A copper-free Sonogashira reaction using nickel ferrite as catalyst in water

Article abstract of DOI:10.1016/j.catcom.2014.11.018

The Sonogashira reaction using nickel ferrite nanoparticles as catalyst and under copper-free conditions was investigated in water as a green solvent. Various types of aryl and alkyl halides were successfully coupled with phenyl acetylene under the optimized reaction conditions with very good to excellent yields at a short time. The catalyst is easily recoverable and can be reused for several runs with a good turnover number.

Full text of DOI:10.1016/j.catcom.2014.11.018

A copper-free Sonogashira reaction using nickel ferrite as catalyst in water
Firouz Matloubi Moghaddam, Ghazal Tavakoli, Hamid Reza Rezvani
PII:
DOI:
Reference:
S1566-7367(14)00471-3
doi: 10.1016/j.catcom.2014.11.018
CATCOM 4140
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
31 August 2014
15 November 2014
17 November 2014
Please cite this article as: Firouz Matloubi Moghaddam, Ghazal Tavakoli, Hamid Reza
Rezvani, A copper-free Sonogashira reaction using nickel ferrite as catalyst in water,
Catalysis Communications (2014), doi: 10.1016/j.catcom.2014.11.018
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ACCEPTED MANUSCRIPT
A copper-free Sonogashira reaction using nickel ferrite as catalyst in water
Firouz Matloubi Moghaddam*, Ghazal Tavakoli and Hamid Reza Rezvani
Laboratory of Organic Synthesis and Natural Products, Department of Chemistry,
Sharif University of Technology, Azadi Street, PO Box 111559516
Tehran, Iran, +982166165309
*
E-mail Address: matloubi@sharif.edu
Abstract
The Sonogashira reaction using nickel ferrite nanoparticles as catalyst and under copper-free
conditions was investigated in water as a green solvent. Various types of aryl and alkyl
halides were successfully coupled with phenyl acetylene under the optimized reaction
conditions with very good to excellent yields at short time. The catalyst is easily recoverable
and can be reused for several runs with good turnover number.
Keywords: Sonogashira reaction, nickel ferrite nanoparticles, water, super paramagnetism
1
.1 Introduction
Compounds containing carbon- carbon triple bonds have found applications in diverse areas
including pharmaceuticals, natural products, bioactive compounds, engineered materials and
molecular organic materials [1-3]. From the synthetic points of view, the Sonogashira
reaction ranks among the most valuable and straightforward processes for the formation of
terminal and internal alkynes [4-6].
Despite the presence of large amounts of reports regarding to coupling of aryl, alkenyl and
alkynyl halides using transition metal catalysts, examples of coupling of alkyl halides are
very rare [7-12]. This is attributed to more electron-rich nature of alkyl halides compared to
2
sp- and sp - hybridized carbon electrophiles making the oxidative-addition step of the
reaction difficult. Furthermore, the β-H elimination step of the reaction to give olefinic
compounds is also prone to be difficult using alkyl halides as one of the coupling partners
[
13].
1

