Cu-isatin schiff base complex supported on magnetic nanoparticles as an efficient and recyclable catalyst for the synthesis of bis(indolyl)methanes and bis(pyrazolyl)methanes in aqueous media

Article abstract of DOI:10.1016/j.jorganchem.2016.08.021

Cu-isatin Schiff base supported on γ-Fe₂O₃as a new catalyst was synthesized and characterized by different methods such as SEM, TEM, XRD, TGA, FT-IR, ICP, VSM and CHN analysis. It was used as a reusable heterogeneous catalyst for the

Full text of DOI:10.1016/j.jorganchem.2016.08.021

Accepted Manuscript
Cu-isatin schiff base complex supported on magnetic nanoparticles as an
efficient and recyclable catalyst for the synthesis of bis(indolyl)methanes and
bis(pyrazolyl)methanes in aqueous media
Sara Sobhani, Solmaz Asadi, Mehri Salimi, Farzaneh Zarifi
PII:
S0022-328X(16)30355-2
10.1016/j.jorganchem.2016.08.021
JOM 19600
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 22 March 2016
Revised Date: 29 July 2016
Accepted Date: 23 August 2016
Please cite this article as: S. Sobhani, S. Asadi, M. Salimi, F. Zarifi, Cu-isatin schiff base complex
supported on magnetic nanoparticles as an efficient and recyclable catalyst for the synthesis of
bis(indolyl)methanes and bis(pyrazolyl)methanes in aqueous media, Journal of Organometallic
Chemistry (2016), doi: 10.1016/j.jorganchem.2016.08.021.
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ACCEPTED MANUSCRIPT
O
R2
2
R1
N
2
+
RCHO
O
R
+
R4
R5
N
N
R3
Ph
O
O
O
O
O
N
SiCH2CH2CH2
Cl
Cu
Cl
γ-Fe2O3
O
O
O
R5
N
SiCH2CH2CH2
R4
R2
N
N
Ph
2
N
R1
N
N
R3
OH
HO
Ph
19 examples
0.5-5 h
80-98 %
14 examples
25-50 min
85-97 %

ACCEPTED MANUSCRIPT
Cu-isatin schiff base complex supported on magnetic nanoparticles as an efficient and
recyclable catalyst for the synthesis of bis(indolyl)methanes and bis(pyrazolyl)methanes in
aqueous media
Sara Sobhani,* Solmaz Asadi, Mehri Salimi, Farzaneh Zarifi
Department of Chemistry, College of Sciences, University of Birjand, Birjand, Iran
E-mail addresses: ssobhani@birjand.ac.ir, sobhanisara@yahoo.com
ABSTRACT
Cu-isatin Schiff base supported on γ-Fe2O3 as a new catalyst was synthesized and characterized
by different methods such as SEM, TEM, XRD, TGA, FT-IR, ICP, VSM and CHN analysis. It
was used as a reusable heterogeneous catalyst for the efficient synthesis of bis(indolyl)methanes
(TON = 320-392) and bis(pyrazolyl)methanes (TON = 340-388) in aqueous media. The catalyst
was easily removed from the reaction mixture using an external magnet and reused eight times
without any significant loss of its reactivity.
Keywords: Heterogeneous catalyst; Copper; Bis(indolyl)methanes; Bis(pyrazolyl)methanes; Iron
oxide; Water.
1. Introduction
Nowadays, green consciousness encourages the chemical community to the search for more
environmentally friendly processes for organic syntheses. In this context, development of new
heterogeneous recyclable catalysts and the use of less toxic materials as solvents and reagents
are two important challenging issues. The use of water as a cheap and safe solvent instead of
expensive, flammable and toxic organic solvents reduces environmental damages caused by
organic solvents. In addition, conducting the reactions in aqueous media caused easy phase
separation of products because most of the organic compounds are not soluble in water [1,2].
Replacement of homogeneous catalysts with heterogeneous analogs, which can be easily
recovered from the reaction mixture eliminates the need for separation through distillation or
extraction [3]. Supporting of homogeneous catalysts is a powerful tool in the development of
heterogeneous catalysts. In recent years, magnetite nanoparticles (MNPs) have been considered
*Corresponding author. Department of Chemistry, College of Sciences, University of Birjand,
Birjand, Iran. Tel.: +985632202065; fax: +985632202065.
E-mail addresses: ssobhani@birjand.ac.ir, sobhanisara@yahoo.com
1

