Hiyama cross-coupling reaction catalyzed by a palladium salt of 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride under microwave irradiation

Article abstract of DOI:10.1002/aoc.3100

An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2] octane chloride ((BeDABCO)₂Pd₂Cl₆) was developed for the Hiyama cross-coupling reaction of various aryl halides with triethoxy(phenyl)silane. The substituted biaryls were produced in excellent yields in short reaction times using a catalytic amount of this catalyst in NMP at 100 °C. Copyright

Full text of DOI:10.1002/aoc.3100

Full Paper
Received: 10 September 2013
Revised: 21 October 2013
Accepted: 28 October 2013
Published online in Wiley Online Library: 10 February 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3100
Hiyama cross-coupling reaction catalyzed by a
palladium salt of 1-benzyl-4-aza-1-azoniabicyclo
[2.2.2]octane chloride under microwave irradiation
Abdol R. Hajipoura,b*, Fatemeh Rafieec and Narges Najafia
An efficient catalytic system using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride ((BeDABCO)2Pd2Cl6) was developed
for the Hiyama cross-coupling reaction of various aryl halides with triethoxy(phenyl)silane. The substituted biaryls were
produced in excellent yields in short reaction times using a catalytic amount of this catalyst in NMP at 100 °C. Copyright ©
2014 John Wiley & Sons, Ltd.
Keywords: palladium catalyst; microwave irradiation; Hiyama cross-coupling reaction
((BeDABCO)2Pd2Cl6) as an efficient and highly active homoge-
neous catalyst for conversion of various aryl halides to substituted
Introduction
Biaryls are a significant class of organic compounds due to
their range of excellent physical and chemical properties. They
present important interest for the synthesis of pharmaceuticals,[1]
herbicides,[2] bioactive products,[3] natural products,[4] conducting
polymers,[5,6] microelectrode arrays[7] and liquid crystal materials.[8]
In view of the importance of biaryls, a number of effective catalytic
methods have been developed for forming these compounds in
cross-coupling reactions.
The Hiyama coupling reaction utilizes organosilane reagents
and aryl halides or triflates for the synthesis of biaryls. In compar-
ison with other organometallic reagents employed for the prepa-
ration of biaryls, organosilanes are very attractive due to their
low cost and toxicity, ease of handling and stability in various
chemical media. Owing the low reactivity of these reagents,
they typically need to be activated by fluoride in order to gener-
ate a more reactive pentacoordinate silicate anion for the
transmetalation step.[9–12]
Transition-metal catalyzed cross-coupling reactions typically
need long reaction times and an inert atmosphere to reach
completion with traditional heating. Microwave irradiation is
known as a state-of-the-art and powerful technology by which
reactions can be brought to completion in seconds or minutes
rather than in hours or days. High-speed Hiyama coupling
reactions have been carried out successfully under controlled
microwave conditions.[13–16] The use of a homogeneous metal
catalyst in conjunction with microwave irradiation has led to an
increased lifetime of the catalyst, saving time and energy, pro-
ducing high yields and decreasing discarded byproducts from
thermal side reactions.[17–19]
biaryls under microwave irradiation (Scheme 1).
1-Benzyl-4-aza-1-azoniabicyclo[2.2.2]octane
chloride
salt
([BeDABCO]Cl) was prepared according to our previous work.[27]
The reaction of [BeDABCO]Cl with PdCl2 in a 1:1 ratio in acetone
reflux gave the (BeDABCO)2Pd2Cl6 complex (1).[28] The efficiency
of this catalytic system was evaluated in a Hiyama cross coupling
reaction under microwave irradiation. The monitoring system for
reaction times, temperature, pressure and power in the microwave
reactor allow for an excellent control of reaction parameters which
generally leads to rapid optimization and more reproducible reac-
tion conditions. The direct control of reaction mixture temperature
was carried out with IR sensors. We examined the effect of various
reaction parameters on the cross-coupling of 4-bromobenzonitrile
with PhSi(OEt)3 as shown in Table 1.
According to experimental evidence, penta-coordinated silicates
are more reactive than related tetra-coordinated silanes. In general,
all the couplings with organosilicon compounds were promoted
by fluoride by formation of the corresponding hypervalent
fluorosilicate, which facilitates the transmetalation step. We investi-
gated the effect of different types of fluoride salts such as KF, NaF,
CsF, CaF2, TBAF.3H2O as well as NaOH and other bases as additives.
