Application of cellulose/chitosan grafted nano-magnetites as efficient and recyclable catalysts for selective synthesis of 3-indolylindolin-2-ones

Article abstract of DOI:10.1016/j.molcata.2014.05.005

Cellulose grafted to nano-magnetites was found to be an efficient biopolymer composite for catalysis of Friedel-Crafts reaction between isatins and indoles, leading to selective synthesis of 3-hydroxy-3-indolylindolin-2- ones. The catalysis process is likely effected by a mass of hydroxyl groups arranged along the backbone of cellulose fibers coated on surface of the nano-sized magnetite support, where they get exposed to the adsorbed substrates. Synergistic push-pull effects, reminiscent of the soft catalysis of metal-less enzymes, via proton donating-accepting functions of the hydroxyl groups anchored on surface of the cellulose shell were invoked to explain the clean and selective bioorganocatalysis of 3-indolylindolin-2-one formation. In addition, more improvement in this selective catalytic performance was realized by employing the magnetite nano-particles coated with chitosan shell.

Full text of DOI:10.1016/j.molcata.2014.05.005

Accepted Manuscript
Title: Application of cellulose/chitosan grafted
nano-magnetites as efficient and recyclable catalysts for
selective synthesis of 3-indolylindolin-2-ones
Author: Kurosh Rad-Moghadam Negin Dehghan
PII:
S1381-1169(14)00202-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2014.05.005
MOLCAA 9105
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
26-3-2014
9-5-2014
10-5-2014
Please cite this article as: K. Rad-Moghadam, N. Dehghan, Application of
cellulose/chitosan grafted nano-magnetites as efficient and recyclable catalysts for
selective synthesis of 3-indolylindolin-2-ones, Journal of Molecular Catalysis A:
Chemical (2014), http://dx.doi.org/10.1016/j.molcata.2014.05.005
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Application of cellulose/chitosan grafted nano-magnetites as efficient and
recyclable catalysts for selective synthesis of 3-indolylindolin-2-ones
Kurosh Rad-Moghadam*and Negin Dehghan
Chemistry department, University of Guilan, Rasht P.O. Box 41335-19141, Iran
;
Fax: +98 131 3220066radmm@guilan.ac.irE-mail:
Highlights
►
Fine and naturally consistent cellulosic-grafted nano-magnetites were prepared►A
selective catalytic synthesis of 3-indolyl-3-hydroxy-2-oxindoles was achieved►The catalysis
is a typically synergistic proton donating-accepting of hydroxyl groups►The efficiency of
catalyst retains even after several recycling.
Abstract
Cellulose grafted to nano-magnetites was found to be an efficient biopolymer composite for
catalysis of Friedel-Crafts reaction between isatins and indoles, leading to selective synthesis
of 3-hydroxy-3-indolylindolin-2-ones. The catalysis process is likely effected by a mass of
hydroxyl groups arranged along the backbone of cellulose fibers coated on surface of the
nano-sized magnetite support, where they get exposed to the adsorbed substrates. Synergistic
push-pull effects, reminiscent of the soft catalysis of metal-less enzymes, via proton
donating-accepting functions of the hydroxyl groups anchored on surface of the cellulose
shell were invoked to explain the clean and selective bioorganocatalysis of 3-indolylindolin-
2-one formation. In addition, more improvement in this selective catalytic performance was
realized by employing the magnetite nano-particles coated with chitosan shell.
Keywords: Bioorganocatalysis; Cellulose; Chitosan; Magnetic recovery; Heterogeneous
catalysis
1. Introduction
1
Page 1 of 26

Heterogenized homogeneous catalysts have received increased attention in the synthetic
organic chemistry from both environmental and economic points of view [1]. Immiscibility
of these catalysts with most regular solvents make them easily separable from reaction
mixtures after use and assures the foremost requirement of easier recycling as well as
preventing the environment pollution. A majority of current catalysts are solids and suitably
meet these criteria by themselves; however, many others including the small organic
molecules and metal ions need to be immobilized on surface of solid inorganic materials or
organic polymers either covalently or by coordination with the ligands existing on surface of
the supports [2]. Despite of the above mentioned benefits, heterogeneous solid catalysts
usually feature slow kinetics associated with their small surface to mass ratio. Although, this
weakness and nonhomogeneous dispersion of catalysts can nearly be solve by reducing the
size of catalysts to nano-dimensions, yet such catalysts usually do not exert explicit
selectivity [3]. Therefore, discovery of heterogeneous selective catalysts, especially those
based on renewable materials, should prove beneficial. In this background and upon the rise
of social consciousness about environmental concerns, a surge of interests was directed
towards application of bio-resource materials in catalyst designing [4]. Cellulose is one of the
most abundant biomass on earth consisting of light weight and stiffed nano-crystallites,
named as nano-whiskers [5]. The intermolecular hydrogen bonding and the van der Waals
interactions between hydrophobic flat top and bottom surfaces of adjacent nano-whiskers
allow intimate and ordered packing of cellulose crystallites, in extent which result in the
biopolymer’s insolubility in water and most solvents [6]. Presence of hydroxyl groups on
surface of cellulose fibers provides a stabilization matrix for anchoring a variety of adsorbed
compounds and to prepare the biomaterial for targeted applications [7]. These interesting
properties make this green material an attractive alternative for conventional synthetic
organic or inorganic supports in catalytic applications [8]. Apart of serving as supports,
cellulosic natural products have found uncommon but important utilities as catalysts due to
the functions of their own groups [9]. Here, we explain a selective and efficient catalytic
synthesis of 3-hydroxy-3-indolylindolin-2-ones from the Friedel-Crafts reaction between
isatins and indoles on surfaces of cellulose and chitosan. Isatins, in addition to versatile
biological activities [10], are familiar for their reactive keto-carbonyl group which readily
undergoes condensation reactions with various carbon nucleophiles [11]. The Friedel-Crafts
reaction of isatins, at this group, with indoles offers a challenging catalytic study, since this
'
reaction gives a mixture of 3,3-diindolylindolin-2-ones and 3-hydroxy-3-indolylindolin-2-
'
ones in most neutral protic solvents and finally leads to sole formation of 3,3-
2
Page 2 of 26

