α-Arylation of oxindoles using recyclable metal oxide ferrite nanoparticles: Comparison between the catalytic activities of nickel, cobalt and copper ferrite nanoparticles

Article abstract of DOI:10.1016/j.catcom.2015.11.020

Three different spinel metal oxide catalytic systems including NiFe₂O₄, CuFe₂O₄ and CoFe₂O₄ were synthesized using co-precipitation technique and their catalytic activities were compared to

Full text of DOI:10.1016/j.catcom.2015.11.020

α-Arylation of oxindoles using recyclable metal oxide ferrite nanoparticles:
Comparison between the catalytic activities of nickel, cobalt and copper ferrite
nanoparticles
Firouz Matloubi Moghaddam, Ghazal Tavakoli, Fatemeh Latifi, Borna
Saeednia
PII:
DOI:
Reference:
S1566-7367(15)30151-5
doi: 10.1016/j.catcom.2015.11.020
CATCOM 4516
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
14 October 2015
25 November 2015
27 November 2015
Please cite this article as: Firouz Matloubi Moghaddam, Ghazal Tavakoli, Fatemeh Latifi,
Borna Saeednia, α-Arylation of oxindoles using recyclable metal oxide ferrite nanopar-
ticles: Comparison between the catalytic activities of nickel, cobalt and copper ferrite
nanoparticles, Catalysis Communications (2015), doi: 10.1016/j.catcom.2015.11.020
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ACCEPTED MANUSCRIPT
α-Arylation of oxindoles using recyclable metal oxide ferrite
nanoparticles: comparison between the catalytic activities of
nickel, cobalt and copper ferrite nanoparticles
Firouz Matloubi Moghaddam,* Ghazal Tavakoli, Fatemeh Latifi and Borna Saeednia
Laboratory of Organic Synthesis and Natural Products, Department of Chemistry,
Sharif University of Technology, Azadi Street, PO Box 111559516, Tehran, Iran
*E-mail Address: matloubi@sharif.edu
Abstract
Three different spinel metal oxide catalytic systems including NiFe2O4, CuFe2O4 and CoFe2O4 were
synthesized using co-precipitation technique and their catalytic activities were compared to each other
in α-arylation of oxindole derivatives under the optimized reaction conditions. Both nickel ferrite and
copper ferrite magnetic nanoparticles show approximately the same behaviour in these reactions but
cobalt ferrite ones indicate slightly different properties and were not as good as the other two
catalysts. These superparamagnetic catalysts allowed that α-arylation of different types of oxindoles
to be occurred in high yields under mild conditions and at very short times.
Keywords: oxindole • α-arylation • superparamagnetic nanoparticles • recyclable catalyst •
heterogeneous catalysis
Introduction
One of the important structures that can be found most frequently in many natural products,
pharmaceutical targets and biologically active molecules is oxindole and its derivatives [1,2]. These
compounds exhibit antiabacterial and antifungal activities [3]. These C-3 functionalized oxindoles can
be used as drugs against a variety of neurodegenerative disorders [5] and also show anti-tumor [6] and
1

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anti-HIV properties [7]. One of the most important oxindoles are C-3 aryl ones playing a significant
role in some biological routes [2,4]. A number of techniques have been reported for synthesizing C-3
functionalized derivatives of oxindoles, especially C-3 arylated ones [4,8-14]
Metal-catalyzed routes for this purpose are of most important and efficient methods. Previously
reported methodologies based on classical chemical reactions [4,15-20] do not work when the
substrate contained the oxindole core. In such cases, intermolecular arylation of the C-3 position of
oxindole in the presence of a metal-based catalyst is what required, something named as metal-
catalyzed α-arylation of carbonyl compounds [11-14]. Hartwig et al. in 2001 reported intramolecular
α-arylation of oxindoles using Pd0 as catalyst to give 3,3-disubstituted oxindoles (Scheme 1a) [4]. In
2008, Durbin and Willis synthesized α-arylated oxindoles using Pd(dba)2 as catalyst (Scheme 1b).
Walsh et al. in 2013 reported α-arylation of acetamides with aryl chlorides in the presence of a
palladium precatalyst and a phosphinic ligand (Scheme 1c) [21]. Application of a strong base is
necessary in all these report to deprotonate the amidic α-proton. These works uses palladium with
phosphine ligands that suffers from some drawbacks. For example, palladium is a high cost, toxic and
moisture-sensitive transition metal that often needs to certain types of ligands, especially phosphinic
ones, to be active and effective [22]. The catalytic systems employed by Walsh and also by Durbin
and Willis are both homogeneous and none of them are recyclable. On the other hand, application of
ligands in many organic reactions can be supposed as a source of limitation because many of these
ligands are not available easily. These reactions are also performed under approximately harsh
reaction conditions. There are some examples of α-arylation of carbonyl compounds using other
transition-metal based catalysts, especially cuprous or cupric salts [23]. Application of such catalysts
is also accompanied with some drawbacks. Cu(I) salts are also air-sensitive and require harsh
conditions to be kept stable. Furthermore, these metal sources may contaminate the final products
leading to limitations on their usage as drugs.
((Scheme 1))
2