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as excellent and ideal supports among different supporting materials, for the synthesis of
heterogeneous catalysts [4-6]. The magnetic nature of MNPs allows the ease of separation,
recovery and reuse of the catalysts by an external magnetic field, without using any filtration or
centrifusion methods, which optimizes operational cost and enhances products purity [7].
Moreover, because of the available surface area of the MNPs is external, their catalytic
performance is enhanced and the internal diffusion is practically avoided. Furthermore, MNPs
are chemically stable and can be prepared by simple methods from readily available materials
[8-15].
Bis(indolyl)methanes have attracted much interest due to their importance as potential
antibacterial and antitumor reagents and their broad applications in material sciences,
pharmaceutical and agrochemical industries [16-19]. They are useful in the treatment of
fibromyalgia, chronic fatigue and irritable bowel syndrome [20,21] and as dietary supplements
for promoting healthy estrogen metabolism in humans [22]. The presence of important indole
ring units in bis(indolyl)methanes makes them as a useful intermediates for interesting organic
transformations [23]. As a result of their biological and synthetic importance, a number of
methods for the preparation of bis(indolyl)methanes by the electrophilic substitution reaction of
indole with various carbonyl compounds in the presence of a catalyst have been reported in the
literature [24-32]. However, most of the existing methods involve toxic metal ions, solvents or
need cumbersome work-up procedures. Some of them cause environmental pollution because of
the difficult catalyst separation from the reaction medium. Moreover, the reactions often require
long reaction times, give moderate yields of the products or are amenable only for aldehydes as
carbonyl compounds. Consequently, new procedures that address these drawbacks are desirable.
Pyrazoles are important classes of heterocyclic compounds that occur widely in the
pharmaceutical industry. They are the core structure of numerous biologically active compounds
[33,34]. For example, 2,4-dihydro-3H-pyrazol-3-one structural motif including 4,4΄-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) are being used as antiinflammatory,
antipyretic, gastric secretion stimulatory, antidepressant, antibacterial and antifilarial agents [35-
38]. Moreover, they are applied as important intermediates in organic synthesis [39] and as bis-
Schiff bases [40]. They also play an important role in analytical chemistry as chelating and
extracting reagents for different metal ions, catalysis, dye and extraction metallurgy [41-46].
Main synthetic method for the preparation of 4,4΄-(arylmethylene)-bis(3-methyl-1-phenyl-1H-
pyrazol-5-ols) is based on the condensation of aldehydes with 3-methyl-1-phenyl-5-pyrazolone.
A variety of catalysts and reagents have been used to facilitate this reaction [47-54]. Even
though these procedures provide an improvement in the synthesis of these compounds, many of
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ACCEPTED MANUSCRIPT
them suffer from limitations such as tedious work-up procedures and using hazardous solvents
or unrecyclable catalysts and the need of excess amounts of the reagent. Therefore, from the
standpoint of environmentally benign organic synthesis, the development of highly active and
easily reusable heterogeneous catalyst for the synthesis of these important scaffolds in aqueous
media is still in demand.
In the course of an investigation targeted towards the achievement of more environmentally
friendly protocols, we have recently introduced new heterogeneous catalysts for various organic
transformations [55-66]. In this regard, herein, we report the synthesis and characterization of
Cu-isatin Schiff base complex immobilized on γ-Fe2O3 (Cu-isatin Schiff base-γ-Fe2O3). We have
used it as a new efficient and reusable heterogeneous catalyst for the synthesis of
bis(indolyl)methanes and bis(pyrazolyl)methanes in aqueous media.
2. Experimental
2.1. General
Chemicals were purchased from Merck Chemical Company. NMR spectra were recorded in
ppm in CDCl3 and DMSO on a Bruker Avance DPX-300, 400 and 500 instrument using TMS
as internal standard. The purity of the products and the progress of the reactions were
accomplished by TLC on silica-gel polygram SILG/UV254 plates. The morphology of the
products was determined by using Hitachi Japan, model s4160 Scanning Electron Microscopy
(SEM) at accelerating voltage of 15 KV. TEM analysis was performed using TEM microscope
(philips CM30). Power X-ray diffraction (XRD) was performed on a Bruker D8-advance X-ray
diffractometer or on a X’Pert Pro MPD diffractometer with Cu Kα (λ = 0.154 nm) radiation.
Thermo gravimetric analysis (TGA) was performed using a Shimadzu thermo gravimetric
analyzer (TG-50). FT-IR spectra were recorded on a JASCO FT-IR 460 plus spectrophotometer.
The content of Cu in the catalyst was detemined by OPTIMA 7300DV ICP analyzer. Elemental
analysis was carried out on a Costech 4010 CHN elemental analyzer. Room temperature
magnetization isotherms were obtained using a vibrating sample magnetometer (VSM, Lake
Shore 7400).
2.2. Synthesis of γ-Fe2O3 supported with isatin (isatin Schiff base-γ-Fe2O3)
The synthesized amino-functionalized γ-Fe2O3 [67] (3 g) was sonicated in absolute ethanol (50
mL) for 30 min. Isatin (1.9 g, 13 mmol) was added slowly to the sonicated mixture and stirred at
80 °C for 24 h. The resulting mixture was cooled to room temperature. The solid was separated
by an external magnet, washed with EtOH (3 × 10 mL) and Et2O (3 × 10 mL) and dried at 50 °C
in oven under vacuum.
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2.3. Synthesis of copper-isatin complex supported on γ-Fe2O3 (Cu-isatin Schiff base-γ-Fe2O3)
Isatin Schiff base-γ-Fe2O3 (3 g) was added to a solution of CuCl2.2H2O (0.21 g) in MeOH (30
mL). The reaction mixture was stirred at room temperature for 24 h. After stirring, the solid was
separated by an external magnet, and washed with MeOH (3 × 10 mL) and Et2O (3 × 10 mL). It
was then dried in an oven at 80 °C overnight to furnish Cu-isatin Schiff base-γ-Fe2O3.
2.4. General procedure for the synthesis of bis(indolyl)methanes
A mixture of carbonyl compound (1 mmol), indole (2 mmol) and Cu-isatin Schiff base-γ-Fe2O3
(0.25 mol%) in water (5 mL) was stirred at 80 °C for the appropriate reaction time (Table 2).
EtOAc (10 mL) was added to the reaction mixture. The catalyst was separated by a magnetic
bar, dried and reused for a consecutive run under the same reaction conditions. The organic layer
was separated and evaporated under reduced pressure to give the crude product. The crude
product was purified by recrystallization in EtOH/H2O.
4a: 1H NMR (300 MHz, CDCl3): δ 5.92 (s, 1H), 6.65 (s, 2H), 7.05 (t, 2H, J = 7.2 Hz), 7.18-7.45
(m, 9H), 7.87 (s, 2H, NH) ppm; 13C NMR (75 MHz, CDCl3): δ 40.2, 111.2, 119.2, 119.6, 119.9,
121.9, 123.7, 126.2, 127.1, 128.3, 128.8, 136.7, 144.1 ppm.
4b: 1H NMR (400 MHz, CDCl3): δ 2.09 (s, 6H), 6.04 (s, 1H), 6.88 (t, 2H, J = 8.0 Hz), 7.01 (d,
13
2H, J = 8.0 Hz), 7.06 (t, 2H, J = 7.6 Hz), 7.23-7.32 (m, 7H), 7.76 (s, 2H, NH) ppm; C NMR
(100 MHz, CDCl3): δ 12.4, 39.2, 109.9, 113.4, 119.0, 119.3, 120.6, 125.9, 128.1, 129.0, 129.1,
131.8, 135.0, 143.7, 181.4 ppm.
4c: 1H NMR (400 MHz, DMSO-d6): δ 5.89 (s, 1H), 6.92 (s, 2H), 7.17-7.24 (m, 3H), 7.30-7.37
13
(m, 6H), 7.46 (s, 2H), 11.10 (s, 2H, NH) ppm; C NMR (100 MHz, DMSO-d6): δ 39.4, 111.4,
114.1, 118.1, 121.7, 123.9, 125.7, 126.5, 128.7, 128.9, 135.7, 144.8 ppm.
4d: 1H NMR (400 MHz, CDCl3): δ 6.03 (s, 1H), 6.72 (s, 2H), 7.06 (t, 2H, J = 7.6 Hz), 7.23 (t,
2H, J = 8.4 Hz), 7.37 (d, 2H, J = 7.6 Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.55 (d, 2H, J = 6.4 Hz), 8.05
(brs, 2H, NH), 8.17 (d, 2H, J = 8.8 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ 40.2, 111.2, 118.1,
119.5, 119.6, 122.3, 123.6, 126.6, 129.5, 136.7, 146.5, 151.8 ppm.
4e: 1H NMR (400 MHz, DMSO-d6): δ 6.43 (s, 1H), 6.79 (s, 2H), 6.91 (t, 2H, J = 7.6 Hz), 7.08 (t,
2H, J = 7.6 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.2 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.48
(t, 1H, J = 7.2 Hz), 7.58 (t, 1H, J = 7.2 Hz), 7.90 (d, 1H, J = 8.0 Hz), 10.94 (2H, s, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 34.6, 112.1, 116.5, 119.0, 119.1, 121.6, 124.4, 124.6, 126.8,
128.0, 131.0, 133.0, 137.1, 138.2, 150.0 ppm.
4f: 1H NMR (400 MHz, DMSO-d6): δ 6.23 (s, 1H), 6.77 (s, 2H) 6.90 (t, 2H, J = 7.6 Hz), 7.07 (t,
2H, J = 8.2 Hz), 7.22–7.30 (5H, m), 7.38 (d, 2H, J = 8.0 Hz), 7.47–7.49 (1H, m), 10.89 (s, 2H,
13
NH) ppm; C NMR (100 MHz, DMSO-d6): δ 36.6, 112.1, 117.0, 118.9, 119.1, 121.5, 124.5,
127.0, 127.4, 128.2, 129.7, 130.7, 133.2, 137.1, 142.3 ppm.
4