diindolylindolin-2-ones in the presence of acid catalysts [12-16]. Thus, there is need to
develop a mild and reliable methodology for synthesis of 3-hydroxy-3-indolylindolin-2-ones
under neutral conditions by using a recyclable catalyst especially in water for reasons of
safety, economical and environmental concerns. In this view, we attempted to synthesize 3-
hydroxy-3-indolylindolin-2-ones from isatins and indoles under catalysis of cellulose coated
nano-magnetic particles in neutral conditions. Oxindole is a privileged pharmacophoric
scaffold in medicinal chemistry [17], and an integral constituent of many natural products
[18-22]. They were reported to possess antibacterial [23], anti-convulsant [24], laxative [25],
growth hormone secretagogues [26], and anticancer activities [27]. In addition, they served as
useful intermediates for synthesis of chiral ligands employed in several enantioselective
catalytic reactions [28]. On the other hand, a number of oxindole alkaloids, having a hydroxyl
substituent at the C-3 position, showed various bioactivities [29,30] and so received
considerable attentions as synthetic targets [31-33]. In continuation of our efforts towards the
development of efficient and environmentally benign synthetic methodologies [34], we
explain a selective synthesis of 3-hydroxy-3-indolylindolin-2-one derivatives in water by
using cellulose as catalyst.
2
2
. Experimental
.1. Preparation of magnetite nano-particles, carboxymethyl cellulose and
carboxymethyl chitosan
The magnetite nano-particles were prepared according to a reported procedure [35].
Typically, FeCl
water (50 mL) contained in a three-necked round-bottom flask (250 mL). The resulting
solution was stirred at 25 °C with rapid mechanical stirring under N atmosphere for 1 h.
3 2 2 2
·6H O (0.02 mol) and FeCl ·4H O (0.01 mol) were dissolved in distilled
2
Concentrated aqueous ammonia (10 mL, 25 wt%) was then added to the solution drop-wise
over 30 min using a dropping funnel. The resulting magnetic particles were collected by a
magnet and rinsed thoroughly with distilled water.
Cellulose and chitosan were carboxymethylated according to the method of Chen and Park
[36]. First, 3 g of cellulose (or chitosan) and 15 g of sodium hydroxide were added to 100 mL
of 2-propanol/water (80/20) solution and heated at 60 °C for 1 h, in order to swell and
alkalize cellulose. After this step, 20 mL of monochloroacetic acid solution (0.75 g/mL in 2-
propanol) was added to the reaction mixture during 30 min. The mixture was stirred for 4 h at
the same temperature and then 200 mL of ethanol (70%) was added with cooling to room
3
Page 3 of 26

temperature to stop the reaction. Finally, the solid was filtered and rinsed sequentially with
0% and absolute ethanol to desalt and dewater the product. Finally, the product was dried in
an oven at 50 °C.
7
2.2. Binding of carboxymethyl chitosan (cm-chitosan) or carboxymethyl cellulose (cm-
cellulose) to magnetite nano-particles
Binding of carboxymethylated cellulose and carboxymethylated chitosan to magnetic nano-
3 4
particles was adopted from a method reported by Chen et al [37]. Thus, 100 mg of Fe O
nano-particles was added to 3 mL of a buffer containing 0.003 M phosphate (pH 6) and 0.1
M NaCl. The reaction mixture was sonicated for 10 min after addition of 0.5 mL of
carbodiimide solution (0.025 g/mL in the buffer). Finally, 2.5 mL of carboxymethyl cellulose
or carboxymethyl chitosan solution (50 mg/mL in the buffer) was added and the resultant
3 4
reaction mixture was sonicated for 60 min. The cellulose-bound or chitosan-bound Fe O
nano-particles were resolved from the reaction mixture by placing their container flasks on a
permanent magnet with a surface magnetization of 0.7 T (Scheme 1). The magnetic nano-
particles settled within a few minutes were washed with water and ethanol. It is noticeable
that NaCl was used for the flocculation of magnetic nano-particles. It is required to accelerate
the magnetic separation, particularly in alkaline solutions [38]. In addition, coating of
magnetite nano-particles with cellulose or chitosan helps to prevent their agglomeration due
to magnetic interactions.
OH
2
CO H
O
O
NaOH (aq)
O
O
HN
C NH
O
HO
O
HO
O
O
n
Cl
n
X
OH
OH
X
HN
X = OH or NH2
NH2
O
O
Fe
O
3 4
O
O
O
O
O
3 4
Fe O
O
O
HO
O
HO
O
O
-
Urea
n
n
X
X
Scheme 1. Preparation of cm-cellulose@Fe O and cm-chitosan@Fe O nano-particles
3
4
3
4
2
.3. Characterization of cm-cellulose@Fe
The nano-particles of cm-cellulose@Fe
ray diffraction spectroscopy (XRD), IR, and scanning electron microscopy. For cm-
3
O
4
and cm-chitosan@Fe
3 4
O
3
O
4
and cm-chitosan@Fe
3
O
4
were characterized by X-
o
o
o
o
cellulose@Fe
3
O
4
, the XRD diffraction peaks (Fig. 1a) at around 31.0 , 35.6 , 43.0 , 53.8 ,
4
Page 4 of 26

