DABCO-catalyzed synthesis of 3-substituted-3-hydroxyindolin-2-ones in aqueous media

Article abstract of DOI:10.1080/00397911.2016.1160411

An efficient and greener protocol for easy access to 3-susbstituted-3-hydroxy-2-oxindoles by the reaction with various substituted isatins and acetophenones is described. This protocol is widely applicable for a variety of isatins and acetophenones using

Full text of DOI:10.1080/00397911.2016.1160411

Synthetic Communications
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DABCO Catalysed Synthesis of 3-Substituted-3-
Hydroxyindolin-2-ones in Aqueous Media
Keshri Nath Tiwari, Darshana Bora, Garima Chauhan, Deepika Yadav, Kavita
Sharma, Ashima Thakur, Lachhman Singh & Vishwadeep Tripathi
To cite this article: Keshri Nath Tiwari, Darshana Bora, Garima Chauhan, Deepika Yadav,
Kavita Sharma, Ashima Thakur, Lachhman Singh & Vishwadeep Tripathi (2016): DABCO
Catalysed Synthesis of 3-Substituted-3-Hydroxyindolin-2-ones in Aqueous Media, Synthetic
Communications, DOI: 10.1080/00397911.2016.1160411
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1160411
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Date: 28 March 2016, At: 07:16

DABCO Catalysed Synthesis of 3-Substituted-3-Hydroxyindolin-2-ones in Aqueous
Media
Keshri Nath Tiwari1,, Darshana Bora1, Garima Chauhan1, Deepika Yadav1, Kavita
Sharma1, Ashima Thakur1, Lachhman Singh1, Vishwadeep Tripathi1
1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Raebareli, India
Corresponding author to Keshri Nath Tiwari: E-mail: keshri.tiwari@niperraebareli.edu.in
Abstract
An efficient and greener protocol for the easy access of 3-susbstituted-3-hydroxy-2-
oxindoles by the reaction with various substituted isatins and acetophenones is described.
This protocol is widely applicable for a variety of isatins and acetophenones using water
as a reaction media and DABCO as catalyst with shorter reaction timing and good to
excellent yield of products.
KEYWORDS: Isatin, Acetophenone, DABCO, Aldol reaction, Hydroxyindolin-2-one
INTRODUCTION
The 3-substituted-3-hydroxy-2-oxindoles[1] have drawn tremendous interest of
researchers in the area of synthetic organic chemistry as well as drug discovery because
of their occurrence in many biologically active compounds such as convolutamydine A
[2], arundaphine [3], dioxibrassinine [4], and donaxaridine [5] etc. (Fig. 1).
1

This kind of structural framework is also found in many complex natural products like
TMC-95A-D [6], celogentin-K [7], paratunamide [8], and maremycins [9]. These molecules
have been shown to display various pharmacological activities including anticancer [1]
and antioxidant properties [10]
.
There are various elegant and efficient methods for synthesizing 3-substituted-3-
hydroxyindolin-2-ones in both racemic as well as chiral version [11-18] documented in
literature. But most of them have several drawbacks such as use of metal catalyst, longer
reaction hours, low yield and cumbersome workup processes. Recently, a great deal of
attention has been paid on the use of water as a reaction media and it has been
demonstrated as a better solvent despite having certain limitations [19-20]. Water has
emerged advantageous over many traditional organic solvents due to its properties like
being non-toxic, easy availability and handling in workup processes [21-23]
.
As a part of our research plan aimed at developing new synthetic methodologies for the
creation of biologically important molecules [24-28], we inspired to investigate greener
protocol for generation of substituted oxindoles. In this line, we wish to report the
synthesis of 3-substituted-3-hydroxy-indolin-2-ones using water as a solvent catalysed by
DABCO with good to excellent yields by aldol reaction (Scheme 1).
RESULT AND DISCUSSION
Initially, the reaction between isatin (1a) and acetophenone (2a) was chosen without
using any base as a catalyst and water as a solvent. Although, the formation of product
2

