Electro-organic synthesis of nanosized particles of 3-hydroxy-3-(1H-indol- 3-yl)indolin-2-one derivatives

Article abstract of DOI:10.1007/s00706-011-0693-1

This article describes an electrochemical method for preparation of nanosized particles of 3-hy-droxyoxindoles. The method is based on the reaction of isatins with indoles in propanol employing an undivided cell in the presence of NaBr as an electrolyte. The product was characterized after purification using infrared (IR), ¹H nuclear magnetic resonance (NMR), ¹³C NMR, mass spectrometry (MS), and scanning electron microscopy (SEM).

Full text of DOI:10.1007/s00706-011-0693-1

Monatsh Chem (2012) 143:1157–1160
DOI 10.1007/s00706-011-0693-1
ORIGINAL PAPER
Electro-organic synthesis of nanosized particles of 3-hydroxy-3-
(1H-indol-3-yl)indolin-2-one derivatives
•
S. Makarem A. R. Fakhari A. A. Mohammadi
•
Received: 11 May 2011 / Accepted: 22 November 2011 / Published online: 13 December 2011
Ó Springer-Verlag 2011
Abstract This article describes an electrochemical
method for preparation of nanosized particles of 3-hy-
droxyoxindoles. The method is based on the reaction of
isatins with indoles in propanol employing an undivided
cell in the presence of NaBr as an electrolyte. The product
derivatives have been prepared by reaction of isatins with
alkylbenzenes or halobenzenes [7], diphenyl urea [8],
barbituric acid [9], and indole [10], and other routes [11].
The basis of nanotechnology is the ability to form
nanosized particles, for example, nanopowders, which are
solid particles with nanoscale size. Many pharmaceutical
companies are performing research to decrease particle
size. Drugs with smaller particle size would be better
absorbed by the digestive tract lining, thus reducing the
amount necessary and making medicines more affordable
[12]. The ability to deliver antibiotics in aerosol form to the
lungs would provide an easier way of treating infections
such as tuberculosis [13]. Decreasing particle size could
increase bioavailability drastically, producing faster-react-
ing drugs with diverse applications in the health industry
[14]. Until now, nanosized organic compounds have been
prepared through different methods in which organic
compounds are first synthesized and only then can be
transformed into nanosized particles using modern high
technology, for example, particle production of progester-
one and medroxyprogesterone using supercritical fluid,
1,3,5-trinitroperhydro-1,3,5-triazine using the ultrahigh-
pressure rapid expansion of supercritical solutions (RESS)
system, and hydrocortisone using supercritical antisolvent
with enhanced mass transfer [15–17]. However, we have
directly synthesized nanosized particles in only one step
through an electrochemical reaction. Electrochemical syn-
thesis of nanosized organic compounds is an innovative
method which has not been previously reported. In con-
nection with the authors’ ongoing work on electro-organic
synthesis, benzofurans [18], 2-amino-4H-chromenes [19],
and preparation of oxindoles [20, 21], this report describes
a new electrochemical procedure for preparation of nano-
sized particles of 3-hydroxyoxindoles in an undivided cell
in the presence of NaBr as an electrolyte.
1
was characterized after purification using infrared (IR), H
nuclear magnetic resonance (NMR), 13C NMR, mass
spectrometry (MS), and scanning electron microscopy
(SEM).
Keywords Indole ꢀ Isatin ꢀ Electrosynthesis ꢀ
Nanosized particles
Introduction
Isatins are known for their manifold biological activities.
Some isatin derivatives are key intermediates in synthesis
of natural products [1]. Different derivatives of isatin have
been synthesized to study their bioactivity. Oxindoles are
well known among these compounds and are useful as
antibacterials, anti-inflammatories [2], laxatives [3],
growth hormone secretagogues [4], and new targets for
cancer chemotherapy [5]. These intermediates are also
useful in synthesis of chiral ligands to obtain high enanti-
oselectivities in numerous catalytic reactions [6]. Oxindole
S. Makarem ꢀ A. R. Fakhari (&)
Department of Chemistry, Faculty of Sciences,
Shahid Beheshti University, G.C., Evin, Tehran, I.R. Iran
e-mail: a-zavareh@sbu.ac.ir
A. A. Mohammadi (&)
Chemistry and Chemical Engineering Research Center of Iran
(CCERCI), PO Box 14335-186, Tehran, I.R. Iran
e-mail: aliamohammadi@ccerci.ac.ir
123