o
5
6.6 and 62.7 corresponding to the (2 2 0), (3 1 1), (4 0 0), (4 2 2), (5 1 1) and (4 4 0) miller
indices are in accordance with the ICDD card number 19-0629 for magnetite. The peak
o
observed at 2θ = 40.35 for the magnetic composite might be related to the presence of α-
o
FeO(OH) (goethite) impurity [39]. In this spectrum, the diffraction peak at around 21.5 could
be assigned to the amorphous cellulose [40]. The scanning electron microscopy of this
composite has displayed the nano-particles of cm-cellulose@Fe
3 4
O as existing in a mixture
with the microcrystalline cellulose fibers (Fig. 1b). The IR spectrum of this composite
-1
displays the characteristic absorption band at around 590 cm arising from stretching
-1
vibrations of Fe-O bonds (Fig 1c). Two main absorptions of this composite at 3440 cm
-1
corresponding to O–H stretching and at 1061 cm due to C-O stretching show no sensible
changes compared to those of cm-cellulose (Fig. 1d). However, the absorption band of C=O
3 4
stretching for the composite of cm-cellulose@Fe O appeared somewhat weak relative to that
of cm-cellulose. The weakness of this peak may be attributed to partial conversion of the
carboxyl groups to esteric ones on grafting of cm-cellulose to magnetite nano-particles.
a
5
Page 5 of 26

b
d
c
Figure 1. (a) The X-ray diffraction pattern, (b) the scanning electron microscopy image, (c) and the IR spectrum
of cm-cellulose@Fe . (d) The IR spectrum of cm-cellulose.
3
O
4
The crystalline structure of cm-chitosan@Fe
shown in Fig. 2a, all of the diffraction peaks can be indexed and assigned to the cubic
structure of Fe , which is in good agreement with the literature values (JCPDS Card No.
8-0315). The characteristic broad reflection around 2θ = 21-23° corresponding to
orthorhombic crystal structure of chitosan (JCPDS Card No. 39-1894) can be seen, obviously
indicating that chitosan was successfully coated on the Fe nano-particles. In the pattern
assigned to magnetite, diffraction peaks at around 18.3°, 30.1°, 35.6°, 37.2°, 43.2°,47.3°,
3.6°, 57.1°, 62.7°, 65.9° and 67.0° correspond to the (111), (220), (311), (222), (400), (311),
422), (511), (440), (531) and (442) reflections, respectively. The large peak widths are
3 4
O was also characterized by XRD analysis. As
3
O
4
8
3
O
4
5
(
ascribed to the formation of nano-sized magnetite particles. The size of particles were
calculated by Debye-Scherrer equation using the (311) peak (2θ = 35.6°) to be 10.4 nm. The
XRD measurements were carried out on a Philips X’Pert diffractometer with CuK
Figure 2 also compares the IR spectrum of cm-chitosan@Fe (Fig. 2b) with that of cm-
chitosan (Fig. 2c). Some absorption bands are common between both the spectra. For
α
radiation.
3
O
4
-1
-1
example, the bands at 1636 cm and 1612 cm could be assigned to the amide C=O
-1
stretching and N-H bending vibrations, respectively. The strong band at around 3420 cm is
due to the O–H stretching vibration, N–H extension vibration and the intermolecular
hydrogen bonds of the polysaccharide moieties. Both the spectra show the characteristic band
-1
at 1737 cm arising from C=O stretching of the carboxylate moiety. However, this band
appeared too weak for cm-chitosan@Fe , due to distribution of intensity between the
3
O
4
vibronic bands of C=O in the region of carboxyl and carboxylate groups and is indicating the
6
Page 6 of 26

depletion of carboxyl groups in the binding reaction with magnetite particles. Another major
-1
difference between the two spectra occurred at around 600 cm and is referred to absorptions
3 4
of Fe-O bonds for cm-chitosan@Fe O .
a
c
d
b
Figure 2. (a) The X-ray diffraction pattern of cm-chitosan@Fe
3 4 3 4
O , (b) the IR spectrum of cm-chitosan@Fe O ,
(
c) the IR spectrum of cm-chitosan and (d) the scanning electron microscopy image of cm-chitosan@Fe O .
3 4
The scanning electron microscopy image shows that the nano-particles of cm-
chitosan@Fe were produced as uniform particles and the average size of the encapsulated
3
O
4
nano-magnetite particles are about 30.5 ± 5.0 nm (Fig. 2d). The obtained histogram
pictorially depicts the narrow normal size distribution of the prepared nano-particles (Fig. 3).
7
Page 7 of 26

