98%; Hexane/EtOAc: from 95:5 to 85:15;
IR (KBr) νmax:3505, 2933, 2848, 1694, 1597, 1508, 1341,
1
1187, 1092, 854, 796, 746, 704, 544 cm-1. H NMR (CDCl3,
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The Journal of Organic Chemistry
(Amylose-1, n-hexane/i-PrOH: 95/5, 1.0 mL/min, λ = 254 1 H), 7.24-7.10 (m, 1 H), 6.96-6.87 (m, 1 H), 6.81-6.74 (m, 1
1
2
3
4
5
6
7
8
nm), tRsyn = 11.23 (major), tRsyn = 13.23 (minor), tRanti = 18.56
(minor), tRanti = 21.16 (major).
H), 5.98 (s, 0.66 Hsyn, OH), 5.93 (s, 0.3Hanti, OH), 2.93-2.78
(m, 1 H), 2.25-2.07 (m, 2 H), 2.05-1.55 (m, 4 H). 13C{1H}
NMR (DMSO-d6, 125 MHz):δ 216.7, 216.3, 178.2, 177.6,
142.8, 142.3, 130.9, 130.0, 129.2, 129.1, 124.7, 124.2, 121.6,
121.2, 109.5, 75.0, 54.9, 53.7, 40.0, 39.0, 25.0, 24.5, 20.0,
19.6 ppm. HPLC (Amylose-1, n-hexane/i-PrOH: 90/10, 1.0
mL/min, λ = 254 nm), tRanti = 23.25 (major), tRanti = 25.67
(minor), tRsyn = 28.67 (major), tRsyn = 30.98 (minor).
3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one (15)44
Yield: 47.2 mg, 96%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3285, 2921, 2864, 1720, 1681, 1615, 1470,
1
1379, 1315, 1188, 1137, 1048, 927, 801, 758, 670 cm-1. H
NMR (DMSO-d6, 500 MHz):δ 10.20 (s, 1 H), 7.30-7.10 (m,
2 H), 6.90-6.74 (m, 2 H), 5.82 (s, 1 H), 3.07 (dd, J1 = 5 Hz,
J2 = 13.5 Hz, 1 H), 2.64-2.55 (m, 1 H), 2.35-2.24 (m, 1 H),
2.06-1.90 (m, 3 H), 1.86-1.76 (m, 1 H), 1.70-1.62 (m, 1 H)
ppm. 13C{1H} NMR (DMSO-d6, 125 MHz):δ 209.1, 178.7,
143.4, 130.9, 128.6, 124.8, 120.8, 109.4, 73.9, 57.4, 41.5,
26.7, 26.6, 24.5 ppm. HPLC (Cellulose-3, n-hexane/i-PrOH:
80/20, 0.7 mL/min, λ = 254 nm), tRanti = 11.52 (minor), tRanti
= 12.52 (major), tRsyn = 13.81 (major), tRsyn = 17.34 (minor).
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49
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59
60
3-hydroxy-3-(2-oxocycloheptyl)indolin-2-one (19)44
Yield: 50.8 mg, 98%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3342, 3195, 2927, 2860, 1690, 1622, 1471,
1449, 1347, 1190, 1136, 1111, 1089, 1023, 1010, 950, 927,
785, 749, 722, 672, 650, 616, 564, 539 cm-1. 1H NMR
(DMSO-d6, 500 MHz):δ 10.17 (s, 1 H), 7.24 (d, J = 7.5 Hz,
1 H), 7.17 (td, J1 = 7.5 Hz, J2 = 1.0 Hz, 1 H), 6.88 (td, J1 =
7.5 Hz, J2 = 1.0 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 5.96 (s,
1 H, OH), 3.33 (s, 1H), 3.10 (dd, J1 = 3.0 Hz, J2 = 11.5 Hz, 1
H), 2.47-2.40 (m, 1 H), 2.28-2.14 (m, 2 H), 2.04-1.97 (m, 1
H), 1.92-1.82 (m, 1 H), 1.76-1.62 (m, 2 H), 1.50-1.22 (m, 2
H) ppm. 13C{1H} NMR (DMSO-d6, 125 MHz):δ 212.0,
178.6, 142.9, 130.6, 128.7, 124.5, 121.0, 109.5, 75.1, 59.2,
43.1, 29.7, 29.4, 24.0, 24.0 ppm. HPLC (Amylose-1, n-
3-hydroxy-3-(4-oxotetrahydro-2H-pyran-3-yl)indolin-2-
one (16)44
Yield: 43.9 mg, 89%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3261, 2916, 2849, 1708, 1621, 1471, 1366,
1213, 1179, 1092, 1028, 982, 750, 720, 671, 589, 564, 547
1
cm-1. H NMR (DMSO-d6, 500 MHz):δ 10.30 (s, 0.66 H),
10.21 (s, 0.34 H), 7.25 (d, J = 7.0 Hz, 1 H), 7.21-7.14 (m, 1
H), 6.92-6.86 (m, 1 H), 6.80 (d, J = 7.5 Hz, 0.65 H), 6.77 (d,
hexane/i-PrOH: 80/20, 0.4 mL/min, λ = 254 nm), tRsyn
=
29.45 (major), tRsyn = 36.56 (minor).
