Eco-friendly Polyethylene Glycol-400 as a Rapid and Efficient Recyclable Reaction Medium for the Synthesis of Anticancer Isatin-linked Chalcones and Their 3-Hydroxy Precursor

Article abstract of DOI:10.1002/jhet.3424

Isatin chalcones and their 3-hydroxy precursors are shown to possess potential anticancer activity and are also versatile substrates and key intermediates for the synthesis of a large variety of bioactive spiro-oxindoles. An environmental friendly tandem

Full text of DOI:10.1002/jhet.3424

Month 2018 Eco-friendly Polyethylene Glycol-400 as a Rapid and Efficient Recyclable
Reaction Medium for the Synthesis of Anticancer Isatin-linked Chalcones
and Their 3-Hydroxy Precursor
b
a
Alpana K. Gupta,a
*
Mausumi Bharadwaj, and Ravi Mehrotra
aDivision of Preventive Oncology, National Institute of Cancer Prevention and Research (ICMR-NICPR), Department of
Health Research (Govt. of India), Noida, India
bDivision of Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research, Noida, India
*E-mail: rm8509@gmail.com; ravi.mehrota@gov.in
Received July 25, 2018
DOI 10.1002/jhet.3424
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Isatin chalcones and their 3-hydroxy precursors are shown to possess potential anticancer activity and are
also versatile substrates and key intermediates for the synthesis of a large variety of bioactive spiro-
oxindoles. An environmental friendly tandem synthesis, using PEG 400 as green solvent cum phase transfer
catalyst, for a series of 3-hydroxy-2-oxindoles and 3-methylene-2-oxindoles has been developed. Reported
one-pot sustainable synthetic strategy was compared with the conventional method and was found to be su-
perior to existing two-step syntheses in terms of simplicity, product yield, and reaction time and have a large
substrate scope.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
the green medium for synthesis of 3-hydroxy-2-oxindoles
[29–31] but has limitations of the low solubility of the
substrates, compatibility with reagents, and mostly
associated with long reaction time. Further, the nature of
catalyst and solvent also affects the adduct of the aldol
condensation reaction as in some cases conjugated enone
(chalcones) are obtained directly instead of β-hydroxyl
ketone [32–34].
Owing to the growing need for more environmentally
acceptable yet efficient reusable solvents, liquid
polyethylene glycols (PEGs) with low molecular weight
are gaining interest because of their unique properties like
nonvolatility, stability at high temperatures, low cost,
reduced toxicity, recyclability, low inflammability, easy
degradability, and high miscibility with organic
compounds [35]. PEGs are the novel mild and efficient
reaction medium cum phase transfer catalyst that are fast
replacing expensive and environmentally harmful
catalysts for chemical synthesis [36,37]. Various
condensation reactions using PEG 400 are widely
reported [38,39], but to the best of our knowledge, there
is the first report exploiting PEG 400 as the green solvent
for one-pot two-step Knoevenagel condensation of isatin
with aromatic/heteroaromatic ketone for the synthesis of
2-Oxindoles have been recognized as privileged
substructures in new drug discovery as many 2-oxindole
derivatives have advanced into clinical trials for the
treatment of cancer [1–3]. Various isatin derivatives
exhibit diverse biological activities such as inhibition of
the proteasome, antagonizing GHSR, and inhibiting the
growth of human cancer cells [4–6]. 3-Substituted-3-
hydroxy-2-oxindoles are the new scaffold for drug
discovery [7], which are also versatile intermediates for
the synthesis of potential bioactive chalcones [8,9], Isatin
chalcones serve as the perfect electron-deficient olefins
because of their high reactivity as Michael acceptors [10]
and thus are suitable substrates for cycloaddition
reactions to generate biologically privileged diverse spiro-
oxindole scaffolds [11,12] (Fig. 1).
Isatins have been utilized in diverse organic reactions
including the construction of diverse heterocycles [13–
16]. Numerous methodologies have been developed to
synthesize these bioactive motifs by reaction of isatin
with ketone that includes catalysts like a base [17–19],
organic molecules, or a metal complex [20–26]. In recent
years, owing to a growing need for more environmentally
acceptable processes, the direction of chemical research
has shifted more towards the use of eco-friendly solvents
and reusable catalysts [27,28]. Water has been used as
a
series of new biological potential 3-methylene
oxindoles via 3-hydroxy precursor without using any
catalyst (Scheme 1).