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On the other hand, among the carbonyl containing compounds, α-arylation of amide enolates is most
challenging due to high pKa values of the substrates [14]. As far as we know, there is a few reports
regarding metal-catalyzed C-3 arylation of oxindoles [24]; so, introducing new efficient
methodologies to this end could be of high importance. Due to the limitations of previous catalytic
systems, there remains a need for introducing low-cost and readily available catalysts with high
efficiency. Magnetic metal oxide nanoparticles, especially those with spinel structure, have attracted
many attentions recently. In fact, the presence of two transition metals in these systems could enhance
their catalytic activity because of the synergistic effect between the two metals [25,26]. These
heterogeneous catalysts not only have considerable catalytic activity, but also can be synthesized
easily. In addition, they can be recovered simply from the reaction media using an external magnetic
field and can be reused for several times. This is the main advantages of these systems especially from
the industrial view point [27-29].
Considering all these facts and many others, we decided to employ superparamagnetic nickel ferrite
nanoparticles as catalyst in the α-aryaltion of oxindoles. These spinel nanoparticles were synthesized
and characterized previously by our group and their excellent catalytic activity in various C-C and C-
heteroatom coupling reactions was demonstrated [30,31]. Herein, in continuation of our previous
works, the applicability of these magnetic nanoparticles as an efficient catalytic system in α-arylation
of oxindoles is reported. Different types of oxindole derivatives having substituents on the aromatic
ring or without that were synthesized and used as substrate in this reaction. Results show that
compared to the previously reported Pd- or Cu-catalyzed α-arylation reactions [14,24,32], this
procedure could functionalized C-3 position of oxindoles successfully with very good yields in
reasonably shorter reaction times. These remarkable results encouraged us to do a comparative
investigation to find a catalyst with best catalytic behavior for this reaction. To this end, two
additional metal oxides, i.e. copper ferrite and cobalt ferrite nanoparticles were synthesized [30] and
their activity as catalyst was examined in the α-aryalation of oxindoles under the same reaction
conditions.
3

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Results and Discussion
Nickel, cobalt and copper ferrite magnetic nanoparticles were synthesized using co-precipitation
method[30]. These nanoparticles were used as catalyst in the α-arylation reaction of oxindole
derivatives and their activities were compared to each other.
Optimum reaction conditions were determined initially using nickel ferrite nanoparticles as catalyst.
The reaction between N-methyl oxindole and bromobenzene was selected as the model reaction and
the effect of each of the parameters on this reaction was considered carefully (Table 1). The reaction
resulted in the formation of two products, 1a and 1b, depends on the reactant ratios and other
conditions.
As can be seen in table 1, when the reaction is conducted in DMSO, Toluene and NMP, the formation
of byproduct 1b is unavoidable. The model reaction also was performed in H2O as the green solvent
but its yield was not good. Finally, using 1,4-dioxane as solvent, not only yield of the reaction was
much better, but also the ratio of products 1a to 1b is very high and it can be said that the reaction
approximately resulted in the selective formation of 1a as the sole product (Table 1, entry 4).
The effect of various organic and inorganic bases also was investigated (Table 1, entries 4, 6-9). Both
K2CO3 and KOt-Bu resulted in full conversion of the substrate under these reaction conditions;
however, using KOt-Bu as base, higher amount of byproduct, 1b, is produced in the reaction (Table 1,
entry 8). Therefore, K2CO3 was selected as the best base (Table 1, entry 4).
((Table 1))
In order to optimize the amount of catalyst required for such transformation, the model reaction was
repeated in the absence of catalyst and also in the presence of 1, 2, 5 and 10 mol% of NiFe2O4
nanaoparticles (Table 1, entries 4, 10-13). As it is shown in table 1, the reaction does not progress in
the absence of catalyst. In addition, when 1 or 2 mol% of nickel ferrite nanoparticles were used,
reaction rate is not so high and their yields are moderate; however, when the catalyst concentration
4