ACCEPTED MANUSCRIPT
Traditionally, this reaction requires a large amount of palladium and CuI as co-catalyst to
2
catalyze the reaction between sp -C halides and terminal acetylenes [14]. The presence of
Cu/O in the reaction media can cause to a side reaction of Glaser-type dimerization of
2
acetylene substrates to afford diyne [2, 15] as well as contamination of the products with
poisonous metal residues [16]. This is one of the main drawbacks of the Sonogashira reaction
that has been partially solved employing copper-free reactions [17, 18]. Most catalytic
systems used for the Sonogashira reaction are homogeneous palladium-based catalysts having
tedious recovery, if not impossible [19]. To solve this problem, researchers have attracted
many attentions to develop new catalytic systems with high efficiency and easy recovery [13,
2
0, 21].
Bimetallic nanomaterials are an important class of heterogeneous catalysts with well-defined
size, shape and composition properties [22, 23]. In these compounds, the addition of the
second metal has a significant effect on geometric and electronic structure of nanoparticles
causing to their better catalytic activity, selectivity and stability [24]. NiFe O nanoparticles,
2
4
one of the known bimetallics, show very good catalytic activity in organic reactions [25].
These nanoparticles show superparamagnetic properties making it possible to recover them
using an external magnetic field after completion of the reaction.
The original Sonogashira reaction was generally performed in organic solvents as reaction
media; but these solvents suffer from safety, health and environmental issues because of their
toxicity, flammability and volatility. Considering the large amounts of solvents used in
organic reactions, this is the main drawback for most chemical industries. So, there is
increasing interest to search for finding new methodologies to perform reactions under
solvent-free conditions or in water in order to comply with the Green Chemistry principles
[
14, 26, 27]. However, the application of water for such chemical transformation is seldom
reported [28]. Approximately, in most of these reports, the reactions need to a long times
about 24 h) to be completed with moderate to good yields.
(
A small glance to the literatures shows clearly the absence of enough researches on the Csp-
alkyl halide coupling reaction in the presence of transition metal catalysts. Historically, in
2
003, Fu et al. [29] reported for the first time the palladium-catalyzed reaction of alkyl
bromides and iodides with alkynes (Scheme 1a). However, these conditions were not
applicable for alkyl chlorides and also, the reactions needed long times and resulted in
moderate yields. Furthermore, this reaction required CuI as co-catalyst causing to the
2

ACCEPTED MANUSCRIPT
formation of some diyne as by-product. Lately, in 2009, Hu et al. [30] described firstly the
Sonogashira coupling of alkyl halides using a nickel-based homogeneous catalytic system
(Scheme 1b). Again in this case, it was necessary to use CuI to improve the reaction
conditions. The time required for the completion of these reactions is also too long. Both of
these reactions were conducted in the presence of hazardous organic solvents. Another main
drawback of these reactions was the homogeneous nature of their catalysts making their
recovery difficult.
((Scheme 1))
Herein, in continuation of previous works and in order to show the applicability of the
previously synthesized catalytic system in diverse organic reactions [31-33], we wish to
report a copper-free Sonogashira reaction of different aryl and alkyl halides with
phenylacetylene using a highly active recyclable heterogeneous catalyst, NiFe O , under
2
4
conventional heating conditions in water as a green solvent (Scheme 1c). Because of the
nanosized characteristic of this catalyst, all reactions can be performed efficiently using small
amount of the catalyst in short times compared to the most reported Sonogashira reactions
using the straightforward reaction conditions.
1
.2 Experimental
1
.2.1 Materials and characterization methods
All materials used are commercially available and were purchased from Merck and used
1
13
without any additional purification. H NMR and C NMR spectra were recorded on a
Bruker (Avance DRX-500) spectrometer using CDCl as solvent at room temperature.
3
Chemical shifts δ were reported in ppm relative to tetramethylsilane as an internal standard.
XRF analysis was recorded on Spectro Xepos Spectrometer. The characterization of the
samples was done by crystallographic phase identification performed on a Sradi P
diffractometer with Cu Kα radiation, a graphite monochromator on the diffracted beam and
oscillation counter. FTIR spectra of samples were taken using an ABB Bomem MB-100
FTIR spectrophotometer. The morphology of the catalyst was observed using a Philips XL30
scanning electron microscope (SEM). Magnetic measurements were carried out at room
temperature and by using an AGFM magnetometer.
1
.2.2 General Procedure for the Sonogashira Reaction
3