Among these promoters, CsF was found to be the most effec-
tive. In order to increase the desired product yield, initially a
mixture of CsF and PhSi(OEt)3 in an appropriate solvent was
stirred at room temperature for 1 h; then the aryl halide and
*
Correspondence to: Abdol R. Hajipour, Pharmaceutical Research Laboratory,
Department of Chemistry, Isfahan University of Technology, Isfahan 84156,
IR Iran. Email: haji@cc.iut.ac.ir
a Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology, Isfahan 84156, IR Iran
Results and Discussion
b Department of Pharmacology, University of Wisconsin Medical School,
Madison, WI 53706-1532, USA
In continuation of our recent investigations on the synthesis
and application of the palladium catalysts,[20–26] 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
c
Department of Chemistry, Faculty of Science, Alzahra University, Vanak,
Tehran, IR Iran
Appl. Organometal. Chem. 2014, 28, 217–220
Copyright © 2014 John Wiley & Sons, Ltd.

A. R. Hajipour et al.
Table 2. Hiyama reaction of aryl halides using catalyst (1) under mi-
crowave irradiationa
Catalyst (1)
X
Si(OEt)3
CsF, NMP
100 °C, 600 W
R
R
Entry
Ar-X
Biaryl product
Time
(min)
Yield
(%)b
Scheme 1. Hiyama cross-coupling reaction of aryl halides by catalyst (1).
1
Ph-I
Ph-Ph
1
1
96
98
94
96
93
97
94
92
95
90
92
86
73
95
90
88
90
70
90
80
68
79
90
2
p-O2N-C6H4-I
m-O2N-C6H4-I
p-MeO-C6H4-I
Ph-Br
p-O2N-C6H4-Ph
m-O2N-C6H4-Ph
p-MeO-C6H4-Ph
Ph-Ph
3
3
Table 1. Optimization of reaction conditions under microwave
irradiationa
4
5
5
2
Entry Solvent
Base
Catalyst
(mol%)
Temperature Conversion
(°C)
(%)b
6
p-O2N-Ph-Br
p-O2N-C6H4-Ph
o-O2N-C6H4-Ph
p-MeO-C6H4-Ph
p-NC-C6H4-Ph
p-OHC-C6H4-Ph
p-MeOC-C6H4-Ph
m-MeOC-C6H4-Ph
o-MeOC-C6H4-Ph
m-Cl-C6H4-Ph
o-Cl-C6H4-Ph
2
7
o-O2N-Ph-Br
3
1
2
3
4
5
6
7
8
9
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Na2CO3
K2CO3
Cs2CO3
NaOH
NaOAc
KF
0.3
0.3
0.3
0.4
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.4
0.1
0.2
0.3
0.3
0.3
0.3
0.2
—
120
120
120
120
120
120
120
120
100
100
100
100
100
120
110
100
60
30
70
64
—
8
p-MeO-C6H4-Br
p-NC-C6H4-Br
p-OHC-C6H4-Br
p-MeOC-C6H4-Br
m-MeOC-C6H4-Br
o-MeOC-C6H4-Br
m-Cl-C6H4-Br
o-Cl-C6H4-Br
6
9
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
5
6
18
21
15
10
100
88
100
100
87
100
77
46
10
55
—
10
14
2
NaF
CaF2
CsF
3
1-Br-naphthalene
9-Br-phenanthrene
2-Br-pyridine
Ph-Cl
1-Ph-Naphthalene
9-Ph-Phenanthrene
2-Ph-Pyridine
Ph-Ph
11
10
8
10 NMP
11 NMP
12 NMP
13 NMP
14 NMP
15 DMF
TBAF
CsF
CsF
5
CsF
p-OHC-C6H4-Cl
p-MeOC-C6H4-Cl
p-O2N-C6H4-Cl
Ph-SO2Cl
p-OHC-C6H4-Ph
p-MeOC-C6H4-Ph
p-O2N-C6H4-Ph
Ph-Ph
10
15
8
CsF
CsF
16 p-Xylene CsF
17 THF CsF
18 Dioxane CsF
5
aReaction conditions: triethoxy(phenyl)silane (1.2 mmol), CsF (2
mmol), NMP (2 ml), 1 h, room temperature, stirring; then aryl
halide (1 mmol), catalyst (1) (0.2 mol%), MW, 130°C, 600 W.
bIsolated yield.
c130°C.