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increases to 5 mol%, very good yield could be obtained in a reasonable time and with minimum
formation of the byproduct (Table 1, entry 13). Further increase in the amount of catalyst (up to 10
mol%) does not give rise to higher reaction rate and better yields of 1a.
Conducting the model reaction at 100 oC, 70 oC , 45 oC and also at room temperature (Table 1, entries
o
13-16) showed that although the reaction rate and conversion is relatively low at 45 C and room
o
o
temperature, the results obtained at 70 C were excellent. At 100 C, the reaction rate was not
increased but higher amount of 1b was formed.
In the final step, reactant ratio was investigated. Results indicated that decreasing the amount of
bromobenzene to 1 equivalent caused the formation of 1a as the sole product (Table 1, entry 17).
Having these reaction conditions in hand, scope of the reaction between different types of aryl halides
and oxindole derivatives was explored (Table 2). As can be seen, the reaction has very good
functional group tolerability and all types of aryl halides containing various substituents on the phenyl
ring can be used in this reaction. Furthermore, not only aryl iodides and bromides but also the less
reactive aryl chlorides could be used effectively under the defined conditions. In all cases, the
reactions were completed in reasonably short times under relatively mild conditions and with very
good to excellent yields. In addition, all the reactions show very good selectivity for the monoarylated
oxindole derivatives. Comparison of 4-chloroacetophenone and 2-chloroacetophenone reveals that the
2-substituted one required longer reaction time to be completed; it can be attributed to more steric
hindrance around the active site of the reaction (i.e. Cl) in the later case.
((Table 2))
On the other hand, the scope of the reaction regarding oxindole was also investigated (Table 2).
Different derivatives of oxindoles including N-methyl, ethyl, phenyl and benzyl oxindoles and also 5-
methoxy-N-benzyl and 5-methyl-N-methyloxindole were synthesized [33] and used in the reaction.
Again, all the reactions were completed in very short times with excellent yields.
5

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Observing such good results encouraged us to test the reaction using other metal oxide nanoparticles
and compared their catalytic activities with NiFe2O4. So, we decided to investigate the activity of
cobalt and copper ferrite nanopartcles in the α-arylation of oxindoles. To this end, magnetic
nanoparticles of copper and cobalt ferrite were synthesized with the same procedure, characterized
and were employed in the C3 functionalization of oxindoles. In order to have a fair comparison
between these catalysts, all the reactions were carried out under the optimized reaction conditions
obtained using nickel ferrite nanoparticle as catalyst (Table 2).
According to the experiments, α-arylation reaction could be catalyzed efficiently using all these three
catalytic systems. Yields and selectivities of NiFe2O4- and CuFe2O4 catalyzed reactions were
comparable. Again, the nature of aryl group in the aryl halide moiety did not affect the results and the
reactions did not show any sensitivity to the functional groups and substituents on the aromatic ring.
However, when the reactions were carried out using cobalt ferrite nanoparticles, the probability for
the formation of diarylated oxindoles increases and conversion of oxindoles to the desired products
was not complete in some cases. The reactions also required longer reaction times to be completed.
The situation was not observed so seriously in the case of copper ferrite.
The reusability of the cataysts in the reaction of bromobenzene with N-methyloxindole was
investigated in the next step (supplementay data) (Figure 1). According to the obtained results, it can
be said that the catalytic efficiency of both nickel and copper ferrite nanoparticles remains
approximately constant during the course of the reactions. However, the catalytic activity of CoFe2O4
is decreased after the 5th run.
((Figure 1))
It is demonstrated that the presence of metal contaminants presented in the iron source can catalyze
the coupling reaction between aryl halides and various types of nucleuphiles [34,35]. So, a control
experiment was done using 5 mol% of FeCl3.6H2O as catalyst (Scheme 2). The result showed that
FeCl3.6H2O is unable to catalyzed the reaction effectively.
6