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In a round-bottom flask equipped with a condenser for refluxing and a magnetic stirring bar,
aryl/ alkyl halide (1 mmol), phenyl acetylene (1 mmol), K CO (1.1 mmol), nickel ferrite
2
3
o
nanoparticles (0.05 mmol) and water (3 ml) were added and heated at 100 C under air
atmosphere. The mixture was vigorously stirred under these reaction conditions and its
completion was monitored by TLC (EtOAc–n-hexane, 25:75).
In each case, after completion of the reaction, the mixture was diluted with diethyl ether and
water. The organic layer was washed with brine, dried over MgSO , and concentrated under
4
reduced pressure using a rotary evaporator. The residue was purified by recrystallization from
ethanol and water.
1
.3 Results and Discussion
The nanoparticles of nickel ferrite were prepared according to the procedure previously
reported by our group [31]. After identification and characterization of the exact structure of
the catalytic system, its activity in the Sonogashira reaction was investigated under
conventional heating conditions.
For optimization of reaction conditions, the coupling of bromobenzene with phenylacetylene
as the model reaction was chosen and the effects of the base, solvent and concentration of
catalyst on the reaction were examined. The results are shown in Table 1. Firstly, different
solvents were employed in this reaction using K CO as base and in the presence of 5 mol%
2
3
of catalyst (entries 1-4). The results clearly showed that water can be used as reaction media
as well as hazardous organic solvents. So, in order to comply with Green Chemistry
principles, water was selected as the best solvent for this reaction (entry 4).
((Table 1))
The type of base employed in these reactions also can affect their yields. So, in the next step,
various types of organic and inorganic bases were investigated (entries 4-8). Among the bases
used, both K CO and Cs CO have the same effects and can conduct the reaction effectively.
2
3
2
3
So, considering more availability of K CO and its lower price, it was chosen as the optimum
2
3
base for the reaction (entry 4).
The amount of the NiFe O required for catalyzing the reactions was optimized in the next
2
4
step. To this end, reaction of phenylacetylene and bromobenzene was carried out both in the
absence and also in the presence of 0.1, 1, 2, 5 and 10 mol% of the catalyst (entries 4, 9-13)
and finally it was demonstrated that use of 5 mol% of catalyst can effectively catalyze the
reaction in a short time with a reasonable yield (entry 4).
4

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Another parameter that considerably could affect the reaction was temperature. So, its effect
o
was also examined by performing the model reaction at room temperature, 60 and 100 C
(entries 4, 14-15). According to the results shown in table 1, the reaction can be carried out
o
optimally at 100 C resulting in higher conversion during shorter times.
With our optimized reaction conditions in hand, the scope of the Sonogashira reaction was
investigated. The results are summarized in Table 2. As can be seen, different types of aryl
halides bearing both electron-donating and electron-withdrawing groups can be coupled
effectively with phenyl acetylene under the defined conditions. Although it is often reported
that the reactivity of aryl chlorides in the coupling reactions is low, employing these
conditions can conduct the reaction between various types of aryl chlorides as well as aryl
iodides and bromides. It is a noteworthy point because of more availability and abundance of
aryl chlorides. Observing the excellent activity of the catalytic system under the defined
reaction conditions, in the next step, the reaction of some activated alkyl halides was
investigated. Again, the results were surprising and all the reactions were completed in short
times with very good yields.
Although active alkyl halides were successfully coupled with phenylacetylene (entries 16-
1
8), the yields of the reaction of inactive alkyl halides were not high enough (entries 19-22).
In fact, the reaction of these alkyl halides such as 1-bromopropan, 2-bromopropane, 1-
chlorobutane and iodoethane requires longer times to be completed. Furthermore, due to the
formation of small amount of byproducts, the final yields of these reactions decreased.
Also, phenyl acetylene was substituted with 1- heptyne as the second coupling partner with
some aryl halides to show further the scope of the procedure. In these cases, again good
conversions in short times were gained (entries 23-26).
((Table 2))
In order to examine the applicability of the defined procedure, a large scale reaction was
performed successfully between 3 mol (600 mg) of 4-bromoacetophenone and 3 mol (330
mL) of phenyl acetylene under optimized reaction conditions (Scheme 2).
((Scheme 2))
To check the reusability of the catalyst, the reaction of bromobenzene with phenyl acetylene
was performed under the optimized reaction conditions. After measuring its yield, the
superparamagnetic nanoparticles of the catalyst were separated using a magnet. These
nanoparticles after washing with water and drying on air were employed in the same reaction
for the second run. This process was repeated 5 times and each time, measuring the isolated
5

