(BeDABCO)2Pd2Cl6 as an efficient homogeneous catalyst for copper-free Sonogashira cross-coupling reaction

Article abstract of DOI:10.1002/aoc.3167

An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2] octane chloride and palladium chloride ((BeDABCO)₂Pd ₂Cl₆) was developed for the Sonogashira reaction. In the presence of a catalytic amount of this efficient, stable homogeneous catalytic system that is non-sensitive to air and moisture, various aryl halides were efficiently coupled with phenylacetylene in good yields in H₂O at 50C under copper-free conditions. Benzyl dabco as an efficient ligand and also a quaternary ammonium salt had an efficient stabilizing effect on the Pd(0) species. Copyright

Full text of DOI:10.1002/aoc.3167

Full Paper
Received: 17 January 2014
Revised: 11 April 2014
Accepted: 25 April 2014
Published online in Wiley Online Library: 20 June 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3167
(BeDABCO)2Pd2Cl6 as an efficient homogeneous
catalyst for copper-free Sonogashira
cross-coupling reaction
Abdol R. Hajipoura* and Fatemeh Rafieeb
An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride and palladium chloride ((BeDABCO)
2Pd2Cl6) was developed for the Sonogashira reaction. In the presence of a catalytic amount of this efficient, stable homogeneous
catalytic system that is non-sensitive to air and moisture, various aryl halides were efficiently coupled with phenylacetylene in
good yields in H2O at 50°C under copper-free conditions. Benzyl dabco as an efficient ligand and also a quaternary ammonium
salt had an efficient stabilizing effect on the Pd(0) species. Copyright © 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: palladium catalyst; Sonogashira reaction; internal alkynes
was examined by optimizing the reaction conditions. We first
carried out the coupling reaction between 4-bromobenzonitrile
Introduction
Sonogashira coupling reactions acetylenes with aryl or alkenyl
halides or triflates have been developed in organic chemistry
and material science for the production of internal alkynes and
enynes.[1–7] Alkynes are used as building blocks for a wide range
of pharmaceuticals, natural products, biological active molecules,
conducting polymers, nonlinear optical and liquid crystal
materials.[8–10] Sonogashira cross-coupling reactions are usually
mediated by phosphane-based palladium complexes.[11–13] Most
research has developed to obtain high catalytic activity with
efficient catalytic systems. Moreover, a number of important
studies have focused on the development of phosphine-free
ligands such as N-heterocyclic carbenes.[14–16] Phosphine ligands
suffer some drawbacks, such as sensitivity to air or moisture, and
requirement for an inert environment and large amounts of
palladium source for carrying out the reaction. Although carbene
ligands are more stable than alkyl phosphines, they must be
synthesized through multiple steps. Therefore, designing efficient
and phosphine-free ligands remains an important issue.
with phenylacetylene as a model reaction. The data showed that
the best results were obtained using H2O as solvent, piperidine as
base and 0.3 mol% of catalyst at 50°C (Table 1). Under these
conditions 4-cyanodiphenylacetylene was obtained as the desired
product and 1,4-diphenylbuta-1,3-diyne was not formed as a by-
product via the homocoupling of phenylacetylene.
These optimized reaction conditions were applied in the
Sonogashira cross-coupling reaction of various aryl halides with
phenylacetylene (Table 2). We examined the electronic and steric
effects on the resulting yields and conversion times of the
reactions. Aryl halides substituted with electron-withdrawing
groups transformed to the corresponding coupled products rather
than electron-donating substituent with better conversion and
shorter reaction times. The chemoselectivity of the procedure was
examined using 2-, 3- and 4-chlorobromobenzene. In these reac-
tions Br acted as a better leaving group. Aryl chlorides converted
to corresponding products more slowly and with lower yields in
comparison to the similar aryl iodides and bromides.
The effect of tetraalkylammonium salts on the activity and
stability of palladium catalysts has been described by Jeffery,[26]
in (BeDABCO)2Pd2Cl6 catalyst quaternary salt the benzyl dabco
as both an efficient ligand and also a quaternary ammonium salt
have an efficient stabilizing effect on inhibiting the aggregation
of Pd(0) nonstable species.
Results and Discussion
In continuation of our recent investigations on the synthesis and
application of palladium catalysts,[17–23] we now wish to report
the extension of a complex of 1-benzyl-4-aza-1-azoniabicyclo
[2.2.2]octane chloride with palladium chloride ((BeDABCO)
2Pd2Cl6) as an efficient and highly active homogeneous catalyst
for the cross-coupling reaction of various aryl halides with
phenylacetylene under copper-free conditions (Scheme 1).
1-Benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride salt
([BeDABCO]Cl) was prepared according to our previous work.[24]
The reaction of [BeDABCO]Cl with PdCl2 in 1:1 ratio in acetone
reflux gave the (BeDABCO)2Pd2Cl6 complex (1).[25]
*
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 Research Laboratory, Department of Chemistry, Isfahan University of
Technology, Isfahan 84156, IR Iran
Application of this palladium salt as catalyst for the
Sonogashira reaction of various aryl halides with phenylacetylene
b Department of Chemistry, Faculty of Science, Alzahra University, Vanak,
Tehran, Iran
Appl. Organometal. Chem. 2014, 28, 595–597
Copyright © 2014 John Wiley & Sons, Ltd.