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4g: 1H NMR (400 MHz, DMSO-d6): δ 5.87 (s, 1H), 6.85 (s, 2H), 6.89 (t, 2H, J = 7.6 Hz), 7.06
13
(t, 2H, J = 7.2 Hz), 7.28 (d, 2H, J = 7.6 Hz), 7.32–7.39 (6H, m), 10.87 (s, 2H, NH) ppm; C
NMR (100 MHz, DMSO-d6): δ 39.4, 111.9, 118.0, 118.7, 119.5, 121.4, 124.1, 126.9, 128.4,
130.6, 130.7, 137.0, 144.5 ppm.
4h: 1H NMR (400 MHz, CDCl3): δ 6.86 (s, 1H), 6.92 (s, 2H), 7.06 (t, 2H, J = 8.0 Hz), 7.15-7.19
(m, 2H), 7.21 (t, 2H, J = 8.4 Hz), 7.41 (d, 5H, J = 8.8 Hz), 8.02 (s, 2H, NH) ppm; 13C NMR (100
MHz, CDCl3): δ 37.2, 111.1, 115.2, 119.3, 119.4, 119.6, 121.8, 124.5, 127.1, 128.1, 128.2,
136.3, 138.5 ppm.
4i: 1H NMR (400 MHz, DMSO-d6): 2.27 (s, 3H), 5.80 (s, 1H), 6.83 (s, 2H), 6.88 (t, 2H, J = 7.2
Hz), 7.03-7.10 (m, 4H), 7.25-7.30 (m, 4H), 7.37 (d, 2H, J = 7.6 Hz), 10.82 (s, 2H, NH) ppm;
4j: 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 5.78 (s, 1H), 6.80 (s, 2H), 6.82-6.89 (m, 4H),
7.04 (t, 2H, J = 7.6 Hz), 7.26 (d, 2H, J = 5.6 Hz), 7.28 (d, 2H, J = 5.4 Hz) 7.35 (d, 2H, J = 8.0
Hz), 10.81 (s, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 39.3, 55.3, 111.9, 113.8, 118.6,
118.9, 119.6, 121.3, 123.9, 127.1, 129.7, 137.1, 137.4, 157.8 ppm.
4k:1H NMR (300 MHz, CDCl3): δ 6.14 (s, 1H), 6.92-7.37 (m, 13H), 10.88 (s, 2H, NH) ppm; 13C
NMR (75 MHz, CDCl3): δ 35.3, 111.9, 118.5, 118.7, 119.5, 121.4, 123.7, 124.2, 125.1, 126.8,
136.9, 150.0, 162.8 ppm;
4l:1H NMR (300 MHz, CDCl3): δ 5.89 (s, 1H), 6.10 (s, 1H), 6.37 (s, 1H), 6.89 (t, 2H, J = 7.5
13
Hz), 7.04-7.06 (m, 4H), 7.33-7.41 (m, 4H), 7.54 (s, 1H), 10.88 (s, 2H, NH) ppm; C NMR (75
MHz, CDCl3): δ 34.0, 106.2, 110.6, 111.9, 116.1, 118.7, 119.4, 121.3, 123.7, 126.8, 136.8,
141.7, 158.0 ppm;
4m: 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 3.61 (s, 3H), 6.86 (s, 2H), 7.05 (s, 4H), 7.27
13
(d, 2H, J = 7.2 Hz), 7.37 (d, 2H, J = 7.2 Hz), 10.95 (s, 2H, NH) ppm; C NMR (100 MHz,
DMSO-d6): 26.5, 46.2, 52.3, 112.1, 118.1, 118.7, 120.8, 121.2, 123.7, 126.2, 137.3, 175.7 ppm.
2.5. General procedure for the synthesis of bis(pyrazolyl)methanes
A mixture of aldehyde (1 mmol), 1-phenyl-3-methyl-5-pyrazolone (2 mmol) and the catalyst
(0.25 mol%) in water (5 mL) was stirred at room temperature for the appropriate reaction time
(Table 3). EtOAc (10 mL) was added to the reaction mixture. The catalyst was separated by a
magnetic bar, dried and reused for a consecutive run under the same reaction conditions. The
organic layer was separated and evaporated under reduced pressure to give the crude product.
The crude product was purified by recrystallization in EtOH/H2O.
1
5a: H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 6H), 4.97 (s, 1H), 7.15-7.21 (m, 1H), 7.23-7.30
(m, 6H), 7.44 (t, 4H, J = 8.0), 7.71 (d, 4H, J = 7.6), 12.43 (s, br, 1H, OH), 13.96 (s, br, 1H, OH)
ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.5, 33.1, 120.5, 125.5, 125.8, 127.1, 128.1, 128.8,
142.1, 146.2 ppm.
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5b: 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.31 (s, 6H), 4.91 (s, 1H), 7.07 (d, 2H, J =
8.0), 7.14 (d, 2H, J = 8.0), 7.24 (t, 2H, J = 7.2), 7.44 (t, 4H, J = 8.0), 7.71 (d, 4H, J = 7.6), 12.40
(s, br, 1H, OH), 13.92 (s, br, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.6, 20.4, 32.7,
120.4, 125.5, 127.0, 128.6, 128.8, 134.7, 139.1, 146.2 ppm.
5c: 1H NMR (400 MHz, DMSO-d6): δ 2.46 (s, 6H), 3.85 (s, 3H), 5.05 (s, 1H), 6.99 (d, 2H, J =
8.4), 7.31 (d, 2H, J = 8.8), 7.39 (t, 2H, J = 7.2), 7.59 (t, 4H, J = 7.6), 7.86 (d, 4H, J = 8.0), 12.54
(s, br, 1H, OH), 14.07 (s, br, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.5, 32.3, 54.9,
113.4, 120.4, 125.5, 128.1, 128.8, 134.0, 146.1, 157.4 ppm.
5d: 1H NMR (500 MHz, DMSO-d6): δ 2.32 (s, 6H), 4.97 (s, 1H), 7.26 (d, 4H, J = 8.2 Hz), 7.34
(d, 2H, J = 8.0 Hz), 7.44 (t, 4H, J = 7.1 Hz), 7.71 (d, 4H, J = 7.6 Hz), 12.40 (brs, 1H, OH), 13.87
(brs, 1H, OH) ppm.
5e: 1H NMR (500 MHz, DMSO-d6): δ 2.35 (s, 6 H), 5.13 (s, 1 H), 7.25–7.27 (m, 2 H), 7.44 (t, 4
H, J = 7.0 Hz), 7.52 (d, 2 H, J = 8.1 Hz), 7.71 (d, 4 H, J = 7.6 Hz), 8.17 (d, 2 H, J = 8.2 Hz),
12.64 (brs, 1 H, OH), 13.86 (brs, 1 H, OH) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 34.0, 56.8,
121.4, 124.2, 126.5, 129.4, 129.8, 146.7, 147.1, 151.2 ppm.
5f: 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 6H), 5.07 (s, 1H), 7.26 (t, 2H, J = 7.2), 7.43-7.46
(m, 6H), 7.70 (d, 4H, J = 8.0), 7.76 (d, 2H, J = 8.4), 12.54 (s, br, 1H, OH), 13.86 (s, br, 1H, OH)
ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.5, 33.2, 108.7, 118.9, 120.5, 125.6, 128.3, 128.9,
132.0, 132.1, 146.3, 148.1 ppm.
5g: 1H NMR (400 MHz, DMSO-d6): δ 2.30 (s, 6H), 4.85 (s, 1H), 6.66 (d, 2H, J = 8.8), 7.05 (d,
2H, J = 8.4), 7.24 (t, 2H, J = 7.2), 7.44 (t, 4H, J = 8.0), 7.71 (d, 4H, J = 7.6), 9.16 (s, 1H, OH),
12.34 (s, br, 1H, OH), 13.92 (s, br, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.6, 32.3,
114.8, 120.4, 125.4, 125.5, 128.0, 128.8, 132.2, 146.1, 155.4 ppm.
5h: 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 6H), 5.18 (s, 1H), 6.69-6.76 (m, 2H), 6.96-7.0
(m, 2H), 7.24 (t, 2H, J = 7.2), 7.44 (t, 4H, J = 8.0), 7.56 (d, 1H, J = 7.2), 7.70 (d, 4H, J = 8.0),
12.40 (s, br, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.7, 27.2, 114.7, 118.5, 120.5,
125.4, 125.5, 126.8, 128.7, 128.8, 129.2, 146.2, 153.8 ppm.
1
5i: H NMR (400 MHz, DMSO-d6): δ 2.30 (s, 6H), 4.85 (s, 1H), 6.66 (t, 2H, J = 8.8), 7.05 (d,
2H, J = 8.4), 7.24 (t, 4H, J = 7.2), 7.44 (t, 4H, J = 8.0), 7.71 (d, 1H, J = 7.6), 12.36 (brs, 1H,
13
OH), 13.92 (brs, 1H, OH) ppm; C NMR (100 MHz, DMSO-d6), δ 11.4, 28.2, 106.1, 110.3,
120.5, 125.5, 128.8, 141.5, 145.9, 154.1 ppm.
5j: 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 6H), 5.14 (s, 1H), 6.76 (s, 1H), 6.91 (t, 1H, J =
3.6), 7.26 (t, 2H, J = 7.6), 7.29 (d, 1H, J = 4.8), 7.45 (t, 4H, J = 7.6), 7.72 (d, 4H, J = 7.6), 12.51
(brs, 1H, OH), 13.99 (brs, 1H,OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.4, 29.4, 120.5,
124.0, 124.1, 125.6, 126.7, 128.9, 145.8, 147.4 ppm.
5k: 1H NMR (400 MHz, DMSO-d6): δ 0.92 (d, 6H, J = 7.9 Hz), 1.38-1.42 (m, 1H), 2.25 (s, 6H),
7.26 (s, 2H), 7.46 (s, 4H), 7.44 (d, 4H, J = 7.6), 12.20 (brs, 1H, OH), 13.79 (brs, 1H, OH) ppm;
6