© 2018 Wiley Periodicals, Inc.

A. K. Gupta, M. Bharadwaj, and R. Mehrotra
Vol 000
Figure 1. Representative 3-hydroxy-2-oxindoles and 3-methylene-2-oxindoles with potential anticancer activity. [Color figure can be viewed at
wileyonlinelibrary.com]
Scheme 1. General procedure for the synthesis of 3-hydroxy-2-oxindoles and 3-methylene-2-oxindoles (3a–j and 4a–j). [Color figure can be viewed at
wileyonlinelibrary.com]
RESULTS AND DISCUSSION
Keeping the focus on the green protocol to avoid
harmful solvents/catalyst, the efficacy of PEG 400 has
been examined for the model reaction of acetophenone
with isatin. For the first stage in chalcone precursor
synthesis, solvent suitability, reaction temperature, and
time were examined with respect to the yield and purity
of the desired product (Table 1). It was observed that the
reaction without solvent or catalyst support did not
proceed at all (Table 1, entry 1). However, to our
pleasant surprise, stirring of an equimolar mixture of
isatin and acetophenone in PEG 400 without using any
Conventional thermal synthesis of isatin-linked
chalcones occurs in two steps: In the first step,
substituted indole-2,3-dione (isatin) and ketone and
diethylamine as catalyst were refluxed in absolute ethanol
to afford 3-hydroxy-2-oxindoles, which in second step,
were dehydrated in the presence of acetic acid/HCl to
furnish the desired 3-methylene-2-oxindoles [40]. Thus,
overall thermal method is cumbersome especially because
of long reaction time and environmental concerns.
Journal of Heterocyclic Chemistry
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Month 2018
PEG 400 as Green Solvent for Synthesis of Anticancer Isatin-linked Chalcones
and Their 3-Hydroxy Precursor
Table 1
hydroxyl precursor, 3a, in high yield and purity
(Scheme 1, route A). After filtration, the obtained solid
product was further purified by crystallization. The
aqueous filtrate was distilled at 100°C to remove water,
and thus, separated PEG 400 was recycled and reused.
In order to find the suitability of another solvent for
the synthesis of title compounds without using any
catalyst, the reaction of isatin with acetophenone was
examined in different solvents such as ethanol, methanol,
dichloroethane, acetonitrile, dimethylformamide, and
water (Table 1, entries 9–14). It was found that a base
was needed inevitably in all these cases even with polar
solvents like ethanol and methanol. Being a hydrophilic
protic solvent, PEG 400 has aprotic ethereal sites that
might be responsible for its catalytical behavior as a
general base and may facilitate the initial formation of
carbanion/enolate from isatin, thereby helping to expedite
the overall rate of the condensation. In addition, the
recyclability of the solvent, PEG 400, was investigated
and revealed the important observation that the PEG 400
was recovered and reused for five runs without loss of its
activity but a weight loss of about 10% of PEG was
observed for every run because of handling loss.
In the second step of one-pot tandem process,
compound 3a generated in situ, when further stirred at
about 100°C for 6 min, undergoes dehydration. Reaction
was monitored using TLC, and on completion, the
reaction mixture was cooled, poured in ice-cold water,
and stirred well when corresponding chalcone, 4a
(Scheme 1, route B), separated out in quantitative yield.
The E-geometry of the chalcone was confirmed by 1H
NMR spectroscopy. The experimental procedure was
remarkably simple and required no toxic catalyst, inert
atmosphere, or corrosive substances, and no side reaction
was observed.
Optimization of solvent for synthesis of 3-hydroxy-2-oxindoles, 3a, in
PEG 400.a
Temperature
(°C)
Time
(min)
Yieldb
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
—
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
Ethanol
60
25 (r.t.)
25 (r.t.)
30
40
50
70
90
100
50
50
10
10
20
20
20
16
16
16
16
16
16
16
16
16
16
—
40
44
46
68
90
96
92
78
—
—
—
8
9
10
11
12
13
14
14
Methanol
Dichloromethane
Acetonitrile
DMF
50
50
50
80
14
—
Benzene
aReaction conditions: isatin (1 mmol) and acetophenone (1 mmol).
bIsolated yield.
