Oxygen-promoted PdCl2-catalyzed ligand-free Suzuki reaction in aqueous media

Article abstract of DOI:10.1039/c0ob00524j

A simple and efficient protocol has been developed for the PdCl ₂-catalyzed ligand-free and aerobic Suzuki reaction of aryl bromides or nitrogen-based heteroaryl bromides with arylboronic acids in good to excellent yields in aqueous ethanol. A systematic investigation on the effect of different atmospheres on the reactivity of the palladium-catalyzed Suzuki reaction has been carried out, the results show that an aerobic atmosphere demonstrates a positive effect on the reactivity of the Suzuki reaction in an aqueous media and a negative effect in a pure organic solvent, which exhibits that the water plays a crucial role for the function of the atmosphere on the palladium-catalyzed ligand-free Suzuki reaction.

Full text of DOI:10.1039/c0ob00524j

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PAPER
Oxygen-promoted PdCl -catalyzed ligand-free Suzuki reaction in aqueous
2
media†
Chun Liu,* Qijian Ni, Pingping Hu and Jieshan Qiu
Received 31st July 2010, Accepted 25th October 2010
DOI: 10.1039/c0ob00524j
A simple and efficient protocol has been developed for the PdCl -catalyzed ligand-free and aerobic
2
Suzuki reaction of aryl bromides or nitrogen-based heteroaryl bromides with arylboronic acids in good
to excellent yields in aqueous ethanol. A systematic investigation on the effect of different atmospheres
on the reactivity of the palladium-catalyzed Suzuki reaction has been carried out, the results show that
an aerobic atmosphere demonstrates a positive effect on the reactivity of the Suzuki reaction in an
aqueous media and a negative effect in a pure organic solvent, which exhibits that the water plays a
crucial role for the function of the atmosphere on the palladium-catalyzed ligand-free Suzuki reaction.
6
Introduction
al. reported the effects of the inert and aerobic atmospheres on
the Pd/C-catalyzed ligand-free aqueous Suzuki reaction. Their
results showed that the atmospheres did not influence the cross-
coupling process. We recently noticed that the Suzuki reaction
of aryl chlorides catalyzed by the in situ-generated palladium
nanoparticles was promoted by the oxygen in PEG-400 at room
Palladium-catalyzed cross-coupling reactions have been recog-
nized as powerful tools for the carbon–carbon bond formation
and have been widely used in the synthesis of natural products,
1
pharmaceuticals and advanced functional materials. Over the
past decade, sterically demanding and electron-rich ligands have
10
temperature. Very recently, we found that the oxygen could
2
been developed for highly effective Suzuki reactions. Due to the
promote the Suzuki reaction of 2-pyridyl bromides in aqueous
water- and/or air-sensitivity of most ligands, numerous efforts
and advances have been made to solve these problems, including
designing oxygen and/or moisture-stable ligands via multi-step
11
isopropanol. Therefore, the influence of the atmosphere on the
palladium-catalyzed Suzuki reaction has not been fully inves-
tigated. Herein, we report an oxygen-promoted cross-coupling
reaction catalyzed by palladium(II) salts in aqueous ethanol at
room temperature and the successful application of this protocol
to the Suzuki reaction of nitrogen-based heteroaryl bromides.
Noticeably, an overall investigation of the effects of different
atmospheres on the Suzuki reaction in both aqueous medium and
pure organic solvents is described.
3
4
synthesis or supporting the ligand on functional supports.
Among the recent achievements on this topic, the development
of “ligand-free” catalytic systems has been one of the most
challenging fields in synthetic organic chemistry, because they are
the simplest and cheapest systems in comparison to the ligand-
5
promoted ones. More importantly, the “ligand-free” catalytic
system makes it possible to carry out the Suzuki reaction under
an aerobic atmosphere and/or in an aqueous media. Recently,
different aerobic ligand-free aqueous catalytic systems have been
Results and discussion
reported to perform the Suzuki reaction at room temperature,
6
for example, Pd/C in aqueous ethanol, Pd(OAc)
2
in aqueous
Optimization of reaction conditions
7
acetone, and Pd(OAc)
2
in aqueous ethylene glycol monomethyl
In our concept, the zero-valent palladium, the catalyst in the
reaction, is generated in situ from palladium(II) salts in the
reaction system. Therefore, we first tested the effects of different
precatalysts on the model cross-coupling of 4-bromoanisole with
phenylboronic acid in 50% aqueous ethanol under air at room
temperature. The results are illustrated in Table 1. It was clear
8
ether.
