Solvent free synthesis of N-alkylated imino indoline-2-one derivatives under microwave irradiation

Article abstract of DOI:10.4314/bcse.v32i2.17

The solvent-free microwave-assisted syntheses of N-alkyl isatin Schiff base derivatives are reported. These isatin derivatives are obtained as a result of the condensation of an isatin compound with a benzyl halide and an aniline derivatives using microwave irradiation condition in high yield and short reaction time.

Full text of DOI:10.4314/bcse.v32i2.17

Bull. Chem. Soc. Ethiop. 2018, 32(2), 393-398.
 2018 Chemical Society of Ethiopia and The Authors
DOI: https://dx.doi.org/10.4314/bcse.v32i2.17
ISSN 1011-3924
Printed in Ethiopia
SHORT COMMUNICATION
SOLVENT FREE SYNTHESIS OF N-ALKYLATED IMINO INDOLINE-2-ONE
DERIVATIVES UNDER MICROWAVE IRRADIATION
Roya Zekavati1*, Abdolhasan Doulah2, Mohammad Kazem Mohammadi3 and Saloomeh Shirali2
1Faculty of Nursing, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
2Department of Cellular and Molecular Biology, Ahvaz Branch, Islamic Azad University,
Ahvaz, Iran
3Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
(Received December 24, 2017; Revised February 20, 2018; Accepted February 26, 2018)
ABSTRACT. The solvent-free microwave-assisted syntheses of N-alkyl isatin Schiff base derivatives are
reported. These isatin derivatives are obtained as a result of the condensation of an isatin compound with a benzyl
halide and an aniline derivatives using microwave irradiation condition in high yield and short reaction time.
KEY WORDS: Microwave, Isatin derivatives, Solvent free, Combinatorial synthesis
INTRODUCTION
Microwave-assisted organic synthesis (MAOS) is a new method for synthesis and methodology
in formation of new organic compounds. This technique is based on application of microwave
irradiation that absorbed by chemical bonds and lead to chemical transformations. Use of
microwave irradiation rather than conventional heating leads to higher product in shorter
reaction time, which in many cases are in the range of second or minute, that is very attractive
than the conventional heating procedure in reflux condition.
Synthesis of new bioactive molecules has been a very interest in organic chemistry. In this
regard, development of new compounds and especially small structures lead to very high
attention for pharmaceutical chemists. This is because growing requirements to introducing of
different structures for evaluating of compounds in drug discovery attempts.
Isatin is a natural product found in a number of plants including those of the genus Isatis [1].
It has also been found as a metabolic derivative of adrenaline in humans [2]. Moreover, it has
been demonstrated that isatin found at higher levels in patients involved with neuro pathological
conditions and also proved to be a competitive MAO-B inhibitor [3, 4]. Various derivatives of
isatin are known to possess a range of pharmacological properties including antiprotozoal [5, 6],
anti glycation [7], anticonvulsant and sedative-hypnotic [8, 9], anti-inflammatory [10],
antibacterial and anti-fungal [11] activities. Thus isatin is a biologically validated starting point
for the design and synthesis of chemical libraries directed at these targets [12]. Due to the
privileged nature of isatin, libraries designed and synthesized around the basic structure of this
scaffold may yield medicinally active compounds with high hit rates [13, 14].
The use of microwave energy in organic synthesis has attracted growing interest in the past
few years. Initially, it was applied to the synthesis of organic compounds in solvent or without
the solvent [15-17]. In recent years, few synthesis methods have reported the use of microwave
reactions for synthesis of organic and organometallic compounds [18, 19].
__________
*Corresponding author. E-mail: zekavati@iauahvaz.ac.ir
This work is licensed under the Creative Commons Attribution 4.0 International License