Bold showed the best optimized reaction conditions.
catalyst at room temperature (25°C) for 20 min generated
3-hydroxy-2-oxindole, 3a, in 40% yield (Table 1, entry
2). However, increasing reaction time did not show much
improvement in yield (Table 1, entry 3), but increasing
reaction temperature from 25 to 70°C showed a steady
increase in yield (Table 1, entries 4–7), with maximum
96% at 70°C. It is found that further increasing the
temperature has detrimental effect on the yield by raising
the possibility of side reactions to occur (Table 1, entries
8 and 9). The reaction time was optimized at 16 min
(Table 1, entry 7) by monitoring the progress of the
reaction using thin-layer chromatography (TLC). The
reaction can be quenched at this stage by pouring the
reaction mixture in ice-cold water to obtain the 3-
Table 2
Comparative data of conventional and PEG 400 method for the synthesis of 3-hydroxy-2-oxindoles (3a–j).
Reaction time (min)
PEG 400a Conventionalb
Route A
Yieldc (%)
Product no.
X
Ar
PEG 400
Conventional
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
F
Cl
Br
CH3
H
F
Cl
Br
CH3
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
8
9
8
11
9
8
10
8
7
40
60
60
50
55
45
60
70
80
50
95
96
92
93
96
95
94
95
95
94
90
78
83
86
92
81
74
78
80
77
3j
9
aIsatin 1 (1 mmol) and ketone 2 (1 mmol) in PEG 400 (5 mL) stirred at 70°C for the specified time.
b1 (1 mmol), 2 (1.1 mmol), and diethylamine (0.5 mL) in ab. ethanol refluxed on water bath for the specified time and kept at room temperature for 2–
3 days.
cIsolated yield.
Journal of Heterocyclic Chemistry
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A. K. Gupta, M. Bharadwaj, and R. Mehrotra
Vol 000
Table 3
Comparative data of conventional and PEG 400 method for the synthesis of 3-methylene-2-oxindoles (4a–j).
Reaction time (min)
PEG 400a
Yieldc (%)
PEG 400
Product no.
X
Ar
Conventionalb
Conventional
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
F
Cl
Br
CH3
H
F
Cl
Br
CH3
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
6
8
8
9
11
8
7
7
8
9
20
25
25
30
25
27
30
27
30
30
96
93
94
95
96
94
92
93
92
96
83
81
87
86
90
89
84
81
79
82
4j
aCompound 3 (1 mmol) in PEG 400 is stirred at 100°C for the specified time.
bCompound 3 (1 mmol) in gl. acetic acid (10 mL) and conc. HCl (0.5 mL) is heated on a steam bath at 95°C for the specified time.
cIsolated yield.
However, the reaction of the corresponding isatin with
acetophenone in the absence of any solvent or catalyst on
stirring at 120°C for 7 min directly afforded the product,
3-methylene-2-oxindoles (chalcones), in high yield and
purity without isolation of intermediate aldol product
(Scheme 1, route C). But by using 1:1 equivalent of
isatin and ketone, 4a was obtained in 65% yield. We
noticed also that increasing the quantity of ketone
enhanced the efficiency of the reaction. Increasing the
quantity of ketone to two equivalent makes the reaction
to go to completion with almost 100% conversions
without formation of any side product and reduces the
reaction time drastically. This could be because excess of
acetophenone acts as catalyst, thus facilitating the
reaction. Although route C is shorter, the use of the
twofold excess of ketone somewhat lowers the
sustainability character of the procedure generating
additional waste. Thus, for the synthesis of isatin-linked
chalcone, route (A + B) using PEG 400 is more
sustainable than the direct route C.
Table 4
Solvent-free direct synthesis of 3-methylene-2-oxindoles (4a–j).
Product
no.
Reaction timea
(min)
Yieldb
(%)
X
Ar
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
F
Cl
Br
CH3
H
F
Cl
Br
CH3
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
7
9
8
9
7
9
8
10
12
9
97
95
94
96
96
94
93
94
95
96
4j
aIsatin 1 (1 mmol) and ketone 2 (2 mmol) stirred at 120°C for the specified
time.
bIsolated yield.
reaction media has also been explored for the synthesis of
Schiff bases of isatins with various aromatic amines like
aniline, 2-aminopyridine, and 2-aminothiazole. Work is
currently underway in our laboratory results and will be
published soon. All reactions were pursued via both
conventional and PEG-mediated method, and the
comparative study of the results confirms the superiority
of the developed method.