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S. Makarem et al.
Results and discussion
The reaction of indole (1 mmol) and 5-bromoisatin
(1 mmol) was completed within 1 h, and 3-hydroxyoxin-
dole 3a was prepared in 90% yield (Scheme 1). In almost
all previously reported works on the reaction of indole
with isatins, one isatin molecule reacted with two mole-
cules of indole, with rare reports in which the reaction
ceased after addition of only one indole molecule to the
isatin molecule [20, 22]. Interestingly, it was found that
this reaction produced 3-hydroxyoxindole, since there was
no evidence of formation of 3,30-bisindolyloxindoles 4.
All 3-hydroxyoxindoles 3 were attributed based on one
peak observed close to 6.30–6.60 ppm for their OH
protons.
Fig. 1 Image of nanosized particles of compound 3a
Surprisingly, it was found that these products were
nanosized particles. An SEM image of the template-syn-
thesized nanoparticles, obtained from powder, is shown in
Fig. 1. The average particle size (dSEM) is \100 nm. The
size and form of the aggregates depended upon the con-
ditions in which the sample was prepared.
Table 1 Effect of temperature and current on reaction of 5-bromo-
isatin 1a and indole 2a to afford nanosized particles of
3-hydroxyoxindole 3a
Entrya
Solvent
t/min
I/A
T/°C
Current
passed/
F mol-1
Yield/%b
After screening several parameters such as solvents,
temperature, and current, it was found that dry propanol at
current density of 10 mA cm-2 at 40 °C promotes the
reaction of 5-bromoisatin (1a) and indole (2a) to afford
3-hydroxyoxindole 3a efficiently (Table 1).
1
2
3
4
5
a
Propanol
Propanol
Propanol
Ethanol
Ethanol
150
60
0.05
0.05
0.02
0.05
0.05
25
40
25
40
25
4.7
1.9
3.0
1.9
4.7
60
90
50
70
40
240
60
Initially, we used graphite and platinum as anode and
cathode instead of magnesium and iron. Our experiments
showed that these electrodes elongate the reaction time and
reduce the yield of products, while using graphite or plat-
inum as anode leads to production of Br2 at the surface of
the anode, making product separation difficult. Thus,
despite the loss of magnesium electrodes during the reac-
tion, this electrode was used as anode due to advantages
such as shorter reaction time, higher yield, and production
of nontoxic Mg2?. In addition, reduction of alcohol on iron
was mentioned in previous reports [23, 24].
150
For all reactions, 0.5 mmol NaBr, iron cathode (5 cm2), and mag-
nesium anode (5 cm2) were used
b
Isolated yields based on 5-bromoisatin 1a
derivatives to extend the scope of the reaction. Hence, a
number of isatin derivatives effectively participated in
condensation with indole derivatives to give corre-
sponding nanosized particles of 3-hydroxyoxindole
compounds in good yields. The results are summarized in
Table 2.
An attempt was made to prepare nanosized particles of
3-hydroxyoxindole derivatives from indole and isatin
Scheme 1
R1
R3
NH
N
H
N
R3
R2
2
O
R2
OH
2
O
+
N
R1
O
R3
R2
R3
N
H
3
N
H
O
4
N
R1
1
123