ACCEPTED MANUSCRIPT
13C NMR (100 MHz, DMSO-d6), δ 12.1, 22.9, 26.1, 27.1, 106.3, 120.9, 125.9, 129.4, 137.9,
145.8, 158.5 ppm.
5l: 1H NMR (400 MHz, DMSO-d6): δ 0.84 (m, 5H), 1.38-1.42 (m, 2H), 1.88-1.92 (m, 2H), 2.21
(s, 6H), 3.55 (s, 1H), 7.26 (t, 2H, J = 6.4), 7.46 (t, 4H, J = 7.6), 7.72 (d, 4H, J = 8.0), 12.20 (brs,
1H, OH), 13.79 (brs, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6), δ 11.7, 21.4, 27.9, 36.9,
39.5, 120.3, 125.4, 128.8, 146.1 ppm.
5m: 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 12H), 5.04 (s, 2H), 7.25 (t, 4H, J = 7.2), 7.37 (d,
2H, J = 8.4), 7.44 (t, 6H, J = 8.0), 7.71 (d, 8H, J = 8.0), 7.87 (d, 4H, J = 8.4), 12.79 (brs, 2H,
13
NH), 13.87 (brs, 2H, NH) ppm; C NMR (100 MHz, DMSO-d6), δ 11.5, 33.1, 120.5, 125.6,
127.4, 128.5, 128.9, 129.2, 146.2, 147.3, 167.2 ppm.
3. Results and Discussion
3.1. Synthesis and characterization of Cu-isatin Schiff base-γ-Fe2O3
Cu-isatin Schiff base-γ-Fe2O3 was synthesized by the steps described in Scheme 1. At first, γ-
Fe2O3 was reacted with 3-aminopropyltriethoxysilane to obtain amino-functionalized γ-Fe2O3.
The reaction of amino-functionalized MNPs with isatin produced isatin Schiff base-γ-Fe2O3.
Finally, the supported copper catalyst was obtained by the reaction of dissolving CuCl2.2H2O in
methanol with the above synthesized isatin Schiff base-γ-Fe2O3. The synthesized Cu-isatin
Schiff base-γ-Fe2O3 was characterized by SEM, TEM, XRD, TGA, FT-IR, ICP, VSM and CHN
analysis.
O
O
O
O
N
(EtO)3SiCH2CH2CH2NH2
γ-Fe2O3
H
N
γ-Fe2O3
O SiCH2CH2CH2
O
γ-Fe2O3
O SiCH2CH2CH2NH2
O
NH
O
CuCl2.2H2O
NH
O
O
O
O
N
N
SiCH2CH2CH2
Cl
Cu
Cl
γ-Fe2O3
O
O
O
O
SiCH2CH2CH2
NH
Scheme 1. Synthesis of Cu-isatin Schiff base-γ-Fe2O3.
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The SEM image of the supported catalyst showed uniformity and spherical morphology of
MNPs (Fig. 1).
Fig. 1. SEM image of Cu-isatin Schiff base-γ-Fe2O3.
From the TEM image (Fig. 2a), it is clear that Cu-isatin Schiff base-γ-Fe2O3 exhibits spherical
morphology with relatively good monodispersity. The particle size distribution of Cu-isatin
Schiff base-γ-Fe2O3 was evaluated using TEM and showed that the average diameter of the
particles was 13 nm (Fig. 2b).
8