was observed but the reaction was found very slow and even after continuing the reaction
for more than 12 hours we could only obtained 35% of the desired product. Therefore, we
screened many organic bases such as DBU, DABCO, Et3N, piperidine and urea (Table 1)
to catalyze the reaction. Although most of the bases provided the desired compound, they
greatly varied in the reaction timing and the yield of the reaction. The best result was
found with DABCO where the reaction was completed in 1 hour for the compound 3a
(Scheme 2). In the beginning, the reaction mixture appeared to be orange colored
suspension but as the reaction progressed, light yellow solid separated out from the
solution. After the TLC indicated the complete consumption of starting materials, the
solid was filtered off and washed with water several times. In some cases the solid
appeared to be pure but in many cases it was found little impure by TLC. Therefore, it
was purified using silica gel column chromatography which provided light yellow solid.
The obtained product was fully characterized by NMR and mass spectral analysis.
In order to prove superiority of water over other organic solvents for this reaction, we
performed a series of experiment by varying the solvents. The reaction was performed on
500 mg scale in many solvents like EtOH, CH3CN, DMF, and THF. Although the same
product was obtained in most of the solvents, EtOH proved to be best amongst all organic
solvents. The issue with most of the organic solvents was that the yield of the reaction
was found low even after continuing the reaction for 24 hours at boiling temperature of
solvent (Table 1). The optimization of various bases and solvents is given in table 1 with
respect to time and yield of the reaction. It is quite evident from the table that the
3

DABCO as a catalyst and water as solvent is the best condition of reaction to get
maximum yield of the desired product.
Reaction condition: Isatin (3.4 mmol), Acetophenone (3.4 mmol), Base (0.2 to 1.0
equivalent), 80 C, Water. *Isolated yield
The structure of all the synthesized compounds (3a-3p) was confirmed by IR, NMR and
mass spectroscopy. In IR spectrum of 3a, the two peaks at 3380 and 3290 cm-1 were
assigned OH and NH group respectively. Owing to lesser solubility of compounds in
CDCl3, the NMR spectra of all the compounds were recorded in acetone d6. In 1H NMR
spectrum of 3a, the sharp singlet at δ 9.41 and broad singlet at δ 5.18 were assigned as
NH and OH protons respectively. This was further confirmed by deuterium exchange
studies. Two doublet, one at δ 4.11 (J = 18 Hz) and one at δ 3.72 (J =18 Hz) were
assigned as CH2 adjacent to the carbonyl group. The high coupling constant is observed
due to germinal coupling between two protons. The all aromatic protons were assigned
and it was found in complete agreement with the literature report (There was slight
change in chemical shift of all the protons because the literature data is recorded in
DMSO d6 while the synthesized compounds were recorded in acetone d6).
A series of 16 compounds with isatin having Cl and Br substitution at 5-position and
acetophenone with various substitution at 4-position was synthesized and characterized
by various spectroscopic techniques (Table 2). These molecules are very good crystalline
solid. Some of the selected synthesized compounds are shown in Figure 2.
4

CONCLUSIONS
In summary, we have developed a green and efficient method for an easy access of 3-
substituted-3-hydroxyindolin-2-ones catalysed by DABCO. The reaction merits the
shorter reaction time, high yield of the products and easy purification process. The
structural framework of synthesized molecules provides an opportunity for further
extension to yield biologically active molecules which is currently under progress in our
laboratory and will be reported with due course of time.
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
EXPERIMENTAL
General Experimental Procedure
A solution of 0.5 gm (3.4 mmol) of isatin (1), 0.408 gm (3.4 mmol) of acetophenone (2)
and 0.080 gm (0.72 mmol) of DABCO in water (15 mL) was heated to 80 C for 1-3
hours. After the completion of reaction which was indicated by TLC, the solid which
separated out was collected and washed with water. In some cases, the reaction mixture
was extracted with ethyl acetate as the solid was not getting filtered off and combined
organic layer was evaporated to give solid reaction mixture. Although, the TLC indicated
the completion of both starting material, the reaction mixture was purified by column
chromatography on silica gel by using 40% of EA: hexane mixture to provide light
yellow product in good to excellent yields.
5