With a set of optimized reaction conditions at hand, the
scope of this reaction was investigated using various 5-
substituted isatins as the presence of small withdrawing
group at 5-position of the 2-oxindole derivatives is
associated with enhanced potency and drug-like
properties [7]. This simple facile one-pot synthesis
strategy with high atomic economy could be applied to
gram scale synthesis. It represents
a
substantial
CONCLUSION
improvement upon conventional synthesis of biological
potential isatin-derived 2-oxindoles and has been
extended to other aromatic ketones like acetylpyridine,
acetylpyrrole, and acetyl furan. All reactions in PEG 400
proceeds smoothly to completion in a short time to afford
the corresponding product, in excellent yield and with
high region selectivity. This is just preliminary data and
scope expansion work of use of PEG 400 as green
A facile tandem route for the synthesis of a series of
biological potential isatin-linked chalcones (4a–j) and
their 3-hydroxy precursors (3a–j) using green solvent
PEG 400 has been developed. Use of eco-friendly
solvent, catalyst-free mild reaction conditions, short
reaction times, high atom economy, and easy workup
procedure are the key features of this method deserving
Journal of Heterocyclic Chemistry
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Month 2018
PEG 400 as Green Solvent for Synthesis of Anticancer Isatin-linked Chalcones
and Their 3-Hydroxy Precursor
attention from a sustainable standpoint. This is just the
preliminary data as scope expansion work with other
isatins and ketones is currently underway in our
laboratory. Developed method will be of great use to
researchers seeking these bioactive motifs as precursors
or intermediates for the synthesis of numerous
pharmaceutically active drugs including spiro-oxindoles.
in a similar manner with slight variation in reaction time
as reported in Table 2. Physical and spectral data of
compounds, 3a–e, were comparable with earlier reported
compounds in our published paper [40].
3-Hydroxy-3-[2-oxo-2-(2-pyridinyl)ethyl]-1,3-dihydro-2H-
indol-2-one (3f). This compound was obtained as shining
white flakes, mp: 200–202°C; IR (KBr, ν cmÀ1): 3400
(OH), 3258 (NHCO), 1715 (CO–Ar), 1682 (NHCO),
1617, 1475, 1399, 1216, 755; 1H NMR (DMSO,
300 MHz, δ ppm): 10.23 (s, 1H), 7.86 (s, 1H), 7.62 (d,
J = 7.8 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.48 (d,
J = 7.6 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.12–6.77 (d,
J = 7.3 Hz, 1H), 6.77–6.80 (t, J = 7.4 Hz, 2H), 6.02 (s,
1H, OH), 4.05 (d, J = 17.6 Hz, 1H), 3.54 (d,
J = 17.6 Hz, 1H); 13C NMR (DMSO, 75 MHz): δ
197.39, 178.8, 153.2, 47.8, 141.2, 136, 131.5, 129,
127.7, 123.2, 120.9, 120.3, 110.2, 74, 44.9; HRMS m/z:
MATERIALS AND METHODS
All fine chemicals like substituted isatins, acetophenone,
and acetylpyridine were purchased from Aldrich
Chemicals Co., USA. Solvents used in this study were of
analytical grade and purchased from Thermo Fisher
Scientific India Pvt. Ltd. Elemental analysis was performed
using a Heraeus CHN-O-rapid analyzer. Melting points
were determined using open capillary tubes in scientific
melting point apparatus and are uncorrected. Infrared (IR)
spectra in KBr were scanned using a Perkin-Elmer model
267 (M+) for C15H12N2O3.
5-Fluoro-3-hydroxy-3-[2-oxo-2-(2-pyridinyl)ethyl]-1,3-
dihydro-2H-indol-2-one (3g).
This compound was
obtained as cream colored shining crystals, mp 198°C; IR
1
557 grating IR spectrophotometer (νmax in cmÀ1). H and
(KBr, ν cmÀ1): 3410 (OH), 3282 (NHCO), 1721 (CO),
13C NMR were recorded on Bruker Advance 400 spectro-
photometer (chemical shift in δ ppm downfield from
tetramethylsilane as an internal reference). The mass spec-
tra were recorded on Jeol SX-102 mass spectrophotometer.