However, there are still open-questions in the aerobic ligand-
free aqueous protocols for the Suzuki reaction. One of them is
the effect of the atmosphere on such a transformation. In 2003,
Jung et al. observed a negative effect of oxygen on the Pd(OAc)
catalyzed ligand-free Suzuki reaction in DMF. Later, Sajiki et
2
-
9
that precatalysts with palladium(II) salts such as Pd(OAc)
2
and
PdCl exhibited high catalytic activity. Using 0.5 mol% PdCl ,
2
2
State Key Laboratory of Fine Chemicals, Dalian University of Technol-
ogy, Zhongshan Road 158, 116012, Dalian, China. E-mail: chunliu70@
yahoo.com; Fax: (+86) 411-3989-3854; Tel: + 86 411 39893854
the cross-coupling reaction could give the cross-coupling product
quantitatively in 30 min (Table 1, entry 2). However, no reaction
occurred when zerovalent palladium sources such as Pd
2
(dba) or
3
†
Electronic supplementary information (ESI) available: Experimen-
tal detail and characterization of cross-coupling products. See DOI:
0.1039/c0ob00524j
Pd/C were used (Table 1, entries 3 and 4), which was consistent
10
5h
1
with both our recent results and Li’s report. Interestingly,
1
054 | Org. Biomol. Chem., 2011, 9, 1054–1060
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Table 1 Effects of precatalysts on the Suzuki reaction of 4-bromoanisole
The reaction of 2-bromoanisole with phenylboronic acid gave
nearly the same results except a little decrease in reactivity because
of the steric effect (Table 2, entries 7–12). As known that the air is
composed mainly of nitrogen (78%) and oxygen (21%), the results
in Table 2 show clearly that an aerobic atmosphere is necessary for
a fast transformation.
a
with phenylboronic acid
Entry
Precatalysts
Isolated yield (%)
The kinetic studies were performed on the Suzuki reaction
of 4-bromoanisole with phenylboronic acid under air or N ,
2
1
2
3
4
5
6
7
Pd(OAc)
PdCl
Pd (dba)
Pd/C (5%)
PdO
2
91
100
No reaction
No reaction
Trace
68
Trace
2
respectively. The results are illustrated in Fig. 1. It is clear that
the reaction proceeded rather slowly and the induction period was
apparent in nitrogen. While the cross-coupling under air resulted
in the absence of the induction period and a sharp increase in the
initial rate. For example, 82% isolated yield was obtained within
10 min under air, which was much higher than that in nitrogen in
the same reaction time. Therefore, a conclusion can be drawn that
it is the oxygen that shortens the induction period and promotes
the Suzuki reaction in the ligand-free 50% aqueous ethanol system.
2
3
b
PdCl
PdCl
2
c
2
a
Reaction conditions: 4-bromoanisole (0.5 mmol), phenylboronic acid
0.75 mmol), palladium loading (0.5 mol%), Base (1.0 mmol), reaction
(
◦
b
time: 30 min, 50% EtOH (4 mL), 25 C, in air. 2 mol% TPPTS was used
in air. 2 mol% TPPTS was used in nitrogen.
c
Table 2 Effects of atmospheres on the reaction of aryl bromides with
a
phenylboronic acid in 50% EtOH
Entry
Aryl bromides
Atmospheres
Open air
Isolated yield (%)
1
2
3
4
5
6
7
8
9
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
2-Bromoanisole
2-Bromoanisole
2-Bromoanisole
2-Bromoanisole
2-Bromoanisole
2-Bromoanisole
100
100
72
49
O
2
balloon
N
H
CO
2
2
balloon
2
balloon
12
CO balloon
Open air
No reaction
87
89
32
26
11
O
2
balloon
N
H
CO
2
2
1
1
1
0
1
2
balloon
2
balloon
CO balloon
No reaction
Fig. 1 Yield vs. time curves of the Suzuki reaction of 4-bromoanisole
with phenylboronic acid in 50% EtOH under air or nitrogen.