Characterisation Data For Selected Compounds
3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3a) m.p. 165-167 C[20]; 90% as light
1
yellow solid; H NMR (Acetone d6, 300 MHz) δ = 9.41 (bs, 1H, NH), 7.95 (d, J = 9 Hz,
2H, Ar-H), 7.61 (t, J = 6 Hz, 1H, Ar-H), 7.48 (t, J = 6 Hz, 2H, Ar-H), 7.35 (d, J = 6 Hz,
1H, Ar-H), 7.19 (t, J = 9 Hz, 1H, Ar-H), 6.93-6.98 (m, 2H, Ar-H), 5.18 (bs, 1H, OH),
4.11 (d, J = 18 Hz, 1H, CH), 3.72 (d, J = 18 Hz, 1H, CH) 13C NMR (Acetone d6, 75
MHz) 197.3, 178.9, 143.9, 137.6, 134.1, 132.4, 130.1, 129.5 (2C), 128.9 (2C), 124.6,
122.4, 110.5, 75.5, 46.4 HRMS (ESI) m/z for C16H13NO3 [M + H]+, calcd, 268.0973,
found, 268.0979
5-bromo-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3g) ) m.p. 177-179 C;
1
75% as light yellow solid; H NMR (Acetone d6, 300 MHz) δ 9.48 (bs, 1H, NH), 7.96 (d,
J = 6 Hz, 2H, Ar-H), 7.62 (t, J = 6 Hz, 1H, Ar-H), 7.55-7.48 (m, 3H, Ar-H), 7.37 (dd, J =
3 Hz, 6 Hz, 1H, Ar-H), 6.90 (d, J = 9 Hz, 1H, Ar-H), 5.27 (bs, 1H, OH), 4.19 (d, J = 18
Hz, 1H, CH) 3.78 (d, J = 18 Hz 1H, CH) 13C NMR (Acetone d6, 75 MHz) 197.7, 178.8,
143.9, 138.0, 135.5, 134.8, 133.3, 130.1 (2C), 129.4, 128.4 (2C), 114.8, 112.8, 75.0,
47.1 HRMS (ESI) m/z for C16H12BrNO3 [M + H]+, calcd, 346.0078, found, 346.0107
5-chloro-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3l) m.p. 140-142 C; 87% as
1
light yellow solid; H NMR (Acetone d6, 300 MHz) δ 9.47 (bs, 1H, NH), 7.96 (d, J = 6
Hz, 2H, Ar-H), 7.62 (t, J = 6 Hz, 1H, Ar-H), 7.50 (t, J = 6 Hz, 2H, Ar-H), 7.42 (d, J = 3
Hz, 1H, Ar-H), 7.23 (dd, J = 6 Hz, 1H, Ar-H), 6.93 (d, J = 9 Hz, 1H, Ar-H), 5.27 (bs,
1H, OH) 4.17 (d, J = 18 Hz, 1H, CH) 3.78 (d, J = 18 Hz, 1H, CH) 13C NMR (Acetone d6,
6

75 MHz) 197.2, 178.5, 142.9, 137.5, 134.6, 134.2, 129.8, 129.5 (2C), 128.9 (2C), 127.1,
125.1, 111.8, 74.5, 46.5 HRMS (ESI) m/z for C16H12ClNO3 [M + H]+, calcd, 302.0583,
found, 302.0584
ACKNOWLEDGMENT
D.B., G.C., K.S., D.Y., Ashima, and L.S. are thankful to the Department of
Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India for providing
fellowship. KNT thanks Director, CSIR-CDRI, Lucknow (Mentor Institute of NIPER,
Raebareli), Dr. P. K. Shukla, Project Director, NIPER Raebareli for their support and
encouragement in carrying out this research work. SAIF-CSIR-CDRI, Lucknow is greatly
acknowledged for providing spectral data. NIPER-RBL communication no. 02.
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9

Table 1. Optimization of solvents and bases
Entry
Solvent
EtOH
CH3CN
DMF
H2O
Base
Time (h)
4 h
Yield (%)*
1
DABCO
DABCO
DABCO
DABCO
DABCO
Imidazole
DBU
60
50
20
90
25
55
85
70
75
40
35
2
4 h
3
6 h
4
1 h
5
THF
6 h
6
H2O
8 h
7
H2O
3 h
8
H2O
Et3N
2 h
9
H2O
Piperidine
Urea
3 h
10
11
H2O
3 h
H2O
No base
12 h
10

Table 2. Various substitutions on isatin and acetophenone with reaction time and yield
Entry
Compounds R1(isatin)
R2(acetophenone)
Time
(h)
1
Yield (%)*
1
H
H
90
81
85
80
79
90
75
78
86
75
80
87
80
84
88
75
3a
3b
3c
3d
3e
3f
2
H
Br
1.5
1
3
H
F
4
H
Me
OMe
NO2
H
3
5
H
1.5
2
6
H
7
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
3
3g
3h
8
Br
1
9
OMe
Me
NO2
H
3
3i
10
11
12
13
14
15
16
1.5
1
3j
3k
3l
1
Br
2
3m
3n
3o
3p
OMe
Me
NO2
2
1.5
3
*Isolated yield
11

Scheme 1. General synthetic scheme for synthesis of 3-susbstituted-3-hydroxyindolin-2-
one
12

Scheme 2. Synthesis of compound 3a
13

Figure 1. Selected biologically active compounds having 3-substituted-3-
hydroxyindolin-2-one motif
14

Figure 2. Some of the synthesized 3-substituted-3-hydroxyindolin-2-ones
15