Synthesis of a new palladium salt using N-benzyl DABCO chloride and its application in Suzuki reaction

Article abstract of DOI:10.1002/aoc.2926

A palladium catalyst was synthesized using N-benzyl DABCO chloride and palladium chloride. The structure of this catalyst was characterized and then the catalyst was used in Suzuki cross- coupling reaction of different aryl halides with arylboronic acids. All substrates afforded the corresponding products in good to high yields in the presence of low amounts of the catalyst. Under the heating conditions employed, cheaper and more available aryl chlorides gave relatively high yields in the Suzuki reaction. Copyright

Full text of DOI:10.1002/aoc.2926

Full Paper
Received: 21 May 2012
Revised: 18 August 2012
Accepted: 18 August 2012
Published online in Wiley Online Library: 4 October 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2926
Synthesis of a new palladium salt using N-benzyl
DABCO chloride and its application in
Suzuki reaction
Abdol Reza Hajipoura,b*, Ifa Mahboobi Dehbanea and Fatemeh Rafieea
A palladium catalyst was synthesized using N-benzyl DABCO chloride and palladium chloride. The structure of this catalyst
was characterized and then the catalyst was used in Suzuki cross- coupling reaction of different aryl halides with arylboronic
acids. All substrates afforded the corresponding products in good to high yields in the presence of low amounts of the
catalyst. Under the heating conditions employed, cheaper and more available aryl chlorides gave relatively high yields in
the Suzuki reaction. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: N-benzyl DABCO chloride; palladium chloride; Suzuki coupling; aryl halide; arylboronic acid
Introduction
Results and Discussion
The cross-coupling of aryl halides with arylboronic acids, namely
the Suzuki–Miyaura coupling reaction, has become one of the
most powerful, versatile and popular tools for the selective con-
struction of carbon–carbon bonds.[1–4] The obtained biaryls are
important structural moieties in numerous polymers, agrochem-
icals, natural products and pharmaceutical intermediates,[5–10]
making the Suzuki reaction an important and common tool in
organic synthesis. Over the past two decades, efforts have been
made to develop efficient catalytic systems for the Suzuki–
Miyaura coupling reaction. In this regard, palladium–phosphine
complexes are among the most commonly employed catalysts
of choice.[11–18] However, some of the phosphorous ligands are
sensitive to air and moisture and economically and environmen-
tally undesirable due to difficulties with their recovery and the
formation of toxic phosphines as byproducts in the reaction.[19]
Therefore, designing efficient and phosphine-free ligands is still
an important issue.[20]
Although simple amines are generally used in cross-coupling
reactions as bases and display some properties as ligands to
stabilize the reactive palladium intermediates,[21,22] only a few
papers have reported the use of simple amines as ligands
combined with Pd(0) to efficiently catalyze the Suzuki–Miyaura
cross-coupling reaction.[23,24] However, in comparison to primary
and secondary amines, employing the tertiary amines as ligands
showed no activity or low activity for the reaction. In 2004, for
the first time Li et al. reported that Pd(OAc)2/DABCO as a tertiary
amine is a stable, inexpensive and highly efficient catalyst system
for the Suzuki–Miyaura reaction of aryl halides and arylboronic
acids.[25] They subsequently examined the effect of different
solvents on the reaction rate and catalyst reusability.[26,27] How-
ever, there is no report concerning the use of DABCO salts in the
Suzuki reaction. In this study, initially a palladium catalyst was
synthesized using 1-benzyl-4-aza-1-azaniabicyclo [2.2.2]octane
chloride (N-benzyl DABCO chloride) and palladium chloride, and
this catalyst was then used in the Suzuki reaction of aryl iodides,
aryl bromides and aryl chlorides with arylboronic acids.
The palladium catalyst was synthesized by the reaction of
N-benzyl DABCO chloride and palladium chloride in acetone as
the solvent. The resulting solids were easily separated and
washed with water to remove the unreacted N-benzyl DABCO
chloride. The structure of the produced catalyst was character-
1
ized using H NMR, 13C NMR, IR and elemental analysis. In 1999,
Bouquillon et al. reported that the addition of quaternary ammo-
nium salt (tetrabutyl ammonium chloride) to PdCl2 led to formation
of stable dinuclear complex.[28] Based on their investigations and
elemental analysis of our catalyst, the structure of synthesized
catalyst was suggested as shown in Scheme 1.