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In continuation to our interest in synthesis of new biologically active compounds, here, we
report the synthesis of some Schiff bases and N-alkylated Isatin derivatives in good yields and
short time in solvent free and microwave irradiation condition [20, 21].
EXPERIMENTAL
Instruments and materials. All compounds were purchased and solvents were purified by
standard methods. Infrared spectra were recorded on a Shimadzu model 420 spectrophotometer.
1H and 13C NMR spectra were recorded on a Bruker spectrometer operated at 300 MHz. 1H and
13C NMR spectra were referenced to external SiMe4. Melting points were measured on an
Electro thermal 9100 melting point apparatus. We used a Micro synthesis Millstone laboratory
microwave oven using a 400 Watts WestPoint microwave operating at 3.67 GHz.
General procedure for the synthesis of N-alkylated imino isatin derivatives
Typical procedure for preparation of (Z)-1-benzyl-3-(phenylimino)indolin-2-one. A mixture of
isatin (0.735 g, 5 mmol), K2CO3 (0.13 g, 9.42 mmol), benzyl chloride (0.630 g, 5 mmol), aniline
(0.525 g, 5 mmol) and CH3CN (3 mL) contained in a 100 mL beaker placed in the microwave
oven (Scheme 1). The beaker was covered with a stem less funnel and subjected to irradiation in
condition as shown in Scheme 1 (operated in 150 W). The residue was allowed to cool to room
temperature and cold water (5 mL) was added. The precipitate thus obtained was filtered off and
washed with water. Recrystallizing with the hot ethanol gave pure and high yielded products.
This procedure was performed for other compounds (2-8).
N
O
Ph-NH2 / Ph-CH2-Cl
K2CO3
O
O
Microwave irradiation
Time = 2-5 min
N
N
H
Scheme 1. Synthesis of N-alkylated isatin Shiff base derivatives.
Characteristic data for synthetized compounds
o
(Z)-1-Benzyl-3-(phenylimino)indolin-2-one (1). m.p. 170–173 C. IR (KBr, cm-1): 3200, 3120,
1730, 1650, 850. 1H NMR (300 MHz, DMSO-d6, ppm): 7.21-7.67 (m, 14H, Ph), 4.34 (s, 2H,
-CH2-). 13C NMR (DMSO-d6, 300 MHz, ppm): 46, 118, 120, 122, 123, 125, 127, 129, 130, 131,
133, 134, 135, 138, 157, 160, 170. 167 (C=O), 165 (C=N), 118-155 (Ph). Found, %: C: 84.99,
H: 6.18, N: 4.56, O: 5.19. C22H17NO calculated, %: C: 84.92, H: 6.18, N: 4.62, O: 5.12.
o
(Z) (4-Methyl)-1-benzyl-3-(4-metylphenylimino)indolin-2-one (2). m.p. 168-172 C. IR (KBr,
cm-1): 3230, 3150, 1730, 1650, 850. 1H NMR (300 MHz, DMSO-d6, ppm): 7.25-7.56 (m, 12H,
Ph), 4.27 (s, 2H, -CH2-), 2.11 (s, 3H, -CH3), 2.23 (s, 3H, -CH3). 13C NMR (DMSO-d6, 300
MHz, ppm): 24, 26, 46, 118, 120, 122, 123, 125, 127, 129, 130, 131, 133, 134, 135, 138, 157,
160, 170. Found, %: C: 84.99, H: 6.18, N: 4.56, O: 5.19. C24H21NO calculated, %: C: 84.92, H:
6.18, N: 4.62, O: 5.12.
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Table 1. Synthesis of new indolin-2-one derivatives under microwave condition.
Entry
1
Ph
Ph
Time
(min)
2
Yield
(%)
90
m.p.
(oC)
170-172
2
3
2
3
92
88
168-170
165-168
H3C
Cl
H3C
Cl
4
5
3
4
90
90
177-179
172-174
HO
HO
O2N
O2N
Cl
Cl
6
7
5
3
90
88
158-160
180-182
CH3
CH3
H3C
H3C
8
3
92
173-175
o
(Z) (4-Chloro)-1-benzyl-3-(4-chlorophenylimino)indolin-2-one (3). m.p. 165-169 C. IR (KBr,
cm-1): 3200, 3120, 1690, 1650, 1400, 960, 850. 1H NMR (300 MHz, DMSO-d6, ppm): 7.37-7.68
(m, 12H, Ph), 4.11 (s, 2H, -CH2-).13C NMR (DMSO-d6, 300 MHz, ppm): 46, 119, 121, 122,
123, 125, 127, 129, 130, 131, 134, 135, 136, 138, 157, 160, 170. Found, %: C: 49.40, H: 3.92,
N: 3.75, O: 4.28. C22H15Cl2NO calculated, %: C: 69.49, H: 3.98, N: 3.68, O: 4.21.
(Z) (4-Hydroxi)-1-benzyl-3-(4-hydroxyphenylimino)indolin-2-one (4). m.p. 177-182 oC. IR
1
(KBr, cm-1): 3300, 3240, 2970, 1630, 1600, 1400, 960, 850. H NMR (300 MHz, DMSO-d6,
ppm): 7.21-7.57 (m, 12H, Ph), 5.23-5.32 (S, 2H), 4.11 (s, 2H, -CH2-). 13C NMR (DMSO-d6, 300
MHz, ppm): 46, 118, 120, 122, 123, 125, 127, 129, 130, 131, 133, 134, 135, 153, 157, 165, 168.
Found, %: C: 76.91, H: 5.08, N: 4.92, O: 14.1. C22H17NO3 calculated, %: C: 76.95, H: 4.99, N:
4.08, O: 13.98.
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(Z) (4-Nitro)-1-benzyl-3-(4-nitrophenylimino)indolin-2-one (5). m.p. 172-175 oC. IR (KBr,
cm-1): 3210, 2925, 1630, 1600, 1545, 1400, 960, 850. 1H NMR (300 MHz, DMSO-d6, ppm):
7.36-7.67 (m, 12H, Ph), 4.23 (s, 2H, -CH2-). 13C NMR (DMSO-d6, 300 MHz, ppm): 45, 116,
121, 122, 123, 125, 127, 129, 130, 131, 133, 134, 135, 138, 150, 166, 172. Found, %: C: 65.73,