Electro-organic synthesis of nanosized particles
1159
Cathode: ROH + 1e-
Or
RO + 1/2 H2
Table 2 Electrochemical condensation of isatins 1 and indoles 2 for
preparation of 3-hydroxyoxindoles 3
Comp.a
R1
R2
R3
M.p./°C
209
Yield/%b
Ref.
+ 1e-
1/2 H2
N
3a
3b
3c
3d
3e
3f
a
H
Br
Br
Br
H
H
90
92
89
87
85
94
–
N
I
1
H
H
Me
H
228
80
–
Et
Me
H
–
In solution:
H
52
–
ROH
+
+ RO
H
Me
H
160
[10]
[10]
N
N
H
H
143 (dec)
H
I
1
H
All reactions were run with 0.147 g isatin (1 mmol), 0.117 g indole
O
(1 mmol), and 0.05 g NaBr (0.5 mmol) in 25 cm3 propanol at 40 °C
O
N
b
Yields based on isatins
+
O
O
N
N
N
2
H
5
I
H
The following mechanism is proposed to account for the
reaction: Deprotonation of alcohol at the cathode led to
formation of an alkoxide anion. Subsequent reaction
between the alkoxide anion and indole gave rise to an
indole anion. Condensation of anion I with 2 yielded
intermediate 5. Finally, product 3 was formed by proton-
ation and rearrangement of 5 (Scheme 2).
HO
O
N
NH
O
O
N
N
H
H
6'
6
I
1
Conclusions
A successful new strategy for efficient, convenient, green
synthesis of 3-hydroxyoxindoles via condensation reaction
of indoles and isatins is described. This reaction, the first
reported for preparation of nanosized particles of organic
compound by electro-organic synthesis, is a useful process
for synthesis of nanosized particles of 3-hydroxyoxindoles.
HO
NH
O
N
H
3
Scheme 2
5-Bromo-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one
(3a, C16H11BrN2O2)
Experimental
A mixture of indole (1 mmol), 5-bromoisatin (1 mmol),
and 51 mg NaBr (0.5 mmol) in 25 cm3 propanol was
stirred and electrolyzed in an undivided cell equipped with
an iron cathode and a magnesium anode at 40 °C under
constant current density of 10 mA cm-2 (I = 50 mA).
After completion of the reaction [monitored by thin-layer
chromatography (TLC), ethyl acetate/n-hexane 2:1], the
solvent was evaporated under reduced pressure, ethanol
(90%) was added to the reaction mixture, and the resulting
solid was centrifuged. The crude products were then
Constant-current coulometry and preparative electrolysis
were performed using a SAMA potentiostat/galvanostat
(Isfahan, Iran). The working electrodes were an iron
cathode (5 cm2) and a magnesium anode (5 cm2). IR
spectra were recorded on a Bruker IFS-66 Fourier trans-
form (FT)-IR spectrophotometer. NMR spectra were
recorded on a Bruker DRX-300 Avance instrument. Mass
spectra were obtained using a QP-1100 EX Shimadzu gas
chromatography (GC)-MS [electrospray ionization (EI) at
70 eV] and an HP (Agilent Technologies) 5937 mass-
selective detector. Scanning electron microscopy (SEM)
was run with an axl30 scanning electron microanalyzer
(Philips, The Netherlands) at acceleration voltage of
20.0 kV. Melting points were obtained using an electro-
thermal melting point apparatus (model 9200). All starting
materials were commercially available, obtained from
Merck, and used without further purification.
ꢀ
gathered for analysis. M.p.: 209 °C; IR (KBr): m = 3,414,
3,234, 1,710, 1,615 cm-1 1H NMR (DMSO-d6): d =
;
10.98 (s, 1H, NH), 10.33 (s, 1H, NH), 7.31–7.34 (m, 2H,
Ar), 7.21–7.26 (m, 2H, Ar), 7.05 (d, 1H, J = 2.2 Hz, Ar),
6.97–7.04 (m, 1H, Ar), 6.83–6.94 (m, 2H, Ar), 6.34 (s, 1H,
OH) ppm; 13C NMR (DMSO-d6): d = 178.9, 142.1, 137.2,
133.9, 129.5, 125.3, 125.1, 123.9, 122.1, 121.5, 120.8,
118.9, 115.9, 111.9, 110.0, 75.3 ppm; MS: m/z (%) = 344
123

1160
S. Makarem et al.
(M??2, 25) 342 (M?, 25), 264 (20), 197 (98), 180 (25),
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;
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;
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Acknowledgments Financial support from the Research Affairs of
Shahid Beheshti University is gratefully acknowledged.
123