A. R. Hajipour and F. Rafiee
Table 2. Sonogashira cross-coupling reaction using catalyst (1)a
Entry
Ar-X
Product[ref.]
Yield
(%)b
1
2
3
4
5
6
7
8
9
Ph-I
Ph―C≡C-Ph[27]
96
94
92
90
87
54
96
97
89
74
95
90
60
p-O2N―C6H4―I
m-O2N―C6H4―I
p-MeO―C6H4―I
Ph―Br
p-O2N―C6H4―C ≡ C―Ph[28]
m-O2N―C6H4―C ≡ C―Ph[29]
p-MeO―C6H4―C ≡ C―Ph[30]
Ph―C ≡ C―Ph[27]
Scheme 1. Sonogashira cross-coupling reaction of aryl halides by
catalyst (1).
p-MeO―C6H4―Br
p-NC―C6H4―Br
o-O2N―C6H4―Br
p-OHC―C6H4―Br
p-MeO―C6H4―C ≡ C-Ph[30]
p-NC―C6H4―C ≡ C-Ph[27]
o-O2N―C6H4-C ≡ C-Ph[27]
p-OHC―C6H4―C ≡ C-Ph[28]
p-MeOC―C6H4―C ≡ C-Ph[27]
p-Cl―C6H4―C ≡ C―Ph[30]
m-Cl―C6H4―C ≡ C―Ph[31]
o-Cl―C6H4―C ≡ C―Ph[31]
10 p-MeOC―C6H4―Br
11 p-Cl―C6H4―Br
12 m-Cl―C6H4―Br
13 o-Cl―C6H4―Br
14 1-Br―naphthalene
Table 1. Optimization of reaction conditions for the Sonogashira
cross-coupling reactiona
Entry Solvent
Base
Catalyst Temperature Conversion
(mol%)
(°C)
(%)b
1-(Phenylethynyl)naphthalene[30] 50
1
NMP
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
0.4
0.4
0.4
0.5
0.5
0.4
0.4
0.5
0.4
—
100
100
85
65
100
90
80
r.t.
50
50
50
50
50
50
50
50
50
80
55
15 9-Br―Phenanthrene 9-(phenylethynyl)
48
phenanthrene[32]
2
DMF
16 p-O2N―C6H4―Cl
17 2-Br―pyridine
18c Ph―Br
19c p-O2N―C6H4―I
20c p-Cl―C6H4―Br
p-O2N―C6H4―C ≡ C―Ph[27]
70
76
93
3
CH3CN
EtOH
DMAc
75
2-(Phenylethynyl)pyridine[27]
4
28
Ph―C ≡ C―CH2OH[33]
5
45
p-O2N―C6H4―C ≡ C―CH2OH[33] 90
6
Dioxane Piperidine
65
p-Cl―C6H4―C ≡ C―CH2OH[34]
89
7
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Pyrrolidine
K2CO3
100
40
8
aReaction conditions: aryl halide (1 mmol), phenylacetylene
(1 mmol), piperidine (2 mmol), H2O (3 ml), catalyst (0.3 mol%), 3 h.
9
100
—
10
11
12
13
14
15
16
17
bIsolated yield after column chromatography.
0.3
0.2
0.3
0.3
0.3
0.3
0.3
100
90
cReaction conditions: aryl halide (1mmol), prop-2-yn-1-ol (1mmol),
piperidine (2mmol), H2O (3ml), catalyst (0.3mol%), 3h.
65
15
Cs2CO3
26
NEt3
18
Experimental
DABCO
25
General
aReaction conditions: 4-bromobenzonitrile (1mmol), phenylacetylene
(1mmol), base (2mmol), solvent (3ml), catalyst (1) (mol%), 45min.
All melting points were taken using Gallenkamp melting point
apparatus. 1H NMR spectra were recorded using 400 MHz in
CDCl3 solution at room temperature (TMS was used as an internal
standard) on a Bruker Avance 500 (Rheinstetten, Germany) and
Varian 400 NMR instruments. FT-IR spectra were recorded on a
spectrophotometer (Jasco-680, Japan). Spectra of solids were
carried out using KBr pellets. Vibrational transition frequencies
are reported as a wavenumber (cmÀ1). We used GC (BEIFIN
3420 gas chromatograph equipped a Varian CP SIL 5CB column;