H: 3.71, N: 10.55, O: 19.90. C22H15N3O5 calculated, %: C: 65.83, H: 3.77, N: 10.47, O: 19.93.
(Z) (3-Chloro-4-methyl)-1-benzyl-3-(3-chloro-4-methylphenylimino)indolin-2-one (6). m.p. 158-
o
162 C. IR (KBr, cm-1): 3210, 2925, 1630, 1600, 1545, 1400, 960, 850. 1H NMR (300 MHz,
DMSO-d6, ppm): 7.17-7.45 (m, 10H, Ph), 4.34 (s, 2H, -CH2-), 2.54 (s, 6H, CH3). 13C NMR
(DMSO-d6, 300 MHz, ppm): 21, 23, 44, 118, 120, 122, 123, 125, 127, 129, 130, 131, 133, 134,
136, 139, 152, 164, 173. Found, %: C: 49.41, H: 3.93, N: 3.73, O: 4.28. C22H15Cl2NO
calculated, %: C: 69.49, H: 3.98, N: 3.68, O: 4.21.
o
(Z) (2-Methyl)-1-benzyl-3-(2-methylphenylimino)indolin-2-one (7). m.p. 180-184 C. IR (KBr,
cm-1): 3170, 2920, 1630, 1545, 1400, 983, 850. 1H NMR (300 MHz, DMSO-d6, ppm): 7.17-7.45
(m, 10H, Ph), 4.34 (s, 2H, -CH2-), 2.34 (s, 6H, CH3). 13C NMR (DMSO-d6, 300 MHz, ppm): 22,
25, 48, 119, 121, 122, 123, 125, 127, 129, 130, 131, 133, 134, 135, 137, 155, 165, 171. Found,
%: C: 84.96, H: 6.20, N: 4.55, O: 5.21. C24H21NO calculated, %: C: 84.92, H: 6.18, N: 4.62, O:
5.12.
o
(Z) (3-Methyl)-1-benzyl-3-(3-methylphenylimino)indolin-2-one (8). m.p. 173-177 C. IR (KBr,
cm-1): 3170, 2920, 1630, 1545, 1400, 983, 850. 1H NMR (300 MHz, DMSO-d6): 7.17-7.45 (m,
10H, Ph), 4.34 (s, 2H, -CH2-), 2.20 (s, 3H,-CH3), 2.12 (s, 3H, -CH3). 13C NMR (DMSO-d6, 300
MHz, ppm): 21, 23, 47, 119, 121, 122, 123, 125, 127, 129, 130, 131, 133, 134, 134, 137, 155,
166, 173. Found, %: C: 84.98, H: 6.19, N: 4.55, O: 5.17. C24H21NO calculated, %: C: 84.92, H:
6.18, N: 4.62, O: 5.12.
RESULTS AND DISSCUSSION
Reaction of isatin with benzyl chloride and aryl amines was investigated under microwave
irradiation in solvent free condition. As shown in Scheme 1, aromatic amine and benzyl chloride
derivatives could be reacted with isatin to the synthesis of corresponding N-alkylated imino
isatin derivatives in excellent yields. The results showed that under this condition, reaction times
reduced to less than 5 minute compare to other conventional heating methods that products are
formed in several minutes [1-4]. Advantages of microwave irradiation in these cases are in
terms of simple application, good yield, no side product formation, have short reaction time and
a diversity of bioactive molecules that can be synthesis with this method. Isatin and aromatic
amines and benzyl halides are very versatile compounds based on simplicity and suitability. In
our research on synthesis processes, it has been found that they are very applicable organic
molecules for microwave synthesis. This is because they are having polar bonds and therefore,
are polar material. These are the best conditions for effective conversion of microwave energy
to the dielectric heating mechanism. We used a very small amount of solvents (acetonitrile) as a
polar solvent that have a dipole moment and can efficiently absorb the electromagnetic energy
of microwave irradiation. They have an ability to absorb the microwave energy, this resulting
in turn in a very rapid and homogeneous heating. Consequently, they display very strong
specific microwave effects, with significant improvements in temperature homogeneity and
heating rates, enabling faster reactions and less degradation of final products when compared to
classical heating. We noticed that the reaction times in this study were 2-5 minutes. These times
are better than other products that formed with classical heating methods. Also the yields of
products were improved as compared with classical heating methods [22, 23].
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CONCLUSION
In conclusion, it has been found that isatin is a very suitable starting material for synthesis of
novel organic compounds. Some of the advantages of our application of this method, are the
easy handling, simple work-up , short reaction times, and excellent yields of the products that
make this protocol a useful addition to available procedures for the synthesis of isatin
derivatives. In this paper, we reported a procedure where the reaction is performed in
microwave irradiation, in order to prevent problems connected with conventional heating (cost,
handling, safety, pollution, and decreases in reactivity by dilution of the reactants).
ACKNOLEDGMENT
The authors wish to thank the Ahvaz Branch, Islamic Azad University for the financial support.
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