J = 8.0 Hz, 0.35 H) 6.06 (s, 0.65 Hsyn, OH), 5.96 (0.35 Hanti
,
OH), 4.55-4.47 (m, 1 H), 4.12-4.10 (m, 2 H), 3.65-3.45 (m,
1.54 H), 3.23-3.19 (m, 0.64 H), 2.08-2.02 (m, 1 H), 1.23-
1.16 (m, 1 H) ppm. 13C{1H} NMR (DMSO-d6, 125 MHz):δ
205.7, 205.0, 177.8, 143.2, 142.7, 132.5, 130.1, 129.0, 128.8,
125.1, 123.2, 121.1, 121.1, 109.6, 109.2, 73.6, 72.7, 68.0,
67.8, 67.0, 66.9, 57.4, 57.1, 42.7, 41.6. HPLC (Cellulose-3,
3-hydroxy-3-(2-oxopropyl)indolin-2-one (20)44
Yield: 40.3 mg, 98%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3357, 3314, 2925, 2856, 1698, 1618, 1470,
1356, 1329, 1176, 1131, 1058, 778, 758, 585, 551 cm-1. H
NMR (DMSO-d6, 500 MHz):δ 10.22 (s, 1 H), 7.24 (d, J =
7.5 Hz, 1 H), 7.17 (td, J1= 7.5 Hz, J2= 1.0 Hz, 1 H), 6.90 (td,
J1 = 7.5 Hz, J2 = 0.5 Hz, 1 H), 6.78 (d, J = 7.5 Hz, 1 H), 3.27
(d, J = 16.5 Hz, 1 H), 3.01 (d, J = 16.5 Hz, 1 H), 2.00 (s, 3 H)
ppm. 13C{1H} NMR (DMSO-d6, 125 MHz):δ 205.2, 178.2,
142.5, 131.5, 129.0, 123.7, 121.4, 109.5, 72.7, 50.3, 30.6
ppm. HPLC (Cellulose-3, n-hexane/i-PrOH: 80/20, 0.8
mL/min, λ = 254 nm), tR = 14.18 (minor), tR = 17.10 (major).
1
n-hexane/i-PrOH: 80/20, 1 mL/min, λ = 254 nm), tRanti
=
19.70 (minor), tRsyn = 27.03 (major), tRsyn = 29.74 (minor),
tRanti = 53.47 (major),
3-(5-(tert-butyl)-2-oxocyclohexyl)-3-hydroxyindolin-2-one
(17)53
Yield: 52.5 mg, 87%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3327, 2962, 1718, 1693, 1625, 1471, 1360,
ASSOCIATED CONTENT
Supporting Information
1
1195, 1148, 1099, 977, 772, 756, 640, 570 cm-1. H NMR
(DMSO-d6, 500 MHz):δ 10.19 (s, 1 H), 7.21 (d, J = 7.5 Hz,
1 H), 7.17 (td, J1 = 7.5 Hz, J2 = 1.0 Hz, 1 H), 6.87 (td, J1 =
7.5 Hz, J2 = 1.0 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 5.84 (s,
1 H, OH), 3.12-3.05 (m, 1 H), 2.70-2.62 (m, 1 H), 2.37-2.29
(m, 1 H), 2.06-2.00 (m, 1 H), 1.99-1.92 (m, 1 H), 1.65-1.55
(m, 2 H), 1.30-1.25 (m, 1 H), 0.96 (s, 9 H) ppm. 13C{1H}
NMR (DMSO-d6, 125 MHz):δ 209.3, 178.7, 172.0, 143.5,
130.8, 128.6, 124.7, 120.9, 109.4, 73.9, 56.6, 42.3, 40.0,
32.4, 27.5, 27.5, 21.0 ppm. HPLC (Chiralpak AS-H, n-
hexane/i-PrOH: 70/30, 0.7 mL/min, λ = 254 nm), tR = 25.09
(major), tR = 51.73 (minor).