a
Reaction conditions: bromoanisole (0.5 mmol), phenylboronic acid
◦
(
0.75 mmol), PdCl
2
(0.5 mol%), K
2
CO
3
(1.0 mmol), 30 min, 25 C.
To further investigate the generality of oxygen-promoted ligand-
free Suzuki reaction, we examined the effect of nitrogen or air
on the Suzuki reaction of 4-bromoanisole with phenylboronic
acid in different solvents. The results are illustrated in Table 3.
Gratifyingly, we observed that the couplings gave higher yields
under air than in nitrogen in aqueous medium. (Table 3, entries 1a–
5a vs. 1b–5b). For example, in 50% aqueous acetone, the reaction
resulted in 82%, 75% and 67% isolated yields in oxygen, air and
nitrogen, respectively (Table 3, entry 1c, 1a and 1b). However,
when the reaction proceeded in pure organic solvent, the reaction
rate was much slower than that in aqueous media. Moreover, it
was noteworthy that the reactivity was much lower under air than
in nitrogen in pure organic solvents (Table 3, entries 6a–11a vs.
6b–11b). The results in pure organic solvents were consistent with
adding a water-soluble ligand TPPTS decreased the catalytic
activity. In open air, PdCl -TPPTS gave a 68% isolated yield
Table 1, entry 6) and little product was obtained when the reaction
2
(
was carried out under nitrogen (Table 1, entry 7). The reason for
this might be that the palladium-TPPTS complex needed a long
induction period to be activated under nitrogen, while the reaction
performed in open air, a partial amount of TPPTS was oxidized
and the coordination ability was reduced. Also the cross-coupling
product was trace when using PdO as a catalyst (Table 1, entry 5).
We suppose that it is difficult to transfer Pd(II) to Pd(0) from PdO
in aqueous media.
As reported in Table 2, we next studied the impacts of different
atmospheres, namely, open air, oxygen, nitrogen, hydrogen, carbon
monoxide, and carbon dioxide, on the cross-couplings of 4-
9
Jung’s report. For instance, in pure ethanol, the reaction afforded
bromoanisole and 2-bromoanisole with phenylboronic acid using
4-methoxybiphenyl in 54% and 83% yields in air and nitrogen,
respectively (Table 3, entry 6a vs. 6b), while 100% and 72% isolated
yields were obtained for the same reaction in air and in nitrogen,
respectively, in 50% aqueous ethanol (Table 2, entry 1 vs. 3). The
results disclosed that the water played a crucial role in the influence
of the atmosphere on the palladium-catalyzed ligand-free Suzuki
reaction. After adding a suitable amount of water, the oxygen-
inhibited Suzuki reaction in pure organic solvent was switched to
the oxygen-promoted system in aqueous media.
◦
0
.5 mol% PdCl
2
as a precatalyst at 25 C, respectively. The same
as our recently published results, both of the cross-couplings
favored an aerobic atmosphere. In case of 4-bromoanisole, the
cross-coupling reaction reached quantitatively in 30 min in both
open air and oxygen (Table 2, entries 1 and 2); 72% isolated yield
in nitrogen (Table 2, entry 3); 49% in hydrogen (Table 2, entry 4);
12% in CO
2
(Table 2, entry 5), and no reaction occurred in CO
(
Table 2, entry 6).
