Copper- and phosphine-free Sonogashira coupling reaction catalyzed by silica-(acac)-supported palladium nanoparticles in water

Article abstract of DOI:10.1002/aoc.3184

A palladium-based catalyst supported on acac-functionalized silica was used as a heterogeneous catalyst for the Sonogashira cross-coupling reaction of various aryl halides and phenylacetylene under copper- and phosphine-free conditions. This catalytic sys

Full text of DOI:10.1002/aoc.3184

Full Paper
Received: 4 March 2014
Revised: 10 May 2014
Accepted: 5 June 2014
Published online in Wiley Online Library: 9 July 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3184
Copper- and phosphine-free Sonogashira coupling
reaction catalyzed by silica–(acac)-supported
palladium nanoparticles in water
Abdol R. Hajipoura,b*, Zohre Shirdashtzadea and Ghobad Azizia
A palladium-based catalyst supported on acac-functionalized silica was used as a heterogeneous catalyst for the Sonogashira
cross-coupling reaction of various aryl halides and phenylacetylene under copper- and phosphine-free conditions. This catalytic
system serves as an efficient and stable catalyst for this cross-coupling reaction and allows easy separation and recycling of the
catalyst. The catalyst could be recycled for five runs without appreciable loss of its catalytic activity. In addition, the reaction was
carried out in water as a green solvent. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: nanoparticles; palladium heterogeneous catalyst; Sonogashira reaction; water
supported on MOF-5 for Sonogashira coupling reaction between
aryl iodides and terminal acetylenes.
Introduction
The Sonogashira cross-coupling reaction is one of the most straight-
forward methods for the production of internal alkynes and
enynes.[1–3] This cross-coupling reaction is definitely a fast-growing
research field with enormous academic and industrial interest due
to extensive use of products in the synthesis of pharmaceutics,
natural products, biologically active molecules and conducting
polymers and in nonlinear optics and liquid crystal materials.[4–8]
The most commonly utilized catalytic systems for this reaction
include phosphine-based palladium catalysts together with CuI
as the co-catalyst in the presence of an amine as a solvent under
degassed conditions. In spite of a mild and high-yielding reac-
tion, this procedure suffers from some drawbacks. The copper
salts used as co-catalyst often generate homocoupling products
of the terminal alkyne (Glaser coupling)[9–13] and many phos-
phine ligands are sensitive to air or moisture and require an inert
environment. Thus numerous phosphine- and copper-free palla-
dium-catalyzed Sonogashira reactions have been developed to
solve these problems.[14] The reaction normally proceeds in the
presence of a homogeneous palladium catalyst, which makes
difficult the recovery of the metal and might result in palladium
contamination of the product. Using a heterogeneous palladium
catalyst such as a solid-supported metal is a solution to overcome
these difficulties. Several examples of Sonogashira reactions
catalyzed by supported palladium nanoparticles have been
reported. For example, recently, Firouzabadi et al.[15] used palla-
dium nanoparticles supported on agarose for the Sonogashira
reaction in polyethylene glycol. Nezhad and Panahi[16] reported
a silica–starch-immobilized palladium nanoparticle catalyst which
was used for the Sonogashira reaction in water without surfactants.
Perfluoro-tagged palladium nanoparticles immobilized on silica gel
through fluorous–fluorous interactions or linked to silica gel by
covalent bonds have been used as catalyst (0.1–0.5 mol% of Pd) in
the alkynylation of terminal alkynes in the presence of pyrrolidine
in refluxing water as solvent by Bernini et al.[17] Polystyrene-
stabilized palladium nanoparticles were used for catalyzing this
reaction in water.[18] Gao et al.[19] used palladium nanoparticles
In recent progress towards more green chemical methods, devel-
opment of more environmentally friendly conditions such as the use
of water as solvent has become one of the most exciting research
topics in organic synthesis. From both economic and environmental
points of view, water as a cheap, readily available, non-flammable
and non-toxic solvent could be a successful replacement for toxic
and expensive organic solvents such as dimethylformamide (DMF),
N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide, etc.[16,18,20–24]
Experimental
General
All melting points were obtained using on a Meltemp apparatus.
1H NMR spectra were recorded at 300 MHz in CDCl3 solutions at
room temperature (tetramethylsilane was used as an internal
standard) with a Bruker Avance 300 instrument (Rheinstetten,
Germany). Fourier transform infrared spectra were recorded with
a Jasco-680 spectrophotometer (Japan). Spectra of solids were
obtained using KBr pellets. GC (Beifin 3420 gas chromatograph
equipped with a Varian CP SIL 5CB column: 30 m, 0.32 mm, 0.25
μm) was used for examination of reaction completion. All chemicals
were purchased from Merck and Aldrich and were used as received.