Figure 3. The histogram of cm-chitosan@Fe O nano-particles.
3
4
2.4. Typical procedure for synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-one
In a typical procedure for the synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-one, a mixture
3 4
of indole (1 mmol, 0.117 g), isatin (1 mmol, 0.147 g), cm-cellulose@Fe O or cm-
o
chitosan@Fe
3
O
4
(0.015 g) in H
2
O/methanol (1:1, 3 mL) was stirred at 60 C for appropriate
time until disappearance of isatin (monitored by TLC, Table 2). Upon completion of the
reaction, the catalyst was separated from the slurry of solid crude product using an external
magnet and washed with 3 mL of methanol. The liquor methanol and H
2
O (5 mL) were
added to the slurry of the solid product in H O/methanol solution. The solids were then
2
filtered and the filter-cake collected and crystallized from ethanol to afford the pure product.
All of the products produced in this way had physical as well as spectroscopic data very
similar to those of the authentic samples prepared from the previously reported methods
[41,42]. The recovered catalyst was dried at 60 °C before recycling in the same reaction or
using in a new synthesis.
3. Results and discussion
The reaction between isatin 1 and indole 2 is hypothesized to follow two acid-demanding
steps delivering sequentially 3-hydroxy-3-indolyl-2-oxindole 3 and 3,3-diindolyl-2-oxindole
4
(Scheme 2).
8
Page 8 of 26

H
N
O
HO
O +
O
N
N
N
H
H
H
1
2
3
H
N
H
H
N
H
N
N
O
O
N
N
H
H
4
5
Scheme 2. The two-step reaction between isatin and indole in the presence of acidic catalysts
Most acidic catalysts are able to catalyze both steps of isatin indolylation and directly lead to
formation of 3,3-diindolyl-2-oxindoles 4. Thus, restriction of this reaction at its first step in
order for sole production of 3-hydroxy-3-indolyl-2-oxindole derivatives 3 needs mild
catalysts to be applied. In this context, and inspired by plenty of knowledge about the role of
hydroxyl groups in soft catalytic effects of enzymes, we led to examine cellulose as a mild
catalyst to control the synthesis of 3-hydroxy-3-indolyl-2-oxindoles. To test this hypothesis
and to find out the optimal conditions, a mixture of equal quantities (1 mmol) of 2-
methylindole and isatin was initially chosen as the model reaction. For this model reaction,
the effects of different variables such as temperature, solvent and the amount of cellulose
were evaluated in terms of reaction times and yields of the product. Results of these
experiments were shown in Table 1.
a
Table 1. Optimization of the model reaction between 2-methylindole and isatin
H
H
Me
Me
N
N
Me
NH
O
HO
O +
Me
+
O
O
N
N
N
N
H
H
H
H
1
2
3b
4b
Time
Temp.
Yield (%)
b
c
entry
Catalyst
Solvent
--
CH Cl
(min)
(°C)
25
Product 3b
Product 4b
MC cellulose
MC cellulose
100
--
--
1
2
2
2
100
25
--
--
9
Page 9 of 26