To evaluate the catalytic activity, it was applied in the Suzuki
cross-coupling reactions of aryl halides and arylboronic acids.
To optimize the reaction conditions, the effects of the solvent,
base, temperature and the amount of catalyst on the cross-
coupling reaction were first investigated using a model reaction
of 4-bromobenzonitrile and 9-bromophenanthrene as a bulky
aryl bromide with phenylboronic acid. Initially, the reaction was
investigated in the presence of 1 equiv. of K2CO3 as the base
and 0.35 mol% of catalyst in different solvents and at various
temperatures. It seems that water can be a suitable and green
solvent for this reaction; however, repeating the reaction for
4-bromobenzonitrile at 60ꢀC and 9-bromophenanthrene at 100ꢀC
proved that water is not an appropriate solvent. Among the vari-
ous solvents, methanol seems to be the best one and gave the
highest yield in a shorter reaction time (Table 1). Since ethanol is
*
Correspondence to: Abdol Reza 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
University of Technology, Isfahan 84156, IR Iran
b Department of Neuroscience, University of Wisconsin, Medical School,
Madison, WI 53706-1532, USA
Appl. Organometal. Chem. 2012, 26, 743–747
Copyright © 2012 John Wiley & Sons, Ltd.

A. R. Hajipour et al.
N
N
N
Acetone, reflux
4 hr
+
+
PdCl2
+
N
N
2
N
Cl-
Cl
Cl
Cl
Cl
Cl
Cl
Pd
Pd
catalyst A
Scheme 1. Synthesis of catalyst A from N-benzyl DABCO chloride and palladium chloride.
Table 1. Optimization of reaction conditions catalyzed by catalyst Aa
Entry
Ar
Solvent
Temperature (ꢀC)
Base
Catalyst (mol%)
Time (min)
Conversion (%)b
1
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
9-Phenanthrene
4-CN&bond;C6H4
4-CN&bond;C6H4
9-Phenanthrene
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN C6H4
DMF
140
100
120
80
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaOAC
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.2
140
190
200
120
30
60
105
130
20
30
20
95
60
15
20
5
100
100
100
92
2
DMF
3
NMP
4
CH3CN
H2O
5
100
60
100
0
6
H2O
7
H2O
100
90
0
8
Dioxane
Methanol
Methanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
67
9
50
100
80
10
11
12
13
14
15
16c
17c
18c
19c
20c
21c
50
60
100
100
100
100
95
60
60
4-CN&bond;C6H4
9-Phenanthrene
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
4-CN&bond;C6H4
9-Phenanthrene
60
60
60
100
100
100
100
100
50
60
5
60
0.1
5
60
0.05
0.05
0.05
5
r.t.
r.t
10
20
aReaction conditions: ArBr (1 mmol), phenylboronic acid (1.2 mmol), base (1 equiv.), 1solvent (2 ml), catalyst A.
bDetermined by GC.
cBase (2 equiv.).
greener and the results are almost the same, ethanol was chosen
as the best solvent. The effects of different bases on this reaction
were examined and the results showed that Cs2CO3 is the best.
However, as K2CO3 is less expensive and is readily available and
the results are similar, K2CO3 was selected as the optimum base.
Increasing the amount of K2CO3 to 2 equiv., the reaction time
decreased from 20 to 5 min. Therefore, 2 equiv. of this base were
used in the subsequent reactions. Finally, the effect of different
amounts of the catalyst was investigated and, as can be seen in
Table 1, various amounts of catalyst did not influence the reaction
time and conversion; therefore the reaction was repeated with
0.05 mol% of catalyst at room temperature. In order to ensure
that the reaction proceeds at room temperature, the reaction of
9-bromophenanthrene was carried out under the stated conditions
and the conversion of 50% in 20 min was a good reason to select
room temperature as the best condition.
expensive and readily available, we also tried to improve the
reaction conditions in order to make them applicable to less
reactive aryl chlorides. To do this, the reaction of 1-chloro-4-
nitrobenzene and phenylboronic acid in the presence of 2 equiv.
of K2CO3 and 0.05 mol% catalyst was chosen and the effects of
different solvents, temperatures and tetrabutylammonium bro-
mide (TBAB) as an ionic liquid were also tried. As demonstrated
in Table 2, adding 0.1 mmol TBAB caused a dramatic increase in
the rate and yield of the reaction. The best result was obtained
when the reaction was carried out in DMF as the solvent and at
100ꢀC in the presence of 0.1 mmol TBAB. To ensure that the
reaction of aryl chlorides proceeded completely, all reactions
were allowed to stay at optimum conditions for 10 h and then
the products were isolated.