30 m, 0.32 mm, 0.25 μm) for examination of reaction completion
and yields. Palladium chloride, aryl halides and all chemicals were
purchased from Merck and Aldrich and were used as received.
bGC yield was determined using n-dodecane as an internal standard.
Catalytic Pd(0) species show a positive Hg(0) test, which
was assigned as probable evidence for catalysis by Pd nano-
particles. To evaluate the proposed mechanism for producing
Pd(0) species, the mercury drop test was used. In the pres-
ence of a heterogeneous catalyst, mercury leads to the amal-
gamation of its surface. In contrast, Hg(0) cannot have a
poisoning effect on homogeneous palladium complexes,
where the Pd(II) metal centre is tightly bound to the ligand.
When a drop of Hg(0) was added to the reaction mixture in
all cases under the optimized conditions, no catalytic activity
was observed for the catalyst. The obtained data can confirm
the Pd(0):Pd(II) cycle.
General Procedure for the Sonogashira Cross-Coupling
Reaction of Aryl Halides
A mixture of the aryl halide (1 mmol), phenylacetylene (1 mmol),
piperidine (2 mmol) and catalyst (1) (0.3 mol%) was added to
H2O (3 ml) in a round-bottom flask equipped with condenser
and heated at 50°C in an oil bath. The mixture was stirred contin-
uously during the reaction and monitored by both TLC and GC.
After the reaction was completed, the mixture was cooled to
room temperature and diluted with n-hexane and water. The
organic phase was dried over MgSO4, filtered and concentrated
under reduced pressure using a rotary evaporator. The residue
was purified by silica gel column chromatography.
Conclusions
In this investigation, a general protocol was applied to the
Sonogashira reaction of various aryl halides using (BeDABCO)
2Pd2Cl6. Catalytic amounts of this ionic complex converted various
aryl halides to the corresponding substituted diphenylacetylenes in
good to excellent yields.
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 595–597

Sonogashira coupling reaction
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Acknowledgements
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran,
and Isfahan Science and Technology Town (ISTT), IR, Iran. Further
financial support from the Center of Excellence in Sensor and
Green Chemistry Research (IUT) is gratefully acknowledged.
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Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web-site
Appl. Organometal. Chem. 2014, 28, 595–597
Copyright © 2014 John Wiley & Sons, Ltd.
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