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((Scheme 2))
Conclusions
In Summary, α-arylation of different oxindole derivatives was examined using magnetic metal oxide
nanoparticles as catalyst. Three different catalytic systems including NiFe2O4, CuFe2O4 and CoFe2O4
were synthesized and characterized and their application in the C3-arylation of oxindoles was
investigated. Also, the catalytic activity, reusability and leaching phenomenon of these catalysts were
compared to each other. Both nickel ferrite and copper ferrite nanoparticles show approximately the
same behavior in these reactions but CoFe2O4 indicate slightly different properties and were not as
good as the two other catalysts. The rate of precipitation and also the reusability of the nickel and
copper ferrite nanoparticles were higher than cobalt ferrite. Leaching test's results showed that in
contrast to most of heterogeneous catalysts, there is no leaching in these catalytic systems. In total, the
three proposed catalytic systems have many advantages over the classic homo- and heterogeneous
catalysts: they are synthesized easily from available and low-cost starting materials; they can be
totally removed from the reaction media and finally, the exposure to air, moisture and elevated
temperatures could not deactivate them.
The proposed conditions applied here lead to more convenient procedure compared to previous
reports using other heterogeneous or homogeneous catalytic systems. Substitution pattern can be
varied on both the oxindole and aryl halide and reactions showed no sensitivity toward electron-
withdrawing or donating substituents on the reactants. All the reactions were completed in very short
times with very good to excellent yields. Therefore, considering these mild conditions and the
possibility for total removal of the metal-based catalyst from the reaction media, this methodology has
enough potential to be used in pharmaceutical and other sensitive synthetic procedures.
Experimental Section
General Procedure for the α-arylation of oxindole derivatives
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An oven-dried reflux tube equipped with a magnetic stir bar and a Teflon stopcock was charged with
aryl halide (1 mmol), oxindole (1 mmol), potassium carbonate (1.1 mmol), catalyst nanoparticles
o
(0.05 mmol) and 1,4-dioxane (2 ml) and heated at 70 C. The mixture was vigorously stirred under
these reaction conditions and completion of the reaction was monitored by TLC (EtOAc: n-hexane,
25:75).
After completion of the reaction, the reaction mixture was cooled to room temperature, the magnetic
nanoparticles of the catalyst were collected using a megnet. Ethyl acetate (5 mL) and water (10 mL)
were added to the mixture in the next step. The aqueous layer was further extracted by ethyl acetate
(2*5 mL). The combined organic layers were washed with saturated brine, dried over CaCl2, filtered,
and concentrated to give a residue which was purified by recrystallization from ethanol and water or
by column chromatography on silica gel using EtOAc: n-hexane, 1:7.
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((List of Tables))
Table 1. Screening the reaction conditions for α-arylation of oxindole derivatives.a
Ph
Ph
Ph
Br
NiFe2O4
O
O
+
O
+
Solvent, Base,
Temp., 30 min.
N
Me
N
Me
N
Me
1b
Yield (%)b
1a
Entry
Solvent
Base
Catalyst
Temperature
(oC)
(mol%)
1a
62
1b
14
11
6
1
2
DMSO
Toluene
H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOAc
KOtBu
Et3N
10
10
10
10
10
10
10
10
10
None
1
100
100
100
100
100
100
100
100
100
100
100
100
100
70
53
3
44
4
1,4-dioxane
NMP
86
7
5
66
13
8
6
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
71
7
45
11
12
10
0
8
82
9
64
10
11
12
13
14
15
16
17c
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Trace
43
Trace
3
2
61
5
85
6
5
86
4
5
45
52
0
5
RT
43
0
5
70
85
0
aReaction conditions: N-methyl oxindole (1 mmol), Bromobenzene (1.2 mmol), Base (1.1 mmol),
Catalyst, Solvent (2 mL), Temperature (oC).
bIsolated yield.
cN-Methyl oxindole (1 mmol), Bromobenzene (1 mmol).
10