3
4
5
MC cellulose
MC cellulose
MC cellulose
CH
3
CN
OH
O
100
100
100
25
25
25
30
42
40
--
--
--
--
CH
3
H
2
d
d
d
d
d
d
d
d
d
d
d
25
60
80
60
6
7
8
9
MC cellulose
MC cellulose
MC cellulose
H O:CH OH
100
100
100
15
45
54
57
88
89
35
42
61
92
92
31
2
3
trace
9
H O:CH OH
2
3
H O:CH OH
2
3
e
--
cm-cellulose@Fe O
3
4
2 3
H O:CH OH
cm-cellulose@Fe
3
O
4
/0.020 g
60
--
1
0
1
2
3
4
5
6
H O:CH OH
15
2
3
60
60
60
60
60
80
1
1
1
1
1
1
Fe (NPs)
3
O
4
H O:CH OH
100
100
100
15
23
11
2
3
f
MC cellulose + Fe O
3
4
2 3
H O:CH OH
trace
--
Chitosan
2 3
H O:CH OH
cm-chitosan@Fe
3
O
4
2 3
H O:CH OH
--
cm-chitosan@Fe
--
3
O
4
/0.020 g
H O:CH OH
15
2
3
24
H O:CH OH
2
3
15
a
b
The reaction was carried out with 1 mmol of each of the reactants. MC cellulose stands for microcrystalline
c
d
e
cellulose. The amount of 3 mL in each case was used. A 1:1 (v/v) solution. Carboxymethyl cellulose-grafted
magnetite. A simple mixture of MC cellulose (0.0075 g) and nano-magnetite (0.0075 g) was used. In each case
f
0
.015 g of catalyst was used, except otherwise stated in the Table. This amount is optimum for cm-
cellulose@Fe and cm-chitosan@Fe
3
O
4
3 4
O .
As this Table shows, microcrystalline cellulose explicitly catalyzes the reaction, giving
selectively 3-hydroxy-3-(2-methylindol-3-yl)-2-oxindole in moderate yields. Both the rate
and yield of this reaction increases by increasing the loading of cellulose. These observations
are in support of a surface catalysis role for cellulose through which the reactants adsorbed on
surface of cellulose become softly activated by the pendant hydroxyl groups. Very likely,
isatin is adsorbed mainly by hydrogen bonding with the hydroxyl groups forcing it to stack
on top of the catalyst where it gets protected from downside nucleophilic attack. Under this
situation, the activated isatins undergo nucleophilic addition from the outer side by indoles to
afford 3-hydroxy-3-indolyl-2-oxindoles. Hydrogen bonding with cellulose oxygen atoms may
also enhance the nucleophilic activity of indoles (Scheme 3). The product is expected to
remain adsorbed on cellulose by virtue of hydrogen bonding of its hydroxyl group and hence
being protected from further reaction with indoles. In addition, cellulose is not acidic enough
to render dehydration of products and to yield azafulvalenes 5, which are suspected
intermediates in the formation of 3,3-diindolyl-2-oxindoles. Table 1 also reveals the impact
of selected solvents on progress of the model reaction, presumably by influencing the
position of adsorption equilibria of products. Polar solvents would tend to displace the
adsorption equilibria of products in favor of solution side and therefore disrobe more catalytic
1
0
Page 10 of 26

sites on surface of cellulose for the reaction of isatins and indoles. The 1:1 solution of
methanol and water gave the best result in terms of yield and reaction time (entry 6). The
efficiency of this solvent system may be attributed to its ability in removal of products from
the surface of cellulose and making the product precipitate from solution before having the
chance to undergo further reaction with another indole molecule. Pure water, however,
appeared as an inefficient solvent (entry 5) throughout the optimization experiments, perhaps
due to its inability to leach the adsorbed products from cellulose and also for negligible
organic mass transfer by this solvent. After determining the 1:1 methanol-water solution as
the optimal solvent, we aimed at improving the catalytic efficiency of cellulose whilst
maintaining its mildness and selectivity. A prime strategy to achieve this goal is to increase
the surface to mass ratio of cellulose particles. The surface hydroxyl groups of cellulose are
very active and those which are concealed within its hierarchical structure can not participate
in the catalytic process. An intuitive approach for increasing the surface of cellulose is
hydrolytic cracking of its fibers into nano-scales. It is known that hydrolysis of cellulosic
fibrils mainly occurs at their more reactive amorphous regions, whereupon the crystalline
nano-sized parts, namely nano-whiskers, remain intact. However, this process is more
laborious and the minute amounts of nano-whiskers obtained in this way tend to aggregate by
hydrogen bonding with each other on drying [43]. These limitations led us to use the readily
available microcrystalline cellulose (MCC), which is a known crystalline pack of nano-
crystalline and microfibril cellulosic mass. To have an increased catalytic surface, we
attempted to partially interrupt the crystalline structure of MCC by binding its
carboxymethylated ingredients to nano-sized magnetite particles. As the scanning electron
microscopy image shows (Fig. 1b), the resulting composite consists of nano-structured
regions and small flakes of cellulose fibers blended with the nano-sized cm-cellulose grafted
magnetite (CGM). This modification provided an artificial morphology with extended surface
for cellulose and as expected gave rise to a greater activity for this catalyst (Table 1, entry 9).
Separate experiments have ruled out the initially argued involvement of magnetite nano-
particles, as the main or co-catalyst, in catalysis of the reaction. Pure magnetite nano-particles
(entry 11) and their simple mixture with MCC (entry 12) have not appeared as efficient as
CGM in catalysis of the model reaction. Grafting to nano-magnetite also make the nano-sized
cellulose particles easily separable from the reaction mixtures by using simple permanent
magnets.
1
1
Page 11 of 26