ACCEPTED MANUSCRIPT
yields exactly confirmed that the catalytic efficiency of the catalyst was not changed and
nanoparticles were not deactivated during catalysis the reactions (Scheme 2).
((Scheme 3))
To verify that the size and morphology of the nanoparticles were not changed during the
process, the SEM images of the recovered nanoparticles were obtained after second (Scheme
3
-a) and fifth (Scheme 3-b) runs. According to these images, any significant alteration was
not observed and size, morphology and dispersity of the NPs remained unchanged. Also, the
leaching of the catalyst was examined. To this end, the reaction between bromobenzene and
phenylacetylene was repeated simultaneously in two different vessels under the optimized
reaction conditions. In each case, the reaction progress was monitored using GC after 20
minutes. Then the catalyst's nanoparticles were collected from one of these vessels using a
magnet, while the other was remained unchanged. Thereafter, both of the reactions were
continued under the same conditions. After another twenty minutes, both the reactions were
stopped and their completion was again examined using GC. The results showed that the
reaction in the absence of the catalyst was not proceeded any more, while the progress of the
reaction in the other vessel was considerable. This observation confirmed that leaching was
not occurred in the reaction medium during the process. So, the proposed catalytic system not
only can catalyze appropriately the Sonogashira reaction of aryl- and alkyl halides, both also
can be reused for several times without any significant activity lost.
((Scheme 4))
On the other hand, it is found previously that the presence of metal contaminants presented in
the iron source can catalyze these reactions [34, 35]. So, in order to verify that this
phenomenon does not affect the reaction, a control experiment was done using 10 mol% of
FeCl as catalyst under the optimized reaction conditions. The reaction of phenyl acetylene
3
with bromobenzene and also 4-bromoanisole was selected as model reactions. Having
comparable results with those in the presence of nickel ferrite, the reaction of bromobenzene
and of 4-bromoanisole were stopped after 1 and 3 hours, respectively. In both cases, the
reactions show no progress using FeCl as catalyst. When let the reactions to stir and heat for
3
2
4 hours, a time much longer than the required time for completion of the reactions
performed using nickel ferrite, a small amounts of the corresponding products were formed,
but in negligible amounts as can be seen in scheme 4.
((Scheme 5))
Another control experiment was done using NiCl as catalyst to confirm the absence of metal
2
contaminants in the nickel source. To this end, the reaction between 4-bromoanisole and
6

ACCEPTED MANUSCRIPT
phenyl acetylene was repeated under the optimized reaction conditions using 10 mol% of
NiCl as catalyst. Again, the reaction was stopped after 3 hours and its conversion and yield
2
were determined exactly. The amount of the desired product in this case was also very small
(Scheme 5).
((Scheme 6))
To carry out the Hg poisoning test, Hg (Hg: NiFe O ; 400: 1) was put in a reaction flask.
2
4
Thereafter, 4-bromobenzaldehyde (1.0 mmol), phenyl acetylene (1.0 mmol) and the requisite
amount of catalyst nanoparticles were added to it. The reaction was carried out under
optimum conditions. The progress of the reaction was monitored with TLC. After continuing
the reaction further for 2.5 h at 100 °C, only a 42% yield could be reached.
1
.4 Conclusion
Summarily, superparamagnetic nickel ferrite nanoparticles were employed in the Sonogashira
reaction of various types of aryl- and alkyl halides in water. This catalyst is readily prepared
from available starting materials and also is a reusable catalyst having very good stability to
air, moisture and elevated temperatures. The proposed procedure applied here for the
Sonogashira reaction leads to better yields in approximately shorter times compared to
previous reports using other catalytic systems. Therefore, considering these and its
compliance with green chemistry principles, this methodology is a useful and general method
for the coupling of terminal alkynes and aryl- or alkyl halides. In addition, because of total
removal of the metal-based catalyst from the reaction media, the procedure can be applied in
pharmaceutical and other sensitive synthetic procedures.
Acknowledgments
We gratefully acknowledge the funding support received for this project from the Sharif
University of Technology (SUT), Islamic Republic of Iran.
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[
(
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Table 1. Optimization of reaction conditions for Sonogashira reaction under conventional
a
heating conditions
9