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a)
b)
Fig. 2. (a) TEM image of Cu-isatin Schiff base-γ-Fe2O3 and (b) particle size distribution
histogram of Cu-isatin Schiff base-γ-Fe2O3.
Powder X-ray diffraction (XRD) pattern of the catalyst is shown in Fig. 3. The reflection planes
of (220), (311), (400), (422), (511) and (440) at 2θ = 30.3˚, 35.7˚, 43.4˚, 53.8˚, 57.4˚ and 63.0˚,
which are attributed to the diffraction scattering of γ-Fe2O3 were readily recognized from the
XRD pattern. These characteristic peaks matched with those of standard γ-Fe2O3 (JCPDS file No
04-0755). The observed diffraction peaks was indicated that γ-Fe2O3 mostly exist in face-
centered cubic structure. In addition, the diffraction plane of (111) at 2θ = 37.4◦ in XRD pattern
of Cu-isatin Schiff base-γ-Fe2O3 is ascribed to Cu.
9

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Fig. 3. XRD pattern of Cu-isatin Schiff base-γ-Fe2O3.
The thermal behavior of Cu-isatin Schiff base-γ-Fe2O3 was investigated by thermogravimetric
analysis (TGA) (Fig. 4). As shown in Fig. 4, the weight loss at around 182 °C was related to the
loss of adsorbed water molecules. TGA showed other decreasing peak from 200 to 600 °C due to
the decomposition of the organic groups.
Fig. 4. TGA diagram of Cu-isatin Schiff base-γ-Fe2O3.
The loading amount of isatin-Schiff base on γ-Fe2O3 was determined by elemntal analysis, and it
was 0.31 mmol/g based on the nitrogen and carbon amounts (0.86% and 3.95%, respectively).
The Cu content of Cu-isatin Schiff base-γ-Fe2O3 was quantified by ICP. The ICP analysis
showed that 0.11 mmol of Cu was anchored on 1 g of Cu-isatin Schiff base-γ-Fe2O3.
10