90
19 NMP
20 NMP
21c NMP
22d NMP
—
100
100
100
100
CsF
CsF
CsF
—
0.2
0.2
5
14
aReaction conditions: 4-bromobenzonitrile (1 mmol), triethoxy
(phenyl)silane (1.2 mmol), base (2 mmol), solvent (2 ml),
catalyst (1), 600 W, 4 min.
biaryls were produced in excellent yields in short reaction times
under homogeneous metal catalyst in conjunction with micro-
wave irradiation.
We examined the electronic and steric effects on the resulting
yields and conversion times of the reactions. The substituent ef-
fects on the aryl iodides proved to be less significant than in
the aryl bromides and the reactivity of aryl bromides with
electron-withdrawing substituent was higher than that of aryl
bromides with electron-donating substituent.
Aryl chlorides converted to corresponding products more slowly
and with lower yields in comparison to the similar aryl iodides and
bromides (Table 2, entries 19–22). The steric hindrance of the
procedure was examined using 2-, 3- and 4-bromoacetophenone
as hindered substituted aryls (Table 2, entries 11–13). Increasing
hindrance in the vicinity of the leaving group can cause a decrease
in the reaction conversion. The chemo-selectivity of the procedure
was examined using 2- and 3-choloro-bromobenzene. In these
reactions Br acted as a better leaving group (Table 2, entries
14 and 15).
bGC yield using naphthalene as internal standard.
cPdCl2 as catalyst.
dPdCl2/DABCO as catalyst.
catalyst were added and the mixture was heated under micro-
wave irradiation. No cross-coupled product was obtained with-
out the additive. Also, we examined homocoupling of PhSi
(OEt)3 in the absence of 4-bromobenzonitrile, and in this case
no biphenyl was observed. According to the obtained results,
NMP as the solvent, CsF as the promoter and 0.2 mol% of catalyst
gave the best results (Table 1, entry 11).
The optimized reaction conditions were used in the Hiyama
coupling reaction of various aryl halides using catalyst 1 under
microwave irradiation. As this catalytic system is not sensitive to
oxygen, the reactions were carried out under air atmosphere.
The results, as summarized in Table 2, show that substituted
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Appl. Organometal. Chem. 2014, 28, 217–220

Hiyama coupling reaction
Microwave irradiation in comparison to conventional reflux
conditions led to dramatically reduced reaction times and higher
yields (Table 3).
The dramatic rate enhancement is due to the rapid and
uniform heating of the reaction mixture and increased catalyst
lifetime by the elimination of wall effects in microwave versus
oil-bath heating. Microwave irradiation raises the temperature
of the whole volume simultaneously (bulk heating), whereas in
the oil-heated tube the reaction mixture in contact with the
vessel wall is heated first.[17]
Owing to the commercial availability of aryl silicon reagents,
this methodology offers a valuable alternative to traditional
methods for biaryl formation such as Suzuki and Stille couplings.
The effect of tetraalkylammonium salts on the activity and
stability of palladium catalysts has been described by Jeffery.[29]
(BeDABCO)2Pd2Cl6 catalyst comprises both N-donor ligand and
quaternary salt. Benzyl DABCO as an efficient ligand and also a
quaternary ammonium salt had an efficient stabilizing effect on
the Pd(0) species. The quaternary salt section inhibited Pd(0)
non-stable species aggregation and also caused an increase in
the polarity of the media, which stabilizes ionic and polar transi-
tion states in the catalytic cycle and leads to an increase in the
whole reaction rate.
Scheme 2. Proposed mechanism for Hiyama coupling reaction.
Conclusions
In this work, a general protocol was applied for the microwave-
promoted Hiyama reaction of various aryl halides using
(BeDABCO)2Pd2Cl6. The catalytic amounts of this ionic complex
converted various aryl halides to the corresponding biaryls in
excellent yields. The dipole characteristics of the catalyst translate
into rapid excitation by microwaves and consequently faster
reactions. The combination of homogenous complex as catalyst,
high dipole moment of quaternary salt part and microwave
irradiation caused to increase lifetime of the catalyst, improve
the yields of the reactions and decrease the reaction times.