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Br
Ni-Ferrite NPs
Temp., Base,
Solvent
Catalyst
Temperature
Time
(min)
30
Yield
Entry
Solvent
Base
o
b
(mol%)
( C)
(%)
1
2
3
4
5
6
7
8
9
DMF
Toluene
THF
K CO
2
5
5
100
100
68
59
54
72
73
43
47
51
0
3
3
3
K CO
2
30
K CO
2
5
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
30
H O
2
K CO
2 3
5
30
H O
2
Cs CO
3
5
30
2
H O
2
NaOAc
NaOH
5
30
H O
2
5
30
H O
2
Et N
5
30
3
H O
2
K CO
2
None
0.1
1
30
3
3
3
3
3
3
3
1
1
1
1
1
1
0
1
2
3
4
5
H O
2
K CO
2
30
20
41
53
74
62
40
H O
2
K CO
2
30
H O
2
K CO
2
2
30
H O
2
K CO
2
10
5
30
H O
2
K CO
2
30
H O
2
K CO
2
5
r.t.
30
a
Reaction condition: bromobenzene (1 mmol), phenyl acetylene (1 mmol), Base (1.1 mmol), catalyst,
Solvent (3 ml) and Temperature.
bIsolated yield
1
0

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Table 2. The Sonogashira reaction of various aryl halides under optimized reaction
a
conditions
5
mol%Ni-Ferrite NPs
R-X
R'
R
R'
o
H O, K CO , 100 C
2
2
3
Time
h)
Yield
Entry
1
RX
Product
b
(
(%)
I
Ph
Ph
Ph
Ph
0.75
1
95
94
92
Br
Cl
2
3
Ph
Ph
1.5
I
4
5
Ph
OMe
OMe
2.5
3
93
91
MeO
Br
Ph
MeO
O
Br
Ph
6
7
8
2
89
90
91
O
O
Cl
Br
Ph
Ph
2.5
2.5
O
H
O
H
O
1
1

ACCEPTED MANUSCRIPT
Cl
H
O
9
H
Ph
3
92
O
Br
1
0
1
Ph
Ph
CN
CN
2
88
85
NC
Cl
1
2.25
NC
Br
1
1
2
3
2
2
89
90
Ph
Br
Ph
O
O
H
1
4
H
4
87
Cl
Ph
Ph
Cl
1
1
5
6
2
3
93
86
O N
2
O N
2
O
O
Ph
Br
Ph
Br
1
1
7
8
2
85
88
Br
1.5
Ph
1
2

ACCEPTED MANUSCRIPT
Ph
1
2
9
0
Br
6
7
78
73
Br
Ph
Ph
2
2
1
2
7
5
70
80
Cl
Br
Ph
I
2
2
3
4
(CH2)4 CH3
2.5
3
83
84
Br
MeO
NC
(CH2)4 CH3
(CH2)4 CH3
CH2)4 CH3
MeO
NC
Br
2
2
5
6
2.25
2.5
87
81
Br
Ph
(
a
Reaction condition: aryl/ alkyl halide (1 mmol), alkyne* (1 mmol), K CO (1.1 mmol), catalyst (5
2
3
o
mol%), H O (3 ml) and 100 C.
2
b
Isolated yield.
*alkyne = phenyl acetylene or 1-heptyne
1
3