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a
Table 3 Effects of atmospheres on the Suzuki reaction of 4-bromoanisole and phenylboronic acid in different solvents
Entry
Solvent
Atmosphere
PdCl
2
(%)
Time/min
10
Isolated yield (%)
b
1
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
1
1
1
1
a
b
c
a
b
a
b
a
b
a
b
a
b
a
b
a
b
a
b
0a
0b
1a
1b
Acetone/H
2
O
Air
Nitrogen
0.5
75
67
b
b
O
2
balloon
82
b
DMF–H
i-PrOH/H
i-Butanol/H
2
O
Air
Nitrogen
Air
Nitrogen
Air
Nitrogen
Air
Nitrogen
Air
Nitrogen
Air
Nitrogen
Air
Nitrogen
Air
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
5
99
83
93
49
b
b
2
O
10
b
b
2
O
60
14
b
4
b
THF–H
Ethanol
i-PrOH
2
O
120
17
63
39
b
54
83
9
30
20
24
35
Trace
55
12
23
8
Acetone
DMF
THF
120
120
120
120
Nitrogen
Air
Nitrogen
Air
1
i-Butanol
1
Nitrogen
42
a
b
◦
Reaction conditions: 4-bromoanisole(0.5 mmol), phenylboronic acid (0.75 mmol), PdCl
Co-sovent/H O (v/v = 1/1)
2
(0.5–1 mol%), K
2
CO
3
(1.0 mmol), solvent (4 mL), 25 C.
2
12
As literature described, the volume ratio between organic
8). To further investigate the catalytic activity of the PdCl
2
-EtOH–
solvent and water could affect the rate of the cross-coupling
reaction. Therefore, we next studied the effects of the ratio of
ethanol to water on the Suzuki reaction of 4-bromoanisole with
H
2
O system, we chose the arylboronic acids containing electron-
7
neutral or electron-withdrawing group as coupling partners,
which provided the products in 99% and 52% isolated yields
using 4-flurophenylboronic acid and 4-formylphenylboronic acid,
respectively (Table 4, entries 12 and 14). These results show that
the stronger the electron-donating group in arylboronic acid is,
the higher the catalytic activity is. This is because an electron-rich
arylboronic acid could accelerate the rate of the transmetalation
step in the Suzuki reaction.
We further reduced the palladium loading down to 0.2 mol%
and 0.1 mol% to test the efficiency of the catalytic system, the
cross-couplings between 4-bromoanisole and phenylboronic acid
were completed quantitatively in 35 min and 40 min, respectively
(Table 4, entries 15 and 16), resulting in the highest TOF up to
phenylboronic acid. The reactions were carried out using K
2
CO
3
◦
as base in the presence of 0.5 mol% PdCl
2
at 25 C in air (see ESI†).
Initially, we tried to proceed the reaction in pure water, but only
a trace of the product was obtained. When the ratio of ethanol
to water was 1 : 2, the reaction still afforded 4-methoxybiphenyl in
a low yield of 37% in 30 min. However, the reactivity enhanced
rapidly with the addition of an incremental amount of ethanol,
and a quantitative isolated yield was obtained when the volume
ratio of ethanol and water was 1 : 1. While further increasing the
amount of ethanol, the isolated yield of the cross-coupling product
decreased a little. The results showed that the ratio of ethanol to
water played a key role in the ligand-free Suzuki reaction. We
deduced that a suitable amount of water in the reaction mixture
-
1
1500 h (Table 4, entry 16). Interestingly, 70% isolated yield of
4-methoxybiaryl was obtained without stirring for 24 h at 25 C,
which further demonstrated that the PdCl
was highly efficient (Table 4, entry 17).
◦
13
could shorten the induction period and increase the initial rate.
2
-ethanol (50%) system
The Suzuki reaction involving heterocycles is of great interest
to the pharmaceutical industry because of the special biological
activities displayed by the heterobiaryl compounds. However, it
is reported that heteroaryl halides show a slower reaction rate
and are unsuitable coupling partners in the Suzuki reaction,
due to the potential binding nature of such substrates to the
metal center resulting in the formation of inactive substrate-metal
Scope and limitations of substrates
The scope and limitations of the PdCl
system for deactivated aryl bromides with various arylboronic
acids were investigated in open air at 25 C. The results in Table 4
exhibited that the Suzuki reaction between 4-bromoanisole and
tolylboronic acids gave a quantitative yield in the presence of
2
-EtOH–H O catalytic
2
◦
14
0
.5 mol% PdCl
2
as catalyst (Table 4, entries 4, 5 and 6). The
complexes. Recently, ligand-free protocols for the synthesis of
5d,15
cross-coupling reaction proceeded also very fast even increasing
the steric effect of aryl bromide or arylboronic acid (Table 4,
entries 7, 9–11). However, increasing the steric effect in both
aryl bromide and arylboronic acid could decrease the reactivity
of the cross-coupling, a 61% isolated yield was obtained in 6 h
between 2-bromoanisole and 2-tolylboronic acid (Table 4, entry
heterobiaryls containing a 2-pyridyl moiety have emerged.