The progress of the reaction was monitored by TLC using
Merck silica gel coated alumina plates (0.25 mm) using
solvent systems of different polarity. All the products were
purified by simple filtration of the reaction mixture and
crystallization except in few cases where the purification
was accomplished by a short column chromatography.
All synthesized compounds were characterized based on
their 1H NMR, 13C NMR, Fourier transform infrared, mass
spectroscopy, and elemental analyses.
1
1668 (NHCO), 1523, 1452, 1336, 1216, 1183, 748; H
NMR (DMSO, 300 MHz, δ ppm): 10.23 (s, 1H, NH),
7.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.25
(d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.82–6.74
(m, 2H), 6.64 (d, J = 7.8, 1H), 6.08 (s, 1H, OH), 4.05 (d,
J = 17.1 Hz, 1H), 3.55 (d, J = 17.3 Hz, 1H); 13C NMR
(DMSO, 75 MHz): δ 194.2, 174.8, 152.2, 147.2, 142.8,
138.2, 134.6, 132.2, 131.1, 129.5, 128.4, 124.2, 110.5,
72.7, 45.4; HRMS m/z: 285 (M+) for C15H11FN2O3.
5-Chloro-3-hydroxy-3-[2-oxo-2-(2-pyridinyl)ethyl]-1,3-
dihydro-2H-indol-2-one (3h).
This compound was
obtained as yellow solid, mp 209°C; IR (KBr, ν cmÀ1):
3451 (OH), 3380 (NHCO), 1715 (CO), 1683 (NHCO),
1604, 1448, 1219, 1175, 820, 767; 1H NMR (DMSO,
300 MHz, δ ppm): 10.17 (s, 1H, NH), 7.22 (d,
J = 7.4 Hz, 1H), 7.11 (d, 1H), 7.08 (d, J = 7.5 Hz, 1H),
6.95–6.74 (m, 2H), 6.13 (d, J = 7.8 Hz, 1H), 6.03 (d,
J = 7.22, 1H), 5.96 (s, 1H), 3.7 (d, J = 17.3 Hz, 1H),
3.25 (d, J = 17.3 Hz, 1H); 13C NMR (DMSO, 75 MHz):
δ 196.9, 177.8, 150.3, 147.3, 141.6, 139, 135.7, 134.4,
132.2, 130.5, 129.9, 129.2, 109.4, 74.8, 44.7; HRMS m/
EXPERIMENTAL
Representative general procedure for synthesis of
3-hydroxy-3-(2-oxo-2-arylethyl)-1,3-dihydro-2H-indol-2-ones
(3a–j) (route A). Isatin 1a (1 mmol) and acetophenone 2
(1 mmol) in PEG 400 (5 mL) were mixed thoroughly and
stirred at 50°C for 8 min. The progress of the reaction
was monitored by TLC using pet ether : ethyl acetate
(3:1) as the solvent system. After completion of the
reaction, the mixture was extracted with ethyl acetate (5–
10 mL). The combined organic layer was dried over
anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The crude product was filtered, dried,
and recrystallized from ethanol as shining white crystals
of 3a, which were found to be TLC pure. However, in
the case of compounds 3c and 3i, a short column
chromatography on silica gel was used to purify the
desired product. All compounds, 3f–j, were synthesized
z: 301 (M+) for C15H11ClN2O3.
5-Bromo-3-hydroxy-3-[2-oxo-2-(2-pyridinyl)ethyl]-1,3-
dihydro-2H-indol-2-one (3i). This compound was obtained
as lemon yellow shining flakes, mp 218°C; IR (KBr, ν
cmÀ1): 3410 (OH), 3316 (NHCO), 1712 (CO), 1676
(NHCO), 1476, 1216, 990, 748; 1H NMR (DMSO,
300 MHz, δ ppm): 10.32 (s, 1H, NH), 8.19 (d,
J = 7.3 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 7.93 (d,
J = 7.5 Hz, 1H), 7.75–7.16 (m, 2H), 6.84 (d, J = 7.5 Hz,
1H), 6.81 (d, J = 7.8, 1H), 6.16 (s, 1H), 4.15 (d,
J = 17.3 Hz, 1H), 3.65 (d, J = 17.3 Hz, 1H); 13C NMR
(DMSO, 75 MHz): δ 191.9, 176.7, 152.3, 148.3, 141.6,
Journal of Heterocyclic Chemistry
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A. K. Gupta, M. Bharadwaj, and R. Mehrotra
Vol 000
139, 137.7, 134.4, 133.2, 130.5, 129.9, 126.3, 109.4, 74.8,
5-Chloro-3-[2-(2-pyridinyl)-2-oxoethylidene]-1,3-dihydro-
45.2; HRMS m/z: 346 (M+) for C15H11BrN2O3.