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Table 2. α-Arylation of oxindole derivatives under optimized conditions.a
Ar
Ar
Ar
R'
R'
R'
MFe2O4 (5 mol%)
+
Ar-X
O
O
O
+
1.4-dioxane, K2CO3
70 oC
N
R
N
R
N
R
1b
1a
Yeild (%)b,c,d
CoFe2O4
93: ND
94: ND
92: ND
90: Trace
90: 4
Time (min)
Entry
ArX
R
R'
NiFe2O4
CuFe2O4
95: ND
NiFe2O4
60
CoFe2O4
90
CuFe2O4
50
1
Iodobenzene
Bromobenzene
Me
Me
H
H
95: NDe
95: ND
2
94: ND
60
90
60
3
Chlorobenzene
Me
H
94: ND
93: ND
80
120
150
180
180
240
300
330
270
150
150
180
300
240
300
300
360
150
180
240
360
180
180
240
420
180
150
240
90
4
4-Bromotoluene
4-Bromoanisole
4-Bromobenzonitrile
Me
H
92: Trace
91: Trace
92: Trace
90: Trace
91: Trace
85: ND
93: Trace
93: Trace
91: Trace
89: Trace
91: Trace
87: Trace
95: ND
90
100
90
5
Me
H
90
6
Me
H
88: 5
100
150
180
180
120
80
90
7
4-Chlorobenzaldehyde
4-Chloroacetophenone
2-Chloroacetophenone
1-Bromonaphthalene
Chlorobenzene
Me
H
85: 5
180
200
180
100
80
8
Me
H
87: Trace
81: Trace
93: Trace
95: Trace
87: 7
9
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Me
H
95: ND
Et
H
94: ND
95: ND
4-Bromoanisole
Et
H
92: ND
91: ND
80
90
4-Bromobenzonitrile
4-Chloroacetophenone
Chlorobenzene
Et
H
93: Trace
90: Trace
93: Trace
90: ND
90: Trace
84: 10
91: 8
91: Trace
89: Trace
95: ND
90
100
180
80
Et
H
150
90
Ph
H
4-Bromoanisole
Ph
H
85: 5
91: ND
120
100
100
90
120
120
90
4-Bromobenzonitrile
4-Chloroacetophenone
Chlorobenzene
Ph
H
93: ND
88: 7
92: ND
Ph
H
91: Trace
95: Trace
92: Trace
90: ND
87: 6
90: ND
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Me
H
91:5
94: ND
100
140
120
200
80
4-Bromoanisole
H
89: 7
92: ND
120
120
180
90
4-Bromobenzonitrile
2-Chloroacetophenone
Chlorobenzene
H
87: 5
91: ND
H
88: Trace
90: ND
88: Trace
90: 7
90: ND
OMe
OMe
OMe
OMe
OMe
Me
Me
91: Trace
90: 5
4-Bromoanisole
89: ND
90: 5
120
120
240
80
140
120
270
90
4- Chloroacetophenone
2-Chloroacetophenone
1-Bromonaphthalene
Chlorobenzene
92: ND
90: 9
91: ND
87: ND
84: 5
85: Trace
93: ND
92: ND
90: Trace
89: 8
95: Trace
93: Trace
94: Trace
93: ND
80
80
4-Bromoanisole
Me
90: 7
100
120
11

ACCEPTED MANUSCRIPT
30
31
4- Chloroacetophenone
2- Chloroacetophenone
Me
Me
Me
Me
91: ND
86: ND
90: 5
82: 6
92: ND
88: ND
90
180
420
80
180
240
[a] Reaction conditions: aryl halide (1 mmol), oxindole (1 mmol), K2CO3 (1.1 mmol), catalyst (5 mol%), 1,4-
dioxane (2 ml) and 70 oC.
[b] All reactions have enough time to be completed with full conversions with respect to oxindoles.
[c] Isolated yield.
[d] 1a:1b ratio.
[e] Not detected.
List of Schemes and Figures
a) Lee and Hartwig
Ar
X
O
10 mol% Pd(OAc)2/ PCy3
+
Ar-Cl
O
NaOtBu, 1,4-dioxane
70 oC, 12h
N
N
b) Durbin and Willis
X
Ar
2 mol% Pd(dba)3,
3 mol% Ligand
O
+
O
KHMDS
THF/ Toluene
70 oC, 30 min
N
R
N
R
R'
c) Walsh et al.
2.5 mol% Pd precatalyst
O
O
Ligand, LiOtBu
ArCl +
Ar
NEt2
NEt2
CPME, 12h, 110 oC
d) This work
X
Ar
R'
R'
Catalyst 1-3 (5 mol%)
O
+
O
1,4-dioxane, K2CO3
70 oC, 30-180 min
N
R
N
R
R''
R= Me, Et, Ph, CH2Ph
R' = H, Me, OMe
X = Cl, Br, I
Catalyst = NiFe2O4,CoFe2O4, CuFe2O4
Scheme 1. Comparison of previous reports on α-aryaltion of oxindoles with this work.
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ACCEPTED MANUSCRIPT
Ph
Br
FeCl3.6H2O(5 mol%)
O
+
O
N
Me
1,4-dioxane, K2CO3
N
Me
70 oC
<1%
Scheme 2. Control experiment for confirming the essential role of metal ferrite nanoparticles as catalyst.
Figure 1. Recovery and reuse of a) nickel ferrite nanoparticles; b) copper ferrite nanoparticles; and c) cobalt
ferrite nanoparticles in the α-arylation reaction of bromobenzene and N-methyl oxindole; Reaction conditions:
bromobenzene (1 mmol), oxindole (1 mmol), catalyst (5 mol %), K2CO3 (1.1 mmol), 1,4-dioxane (2 mL) and 70
oC.
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