Unfortunately, the ligand-free Suzuki reaction usually encounters
with a low reactivity against 2-halopyridines. In this regard, the
5d
best was Sajiki et al. who reached quantitative formation of 2-
phenylpyridine using 3.5 mol% Pd/C (10%) in 50% isopropanol
◦
at 80 C for 24 h under argon. Very recently, we reported a
1
056 | Org. Biomol. Chem., 2011, 9, 1054–1060
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a
Table 4 The Suzuki reaction of aryl bromides with arylboronic acids
Entry
1
Ar–Br
R
Product
Time/min
25
Isolated yield (%)
100
H
2
H
10
99
3
4
H
8
99
98
2-CH
3
3
3
15
5
3-CH
15
99
6
7
4-CH
10
40
100
95
H
8
9
2-CH
3-CH
4-CH
3
3
3
360
15
61
99
1
1
0
1
15
15
100
99
2-OCH
3
1
1
2
3
4-F
4-F
30
30
99
98
1
1
4
5
4-CHO
H
45
35
52
b
99
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Table 4 (Contd.)
Entry
Ar–Br
R
Product
Time/min
40
Isolated yield (%)
c
1
6
H
99
d
1
7
H
24 h
70
a
b
◦
Reaction conditions: aryl bromides (0.5 mmol), arylboronic acids (0.75 mmol), PdCl
2
(0.5 mol%), K
2
CO
3
(1.5 mmol), 50% EtOH (4 mL), 25 C, in air.
c
d
The PdCl
2
loading was 0.2 mol%. The PdCl
2
loading was 0.1 mol%. The PdCl
2
loading was 0.5 mol%, without stirring.
a
Table 5 The Suzuki reaction of 2-bromopyridine with arylboronic acids
isolated yields (Table 6, entries 2, 3, 5 and 6). While increasing the
steric hindrance of arylboronic acids, the reactivity decreased and
gave 67% and 55% corresponding coupling products in 300 min
when 2-tolylboronic acid or 2-methoxyl phenylboronic acid was
used, respectively (Table 6, entries 1 and 4). It was worth noting
that the reaction between 2-bromopyridine and 4-tolylboronic
acid could be completed in 10 min (Table 6, entry 3), even after
Entry
R
Time/min
Isolated yield (%)
b
1
2
3
4
5
4-CH
H
H
H
H
3
480
150
100
100
100
40c
82
reducing the loading of PdCl to 0.5 mol%, the reaction gave 93%
2
d
29
isolated yield in 70 min (Table 6, entry 7). The couplings of 5-
bromopyrimidine with phenylboronic acid or 4-tolylboronic acid
gave nearly quantitative yields in 60 min and 40 min, respectively
98e
41
a
Reaction conditions: 2-bromopyridine (0.5 mmol), arylboronic acids
(Table 6, entries 8 and 9). Moreover, 80% 4-tolylpyrimidine was
(
(
0.75 mmol), PdCl
2
(1.5 mol%), K
3
PO
4
·7H
2
O (1.5 mmol), 50% EtOH
loading was 1.0 mol%, and the reaction
◦
b
obtained in 150 min when 0.5 mol% PdCl
entry 10).
2
was used (Table 6,
4 mL), 80 C, in air. The PdCl
2
◦
c
d
proceeded at 25 C. 1.5 mmol K
used. The reaction proceeded in N atmosphere.