The catalyst was synthesized according to previous work.[31] In
summary, acid-activated silica gel was dried at 150°C overnight
and cooled in a desiccator. To prepare 3-iodopropyltrimethoxysilane
*
Correspondence to: Abdol R. Hajipour, Pharmaceutical Research Laboratory,
Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR
Iran. E-mail: haji@cc.iut.ac.ir
a Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan Uni-
versity of Technology, Isfahan 84156, IR, Iran
b Department of Pharmacology, University of Wisconsin, Medical School, 1300
University Avenue, Madison, WI, 53706-1532, USA
Appl. Organometal. Chem. 2014, 28, 696–698
Copyright © 2014 John Wiley & Sons, Ltd.

Sonoghashira cross-coupling reaction
supported silica gel, activated silica gel (5 g) was suspended in a
solution of 3-iodopropyltrimethoxysilane (5 mmol) in toluene. The
suspension was refluxed for 24 h. After cooling, the particles were
collected by filtration and exhaustively washed with ethanol, and
dried under reduced pressure to give iodopropyl–silica gel.
Iodopropyl–silica gel was re-suspended in 30 mL of acetonitrile,
and 5 mmol (0.50 g) of acetylacetone and 5 mmol (0.69 g) of
K2CO3 were added and refluxed for 24 h. The solids were washed
with water and subjected to Soxhlet extraction with ethanol for 5
h and dried under reduced pressure. Finally, the resulting solid
was stirred with acetonitrile in the presence of 0.05 g of Pd(OAc)2
and, after washing the solids with acetonitrile, the Pd(II)–acac sup-
ported on silica was refluxed in acetonitrile to form a black solid.
The black solid was washed with acetone and dried under vacuum
at room temperature to obtain the desired palladium-based catalyst
supported on acac-functionalized silica (SiO2-acac-PdNPs). The
amount of Pd was 0.04 mmol gÀ1 (4.26 mg gÀ1) determined using
atomic absorption spectroscopy.
Table 1. Optimization of Sonogashira reaction conditionsa
Entry
Solvent
Base
Catalyst (mol%) Conversionb (%)
1
NMP
DMF
CH3CN
H2O
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
NaOAc
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.04
0.08
95
65
0
2
3
4
92
38
20
65
80
75
40
96
97
5
Dioxane
EtOH
H2O
6
7
8
H2O
NEt3
9
H2O
K2CO3
10
11
12
H2O
Na2CO3
H2O
Piperidine
Piperidine
H2O
aReaction conditions: iodobenzene (1 mmol), phenylacetylene
(1 mmol), 2 equiv. base, 1.5 mL solvent and 1 h.
bGC conversion.
General Procedure for the Sonogashira Coupling Reaction of
Aryl Halides
solvents used (NMP, DMF, EtOH, H2O, dioxane and acetonitrile),
NMP gives the best result. Water also gives a good yield (entry 4) so
we chose water as the preferred solvent for a green chemistry
context. Then the influence of base was explored (entries 7–10).
Piperidine proves to be the most effective base.
The amount of catalyst was also optimized in the Sonogashira
reaction as shown in Table 1 (entries 4, 11, 12). By increasing the
amount of catalyst from 0.02 to 0.04 mol%, the yield of product
increases; when using 0.08 mol% catalyst, the yield does not
increase considerably.
The catalyst was applied to the Sonogashira reaction of various
aryl halides and phenylacetylene, under optimized reaction condi-
tions (H2O, piperidine, 10 mg (0.0004 mmol Pd, 0.04 mol%) of
catalyst) and the results are summarized in Table 2. The results
show that the catalyst displays high efficiency for Sonogashira
cross-coupling reactions of various aryl halides with phenylacetylene.
It can be observed that aryl halides containing electron-
withdrawing or electronically neutral substituents transform to
the corresponding coupled products with better yields and in
shorter reaction times than aryl halides with electron-donating
substituents. It is worth noting that no traces of Glaser coupling
product are observed for the reactions involving iodobenzenes
(5% of Glaser coupling product is observed in the reaction of
4-iodoanisole with phenylacetylene). But the homocoupled prod-
uct arising out of the phenylacetylene is formed in the case of less
reactive aryl bromides and chlorides. By means of GC analysis the
extent of Glaser coupling product is determined to be about 3–8%.
2-, 3- and 4-Chlorobromobenzene (Table 2, entries 12, 13
and14) were used to examine the chemoselectivity of the proce-
dure. Even though this procedure is also applicable to C--Cl
bonds, because Br acts as a better leaving group and has higher
activity in comparison to Cl, by employing a stoichiometric
amount of phenylacetylene, only the Br is substituted.