ACCEPTED MANUSCRIPT
((Scheme 1))
R2
N
a) Fu et al.
N
R2
2
R = 1-adamantyl
Ralkyl-X
+
R'
Ralkyl
R'
R'
2.5% [Pd], 7.5% CuI
1
.4 equiv. Cs CO , 16 h
2 3
o
DMF/Et O, 40-45 C
2
b) Hu et al.
NMe2
5
mol% 1, 3mol% CuI
0
or 20 mol% NaI
Ralkyl-X
+
R'
Ralkyl
N
Ni Cl
1
.4 eq Cs CO , dioxane
2 3
00 C, 16 h
o
1
NMe2
1
c) This work
5
mol%Ni-Ferrite NPs
R
R'
R-X
R'
o
H O, K CO , 100 C, 0.75-7 h
2
2
3
R = alkyl or aryl
((Scheme 2))
Br
1
0 mol% NiFe O
2 4
Ph
Ph
o
H O, K CO , 100 C
2
2
3
O
84% yield
O
3
mol (600 mg)
3 mol (330 ml)
1
4

ACCEPTED MANUSCRIPT
((Scheme 3))
((Scheme 4))
1
5

ACCEPTED MANUSCRIPT
((Scheme 5))
Br
1
0 mol% FeCl3
Ph
Ph
Ph
o
H O, K CO , 100 C
2
2
3
1
h, 0%
2
4 h, trace
Br
1
0 mol% FeCl3
Ph
Ph
MeO
o
H O, K CO , 100 C
2
2
3
MeO
3
h, 0%
2
4 h, trace
(
(Scheme 6))
Br
1
0 mol% NiCl2
Ph
Ph
MeO
o
H O, K CO , 100 C
2
2
3
MeO
3
h, 0%
Legends
Scheme 1. Comparison of the previous C -alkyl halide Snogashira couplings with present
sp
work [30, 31]
Scheme 2. Sonogashira reaction in large scale.
Scheme 3. Recovery and reuse of nickel ferrite nanoparticles for the Sonogashira reaction.
Reaction conditions: bromobenzene (1 mmol), phenyl acetylene (1 equiv.), nano nickel ferrite
(
5 mol %), K CO (1.1 mmol), water (3 ml) and reaction stirred at 100 °C.
2 3
1
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ACCEPTED MANUSCRIPT
Scheme 4. SEM pattern of recovered nickel ferrite nanoparticles after second (a) and fifth (b)
runs of the Sonogashira reaction
Scheme 5. Investigation of the probability of catalytic activity of metal contaminants
presented in iron source. a) Reaction of bromobenzene with phenyl acetylene in the presence
of 10 mol% of FeCl under optimized conditions; b) Reaction of 4-bromoanisole with phenyl
3
acetylene in the presence of 10 mol% of FeCl under optimized reaction conditions.
3
Scheme 6. Investigation of the probability of catalytic activity of metal contaminants
presented in nickel source: Reaction of 4-bromoanisole with phenyl acetylene in the presence
of 10 mol% of NiCl under optimized reaction conditions.
2
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ACCEPTED MANUSCRIPT
Graphical abstract
A copper-free Sonogashira reaction using nickel ferrite as catalyst in water
Firouz Matloubi Moghaddam, Ghazal Tavakoli and Hamid Reza Rezvani
5
mol%Ni-Ferrite NPs
R
R'
R-X
R'
o
H O, K CO , 100 C, 0.75-7 h
2
2
3
R = alkyl or aryl
R' = Ph or C H
5
11
X = I, Br, Cl
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8

ACCEPTED MANUSCRIPT
Highlights
A copper-free Sonogashira reaction using nickel ferrite as catalyst in water
Firouz Matloubi Moghaddam, Ghazal Tavakoli and Hamid Reza Rezvani





Nickel ferrite nanoparticles were applied successfully in Sonogashira reaction.
Reactions were performed under green conditions using water as solvent.
All the reactions were completed in short times with excellent yields.
The magnetic catalyst can be separated easily using an external magnetic field.
The catalyst is recyclable and reusable without activity lost.
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