2
CO
3
was used. 1.5 mmol NaOH was
e
2
Conclusions
fast protocol for the ligand-free Suzuki reaction of 2-halogenated
pyridines in 50% aqueous isopropanol. A 96% isolated yield of 2-
In summary, we have developed a simple, efficient and ligand-
free protocol for the Suzuki reaction of aryl bromides or N-
hetroaryl bromides with arylboronic acids catalyzed by the Pd(II)
salts in 50% ethanol. It was noteworthy that the presence of
water could reverse the role of atmospheres on the palladium-
catalyzed ligand-free Suzuki reaction, converting the oxygen-
inhibited system in pure organic solvent into the oxygen-promoted
protocol in aqueous media. Furthermore, this aerobic and water-
involved protocol is in accordance with the concept of green
chemistry and of great interest for practical production. The nature
of the oxygen and water in this type of transformation and the
applications of the catalytic system to other transformations are
currently under investigation in our laboratory.
phenylpyridine was obtained in the presence of 1.5 mol% Pd(OAc)
2
◦
11
at 80 C for 30 min in air. Considering the high catalytic activity
of PdCl -ethanol (50%) system, we also attempted to extend this
system to the synthesis of 2-aryl-substituted pyridyl derivatives,
and the results are summarized in Table 5. Using 1 mol% PdCl
2
2
as catalyst, the Suzuki coupling between 2-bromopyridine and 4-
tolylboronic acid only gave the coupling product in 40% isolated
◦
yield after 8 h at 25 C (Table 5, entry 1). However, the reactivity of
2
-bromopyridine with phenylboronic acid enhanced dramatically
◦
using 1.5 mol% PdCl
2
as catalyst in 150 min at 80 C and gave
8
2% isolated yield (Table 5, entry 2). When other bases such as
NaOH and K PO O were tested under the above conditions,
·7H
we found that the coupling could be completed in 100 min when
using K PO O (Table 5, entry 4). While it only provided 2-
·7H
phenylpyridine in 41% isolated yield under N (Table 5, entry
), which further demonstrated the promotion of O on the
-50% ethanol system. In comparison
3
4
2
Experimental section
3
4
2
2
General remarks
5
2
Suzuki reaction in the PdCl
to Sajiki’s and Pan’s reports, the PdCl
manifested higher catalytic activity.
2
Unless otherwise noted, all the reactions were carried out under
air. All aryl halides and arylboronic acids were purchased from
6
5e
2
-ethanol (50%) system
1
Alfa Aesar, Avocado and used without purification. H NMR
Under the optimized conditions, the scope of the reactions
using 2-bromopyridine and arylboronic acids was investigated.
The results are summarized in Table 6. The reactions of 2-
bromopyridine with a series of 4-substituted arylboronic acids
provided the desired heterobiaryl products with more than 90%
spectra were recorded on a Varian Inova 400 spectrometer.
Chemical shifts are reported in ppm relative to TMS. Mass
spectroscopy data of the product were collected on a MS-EI
instrument. All products were isolated by short chromatography
on a silica gel (200–300 mesh) column using petroleum ether
1
058 | Org. Biomol. Chem., 2011, 9, 1054–1060
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Table 6 The Suzuki reaction of N-heteroaryl bromides with arylboronic
solvent was concentrated under vacuum and the product was
isolated by short chromatography on a silica gel (200–300 mesh)
column.
a
acids
b
Entry Ar–B(OH)
1
2
Product
Time/min Yield (%)
300
67
99
99
55
Acknowledgements
The authors thank the financial support from State Key
Laboratory of Fine Chemicals (KF0801), Science Research
Foundation of DUT (2008), Graduate Student Reform Fund
of DUT, the National Natural Science Foundation of China
2
3
4
20
(
20725619, 20836002, 20923006, 21076034), and the Program for
Changjiang Scholars and Innovative Research Team in University
IRT0711).
10
(
300
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2
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·7H
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Typical experimental procedure for the Suzuki reaction of aryl
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A mixture of aryl bromide (0.5 mmol), arylboronic acid
(
(
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