H
N
N
O
N H
H
N
O
H
O
H
O
H
O
H
H
H
X
X
O
O
O
O
O
O
O
O
O
O
O
OH
O
XH
O
O
O
O
O
HO
O
HO
O
O
O
O
O
X = NH or O
Fe O
Fe O
3 4
3
4
Scheme 3. A proposed push-pull proton donating and accepting mechanism for cm-cellulose@magnetite (X =
O) and for cm-chitosan@Fe (X= NH) catalysis.
3
O
4
Our next attention was turned toward examining the catalytic activity of chitosan as a close
derivative of cellulose. Interestingly, chitosan was found as efficient catalyst as MCC and
selectively catalyzed the model reaction to give a moderate yield (Table 1, entry 13) of the
product 3b. As in the case of cellulose, better results in terms of yield and reaction time were
obtained by using carboxymethyl chitosan-coated magnetite nano-particles (cm-
3 4
chitosan@Fe O , entry 14). The nano-particles were prepared by carboxymethylation of
chitosan at the hydroxyl groups of the pyranosyl units and covalent binding of the resultant
carboxymethyl chitosan (cm-chitosan) to magnetite nano-particles, according to a reported
procedure [36]. Chitosan is soluble in aqueous media at pH<6, hence, grafting of chitosan to
magnetite nano-particles also makes its separation easy from even acidic media. The model
3 4
reaction in dichloromethane solution and in the presence of cm-chitosan@Fe O only
o
furnished a trace amount of desired product at 60 C. The yield could be increased by
increasing the polarity of solvent, for instance 86% by using methanol as solvent. However,
inferior yields were obtained with acetonitrile or water in the presence of cm-
chitosan@Fe
were determined as the optimal conditions for this model catalytic reaction (entry 14). The
supremacy of cm-chitosan@Fe with respect to cm-cellulose@Fe in catalysis of the
reaction can be ascribed to its uniform nano-structure and hence to its greater surface to mass
3 4
O . Accordingly, a 1:1 mixture of methanol and water, as solvent, and 60 °C
3
O
4
3 4
O
ratio (Fig. 2d). Therefore, cm-chitosan@Fe
reaction of indole and isatin derivatives.
3 4
O was selected as the optimal catalyst for the
Various derivatives of indole and isatin underwent the Friedel-Crafts reaction under catalysis
of cm-chitosan@Fe to selectively deliver the expected adducts 3a-f in fairly high yields
and in short reaction times (Table 2). Electron-donating or electron-accepting substituents on
3
O
4
1
2
Page 12 of 26

5-position of isatin induce no sensible variations on the rates and yields of formation of the
products 3a-f. Noteworthy, TLC monitoring displayed that in the confident times determined
for the reactions (Table 2) no considerable amounts of 3,3-diindolyl-2-oxindoles were
formed, subject to restricting the molar ratio of indoles to isatins not exceed 1.5.
a
Table 2. The synthesis of 3-hydroxy-3-indolyl-2-oxindole derivatives.
H
N
R2
O
R1
HO
1
cm-chitosan@ Fe O R
3
4
R2
O
+
o
O
6
0 C, H O: MeOH
N
N
2
N
H
H
H
1
2
3a-f
c
Yield
%)
1
2
M.p.
( C)
Entry
R
R
Product
o
(
H
N
HO
8
8
2
7
9
6
3
a
H
H
H
293-295
183-185
206-209
176-179
188-201
O
N
H
H
Me
HO
N
9
8
8
8
3
b
Me
H
O
N
H
H
N
HO
3
c
Cl
Cl
Br
Cl
O
O
O
N
H
H
N
Me
HO
3
d
Me
H
Cl
Br
N
H
H
N
HO
3
e
N
H
1
3
Page 13 of 26

H
Me
HO
N
9
0
3
f
Br
Me
Br
134-137
O
N
H
a
°
3 4
The reaction conditions: 1 mmol of each reactant in the presence of 0.015 g of cm-chitosan@Fe O at 60 C in
b
c
3
2
mL of H O/MeOH (1:1). The reactions were completed in around 15 min. Isolated yield.
Cellulose and magnetite are widely spread in nature and chitosan is produced from chitin, the
second most abundant polysaccharide on earth, so are regarded as highly biocompatible
materials. Nevertheless, the sustainability of the present synthetic method was proved by
checking the feasibility of the catalyst recovering. At the end of the reaction between 2-
methylindole and isatin, the catalyst was removed by using an external magnet, washed with
methanol and dried at 60 °C before application in the next cycle with a mixture of fresh 2-
methylindole and isatin. These experiments show that the catalyst preserves its activity even
after 7 recycling and indicate the OH groups arranged on surface of the supported catalyst do
not participate in any side transformation (Table 3).
Table 3. Recycling of the catalyst cm-chitosan@Fe
3
O
4
and the yield of the model reaction
The recycle
Yield (%)
Fresh
92
91
91
89
89
89
88
89
1
2
3
4
5
6
7
Reaction conditions: isatin(1 mmol), 2-methylindole(1 mmol), the catalyst (0.015 g), and H
solvent (3 mL) at 60 C.
2
O/MeOH (1:1) as
°
A comparison between cm-cellulose@Fe
for synthesis of 3-hydroxy-3-indolyl-2-oxindole, was made in Table 4. This table represents
cm-cellulose@Fe as an alternative effective catalyst for selective indolylation of isatins.
3 4
O and some familiar catalysts, previously reported
3
O
4
However tetramethylguanidinium triflate (TMGTf, entry 1) is a remarkably efficient catalyst
for delivering relatively high yield of the product, particularly at room temperature, it is
expensive and its recovery after workup from aqueous extract is an energy consuming
1
4
Page 14 of 26