With optimal conditions in hand, we carried out the reaction of
various aryl halides with phenylboronic acid (Table 3). Bulky aryl
halides such as 1-bromonaphthalene and 9-bromophenanthrene
reacted much more slowly with phenylboronic acid and their
As the application of aryl chlorides in the Suzuki reaction has
attracted much attention in recent years, because they are less
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Appl. Organometal. Chem. 2012, 26, 743–747

Palladium salt of N-benzyl DABCO chloride
Table 2. Optimization of reaction conditions for aryl chloridesa
Entry
Solvent (v/v)
Ethanol
Temperature (ꢀC)
Additives
Time (h)
Conversions (%)b
1
2
3
4
5
6
7
r.t
—
—
7
5
5
5
Ethanol
60
PEG(400)
PEG(400)/H2O (2:1)
DMF
110
110
110
100
100
—
10
10
10
1
30
30
40
60
50
—
—
DMF
TBAB
TBAB
DMF/H2O (2:1)
5
aReaction conditions: 1-chloro-4-nitrobenzene (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2 equiv.), catalyst A (0.05 mol%), solvent (2 ml).
bDetermined by GC.
Table 3. Coupling reactions of aryl halides with arylboronic acids under the optimized conditionsa
Entry
X
R1
R2
Temperature (ꢀC)
Time (h)
Yield (%)b [ref.]
1
Br
I
H
H
r.t
r.t
0.25
0.33
1.25
0.25
0.7
99[29]
99[29]
89[29]
87[29]
98[29]
93[29]
96[30]
98[30]
80[31]
85[31]
50[32]
85[32]
90[29]
97[29]
50[35]
95[29]
86[29]
97[36]
98[33]
91[29]
80[34]
90[34]
90[34]
85[29]
88[30]
87[29]
98[29]
5[29]
2
H
H
3
I
4-OMe
4-OMe
4-OMe
H
r.t
4
I
H
60
r.t
5
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
H
6
4-COCH3
4-CHO
H
r.t
0.42
0.25
0.2
7
H
r.t
8
4-CN
H
r.t
9
1-Naphthalene
1-Naphthalene
9-Phenanthrene
9-Phenanthrene
4-NO2
H
r.t
1.25
0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25c
26c
27c
28
H
60
r.t
H
0.7
H
60
r.t
1
H
3
4-NO2
H
60
r.t
0.25
24
2-NO2
H
4-NO2
H
r.t
2
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
4-Cl
H
r.t
0.5 min
1 min
2 min
3 min
1.25
0.5
3-Cl
H
r.t
2-Cl
H
r.t
4-Cl
OMe
OMe
OMe
OMe
H
r.t
4-COCH3
4-CHO
r.t
r.t
4-CN
r.t
0.6
H
100
100
100
100
r.t
10
4-CHO
H
10
4-COCH3
4-NO2
H
10
H
10
4-NO2
H
7
aReaction conditions: aryl halide (1 mmol), arylboronic acid (1.2 mmol), K2CO3 (2 equiv.), catalyst A (0.05 mol%), ethanol (2 ml) at room temperature.
bIsolated yields.
cThe reactions were carried out in the presence of TBAB (0.1 mmol) and in DMF as the solvent for 10 h.
Appl. Organometal. Chem. 2012, 26, 743–747
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A. R. Hajipour et al.
Table 4. the comparison of TON and TOF for catalyst A and other DABCO based catalytic systems
Aryl halide
Catalytic system
Pd(OAC)2/DABCO/
acetone
Pd(OAC)2/DABCO/
PEG-400
Pd(OAC)2/DABCO/
DMF
Catalyst A
TON
TOF
TON
TOF
TON
TOF
TON
TOF
4-Bromoacetophenone
4-Bromoanisole
4-Iodoanisole
8500
32.3
9700
—
212.5
16.2
692.8
—
960
990
930
980
—
96
61.9
232.5
98
32
2
930
980
890
990
990
2214.3
1400
712
30
1.9
—
—
1.9
—
Iodobenzene
—
3000
3960
Bromobenzene
—
—
—
31.3
yields were lower. Increasing the reaction temperature in these
cases resulted in a small increase in yields (Table 3, entries 10
and 12). The chemoselectivity of the method was investigated
using ortho-, meta- and para-bromochlorobenzene as the model
substrates. In each case, only Br as the better leaving group was
substituted and Cl did not react at all (Table 3, entries 17–20).