3-Hydroxy-5-methyl-3-[2-oxo-2-(2-pyridinyl)ethyl]-1,3-
dihydro-2H-indol-2-one (3j). This compound was obtained
2H-indol-2-one (4h). This compound was obtained as red
fluffy solid, mp 254°C; IR (KBr, ν cmÀ1): 3200 (NHCO),
1690 (CO), 1655 (NHCO), 1590 (C═C), 1620, 1421,
1320, 1284, 1013, 760; 1H NMR (DMSO-d6, δ ppm):
10.78 (s, 1H, NH), 8.46 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H),
7.69 (t, J = 7.8 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.37
(d, J = 7.4 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H) 6.78 (s,
1H); 13C NMR (DMSO, 75 MHz): δ 190.6, 168.2, 143.6,
142.3, 139.4, 138.8, 136.7, 133.2, 133.6, 132.7, 129.4,
125.1, 121.3, 119.5, 111.3; HRMS m/z: 283 (M+) for
as light yellow solid, mp 186–187°C; IR (KBr, ν cmÀ1):
3374 (OH), 3280 (NHCO), 1715 (CO), 1680 (NHCO),
1
1469, 1354, 1227, 750; H NMR (DMSO, 300 MHz, δ
ppm): 10.26 (s, 1H, NH), 8.71 (d, J = 7.4 Hz, 1H), 7.74
(d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.2–7.12
(m, 2H), 6.81 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8, 1H),
6.10 (s, 1H), 4.27 (d, J = 17.3 Hz, 1H), 3.64 (d,
J = 17.3 Hz, 1H), 2.48 (s, 3H, CH3); 13C NMR (DMSO,
75 MHz): δ 196.9, 177.8, 150.3, 147.3, 141.6, 139,
135.7, 134.4, 132.2, 130.5, 129.9, 129.2, 109.4, 74.8,
44.7, 24.8; HRMS m/z: 281 (M+) for C16H14N2O3.
C15H9ClN2O2.
5-Bromo-3-[(2-(2-pyridinyl)-2-oxoethylidene]-1,3-dihydro-
2H-indol-2-one (4i). This compound was obtained as dark
red needles, mp 270°C; IR (KBr, ν cmÀ1): 3280 (NHCO),
1702 (CO–Ar), 1683 (NHCO), 1621, 1445, 1343, 1297,
Representative procedure for synthesis of 3-(2-oxo-2-
arylethylidene)-1,3-dihydro-2H-indol-2-one (4a–j) (route
1
1025, 1011, 760; H NMR (DMSO-d6, δ ppm): 10.93 (s,
B).
3-Hydroxy-2-oxindole 3a (1 mmol) generated, in
1H, NH), 8.79 (s, 1H), 8.68 (d, J = 7.4 Hz, 1H), 8.43 (d,
J = 7.1 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.08 (d,
J = 7.8 Hz, 1H), 7.7 (d, J = 7.3 Hz, 1H), 7.57 (t,
J = 7.4 Hz, 1H), 6.83 (s, 1H); 13C NMR (DMSO,
75 MHz): δ 190.8, 166.7, 147.8, 143.5, 137.4, 134.6,
130.6, 128.2, 126.6, 125.9, 125.3, 122.8, 121.9, 121.4,
110.4; HRMS m/z: 228 (M+) for C15H9BrN2O2.
situ, was further heated in the same vessel in PEG 400 at
100 °C with constant stirring for 6 min. The reaction was
monitored by TLC when solution turned dark red. On
completion, the reaction mixture was cooled and poured
in cold water to obtain the desired bright colored
compound. The crude product was recrystallized from hot
ethanol as shining red crystals of pure chalcone, 4a.