process. Other catalysts either result in lower reaction rates (entries 2-5) or create harsh
conditions (entry 3). β-cyclodextrin is an efficient homogeneous catalyst for this reaction,
however, separation of this neutral catalyst from the reaction mixture is not as easy as the
2 3
magnetic nano-particles. The aqueous solutions of K CO or ZnO (entries 2,3) have the
advantages of being cheap and effective catalysts for this reaction, but selectivity of these
catalysts, unlike cm-chitosan@Fe
they provide.
3 4 3 4
O and cm-cellulose@Fe O , is due to the basic conditions
3 4
Table 4. A comparison between cm-chitosan@Fe O and some known catalysts used for synthesis of
3
-hydroxy-3-indolyl-2-oxindole.
Entry
Catalyst/conditions
Time
5 min
Yield
96%
92%
95%
93%
92%
92 %
88 %
Ref.
1
2
3
4
5
6
TMGTf/ r.t.
41
42
K
2
CO
ZnO/H
β-CD/ H
Kaolin/ KOH / r.t.
cm-chitosan@Fe / MeOH:H
2
cm-cellulose@Fe / MeOH:H O /60 °C
3
/ H
O /80 °C
O /40 °C
2
O / r.t.
70 min
90 min
50 min
150 min
15 min
15 min
2
44
2
32
45
a
3
O
4
2
O /60 °C
This work
This work
a
7
3
O
4
a
Reaction was conducted with 15 mg of the catalyst and 1 mmol of each of the reactants.
4. Conclusion
In summary, cellulose and chitosan were found as mild catalysts for indolylation of isatins in
the neutral medium of methanol-water solution. Surprisingly, the reaction stops at the first
step to selectively give 3-indolyl-3-hydroxy-2-oxindoles. Better results in terms of reaction
times and yields were obtained by grafting carboxymethyl cellulose or carboxymethyl
chitosan to magnetite nano-particles. Scanning electron microscopy images displayed nano-
dimentional regions on surface of the grafted cellulose which are supposed to provide an
extended surface for catalysis. Grafting of carboxymethyl chitosan to magnetite nano-
particles provided uniform nano-sized particles and as expected led to greater catalytic
activity than chitosan and even carboxymethyl cellulose-grafted magnetite. The catalysis is
suggested to be effected by the aid of proton-donating and proton-accepting capacity of the
hydroxyl groups arranged on surface of the cellulosic coatings. The hypothesis of magnetite
role as the main or a co-catalyst in these catalytic systems was ruled out. It was shown that
3 4
magnetite nano-particles are not as effective as cm-chitosan@Fe O in catalyzing the
1
5
Page 15 of 26

indolylation of isatins. Various isatins and indoles were employed to show the efficiency of
the present method for selective synthesis of 3-indolyl-3-hydroxy-2-oxindoles.
Acknowledgment
We gratefully acknowledge the financial support of this work by the Research Council of
University of Guilan.
References
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1
7
Page 17 of 26

OH
2
CO H
O
O
NaOH (aq)
O
O
HN
C NH
O
HO
O
HO
O
O
n
Cl
n
X
OH
X
HN
X = OH or NH
2
NH
2
O
O
Fe
O
3 4
O
O
O
O
O
Fe O
3
4
OH
O
O
HO
O
HO
O
O
-
Urea
n
n
X
X
Scheme 1. Preparation of cm-cellulose@Fe O and cm-chitosan@Fe O nano-particles
3
4
3
4
1
8
Page 18 of 26

a
b
d
c
Figure 1. (a) The X-ray diffraction pattern, (b) the scanning electron microscopy image, (c) and the IR spectrum
of cm-cellulose@Fe . (d) The IR spectrum of cm-cellulose.
3
O
4
1
9
Page 19 of 26

a
c
d
b
Figure 2. (a) The X-ray diffraction pattern of cm-chitosan@Fe
3 4 3 4
O , (b) the IR spectrum of cm-chitosan@Fe O ,
(
c) the IR spectrum of cm-chitosan and (d) the scanning electron microscopy image of cm-chitosan@Fe O .
3 4
2
0
Page 20 of 26

Figure 3. The histogram of cm-chitosan@Fe O nano-particles.
3
4
H
N
O
HO
O +
O
N
N
N
H
H
H
1
2
3
H
N
H
H
N
H
N
N
O
O
N
N
H
H
4
5
Scheme 2. The two-step reaction between isatin and indole in the presence of acidic catalysts
2
1
Page 21 of 26