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FT-IR spectra of amino-functionalized γ-Fe2O3, isatin Schiff base-γ-Fe2O3 and Cu-isatin Schiff
base-γ-Fe2O3 are shown in Fig. 5. The band at around 550-670 cm−1 was assigned to the
stretching vibrations of Fe-O bond in these compounds. The observed peaks at 1085, 3438, 3480
and around 2869-2906 cm-1 in the FT-IR spectrum of amino-functionalized γ-Fe2O3
corresponded to C–N, N–H and C–H stretching modes of the alkyl chain, respectively. N-H
bending was appeared at 1631 cm-1. In the FT-IR spectrum of isatin Schiff base-γ-Fe2O3, new
bands were observed at 1455, 1608 and 1718 cm-1 due to the C=C, C=N and C=O stretching
vibrations, respectively. These bands proved that isatin has been successfully reacted with
amino-functionalized γ-Fe2O3. N-H stretching band of the amide group in isatin overlaped with
the broad O-H band, which was found at 3390 cm-1. In the FT-IR spectra of Cu-isatin Schiff
base-γ-Fe2O3 (Fig. 5c), the C=N and C=O stretching frequencies were shifted to the lower wave
numbers (1600, 1704 cm-1), which showed the successful coordination of nitrogen and oxygen to
the metal center.
Fig. 5. FT-IR spectra of (a) amino-functionalized γ-Fe2O3, (b) isatin Schiff base-γ-Fe2O3 and (c)
Cu-isatin Schiff base-γ-Fe2O3.
The magnetic properties of the samples containing a magnetite component were studied by a
vibrating sample magnetometer (VSM) at 300 K. Fig. 6 shows the absence of hysteresis
phenomenon and indicates that Cu-isatin Schiff base-γ-Fe2O3 have superparamagnetism at room
temperature. The saturation magnetization values for γ-Fe2O3 and Cu-isatin Schiff base-γ-Fe2O3
were 68.9 and 65.2 emu/g, respectively. A slight decrease of the saturation magnetization of Cu-
isatin Schiff base-γ-Fe2O3 was due to the immobilization of Cu complex of 2-aminothiophenol on
the surface of γ-Fe2O3 MNPs.
11

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Fig. 6. Magnetization curves of γ-Fe2O3 and Cu-isatin Schiff base-γ-Fe2O3
3.2. Synthesis of bis(indolyl)methanes and bis(pyrazolyl)methanes in aqueous media in the
presence of Cu-isatin Schiff base-γ-Fe2O3 as a heterogeneous catalyst
The reaction of indole with benzaldehyde in water was chosen as a model reaction to optimize
the reaction conditions (Table 1). At first the model reaction was carried out in the presence of
0.25 mol% of Cu-isatin Schiff base-γ-Fe2O3 in water at 25, 50 and 80 ºC. Highest yield of the
desired product was obtained at 80 ºC (Table 1, entries 1-3). Increasing the molar ratio of the
catalyst to 0.5 mol% did not have any significant effect on the progress of the reaction (Table 1,
entry 4). To examine the solvent effect on the progress of the reaction, the model reaction was
carried out in various organic solvents such as MeOH, EtOH, toluene, CH3CN and also under
solvent-free conditions (Table 1, entries 5-9). Comparison of the results with those obtained in
water (Table 1, entry 3) showed that water was the best solvent for this reaction. To indicate the
impact of the catalyst on the progress of the reaction, the model reaction was performed in the
absence of the catalyst and Cu-isatin Schiff base (Table 1, entries 10 and 11). After 24 h, a trace
amount of the product was formed in the absence of the catalyst, which confirmed the
importance of the presence of the catalyst for this reaction. The results showed that the catalytic
activity of Cu-isatin Schiff base-γ-Fe2O3 was higher than of Cu-isatin Schiff base (Table 1, entry
11).
Table 1. The electrophilic substitution reaction of indole with benzaldehyde under various
conditions.
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Ph
Cu-isatin Schiff base-γ-Fe2O3
PhCHO
+
2
N
N
H
N
H
H
Entry
Catalyst
(mol%)
0.25
0.25
0.25
0.5
Solvent
T (ºC)
Time (h)
Yield (%)a
1
2
H2O
H2O
r.t.
50
80
80
80
80
80
80
80
80
80
4
4
44
61
3
H2O
2
95
4
H2O
2
95
5
0.25
0.25
0.25
0.25
0.25
-
MeOH
EtOH
Toluene
CH3CN
4
54
6
5
61
7
6
43
8
5
35
b
9
-
3
78
10c
11d
H2O
H2O
24
2
trace
81
0.5
aIsolated yield, Reaction conditions: benzaldehyde (1 mmol), indole (2 mmol), Cu-isatin
Schiff base-γ-Fe2O3 (except in entry 10), solvent (5 mL, except in entry 9).
bNo solvent.
cNo catalyst.
dCu-isatin Schiff base.
After determining the optimum reaction conditions, to establish the scope of this method, Cu-
isatin Schiff base-γ-Fe2O3 was applied for the synthesis of bis(indolyl)methanes using indoles
with various carbonyl compounds (Table 2). As shown in Table 2, the electrophilic substitution
reaction of benzaldehyde proceeded well with different substituted indoles (Table 2, entries 1-3).
Various benzaldehydes substituted by either electron-withdrawing or electron-releasing groups
reacted with indole 1 in good to high yields (Table 2, entries 4-10). Acid-sensitive aldehydes,
such as thiophene-2-carbaldehyde and furfural underwent smooth reactions without any
decomposition or polymerization under the present reaction conditions (Table 2, entries 11 and
12). Moreover, the reaction of methyl 2-oxo-propanoate as a ketone worked well and the
expected product was achieved in 90% yield (Table 2, entry 13).
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Table 2. Synthesis of various bis(indolyl)methanes in aqueous media catalyzed by Cu-isatin
Schiff base-γ-Fe2O3.
R5
R4
O
R2
2
Cu-isatin Schiff base-γ-Fe2O3
R2
2
(0.25 mol%)
H2O, 80 °C
R1
R1
+
R4
R5
N
R3
N
R3
1: R1, R2, R3=H
2: R1= Me, R2, R3= H
3: R1, R3= H; R2= Br
4
Entry Indole
R4
R5
Product Time Yield TONb
M.p. (ºC)
Found reported
Ref
(h)
2
(%)a
95
96
90
95
92
98
92
90
81
80
98
95
90
1
2
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
380 114-115 112-113
384 245-246 244-246
68
69
70
68
71
71
71
72
71
71
68
68
73
1
2
3
1
1
1
1
1
1
1
1
1
1
4a
4b
4c
4d
4e
4f
1
3
C6H5
2
360 246-248
250
4
4-O2N-C6H4
2-O2N-C6H4
2-Cl-C6H4
4-Cl-C6H4
2,6-Cl2-C6H3
4-Me-C6H4
4-MeO-C6H4
2-Thienyl
2-Furyl
1
380 234-235 235-236
368 140-142 140-142
5
1
6
0.5
2
392
368
70-72
74-76
71-72
75-76
7
4g
4h
4i
8
2
360 107-108 108-109
324 99-100 99-101
9
5
10
11
12
13
4
320 189-190 189-191
392 147-149 149-150
380 313-314 310-312
360 157-159 158-159
4j
1
4k
4l
0.75
0.75
Me
CO2Me
4m
aIsolated yield. Conditions: indole (2 mmol), carbonyl compound (1 mmol), Cu-isatin Schiff
base-γ-Fe2O3 (0.25 mol%), water (10 mL), 80 ºC.
bTON = turnover number (mol of the product/mol of the catalyst).
A plausible mechanism for the synthesis of bis(indolyl)methanes in the presence of Cu-isatin
Schiff base-γ-Fe2O3 as the catalyst is shown in Scheme 2. The condensation reaction proceeds
through the activation of the carbonyl group by Cu-isatin Schiff base-γ-Fe2O3. Indole attacks to
the activated carbonyl group to form an intermediate which is subsequently attacks by a second
molecule of indole to produce bis(indolyl)methanes.
14