An aryl halide (1.0 mmol) and phenylacetylene (1.0 mmol) were
added to a mixture of SiO2-acac-PdNPs (10mg, 0.04 mol% Pd), pi-
peridine (2.0 mmol) and water (1.5 ml) in a glass flask equipped
with a condenser and refluxed under conventional heating
conditions while stirring vigorously and monitoring by both TLC
and GC. After completion of the reaction, the mixture was cooled
to room temperature and was poured into a separating funnel
and extracted three times with hexane (10 ml). The combined
organic phases were dried over CaCl2, filtered, and the solvent
was evaporated under reduced pressure using a rotary evapora-
tor. The residue was purified by silica gel column chromatogra-
phy. The products were characterized by comparing their m.p.
and IR, 1H NMR and 13C NMR spectra with those found in the
literature.[25–30]
Results and Discussion
In continuation of our recent investigations of the synthesis and
application of SiO2-acac-PdNPs in carbon–carbon cross-coupling
reactions,[31] we now report the extension of this heterogeneous
nanocatalyst for the cross-coupling reaction of phenylacetylene
with various aryl halides under copper- and phosphine-free
conditions (Scheme 1).
The effects of various reaction parameters (solvent, base and
amount of catalyst) on the cross-coupling reaction of phenylacetylene
and iodobenzene as the model substrates have been studied. First we
examined the effect of solvents (Table 1, entries 1–6). Among the
To show the effect of steric hindrance in the Sonogashira cross-
coupling reaction, we tried the cross-coupling of 2-bromonitrobenzene
and 4-bromonitrobenzene with phenylacetylene and find that
increasing the hindrance in the vicinity of the leaving group causes
the reaction of 2-bromonitrobenzene to take place in a longer time
and also decreases the reaction yield (entries 10, 11).
Catalyst recycling studies were also carried out using the
reaction of iodobenzene with phenylacetylene under optimized
reaction conditions. After the first run, the catalyst was separated
Scheme 1. Sonogashira cross-coupling reactions of aryl halides with
phenylacetylene.
Appl. Organometal. Chem. 2014, 28, 696–698
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. R. Hajipour et al.
Table 2. Sonogashira cross-coupling reaction of various aryl halidesa
conditions. This heterogeneous catalyst permits easy separation
of the product from the catalyst. The stability of this catalyst to-
wards air and its compatibility with a wide variety of aryl halides
make it perfect for the Sonogashira cross-coupling reaction.
Copper- and phosphine-free, high catalytic activity, using water
as the solvent, short reaction times, good chemoselectivity, high
isolated yields, utilization of low concentration of palladium
(0.04 mol%) and reusability of the catalyst are the highlights of
this catalytic system.
Entry
R
X
Time (h)
Yieldb (%)
1
H
I
0.5
0.42
0.58
2.5
5
90
93
90
92
78
89
50
60
43
75
40
75
55
45
58
62
48
2
4-NO2
3-NO2
4-MeO
H
I
Acknowledgements
3
I
4
I
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran.
Further financial support from the Center of Excellence in Sensor
and Green Chemistry Research (IUT) is gratefully acknowledged.
5
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
6
4-CN
4-MeO
4-CHO
4-MeCO
4-NO2
2-NO2
4-Cl
3
7
20
8
8
9
7
References
10
11
12
13
14
15
16
17
5
[1] R. Chinchilla, C. Nájera, Chem. Soc. Rev. 2011, 40, 5084.
[2] Z. Novák, A. Szabo, J. Répási, A. Kotschy, J. Org. Chem. 2003, 68, 3327.
[3] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467.
[4] L. Arnt, R. B. Breitenkamp, G. N. Tew, Polym. Adv. Technol. 2005, 16, 189.
[5] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44,
4442.
[6] W. Zhang, J. S. Moore, Angew. Chem. Int. Ed. 2006, 45, 4416.
[7] A. Hamajima, M. Isobe, Org. Lett. 2006, 8, 1205.
[8] D. Mujahidin, S. Doye, Eur. J. Org. Chem. 2005, 2689.
[9] C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422.
[10] T. Suzuka, Y. Okada, K. Ooshiro, Y. Uozomi, Tetrahedron 2010, 66, 1064.
[11] X. Wang, W. Qin, N. Kakusawa, S. Yasuike, J. Kurita, Tetrahedron Lett.
2009, 50, 6293.
[12] T. Katayama, K. Kamata, K. Yamaguchi, N. Mizuno, Chem. Sus. Chem.
2009, 2, 59.
17
3
3-Cl
9
2-Cl
16
6
1-Bromonaphthalene
4-NO2
H
Cl
Cl
7
11
aReaction conditions: aryl halides (1 mmol), phenylacetylene
(1 mmol), piperidine (2 mmol), catalyst (10mg, 0.04 mol%) and
1.5 mL water.
bIsolated yield.
[13] T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 833.
[14] a) J. H. Li, Y. Liang, Y. X. Xie, J. Org. Chem. 2005, 70, 4393. b) J. A. Loch,
M. Albrecht, E. Peris, J. Mata, J. W. Faller, R. H. Crabtree, Organometal-
lics 2002, 21, 700. c) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,
1290. d) R. A. Batey, M. Shen, A. Lough, J. Org. Lett. 2002, 4, 1411.
e) M. Eckhardt, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 13642. f) B. S. Yong,
S. P. Nolan, Chemtracts: Org. Chem. 2003, 205. g) S. Rau, K. Lamm,
H. Goerls, J. Schoeffel, D. Walther, J. Organomet. Chem. 2004, 689, 3582.
[15] H. Firouzabadi, N. Iranpoor, F. Kazemi, M. Gholinejad, J. Mol. Catal. A
2012, 357, 154.
[16] A. K. Nezhad, F. Panahi, Green Chem. 2011, 13, 2408.
[17] R. Bernini, S. Cacchi, G. Fabrizi, G. Forte, F. Petrucci, A. Pastrano,
S. Niembro, A. Shafir, A. Vallribera, Org. Biomol. Chem. 2009, 7, 2270.
[18] A. Ohtaka, T. Teratani, R. Fujii, K. Ikeshita, T. Kawashima, K. Tatsumi,
O. Shimomura, R. Nomura, J. Org. Chem. 2011, 76, 4052.
[19] S. Gao, N. Zhao, M. Shu, S. Che, Appl. Catal. A 2010, 388, 196.
[20] M. Bakherad, S. Jajarmi, J. Mol. Catal. A 2013, 370, 152.
[21] T. Suzuka, Y. Okada, K. Ooshiro, Y. Uozumi, Tetrahedron 2010, 66, 1064.
[22] H. Firouzabadi, N. Iranpoor, M. Gholinejad, J. Mol. Catal. A 2010,
321, 110.
Table 3. Reuse of catalyst system for Sonogashira cross-coupling of
iodobenzene with phenylacetylenea
Number of cycles
Conversionb (%)
1
2
3
4
5
6
7
95
95
93
90
90
77
71
aReactions were carried out using 1 mmol of iodobenzene, 1 mmol
phenylacetylene, 2 mmol piperidine, 10 mg (0.04 mol%) of
catalyst and 1.5 ml water for 1 h at reflux temperature.
bGC conversion.
by filtration, washed with water and acetone three times and
allowed to dry at room temperature under vacuum. Then the
recovered catalyst was used in the next run under the same
reaction conditions as first used. The catalyst was recycled for five
runs without significant loss of activity (Table 3).
[23] F. Coccia, L. Tonucci, N. Alessandro, P. D’Ambrosio, M. Bressan, Inorg.
Chim. Acta 2012, 399, 12.
[24] N. Iranpoor, H. Firouzabadi, A. Tarassoli, M. Fereidoonnezhad, Bull.
Chem. Soc. Jpn. 2010, 83, 1367.
[25] A. N. Marziale, J. Schlüter, J. Eppinger, Tetrahedron Lett. 2011, 52, 6355.
[26] D. A. Alonso, C. Nájera, M. C. Pacheco, Adv. Synth. Catal. 2003, 345, 1146.
[27] M. Wu, J. Mao, J. Guo, S. Ji, Eur. J. Org. Chem. 2008, 23, 4050.
[28] F. Yang, X. Cui, Y. Li, J. Zhang, G. Ren, Y. Wu, Tetrahedron 2007, 63, 1963.
[29] A. Elangovan, Y. H. Wang, T. I. Ho, Org. Lett. 2003, 5, 1841.
[30] P. Li, L. Wang, H. Li, Tetrahedron 2005, 61, 8633.
Conclusions
In conclusion, the Sonogashira coupling reaction of aryl halides
with phenylacetylene proceeds efficiently in water using SiO2-
acac-PdNPs as the catalyst in the absence of copper co-catalyst
and phosphine ligands at reflux temperature under aerobic
[31] A. R. Hajipour, Z. Shirdashtzade, G. Azizi, J Chem. Sci. 2014, 126, 85.
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 696–698