a
Table 1. Optimization of the model reaction between 2-methylindole and isatin
H
H
Me
Me
N
N
Me
NH
O
HO
O +
Me
+
O
O
N
N
N
N
H
H
H
H
1
2
3b
4b
Time
Temp.
Yield (%)
b
c
entry
1
Catalyst
Solvent
(min)
(°C)
25
Product 3b
Product 4b
MC cellulose
--
CH Cl
CH
CH
100
--
--
2
3
4
5
MC cellulose
MC cellulose
MC cellulose
MC cellulose
2
2
100
100
100
100
25
25
25
25
--
--
--
--
--
--
3
CN
OH
O
30
42
40
3
H
2
d
25
60
80
60
6
7
8
9
MC cellulose
MC cellulose
MC cellulose
H O:CH OH
100
100
100
15
45
54
57
88
89
35
42
61
92
92
31
2
3
d
d
d
d
d
d
d
d
d
d
trace
9
H O:CH OH
2
3
H O:CH OH
2
3
e
--
cm-cellulose@Fe O
3
4
2 3
H O:CH OH
cm-cellulose@Fe
3
O
4
/0.020 g
60
--
10
11
12
13
14
15
16
H O:CH OH
15
2
3
60
60
60
60
60
80
Fe (NPs)
3
O
4
H O:CH OH
100
100
100
15
23
11
2
3
f
MC cellulose + Fe O
3
4
2 3
H O:CH OH
trace
--
Chitosan
2 3
H O:CH OH
cm-chitosan@Fe
3
O
4
2 3
H O:CH OH
--
cm-chitosan@Fe
--
3
O
4
/0.020 g
H O:CH OH
15
2
3
24
H O:CH OH
2
3
15
a
b
The reaction was carried out with 1 mmol of each of the reactants. MC cellulose stands for microcrystalline
c
d
e
cellulose. The amount of 3 mL in each case was used. A 1:1 (v/v) solution. Carboxymethyl cellulose-grafted
magnetite. A simple mixture of MC cellulose (0.0075 g) and nano-magnetite (0.0075 g) was used. In each case
f
0
.015 g of catalyst was used, except otherwise stated in the Table. This amount is optimum for cm-
cellulose@Fe and cm-chitosan@Fe
3
O
4
3 4
O .
2
2
Page 22 of 26

H
N
N
O
N H
H
N
O
H
O
H
O
H
O
H
H
H
X
X
O
O
O
O
O
O
O
O
O
O
O
OH
O
XH
O
O
O
O
O
HO
O
HO
O
O
O
O
O
X = NH or O
Fe O
Fe O
3 4
3
4
Scheme 3. A proposed push-pull proton donating and accepting mechanism for cm-cellulose@magnetite (X =
O) and for cm-chitosan@Fe (X= NH) catalysis.
3
O
4
2
3
Page 23 of 26

a
Table 2. The synthesis of 3-hydroxy-3-indolyl-2-oxindole derivatives.
H
N
R2
O
R1
HO
1
cm-chitosan@ Fe O R
3
4
O
+
R2
o
O
6
0 C, H O: MeOH
N
N
2
N
H
H
H
1
2
3a-f
c
Yield
%)
1
2
M.p.
( C)
Entry
R
R
Product
o
(
H
N
HO
8
8
2
7
9
6
0
3
a
H
H
H
293-295
183-185
206-209
176-179
188-201
134-137
O
N
H
H
Me
HO
N
9
8
8
8
9
3
b
Me
H
O
N
H
H
N
HO
3
c
Cl
Cl
Br
Br
Cl
O
O
O
O
N
H
H
N
Me
HO
3
d
Me
H
Cl
Br
Br
N
H
H
N
HO
3
e
N
H
H
N
Me
HO
3
f
Me
N
H
a
°
3 4
The reaction conditions: 1 mmol of each reactant in the presence of 0.015 g of cm-chitosan@Fe O at 60 C in
mL of H O/MeOH (1:1). The reactions were completed in around 15 min. Isolated yield.
2
b
c
3
2
4
Page 24 of 26

Table 3. Recycling of the catalyst cm-chitosan@Fe O and the yield of the model reaction
3
4
The recycle
Yield (%)
Fresh
92
91
91
89
89
89
88
89
1
2
3
4
5
6
7
Reaction conditions: isatin(1 mmol), 2-methylindole(1 mmol), the catalyst (0.015 g), and H
solvent (3 mL) at 60 C.
2
O/MeOH (1:1) as
°
3 4
Table 4. A comparison between cm-chitosan@Fe O and some known catalysts used for synthesis of
3
-hydroxy-3-indolyl-2-oxindole.
Entry
Catalyst/conditions
Time
5 min
Yield
96%
92%
95%
93%
92%
92 %
88 %
Ref.
1
2
3
4
5
6
TMGTf/ r.t.
41
42
K
2
CO
ZnO/H
β-CD/ H
Kaolin/ KOH / r.t.
cm-chitosan@Fe / MeOH:H
2
cm-cellulose@Fe / MeOH:H O /60 °C
3
/ H
O /80 °C
O /40 °C
2
O / r.t.
70 min
90 min
50 min
150 min
15 min
15 min
2
44
2
32
45
a
3
O
4
2
O /60 °C
This work
This work
a
7
3
O
4
a
Reaction was conducted with 15 mg of the catalyst and 1 mmol of each of the reactants.
2
5
Page 25 of 26

Graphical Abstract
Application of cellulose/chitosan grafted nano-magnetites as efficient and
recyclable catalysts for selective synthesis of 3-indolylindolin-2-ones
Kurosh Rad-Moghadam* and Negin Dehghan
H
O
H
X
O
Z
O
O
O
O
O +
R
O
OH
O
N
H
N
H
O
O
HO
O
O
O
X = NH or O
H
R
N
Fe O
3
4
HO
Z
O
N
H
2
6
Page 26 of 26