To compare the efficiency of this catalyst with other DABCO-
based catalytic systems, the turnover number (TON) and turnover
frequency (TOF) were calculated. As can be seen in Table 4, the
TON and TOF of this catalyst were comparable and in some cases
even better than in other catalytic systems.
The yield of catalyst A with this procedure was 70%. 1H NMR
(500 MHz, DMSO): dppm 3.01 (t, 6H, J = 6.8 Hz, CH2), 3.29 (t, 6H,
J = 6.8 Hz, CH2), 4.48 (s, 2H, CH2), 7.48 (br s, 5H, Harom); 13C NMR
(125 MHz, DMSO): dppm 45.67 (C═NDABCO), 52.55 (C═NDABCO),
67.54 (CH2), 127.96 (Carom), 129.88 (Carom), 131.09 (Carom), 134.08
(Carom); decomp. 298ꢀC. Anal. Calcd for C26H38Cl6N4Pd2: C 37.53,
H 4.60, N 6.73. Found: C 37.10, H 4.37, N 6.41.
General Procedure for the Catalyst A-Catalyzed Suzuki–Miyaura
Coupling Reaction for Aryl Iodides and Aryl Bromides
A mixture of aryl halide (1 mmol), arylboronic acid (1.2 mmol),
K2CO3 (2 mmol) and catalyst A (0.05 mol%) was added to ethanol
(2 ml) and stirred at room temperature (or at 60ꢀC for some sub-
strates) for an appropriate amount of time. After completion of
the reaction, as indicated by thin-layer chromatography and GC,
the solvent was evaporated. Then, 30 ml water was added to
the mixture and the product was extracted with n-hexane or
ethyl acetate (3 Â 10 ml). The organic phase was dried over CaCl2,
concentrated under vacuum and purified by column chromatog-
raphy on silica gel (n-hexane:EtOAc, 9:1).
Conclusion
Using readily available and inexpensive materials such as N-benzyl
DABCO chloride and palladium chloride, we developed an efficient
catalytic system for the Suzuki cross-coupling reaction of aryl
iodides and bromides at room temperature. The reaction temper-
ature was increased to 100ꢀC for promoting the reaction of less
reactive aryl chlorides. Under optimal conditions, for all aryl halides
the corresponding coupling products can be achieved in good to
high yields.
General Procedure for Catalyst A-Catalyzed Suzuki–Miyaura
Coupling Reaction for Aryl Chlorides
Experimental
A mixture of aryl chloride (1 mmol), phenylboronic acid (1.2 mmol),
K2CO3 (2 mmol), TBAB (0.1 mmol) and catalyst A (0.05 mol%) was
added to DMF (2 ml). The reaction mixture was stirred in an oil
bath at 100ꢀC. After 10 h, the mixture was cooled to room temper-
ature, 30 ml water was added and the product was extracted with
n-hexane (3 Â 10 ml). The organic phase was dried over CaCl2, con-
centrated under vacuum and purified by column chromatography
on silica gel (n-hexane:EtOAc, 9:1).
All chemical reagents were purchased from Merck and were used
without further purification. H NMR spectra were recorded on a
1
Bruker 500 spectrometer using tetramethylsilane as an internal
standard in CDCl3 or DMSO and FT-IR spectra were obtained as
KBr pellets on a JASCO 680-Plus spectrophotometer. Melting
points were determined with a Gallenkamp melting apparatus
and are uncorrected. Also we used gas chromatography (GC)
(BEIFIN 3420 gas chromatograph equipped with a Varian CP
SIL 5CB column: 30 m, 0.32 mm, 0.25 mm) for examination of
reactions conversions.
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.
General Procedure for the Synthesis of Palladium Salt
(Catalyst A)
To a mixture of 0.25 mmol (0.0597 g) N-benzyl DABCO chloride
and 0.25 mmol (0.044 g) palladium chloride, 3 ml acetone was
added in a round-bottom flask equipped with a condenser and
placed in an oil bath under reflux conditions. After 4 h, the reac-
tion mixture was filtered and the resulting solids were washed
with water (5 ml) to remove the unreacted N-benzyl DABCO
chloride. The yellow-brownish catalyst was air-dried and weighed.
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