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Cu-isatin Schiff base-
Cu-isatin Schiff base-
γ-Fe2O3
g-Fe2O3
O
N
Ar
H
O
H
HO
H
H
Ar
Ar
N
Cu-isatin Schiff base-
Cu-isatin Schiff base-
γ-Fe2O3
γ-Fe O
g
2
2
3
3
-H2O
H
Ar
N
H
Ar
N
Cu-isatin Schiff base-
Cu-isatin Schiff base-
N
H
γ-Fe O
g-Fe2O3
HN
Scheme 2. A plausible mechanism for the synthesis of bis(indolyl)methanes catalyzed by Cu-
isatin Schiff base-γ-Fe2O3.
Following the initial success in the synthesis of bis(indolyl)methanes, we investigated the
application of Cu-isatin Schiff base-γ-Fe2O3 in the synthesis of bis(pyrazolyl)methanes. The
results are summarized in Table 3. Different aryl aldehydes containing electron-donating and
electron-withdrawing groups, heteroaryl and alkyl aldehydes reacted well with 3-methyl-1-
phenyl-5-pyrazolone at room temperature and the desired products were isolated in 85-97%
yields (Table 3, entries 1-12). It is worth to note that both carbonyl groups in terephthalaldehyde
reacted with 3-methyl-1-phenyl-5-pyrazolone and produced the desired product in 87% yield
(Table 3, entry 13).
Table 3. Synthesis of bis(pyrazolyl)methanes in aqueous media catalyzed by Cu-isatin Schiff
base-γ-Fe2O3.
15

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R
N
N
Ph
Cu-iastin Schiff base-γ-Fe2O3 (0.25 mol%)
N
N
Ph
2
N
RCHO
+
O
H2O, r.t.
N
OH
HO
Ph
5
Entry
R
Product
Time
(min)
Yield TONb
(%)a
M.p. (ºC)
Found Reported
Ref.
1
2
C6H5
30
35
30
30
45
45
40
30
45
30
40
40
50
95
91
85
90
96
90
97
85
92
93
86
90
87
380 168-170 170-172
74
68
75
74
74
76
74
77
77
78
79
-
5a
5b
5c
5d
5e
5f
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-O2N-C6H4
4-CN-C6H4
4-OH-C6H4
2-OH-C6H4
2-Furyl
364
95-97
92-94
3
340 175-176 172-174
360 212-214 215-217
384 228-230 225-227
360 211-213 210-212
388 153-155 155-157
340 230-231 229-230
368 189-190 189-191
372 190-191 190-192
344 211-212 213-214
4
5
6
7
5g
5h
5i
8
9
10
11
12
13
2-Thienyl
5j
-CH(CH3)2
-(CH2)3CH3
4-OHC-C6H4
5k
5l
360 125-127
-
348 286-287 286-288
80
5m
16

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aIsolated yield; Reaction conditions: benzaldehyde (1 mmol), 3-methyl-1-phenyl-5-pyrazolone
(2 mmol), catalyst (0.25 mol%), water (10 mL)
.
bTON = turnover number (mol of the product/mol of the catalyst).
We have also studied the reusability of Cu-isatin Schiff base-γ-Fe2O3 for the synthesis of
bis(pyrazolyl)methane 5a. After completion of the reaction, the catalyst was easily separated
from the reaction mixture using a magnetic bar (Fig. 7), dried and reused for the next run. The
recycled catalyst was successfully reused for eight runs (Fig. 8). FT-IR spectrum of the
recovered catalyst after eight runs (Fig. 9b) was almost identical to the spectrum of the fresh
catalyst (Fig. 9a), indicating that the structure of the catalyst was unchanged by the reaction.
(a)
(b)
Fig. 7. (a) Reaction mixture, (b) separation of Cu-isatin Schiff base-γ-Fe2O3 from the reaction
mixture by a magnetic bar.
Fig. 8. Reusability of Cu-isatin Schiff base-γ-Fe2O3 for the synthesis of bis(pyrazolyl)methane
5a.
17