TGA, DSC, Powder XRD, IR and UV-visible spectral analysis
of compound 4, β-CD and IC-5; table for solvent optimization
and characterization data along with copies of 1H NMR and 13
spectra of all aldol products have been given in supporting
information.
C
AUTHOR INFORMATION
Corresponding Author
*Jyoti Agarwal
Email id: jyotiagarwa@gmail.com, jagarwal@pu.ac.in
ORCID: 0000-0001-5516-7906
3-hydroxy-3-(2-oxocyclopentyl)indolin-2-one (18)44
Yield: 40.8 mg, 88%; Hexane/EtOAc: from 80:20 to 50:50;
IR (KBr) νmax:3236, 2925, 2848, 1709, 1618, 1470, 1332,
*Khushwinder Kaur
Email id: makkarkhushi@gmail.com
1
1193, 1154, 1099, 997, 939, 752, 594, 488 cm-1. H NMR
Present Addresses
(DMSO-d6, 500 MHz):δ 10.29 (s, 1 H), 7.36 (d, J = 7.5 Hz,
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The Journal of Organic Chemistry
Page 10 of 11
13. Agarwal, J.; Rani, R.; Peddinti, R. K. Mechanochemical
†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
1
2
Grinding Diels–Alder Reaction: Highly Efficient and Rapid
Access to Bi-, Tri-, and Tetracyclic Systems. Synlett, 2017, 28,
1336-1340.
Author Contributions
3
4
5
6
7
8
9
14. Zhang, L.; Luo S.; Cheng, J-P. Non-covalent immobilization of
asymmetric organocatalysts. Catal. Sci. Technol., 2011, 1, 507-
516.
The manuscript was written through contributions of all authors.
Notes
15. Jouffroy, M.; Armspach D.; Matt, D. Cyclodextrin and
There is no conflicts of interest.
phosphorus(III):
a vaersatile combination for coordination
chemistry and catalysis. Dalton Trans., 2015, 44, 12942-12969.
16. Doyaguez, E. G.; Rodriguez-Hernandez, J.; Corrales,
G.;Fernandez-Mayoralas, A.; Gallard, A. Water-soluble pendant
copolymers bearing proline and permethylated β-cyclodextrin:
ph-dependent catalytic nanoreactors. Macromolecules, 2012,
45, 7676−7683.
17. Shinde, V. V.; Jeong D.; Jung, S. Supramolecular
aminocatalysis via inclusion complex: Amino-doped β-
cyclodextrin as an efficient supramolecular catalyst for the
synthesis of chromenopyrimido[1,2-b]indazol in water. J. Ind.
Eng. Chem., 2018, 68, 6–13.
18. Kaur, K.; Uppal, S.; Kaur, R.; Agarwal J.; Mehta, S. K.Energy
efficient, facile and cost effective methodology for formation of
an inclusion complex of resveratrol with hp-β-CD. New J.
Chem., 2015, 39, 8855–8865.
19. Prado, A. D.; Sierra, M. P.; Juan-y-Seva, M.; Navarro,
R.;Reinecke, H.;Hernandez, J. R.; Elvira, C.;Mayoralas, A.
F.;Gallardo, A. Aqueous micro and nanoreactors based on
ACKNOWLEDGMENT
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We are grateful to Department of Science and Technology-
INSPIRE, Delhi (Grant no. IFA-13-CH-101), Science and
Engineering
Research
Board,
Delhi
(Grant
no.
EMR/2017/000453) and UGC, Delhi (Grant No. F.30-
94/2015(BSR)) for providing financial assistance. D.R. thanks
UGC, New Delhi for the award of research fellowship.
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