Physical and spectral data of compounds, 4a–e, were
comparable with earlier reported compounds in our
published paper [40]. All compounds, 4f–j, were
synthesized in a similar manner with slight variation in
5-Methyl-3-[2-(2-pyridinyl)-2-oxoethylidene]-1,3-dihydro-
2H-indol-2-one (4j). This compound was obtained as dark
red fluffy flakes, mp 220°C; IR (KBr, ν cmÀ1): 3190
(NHCO), 1690 (CO), 1655 (NHCO), 1590 (C═C), 1604
1
(C═C), 1334, 1216, 1014, 748; H NMR (DMSO-d6, δ
reaction time as reported in Table 3.
3-[2-(2-Pyridinyl)-2-oxoethylidene]-1,3-dihydro-2H-indol-2-
ppm): 10.68 (s, 1H, NH), 8.83 (s, 1H), 8.64 (d,
J = 8.2 Hz, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.26 (d,
J = 7.9 Hz, 1H), 8.14 (d, 1H), 8.02 (d, J = 7.3 Hz, 1H),
7.57 (t, J = 7.3 Hz, 1H), 6.86 (s, 1H), 2.27 (s, 3H, CH3);
13C NMR (DMSO, 75 MHz): δ 189.8, 168.5, 143.8,
140.5, 136.4, 132.6, 132.4, 129.3, 127.7, 126.6, 125.3,
122.8, 121.9, 121.4, 110.4, 21.5; HRMS m/z: 263 (M+)
for C16H12N2O2.
one (4f).
This compound was obtained as bright red
shining needles, mp 189–190°C; IR (KBr, ν cmÀ1): 3189
(NHCO), 1712 (CO), 1644 (NHCO), 1616 (C═C),1617,
1
1460, 1333, 1290, 1023, 998, 750; H NMR (DMSO-d6,
δ ppm): 10.77 (s, 1H, NH), 8.07 (s, 1H), 8.04 (d,
J = 8.2 Hz, 1H), 7.99 (t, J = 7.8 Hz, 2H), 7.71 (d,
J = 7.8 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.33 (d,
J = 7.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H);
13C NMR (DMSO, 75 MHz): δ 191.3, 169.8, 141.2,
137.8, 137.3, 134.4, 133.5, 132.5, 129.0, 128.7, 126.2,
120.9, 124.3, 120.7, 109.4; HRMS m/z: 249 (M+) for
Representative procedure for direct synthesis of 3-(2-oxo-2-
arylethylidene)-1,3-dihydro-2H-indol-2-one (4a–j) (route C).
Isatin (1 mmol) and acetophenone (3 mmol) were mixed
thoroughly using a pestle and mortar without any solvent
or catalyst, and the mixture was heated at 120°C with
stirring for 7 min. The reaction was monitored by TLC,
and on completion, reaction mixture was cooled to obtain
the desired bright colored compound. The crude product
was recrystallized from hot ethanol as shining red crystals
of pure chalcone, 4a. All compounds, 4b–j, were
synthesized in a similar manner with slight variation in
reaction time as reported in Table 4.
C15H10N2O2.
5-Fluoro-3-[2-(2-pyridinyl)-2-oxoethylidene]-1,3-dihydro-
2H-indol-2-one (4g).
This compound was obtained as
shining brown needles, mp 236°C; IR (KBr, ν cmÀ1):
3220 (NHCO), 1700 (CO), 1656 (NHCO), 1605 (C═C),
1
1425, 1334, 1216, 994, 748; H NMR (DMSO, δ ppm):
11.0 (s, 1H, NH), 7.57 (d, J = 7.2 Hz, 1H), 7.48 (d,
J = 7.7 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.06 (d,
J = 7.8 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 7.03 (d,
J = 7.4 Hz, 2H), 6.88 (d, 1H); 13C NMR (DMSO,
75 MHz): δ 192.9, 168.2, 145.6, 142.3, 140.3, 138.8,
136.7, 133.2, 132.6, 132.3, 129.4, 126.3, 122.3, 121.5,
109.4; HRMS m/z: 267 (M+) for C15H9FN2O2.
Representative general procedure for conventional thermal
synthesis of 3a–j and 4a–j. An equimolar concentration of
the corresponding isatin (10 mmol) and ketone (10 mmol)
in the presence of catalytic amount of diethylamine
(0.5 mL) was refluxed in absolute ethanol (20 mL) on a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
PEG 400 as Green Solvent for Synthesis of Anticancer Isatin-linked Chalcones
and Their 3-Hydroxy Precursor
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet