Preparation and characterization of isatin complexed with Cu supported on 4-(aminomethyl) benzoic acid-functionalized Fe3O4 nanoparticles as a novel magnetic catalyst for the Ullmann coupling reaction

Article abstract of DOI:10.1007/s11164-019-03760-0

Isatin complexed with Cu supported on 4-(aminomethyl) benzoic acid-functionalized Fe₃O₄ nanoparticles (Cu-IS-AMBA-MNPs) as a new catalyst was designed, prepared and characterized by appropriate analyses. The heterogeneous reusable catalyst was successfully used for the efficient and widespread syntheses of diaryl ethers and diarylamines via the Ullmann coupling reaction. This green catalyst was easily removed, reused several times with no significant loss of its activity, and provided a clean synthesis with excellent yield and reduced time.

Full text of DOI:10.1007/s11164-019-03760-0

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03760-0
Preparation and characterization of isatin complexed
with Cu supported on 4‑(aminomethyl) benzoic
acid‑functionalized Fe3O4 nanoparticles as a novel
magnetic catalyst for the Ullmann coupling reaction
Mohammad Mehdi Khodaei1 · Abdolhamid Alizadeh1 · Maryam Haghipour1
Received: 12 October 2018 / Accepted: 28 January 2019
© Springer Nature B.V. 2019
Abstract
Isatin complexed with Cu supported on 4-(aminomethyl) benzoic acid-functional-
ized Fe3O4 nanoparticles (Cu-IS-AMBA-MNPs) as a new catalyst was designed,
prepared and characterized by appropriate analyses. The heterogeneous reusable
catalyst was successfully used for the efcient and widespread syntheses of diaryl
ethers and diarylamines via the Ullmann coupling reaction. This green catalyst was
easily removed, reused several times with no signifcant loss of its activity, and pro-
vided a clean synthesis with excellent yield and reduced time.
Keyword Magnetically recoverable nanocatalyst · Ullman coupling reaction ·
Nanoparticles · Diaryl ethers · Copper
Introduction
Diaryl ethers and diarylamines are a class of important organic compounds in many
biologically active natural products and play signifcant roles in the chemical indus-
try and in medicinal chemistry [1, 2]. A large number of them have displayed par-
ticular and signifcant biological and pharmacological activities such as the isodity-
rosine family and its derivatives (e.g., the antibiotic vancomycin and the antitumor
bouvardin) and commercial dyes [3–6]. Diaryl ethers have received the interests of
investigators during this decade [2].
Traditionally, aryl ethers are prepared with Ullmann-type reactions between
phenols and aryl halides mediated with a transition metal such as Pd and Cu
[7–10]. This procedure is mostly performed at high temperatures and needs stoi-
chiometric amounts of copper [11]. The Ullmann reaction was reported for the
* Mohammad Mehdi Khodaei
mmkhoda@razi.ac.ir
1
Department of Organic Chemistry, Razi University, Kermanshah 67149-67346, Iran
Vol.:(0123456789)
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M. M. Khodaei et al.
frst time in 1901 and has for a long time been applied by chemists and research-
ers to form a C–C bond between two aromatic nuclei in the presence of copper
powder as a catalyst [12, 13]. Copper-based catalysts, because of their low-priced
raw materials, simple working and low toxicity are more applicable and attractive
than Pd-based catalysts to form the C–O bond in diaryl ethers [14].
In recent decades, principal investigations have been handled and introduced
in promoting the Cu-catalyzed Ullmann coupling reaction by using heterogene-
ous reusable catalysts [15–18] and many unique ligands. Some of them include
1,10-phenanthroline and its derivatives [19], ethylene glycol [20], diethylsali-
cylamide, oxime-type and Schif-base ligands [21], thiophene-2-carboxylate [22],
bidentate phosphines [23], and diphosphinidene cyclobutane [24], 2,2,6,6-tetra-
methylheptane-3,5-dione [25], phosphazene P4-tBu base [26], and N,N-dimethyl-
glycine [27].
The importance of copper nanomaterial for organic chemistry reactions is undis-
putable. Copper nanoparticles have been used as a heterogeneous catalyst in vari-
ous chemical transformations. Copper nanoparticle-catalyzed reactions are advanta-
geous over conventional metal-catalyzed reactions in terms of better yields, shorter
reaction times, low catalyst loading, high atom economy, inexpensiveness, and recy-
clability of the catalyst. It has been shown that most of the transformations proceed
mechanistically via the formation of organometallic intermediates [C–Cu–X] during
the interaction with copper nanoparticles [28].
In spite of considerable progress in the heterogeneous recoverable copper-cat-
alyzed Ullmann reaction, the reusability of the catalyst support still attracts much
attention. Carbon nanotubes (CNTs) have been widely studied as supports for depos-
iting of metal nanoparticles as heterogeneous catalysts due to their unusual struc-
ture, excellent electronic conductivity, and enhanced approachability of reactants to
the active sites [27, 29].
Also, magnetic nanoparticles (MNPs) can be used as supports in the preparation
of heterogeneous recoverable catalysts for the Ullmann reaction. They have several
unique magnetic properties including superparamagnetic, high coercively, low Curie
temperature, high magnetic susceptibility, and large surface-to-volume ratio. Devel-
opment of suitable surface coating for efcient protection strategies to maintain the
stability of MNPs is signifcant and necessary [30]. Surface functionalized MNPs
have been extensively used in biotechnology and catalysis [31–35]. The design of
new magnetically separable systems has attracted major consideration in recent dec-
ades as an appealing choice to enhance the efcient separation of heterogeneous
nanocatalysts from products by their response to an external magnetic feld [36, 37].
Eco-friendliness and biodegradability as well as excellent magnetic properties can
be indicated for functional many organic compounds grafted to MNPs [38–41].
Here, we report a biocompatible catalyst for the Ullmann coupling reaction
between aryl halides with phenols and aryl boronic acid with anilines using isatin
complexed with Cu supported on 4-(aminomethyl) benzoic acid-functionalized
Fe3O4 nanoparticles (Cu-IS-AMBA-MNPs) as a novel heterogeneous recoverable
nanocatalyst (Scheme 1). Isatin has been used as a Schif base connected to Cu sup-
ported on AMBA-MNPs and characterized by diferent techniques, such as SEM,
XRD, TGA, FT-IR, VSM, EDX and ICP-AES.
1 3

Preparation and characterization of isatin complexed with…
Scheme 1 Ullmann coupling reaction with Cu-IS-AMBA-MNPs
Experimental
Chemicals and apparatus
The X-ray powder difraction (XRD) of the prepared catalyst was performed on
a Philips PW 1830 X-ray difractometer with a CuKα source (λ=1.5418 Å) in a
range of Bragg’s angle (10°–80°) at room temperature. Fourier-transform infrared
(FT-IR) spectra were recorded using a FT-IR spectrometer (Vector 22, Bruker) in
the range of 400–4000 cm−1 at room temperature. Scanning electron microscopy
(SEM) analysis was carried out using a VEGA//TESCAN KYKY-EM 3200 micro-
scope (acceleration voltage 26 kV). The spectrum of elemental analysis of the cata-
lyst was recorded by energy dispersive X-ray (EDX; VEGA3 XUM/TESCAN).
Thermogravimetric analysis (TGA) was carried out on a Stanton Red craft STA-780
(London, UK). NMR spectra were recorded with a Bruker DRX-400 ADVANCE
1
instrument (300.1 MHz for H, 75.4 MHz for 13C). The spectra were measured in
DMSO-d6 as a solvent. Magnetic measurements were performed using a vibration
sample magnetometer (VSM, MDK, and Model 7400) analysis. The metal loading
was detected by an inductively coupled plasma-atomic emission spectrometer (ICP-
AES). Melting points were measured on an Electrothermal 9100 apparatus.
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M. M. Khodaei et al.
General procedure
Preparation of 4‑(aminomethyl) benzoic acid functionalized MNPs (AMBA‑MNPs)
First, the MNPs were synthesized using the coprecipitation method described
in the literature [42]. In a typical procedure, FeCl3·6H2O (2.43 g, 0.09 mol) and
FeCl2·4H2O (0. 89 g, 0.0045 mol) were dissolved in 100 mL of deionized water
and the solution was sonicated until the salts completely dissolved. Then, 0.3 g of
AMBA in 10 mL of NH4OH solution was added to the prepared mixture with vig-
orous stirring under constant nitrogen fow to form a black suspension which was
refuxed at 100 °C for 12 h. Then, AMBA-MNPs nanoparticles were separated from
the aqueous solution by a magnetic feld, washed with deionized water fve times
and subsequently dried in an oven overnight (Scheme 2).
Preparation of supported isatin on AMBA‑MNPS nanoparticles (IS‑AMBA‑MNPs)
The prepared AMBA-MNPs (1 g) were scattered in 50 mL of ethanol using sonica-
tion for 30 min, and then 0.2 g of isatin (IS) was added to the mixture to form the
black suspension. Next, this suspension was refuxed with strong stirring for 6 h.
The IS-AMBA-MNPs were separated from the aqueous solution by magnetic decan-
tation, washed with deionized water several times and dried in an oven overnight
(Scheme 3). All of the synthesis steps were carried out under N2 fow.
Preparation of copper supported on IS‑AMBA‑MNPs (Cu‑IS‑AMBA‑MNPs)
The obtained IS-AMBA-MNPs (0.5 g) were dispersed in 50 mL of ethanol by soni-
cation for 30 min, and then 0.045 g of CuCl2 added to the above mixture. A brown
suspension was formed and refuxed with vigorous stirring for 8 h. The catalyst (Cu-
IS-AMBA-MNPs) was separated from the solution by an external magnet, washed
with deionized water several times, and dried in an oven overnight (Scheme 4). The
whole synthesis was carried out under N2 fow.
Scheme 2 Preparation of AMBA-MNPs
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Preparation and characterization of isatin complexed with…
Scheme 3 Preparation of IS-AMBA-MNPs
Scheme 4 Preparation of Cu-IS-AMBA-MNPs
General procedure for the synthesis of diaryl ethers and diarylamines
via Ullmann coupling reaction using Cu‑IS‑AMBA‑MNPs as the catalyst
General procedure for O‑arylation reactions
To prepare diaryl ethers using the Ullmann coupling reaction via O-arylation
reactions, aryl halide (1 mmol), phenol derivative (1 mmol) and 0.2 g (1.5 mmol)
of K2CO3 in DMF (5 mL) were placed into a round-bottom fask containing
0.05 g (0.02 mmol) of the catalyst. The above mixture was refuxed at 110 °C for
3 h under vigorous stirring. When the reaction was complete, the reaction mix-
ture was cooled and the solvent was removed under reduced pressure. Then, the
mixture was diluted with CH2Cl2 and the catalyst was separated by an external
magnet. The fltrate was evaporated on a rotary evaporator and the crude product
was purifed by column chromatography using ethyl acetate/n–hexane.
General procedure for N‑arylation reactions
The mixture of phenylboronic acid (1 mmol), aromatic amine (1.2 mmol) and
0.12 g (2 mmol) of KF in DMSO (4 mL) were added to Cu-IS-AMBA-MNPs
(0.06 g, 0.025 mmol) at 130 °C under nitrogen atmosphere for 2 h with vigor-
ous stirring. Then, after completion of the reaction, the catalyst was separated
by an external magnet and washed with dry CH2Cl2 three times and checked for
its reusability. The solvent of the reaction mixture was evaporated by a rotary
evaporator and then ethyl acetate and water were added to the residue. The
organic layer was dried over anhydrous MgSO4.The solvent was evaporated under
1 3

M. M. Khodaei et al.
reduced pressure and the crude product was purifed by column chromatography
using ethyl acetate/n-hexane.
Selected spectra for a few products are given below
4-Nitrophenyl 3-methylphenyl ether (Table 2, entry 5): m.p.: 62–63 °C; IR (KBr):
1
νmax =3120, 2925, 2857, 1567, 1348, 1094 cm−1; H NMR (400.13 MHz, DMSO):
δ=2.32 (s, 3H, CH3), 7.28–7.38 (m, 3H), 7.42 (s, 1H), 7.53 (d, 2H, J=8.8 Hz), 7.62
(d, 2H, J=8.8 Hz) ppm.; 13C NMR (100.6 MHz, DMSO): δ=26.4, 123.1, 124.7,
126.0, 126.1, 127.2, 127.3, 128.1, 128.7, 129.3, 133.1 ppm.
2-Phenoxynaphthalene (Table 2, entry 6): m.p.: 97–98 °C; IR (KBr): νmax =3067,
1
2920, 1567, 1349, 1097 cm−1; H NMR (400.13 MHz, DMSO): δ=7.33–7.75 (m,
7H), 7.85 (d, 2H, J=8.0 Hz), 8.28 (d, 2H, J=8.0 Hz) ppm.; 13C NMR (100.6 MHz,
DMSO): δ=119.2, 120.3, 121.3, 123.0, 124.8, 126.0, 126.1, 127.2, 127.3, 128.1,
128.6, 129.4, 132.8, 133.2 ppm.
3-Nitrophenyl-2,6-dimethoxyphenyl ether (Table 2, entry 12): m.p.: 35–37 °C; 1H
NMR (400.13 MHz, DMSO): δ=4.10 (s, 6H, OCH3), 6.59–6.67 (m, 3H), 7.17–7.19
(m, 2H), 7.31–7.37 (m, 2H) ppm.; 13C NMR (100.6 MHz, DMSO): δ=52.0, 118.1,
118.6, 119.9, 120.3, 124.7, 127.3, 129.8, 131.1, 131.5, 133.6 ppm.; anal. calcd. for
C14 H13 NO5 (275.08): C, 61.09; H, 4.76; N, 5.09%; found: C, 61.40; H, 4.79; N,
5.04%.
1
3-Nitrophenyl-2,6-dimethylphenyl ether (Table 2, entry 13): m.p.: 42–43 °C; H
NMR (400.13 MHz, DMSO): δ=2.12 (s, 6H, CH3), 7.03–7.10 (m, 3H), 7.24–7.27
(m, 3H), 7.35 (s, 1H) ppm.; 13C NMR (100.6 MHz, DMSO): δ=20.3, 120.6, 120.9,
123.2, 126.5, 127.2, 128.1, 129.6, 130.0, 132.0, 135.0 ppm.; anal. calcd. for C14 H13
NO3 (243.09): C, 69.12; H, 5.39; N, 5.76%; found: C, 69.40; H, 5.43; N, 5.71%.
Diphenylamine (Table 4, entry 1): m.p.: 53–54 °C; IR (KBr): νmax =2954, 1503,
1
1427, 1221 cm−1; H NMR (400.13 MHz, DMSO): δ=5.60 (s, 1H, N–H), 7.15 (d
of d, J=14.6 Hz, J=7.2 Hz, 2H), 7.25 (d of d, J=14.6 Hz, J=7.2 Hz, 4H), 7.38
(d, J=2.4 Hz, 4H) ppm.; 13C NMR (100.6 MHz, DMSO): δ=119.9, 121.0, 123.7,
136.3 ppm.
4-Methyl-N-phenylaniline (Table 4, entry 3): m.p.: 65–66 °C; IR (KBr):
1
νmax =2953, 1528, 1435, 1216 cm−1; H NMR (400.13 MHz, DMSO): δ=2.28
(s, 3H, CH3), 5.61 (s, 1H, N–H), 7.10–7.16 (m, 2H), 7.21–7.27 (m, 3H), 7.42 (d,
J=2.0 Hz, 2H), 7.56 (d, J=2.0 Hz, 2H) ppm.; 13C NMR (100.6 MHz, DMSO):
δ=122.2, 123.0, 123.7, 123.9, 127.4, 131.5, 135.3, 135.9 ppm.
N-(4-Chloro-2,6-dimethylphenyl)-4-nitroaniline (Table 4, entry 11): m.p.:
1
78–79 °C; H NMR (400.13 MHz, DMSO): δ=2.12 (s, 6H, 2CH3), 5.59 (s, 1H,
N–H), 7.32 (d, J=6.6 Hz, 2H),7.42 (s, 2H), 7.50 (d, J=6.6 Hz, 2H) ppm.; 13C NMR
(100.6 MHz, DMSO): δ=20.2, 113.1, 115.7, 122.0, 127.1, 127.5, 132.0, 136.5,
137.0 ppm.; anal. calcd. for C14 H13 ClN2O2 (276.07): C, 60.77; H, 4.74; N, 10.12%;
found: C, 61.11; H, 4.77; N, 9.99%.
1
N-(2,6-Dimethoxyphenyl)-4-nitroaniline (Table 4, entry 11): m.p.: 85–87 °C; H
NMR (400.13 MHz, DMSO): δ=3.87 (s, 6H, 2OCH3), 5.54 (s, 1H, N–H), 6.88 (s,
2H), 6.97 (s, 1H), 7.15 (d, J=6.8 Hz, 2H), 7.34 (d, J=6.8 Hz, 2H) ppm.; 13C NMR
(100.6 MHz, DMSO): δ=50.1, 113.5, 114.4, 121.8, 124.0, 126.8, 128.8, 129.2,
1 3

Preparation and characterization of isatin complexed with…
130.3 ppm.; anal. calcd. for C14 H14 N2O4 (274.10): C, 61.31; H, 5.14; N, 10.21%;
found: C, 61.60; H, 5.18; N, 10.08%.
Results and discussion
Characterization of the catalyst
FT‑IR spectra of the catalyst
The FT-IR spectra of AMBA-MNPs, IS-AMBA-MNPs and Cu-IS-AMBA-MNPs
are displayed in Fig. 1. The peaks of Fe3O4 appeared at 624 and 570 cm−1, which
can be ascribed to the stretching vibrations of the Fe–O bond. The monitored peaks
at 3450 and around 2923 and 2860 cm−1 in the FT-IR spectrum of AMBA-MNPs
correspond to the N–H and C–H stretching bands of the alkyl chain, respectively.
The adsorption peaks at 1632, 1375 and 1086 cm−1 are related to the asymmetric
Fig. 1 FT-IR spectra for AMBA-MNPs, IS-AMBA-MNPs and Cu-IS-AMBA-MNPs
1 3

M. M. Khodaei et al.
and symmetric stretching vibration of COO (carboxylate group) of the 4-(aminome-
thyl)benzoic acid moiety. In the FT-IR spectrum of IS-AMBA-MNPs, new bands
were observed at 1623 and 1722 cm−1 due to the C=N and C=O stretching vibration
bands, respectively. These bands confrmed that isatin has been successfully reacted
with the amino present in the structure of the AMBA-MNPs. The N–H stretching
peak of the amide group in isatin appeared at 3386 cm−1. In the FT-IR spectra of
Cu-IS-AMBA-MNPs (Fig. 1), the C=N and C=O stretching bands were shifted to
the lower wave numbers (1600 and 1706 cm−1), which revealed the successful coor-
dination of nitrogen and oxygen to the metal center.
XRD pattern analysis of the catalyst
Powder X-ray difraction patterns of the IS-AMBA-MNPs and Cu-IS-AMBA-
MNPs are shown in Fig. 2. The refection planes of X-ray difraction using a CuKα
irradiation was applied to characterize the demonstration of the crystal structure
of the samples after the functionalization step. As shown in Fig. 2, the peaks at
2θ=42.87°, 50.26° and 74.56° assigned with the (111), (200) and (220) planes were
attributed to Cu (II) [8]. Also, 2θ=30.2°, 35.30°, 43. 3°, 53.65°, 57.3°, and 62.8°
peaks corresponding to the (220), (311), (400), (422), (511), and (440) planes were
obtained due to the cubic spinel structure of Fe3O4 NPs. The results are in good
agreement with standard patterns of the inverse cubic spinel magnetite crystal struc-
ture (JCPDS No. 19-0629). The prepared sample has good crystallinity due to the
presence of sharp peaks in the XRD pattern. The crystallite size of the catalyst was
Fig. 2 XRD patterns of IS-AMBA-MNPs (a) and Cu-IS-AMBA-MNPs (b)
1 3

Preparation and characterization of isatin complexed with…
evaluated and was found to be 18 nm using Scherrer’s formula based on the XRD
peak at 30.
TGA analysis of the catalyst
The thermal behavior of Cu-IS-AMBA-MNPs was studied by TGA under an
air atmosphere with a heating rate of 10 °C min−1 within a temperature range of
0–650 °C (Fig. 3). The composition ratio of the catalyst can be estimated from the
residual mass percentage. As shown in Fig. 3, the frst weight loss stage at nearly
100 °C (0.52%) was assigned to the evaporation of adsorbed water molecules. The
second weight loss at 100–400 °C (8.0%) can be ascribed to loss of CuCl2 and the
isatin group. The fnal weight loss at 400 to 650 °C (5.11%) corresponds to 4-(ami-
nomethyl)benzoate. On the basis of these results, the good grafting of AMBA-IS-Cu
on the Fe3O4 nanoparticles is confrmed.
SEM images of the catalyst
The SEM images of the AMBA-MNPs and Cu-IS-AMBA-MNPs are presented
in Fig. 4, according to which the SEM image of the supported nanocatalyst has a
spherical morphology and good dispersity. It was estimated to have individual crys-
tallite sizes ranging 10 and 30 nm.
Fig. 3 TGA diagram of Cu-IS-AMBA-MNPs
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M. M. Khodaei et al.
Fig. 4 SEM images of AMBA-MNPs (a) and Cu-IS-AMBA-MNPs (b)
EDX analysis of the catalyst
The EDX analysis of Cu-IS-AMBA-MNPs is displayed in Fig. 5, from which it
can be seen that Cu-IS-AMBA-MNPs is composed of the expected elements in the
structure of the catalyst, namely carbon (C), oxygen (O), nitrogen (N), iron (Fe),
copper (Cu) and chlorine (Cl), indicating that Cu has been properly connected to
IS-AMBA-MNPs.
Fig. 5 EDX spectrum of Cu-IS-AMBA-MNPs
1 3

Preparation and characterization of isatin complexed with…
Magnetic properties of the catalyst
The magnetic properties of the AMBA-MNPs, IS-AMBA-MNPs, and Cu-
IS-AMBA-MNPs were characterized by VSM at 300 K (Fig. 6). The magnetization
curves for these nanoparticles show no hysteresis in their magnetizations. Moreover,
the absence of coercivity and remanence for the three nanoparticles indicate that
these nanoparticles were superparamagnetic. The saturation magnetization values
for AMBA-MNPs, IS-AMBA-MNPs, and, Cu-IS-AMBA-MNPs were 69.2, 54.5
and 42.6 emu g−1, respectively. A low decrease of the saturation magnetization of
Cu-IS-AMBA-MNPs occurred because of the connection of Cu on the surface of
the IS-AMBA-MNPs nanoparticles. In other words, these diferences are due to the
various coating layers and their thicknesses on the surface of the MNPs. However,
the prepared magnetite catalyst still has good magnetic properties and can be easily,
quickly and completely separated from the reaction medium by a magnetic feld.
Catalytic application of the catalyst
The catalytic activity of the nanocatalyst was evaluated by using Cu-IS-AMBA-
MNPs to synthesis diphenyl ether from the reaction of iodobenzene and phenol. For
optimization of the conditions, the efect of solvent, temperature and the amount of
the catalyst was studied in this reaction. As can be seen in Table 1, the nature of the
solvent afects the efciency of the coupling reaction (Table 1, entries 1–5). It was
found that DMF was the best among the other solvents, which included CH3OH,
CH3CN, H2O, and DMSO, but none were as efective as DMF. Another efcient fac-
tor in the catalytic performance of Cu-IS-AMBA-MNPs is the amount of the cata-
lyst based on the obtained results. The reaction was performed with various amounts
of the catalyst (40, 50, and 60 mg), and the best performance was obtained when
Fig. 6 Magnetization curves of AMBA-MNPs, IS-AMBA-MNPs and Cu-IS-AMBA-MNPs
1 3

M. M. Khodaei et al.
Table 1 Optimization of the reaction conditions in the synthesis of 3a
Entry Catalyst
Solvent Amount of the Temperature (°C) Time (h) Yield (%)a
catalyst (mg)
1
2
3
4
5
6
7
8
Cu-IS-AMBA-MNPs CH3OH 40
Cu-IS-AMBA-MNPs CH3CN 40
60
60
60
60
4
4
4
4
4
4
4
4
4
4
4
4
3
3
3
3
32
35
21
31
38
58
60
38
55
77
79
84
98
98
68
–
Cu-IS-AMBA-MNPs H2O
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMF
40
40
40
60
Cu-IS-AMBA-MNPs CH3OH 40
Cu-IS-AMBA-MNPs CH3CN 40
Refux
Refux
Refux
100
100
110
110
110
110
110
110
Cu-IS-AMBA-MNPs H2O
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMF
40
40
40
40
40
50
60
50
50
9
10
11
12
13
14
15
16
CuCl2
DMF
DMF
–
aYields refer to isolated products
50 mg of the catalyst (0.02 mmol%) was used. Finally, the efect of temperature was
investigated and the best result was obtained at 110 °C in the presence of 50 mg
(0.02 mmol) of the catalyst using 5 mL of DMF. The control experiment shows that
O-arylation did not occur in the absence of the catalyst (Table 1, entry 16).
To explore the scope and limitations of this catalyst, a variety of phenols reacted
with diferent substituted phenyl halides under the optimal reaction conditions and
the results are collected in Table 2. It is shown that all of the substrates reacted well
with high yields. In O-arylation, the presence of ortho substituents on the phenol
ring was tolerated (Table 2, entries 12 and 13). In addition, para and ortho sub-
stituents on aryl halide were suitable for the preparation of diphenyl ethers. It is
interested to note that chlorobenzene tolerated the reaction conditions and gave the
corresponding product in high yield. To investigate the role of immobilized cop-
per supported on MNPs, a further experiment was carried out in the presence of
CuCl2 (Table 1, entry 15). Based on the results gained in the presence of CuCl2, the
obtained yield is not comparable with the yield of the reaction in the presence of the
catalyst. Thus, the immobilized magnetic NPs not only aid easy separation of the
catalyst from the reaction mixture but also improve the yields of the reactions.
Encouraged by the satisfactory results in the synthesis of diaryl ethers, we
decided to extend the investigation of the catalytic activity of Cu-IS-AMBA-MNPs
into the synthesis of diphenylamine from phenyl boronic acid (1 mmol) and aniline
(1.2 mmol). The efects of solvent, temperature, and the amount of Cu-IS-AMBA-
MNPs were examined to optimize the reaction conditions (Table 3). Acetonitrile,
methanol, water, DMF, and DMSO were evaluated as the solvent of which it was
1 3

Preparation and characterization of isatin complexed with…
Table 2 Synthesis of diaryl ethers 3a–3k in the presence of the catalysta
Entry Aryl halide
Phenols
Pro
Yieldb
(%)
TONc
Melting Point (oC)
duct
Found
Reported [Ref]
OH
I
1
3a
3b
3c
97
99
97
46
47
46
31-32
48-49
22-23
31 [43]
OH
I
NO2
2
47 - 49 [44]
OH
OH
I
Me
3
21.5 - 22 [44]
I
4
3d
96
95
45
45
21-22
20 [45]
Me
Me
I
OH
5
3e
62-63
61.9 - 62.2 [45]
NO2
I
OH
6
3f
97
95
96
46
45
46
97-98
30-31
56-57
96 - 98 [45]
31[43]
NO2
Br
OH
7
3g
3h
Br
OH
8
56 - 58 [46]
NO2
OH
Cl
Br
9
3i
96
46
62-63
63 - 64 [47]
NO2
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M. M. Khodaei et al.
Table 2 (continued)
Entry Aryl halide
Phenols
Pro
duct
Yieldb
(%)
TONc
Melting Point (oC)
Found
Reported [Ref]
OH
Br
NO2
10
3j
95
94
45
45-46
46 [48]
Cl
Cl
OH
11
3k
3l
44
32-34
31 [43]
Br
OH
MeO
Me
OMe
Me
12
90
42
35-37
-
-
NO2
Br
OH
13
3m
91
43
42-43
NO2
aReaction conditions: Phenyl halide (1 mmol), phenol derivative (1 mmol), K2CO3 (1.5 mmol), and the
catalyst (0.05 g) in DMF (5 mL) at 110 °C
bYields refer to the isolated products
cTON=(mmol of product/mmol of catalyst)
found that DMSO is the best (Table 3, entries 1–5). The temperature and catalyst
loading were examined and the results show that increasing the reaction temperature
or the catalyst loading leads to an increase in yield (Table 3, entries 6–10, 13, 14).
Thus, the optimal conditions were 0.06 g (0.025 mmol) of Cu-IS-AMBA-MNPs in
DMSO (4 mL) solvent at 130 °C in 2 h, and the yield of product was 97%.
The generality and applicability of this catalyst in the synthesis of diarylamines
were investigated under the optimized reaction conditions. The results in Table 4
show that anilines and phenylboronic acid derivatives with both electron-with-
drawing and electron-releasing groups reacted efciently and aforded the products
with excellent yields. N-arylation of iodobenzene aforded similar results to the
bromobenzene.
The most important advantages of heterogeneous solid catalysts in organic reac-
tions are recoverability and reusability. Thus, the recoverability and reusability of
the catalyst were investigated using the selected model reaction of iodobenzene
and phenol in DMF (Table 2, entry 1). The reaction mixture was cooled to room
temperature when the reaction was complete. Then, the catalyst was recovered by a
1 3

Preparation and characterization of isatin complexed with…
Table 3 Optimization of the reaction conditions in the synthesis of 6a
Entry Catalyst
Solvent Amount of the Temperature (°C) Time (h) Yield (%)a
catalyst (mg)
1
2
3
4
5
6
7
8
Cu-IS-AMBA-MNPs CH3OH 40
Cu-IS-AMBA-MNPs CH3CN 40
60
60
60
60
4
4
4
4
4
4
4
4
4
4
2
2
2
2
2
32
30
22
33
42
45
48
20
65
72
78
80
95
97
62
Cu-IS-AMBA-MNPs H2O
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMSO
40
40
40
60
Cu-IS-AMBA-MNPs CH3OH 40
Cu-IS-AMBA-MNPs CH3CN 40
Refux
Refux
Refux
100
100
130
130
130
130
130
Cu-IS-AMBA-MNPs H2O
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMF
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMSO
Cu-IS-AMBA-MNPs DMSO
40
40
40
40
40
50
60
60
9
10
11
12
13
14
15
CuCl2
DMSO
aYields refer to isolated products
magnetic feld, washed with water and ethanol, and dried for the next run. Accord-
ing to the obtained results, the catalyst has good activity, reusability, and stability in
the reaction media and could be reused fve times with no loss of activity (Fig. 7).
The reaction in the absence of the catalyst under the same conditions aforded no
product. The concentration of Cu in the catalyst was 2.7 wt% (0.42 mmol g−1) which
was determined using ICP-AES.
The capability and efciency of the catalyst compared with the catalysts reported
in the literature for the synthesis of diphenyl ether and diphenylamine derivatives
were studied. Thus, the reactions of phenyl iodide with phenol and boronic acid with
aniline were examined as representative examples and conducted in the presence of
diferent catalysts. The results indicate that these methods are comparable to some
previously reported methods in terms of reaction times and yields (Tables 5, 6).
Conclusion
A new and efcient copper–isatin complex supported on 4-(aminomethyl) benzoic
acid-functionalized Fe3O4 nanoparticles has been developed as a highly active and
recoverable heterogeneous and stable catalyst for the preparation of diaryl ethers
and diarylamines. These compounds were synthesized via the Ullmann coupling
reaction between aryl halides with phenols and boronic acid with arylamines. The
catalyst could be reused for several sequential cycles with no marked loss of its
activity.
1 3

M. M. Khodaei et al.
Table 4 Synthesis of diarylamines 6a-6 k in the presence of the catalysta
Entry
Boronic acid
Aniline
Product Yieldb TON
(%)
Melting Point (oC)
Found
Reported
[Ref]
B(OH)2
NH2
NH2
1
2
6a
95
38
39
53-54
52 – 54 [49]
B(OH)2
6b
97
64-66
65 - 66 [50]
Cl
NH2
B(OH)2
B(OH)2
3
4
5
6c
6d
6e
95
96
98
38
91-92
84-85
137
90 [51]
Me
NH2
38.5
39.2
85 - 87 [49]
135 - 136 [51]
NO2
NH2
B(OH)2
B(OH)2
NO2
NH2
6
7
8
6f
6g
6h
95
96
95
38
38.4
38
136-137 135 - 136 [51]
NO2
B(OH)2
NH2
80-82
81 - 83 [52]
Me
Cl
NH2
B(OH)2
NO2
136-137 135 - 137 [53]
Cl
1 3

Preparation and characterization of isatin complexed with…
Table 4 (continued)
Entry
Boronic acid
Aniline
Product Yieldb TON
(%)
Melting Point (oC)
Found
Reported
[Ref]
B(OH)2
Me
NH2
9
6i
6j
97
98
94
39
39.2
37
91-92
72-74
78-79
90 [51]
B(OH)2
NO2
NH2
NH2
10
11
73 - 75 [49]
B(OH)2
-
6k
Me
Me
NO2
Cl
B(OH)2
NH2
-
12
6l
92
36
85-87
MeO
OMe
NO2
aReaction conditions: Aniline (1.2 mmol), boronic acid (1 mmol), KF (2 mmol), and the catalyst (0.06 g)
in DMSO (4 mL) at 130 °C
bYields refer to the isolated products
Fig. 7 Reusability of the catalyst
1 3

M. M. Khodaei et al.
1 3

Preparation and characterization of isatin complexed with…
1 3

M. M. Khodaei et al.
Acknowledgement We thank the Research Council of Razi University for generous fnancial support of
this work.
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