A general catalytic cycle for the Hiyama reaction has been
presented in Scheme 2. Initially, Pd(II) converts to Pd(0), followed
by the oxidative addition of aryl halide to Pd(0) to form aryl
palladium(II) intermediate 1. Triethoxy(phenyl)silane is activated
by CsF and produced pentacoordinate phenylsilicate anion,
which reacts with intermediate 1. After the transmetalation
reaction, intermediate 2 is obtained. Finally, reductive elimination
of intermediate 2 produces the desired coupling products.[30]
Catalytic Pd(0) species show a positive Hg(0) test. To evaluate
the proposed mechanism for producing Pd(0) species, the
mercury drop test was operated. In the presence of a heteroge-
neous catalyst, mercury leads to the amalgamation of its
surface. In contrast, Hg(0) cannot have a poisoning effect on
homogeneous palladium complexes, where the Pd(II) metal
center is tightly bound to the ligand. When a drop of Hg(0)
was added to the reaction mixture in the all cases under the
mentioned optimized conditions, no catalytic activity was
observed for the catalyst. The obtained data can confirm the
Pd(0):Pd(II) cycle.
Experimental
General
All melting points were taken on a Gallenkamp melting appara-
tus. 1H NMR spectra were recorded using 400 MHz in CDCl3
solution at room temperature (tetramethylsilane was used as an
internal standard) on
a Bruker Avance 500 instrument
(Rheinstetten, Germany) and Varian 400 NMR. 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 wavenumber (cmÀ1). We used a
Milestone microwave (Microwave Labstation- MLS GmbH- ATC-FO
300) for synthesis. Furthermore, we used GC (BEIFIN 3420 gas
chromatograph equipped with 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.
Table 3. Hiyama coupling reaction under conventional heating
conditions using an oil batha
Entry
Ar-X
Biaryl product
Time (h) Yield (%)b
1
2
3
4
5
6
7
p-O2N-Ph-I
p-O2N-Ph-Ph
2-Ph-pyridine
p-MeO-Ph-Ph
m-O2N-Ph-Ph
p-NC-Ph-Ph
1
20
15
2
94
95
90
85
97
89
90
2-Br-pyridine
p-MeO-Ph-Br
m-O2N-Ph-I
General Procedure for the Synthesis of Palladium Salt (Catalyst 1)
p-NC-Ph-Br
8
To a mixture of 0.25 mmol (0.0597 g) N-benzyl DABCO chloride
and 0.25 mmol (0.044 g) palladium chloride, 3ml acetone was
added in a round-bottom flask equipped with condenser and
placed in an oil bath under reflux conditions. After 4 h, the
reaction 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
p-OHC-C6H4-Cl
1-Br-naphthalene
p-OHC-C6H4-Ph
1-Ph-naphthalene
15
10
aReaction conditions: triethoxy(phenyl)silane (1.2 mmol), CsF (2 mmol),
NMP (2 ml), 1 h, room temperature; then aryl halide (1 mmol),
catalyst (1) (0.2 mol%), oil bath, 100°C.
bIsolated yield.
Appl. Organometal. Chem. 2014, 28, 217–220
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A. R. Hajipour et al.
weighed. The yield of catalyst (1) with this procedure was 70%. 1H
NMR (500 MHz, DMSO): δppm 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): δppm 45.67 (C―NDABCO), 52.55 (C―NDABCO), 67.54
(CH2), 127.96 (Carom), 129.88 (Carom), 131.09 (Carom), 134.08 (Carom);
FT-IR (KBr, cmÀ1): υ 3016, 2991, 1621, 1585, 1457, 1412, 1372,
1318, 1215, 1078, 1054, 906, 850, 808, 769, 709; UV–visible (DMSO,
nm): 275, 309; decomp.: 298°C. Anal.: calcd for C26H38Cl6N4Pd2: C
37.53, H 4.60, N 6.73; found C 37.10, H 4.37, N 6.41.
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General Procedure for the Hiyama Cross-Coupling Reaction
of Aryl Halides
A mixture of CsF (2 mmol) and triethoxy(phenyl)silane (1.2 mmol)
in NMP (2 ml) was stirred at room temperature for 1 h; then the
aryl halide (1 mmol) and palladium salt catalyst (1) (0.2 mol%) were
added and the mixture was placed in a Milestone microwave
reactor. Initially the microwave irradiation was set at 600 W and
the temperature was ramped from room temperature to the
desired temperature (100°C). The mixture was held at this temper-
ature until the reaction was complete. It was stirred continuously
during the reaction and monitored by both TLC and GC. After
the reaction was complete, the mixture was cooled to room
temperature and extracted with Et2O (30 ml). The organic phase
was washed with H2O (30 ml) and dried over MgSO4, filtered and
concentrated under reduced pressure using a rotary evaporator.
The residue was purified by silica gel column chromatography.
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Acknowledgments
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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Appl. Organometal. Chem. 2014, 28, 217–220