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Fig. 9. FT-IR spectra of (a) fresh, and (b) reused Cu-isatin Schiff base-γ-Fe2O3.
Hot filtration test is a standard method to check heterogenity of a reaction. The reaction of 3-
methyl-1-phenyl-5-pyrazolone with benzaldehyde in the presence of Cu-isatin Schiff base-γ-
Fe2O3 has been carried out under optimized reaction conditions. When 40% of
bis(pyrazolyl)methane 5a was formed, the catalyst was removed from the reaction mixture by a
magnetic bar and the reaction was monitored for an additional time. No further product
formation was observed even after 24 h. ICP analysis of the separated catalyst from the reaction
mixture confirmed no copper leaching. These results showed the heterogeneous nature of the
catalyst.
A proposed mechanism for the synthesis of bis(pyrazolyl)methanes catalysed by Cu-isatin Schiff
base-γ-Fe2O3 is shown in Scheme 3. The first step involved the formation of an intermediate by
the nucleophilic addition of 1-phenyl-3-methyl-5-pyrazalone to activated aldehydes by the
catalyst followed by dehydration. Then the second molecule of 1-phenyl-3-methyl-5-pyrazolone
is added to this intermediate via Michael addition to give bis(pyrazolyl)methanes.
18

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Scheme 3. A plausible mechanism for the synthesis of bis(pyrazolyl)methanes catalyzed by Cu-
isatin Schiff base-γ-Fe2O3.
Finally, the activity of our catalyst for the synthesis of bis(indolyl)methanes and
bis(pyrazolyl)methanes was compared with some other reported heterogeneous catalysts in
Table 4 and 5. As is evident from Table 4 and 5, Cu-isatin Schiff base-γ-Fe2O3 is the most
effective catalyst for the synthesis of bis(indolyl)methanes and bis(pyrazolyl)methanes in terms
of TON.
Table 4. Comparison of catalytic activity of Cu-isatin Schiff base-γ-Fe2O3 with some
other heterogeneous catalysts reported for the synthesis of bis(indolyl)methanes.
Entry
Catalyst (mol%)
Conditions
Solvent-
19
Time
(h)
Yield
(%)a
TONb
150-
[Ref]
81
c
1
NPS-γ-Fe2O3 (0.5)
0.33-6
75-95

ACCEPTED MANUSCRIPT
free, 80 °C
190
2
3
Fe3O4@ γ-Fe2O3-SO3H EtOH, r.t.
0.08-1
1.15
90-98
9-9.8
82
83
(10)
Fe3O4@SiO2@Me&Et- Solvent-
94
94
PhSO3H (1)
free, 90 °C
4
5
6
Fe(oxd)-Fe3O4 (5)
H2O, 100
°C
1-4
1.5
68-92
80-95
80-98
13.6-
18.4
84
85
LPMNPe (2.5)
H2O, 50
°C
32-38
Cu-isatin Schiff base-
H2O, 80
°C
0.5-5
320-
392
This
γ-Fe2O3 (0.25)
work
aIsolated yield.
bTON = turnover number (mol of the product/mol of the catalyst).
cNPS-γ-Fe2O3 = n-propylsulphonated γ-Fe2O3.
dox = Oxalate
eLPMNP = L-proline-modified magnetic nanoparticles.
20

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Table 5. Comparison of catalytic activity of Cu-isatin Schiff base-γ-Fe2O3 with some other
heterogeneous catalysts reported for the synthesis of bis(pyrazolyl)methanes.
Entry
1
Catalyst (mol%)
ZnO NPsc (2)
Conditions
Time (min) Yield (%)a TONb
[Ref]
86
EtOH/H2O,
reflux
15-20
85-94
42.5-47
2
3
NPS-γ-Fe2O3 (2)
H2O, r.t.
120-180
60-270
81-94
77-90
40.5-47
87
88
[Sipmim]HSO4
(8.3)
EtOH, reflux
9.2-
10.8
d
4
5
[Dsmi]AlCl4 (1)
Solvent-free,
50 °C
30-60
5-20
72-93
80-98
72-93
89
90
Ce(SO4).4H2Oe
(2.5)
EtOH /H2O,
reflux
32-39.2
6
Cu-isatin Schiff
base-γ-Fe2O3
(0.25)
H2O, 80 °C
30-300
95-85
340-
380
This
work
aIsolated yield.
bTON = turnover number (mol of the product/mol of the catalyst).
cNPs = nanoparticles.
d[Dsmi]AlCl4 = 1,3-disulfonic acid imidazolium tetrachloroaluminate.
4. Conclusion
In summary, we have synthesized Cu-isatin Schiff base supported on γ-Fe2O3 as a new catalyst
and characterized it by different methods such as SEM, TEM, XRD, TGA, FT-IR, ICP, VSM
and CHN analysis. The synthesized catalyst was applied as a magnetically recyclable
heterogeneous catalyst for the synthesis of a wide range of bis(indolyl)methanes by electrophilic
substitution reaction of different indoles with various aldehydes and ketones in aqueous media in
good to high yields. This catalytic system was also effective for the synthesis of
bis(pyrazolyl)methanes in aqueous media. ICP analysis of the separated catalyst from the
21

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reaction mixture in the hot filtration test confirmed no copper leaching and showed the
heterogeneous nature of the catalyst. The true heterogeneous Cu-isatin Schiff base-γ-Fe2O3 could
be reused with the aid of a magnetic bar for eight consecutive cycles without any drastic loss of
its reactivity. The present protocol offers several advantages such as generality, simplicity, using
a reusable and stable catalyst, an environmentally benign reaction media, and avoiding hazardous
organic solvents and toxic catalysts. These properties make this protocol an environmentally
compatible process for the synthesis of a variety of bis(indolyl)methanes and
bis(pyrazolyl)methanes.
Acknowledgement
Financial support of this project by University of Birjand Research Council is appreciated.
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Highlights
•
•
•
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•
Cu-isatin Schiff base supported on γ-Fe2O3 as a new catalyst was synthesized.
It was characterized by SEM, TEM, XRD, TGA, FT-IR, ICP and CHN analysis.
It catalyzed the synthesis of bis(indolyl)methanes and bis(pyrazolyl)methanes.
The catalyst was easily separated by a magnetic bar and reused eight times.
No significant loss of the catalyst activity was observed after eight times reuse.