18-Crown-6 promoting Pd/C-catalyzed cross-coupling reaction of aryl bromides and arylboronic acids in aqueous media

Article abstract of DOI:10.1002/aoc.2891

Pd/C-catalyzed Suzuki-Miyaura cross-coupling between aryl bromides and arylboronic acids in 50% methanol aqueous solution proceeded smoothly in the presence of 18-crown-6. Various aryl bromides bearing electron-withdrawing groups and electron-donating gro

Full text of DOI:10.1002/aoc.2891

Research Article
Received: 5 January 2012
Revised: 10 May 2012
Accepted: 11 May 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2891
18-Crown-6 promoting Pd/C-catalyzed cross-
coupling reaction of aryl bromides and
arylboronic acids in aqueous media
Wenyi Chua, Xinmin Lia,b, Yanjun Houa,b, Hua Wanga,b, Hongyu Lia,b,
Xiaobin Yuana,b and Zhizhong Suna,b*
Pd/C-catalyzed Suzuki–Miyaura cross-coupling between aryl bromides and arylboronic acids in 50% methanol aqueous
solution proceeded smoothly in the presence of 18-crown-6. Various aryl bromides bearing electron-withdrawing groups
and electron-donating groups coupled with arylboronic acid in high yields. In addition, the catalyst could be recycled five
times without loss of activity. Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: Pd/C; 18-crown-6; Suzuki–Miyaura reaction; recycle; biaryl
was effective using Pd/C and K2CO3 in anisole without other
ligands or promoters, but the protocols were limited to the
Introduction
The palladium-catalyzed Suzuki–Miyaura coupling reaction[1–5]
between aryl halides and arylboronic acids is one of the most
important carbon–carbon bond-forming processes in synthetic
organic chemistry.[6–10] In the past few years, great advances
have been made in developing active and efficient catalysts by
modifying traditional ligands and discovering new ones.[11–13]
However, these ligands and Pd precursors are expensive and
the palladium catalysts are usually not reusable. To overcome
these difficulties, the application of a reusable palladium-
catalyzed Suzuki– Miyaura cross-coupling reaction has been
developed.[14,15] Palladium on carbon (Pd/C) is one of the most
frequently used catalysts in industrial applications because of its
high catalytic activity, low cost and easy removal from the
reaction mixture.[16,17] The first example of a Pd/C-catalyzed
Suzuki reaction was reported by Marck and coworkers in
1994.[18] Initially, Pd/C was considered as a heterogeneous
catalyst for the Suzuki reaction, enabling straightforward removal
of the catalyst from the reaction mixture by passing through
a filter.[19,20] However, Conlon has reported that the Suzuki
reaction proceeds by a homogeneous pathway when using
Pd/C as the catalyst.[21] The group of Chen also reported that
leached/dissolved Pd species are the true active species and Pd
absorbed on active carbon has no heterogeneous contribution
to the reaction.[22] In recent years, further interesting examples of
Suzuki reactions catalyzed by Pd/C have been reported.[23–32]
Andrus reported a novel bis-phenanthryl NHC ligand for the
efficient coupling of aryl chlorides at room temperature with
KF/18-crown-6 in THF.[30] Sajiki and coworkers developed a
ligand-free Pd/C-catalyzed system in which aryl bromides were
coupled with various arylboronic acids in good yields at room
temperature, but the aryl bromides bearing electron-donating
groups, such as methoxy, showed lower reactivity and took
longer to go to completion.[31] Mayur V. Khedkar and coworkers
found that coupling between aryl halides and arylboronic acids
more reactive aryl iodides and required high temperatures.[32]
Herein, we report an efficient Pd/C-catalyzed Suzuki reaction of
aryl bromides and arylboronic acids promoted by 18-crown-6.
This method was applied to a wide variety of substrates under
mild conditions. In particular, the catalyst could be recovered
and recycled five times without loss of activity.
Results and Discussion
Upon preliminary investigation, it was found that the reaction of aryl
bromides and arylboronic acids proceeded smoothly to give cou-
pled biaryls in the presence of Pd/C. The addition of 18-crown-6
could improve the effectiveness of the catalyst for the Suzuki
reaction. Initially, the reaction conditions were optimized starting
from 4-bromonitrobenzene and phenylboronic acid catalyzed by
Pd/C with varying amounts of 18-crown-6, as shown in Table 1.
The reaction was completed in 12 h in the absence of
18-crown-6 (Table 1, entry 1). Increasing the amount of
18-crown-6 from 0.5 equiv. to 1.0 equiv., resulting in a remarkable
acceleration of the rate and reaction time, was reduced to 1 h
(Table 1, entries 2 and 3). Further increasing the amount of
18-crown-6 did not cause a reduction in the reaction time
*
Correspondence to: Zhizhong Sun, School of Chemistry and Materials Science,
Heilongjiang University, 150080 Harbin, People’s Republic of China. E-mail:
sunzz@hlju.edu.cn
a School of Chemistry and Materials Science, Heilongjiang University, 150080
Harbin, People’s Republic of China
b Key Laboratory of Chemical Engineering Process and Technology for High-
Efficiency Conversion, College of Heilongjiang Province, 150080 Harbin,
People’s Republic of China
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

W. Chu et al.
Table 1. Effect of the amount of 18-crown-6 on the Suzuki reactiona
Entry
18-crown-6 (equiv.)
Time (h)b
Yield (%)c
1
2
3
4
0
12
6
90
96
98
97
0.5
1.0
2.0
1
1
aReaction conditions: 4-bromonitrobenzene (0.5mmol), phenylboronic acid (0.6mmol), K2CO3 (1.0mmol), 10 wt% Pd/C(2 mol%, 0.01 mmol), 50%
methanol (4ml), 45ꢀ, the reaction was monitored by thin-layer chromatography.
bCompletion time.
cIsolated yield.
(Table 1, entry 4). Therefore, 1.0 equiv. of 18-crown-6 was
selected as the additive in this catalytic system.
excellent result, whereas the use of pure H2O gave quite a
poor result (Table 3, entry 3). On the other hand, dioxane,
acetone and DMF, usually used as solvents in the Suzuki reac-
tions, resulted in low yields (Table 3, entries 4–6). In addition,
small amounts of benzene and phenol were observed in the
reactions formed by protodeboronation of phenylboronic acid.
Next, we applied the optimized conditions for the Suzuki cross-
coupling reaction of a range of aryl halides with arylboronic acids
in the presence of 2 mol% Pd/C at 45 ꢀC in 50% methanol aque-
ous solution. As illustrated in Table 4, various aryl bromides
containing an electron-withdrawing group such as 4-NO2 and
4-CHO, and electron-donating groups such as 4-OCH3, reacted
smoothly with phenylboronic acid to provide the corresponding
cross-coupling products in high yields (Table 4, entries 1–4).
Regarding the aryl boronic acid, the coupling reaction using
electron-rich aryl boronic acid proceeded quite efficiently relative
to non-substituted phenylboronic acids. (Table 4, entries 5–9). For
example, 3,4-dimethoxyphenylboronic acid underwent Suzuki
coupling with 4-bromonitrobenzene to afford the desired prod-
uct in 99% yield in 0.5 h (Table 4, entry 5). Noticeably, the cross-
coupling reaction of ortho-substituted aryl bromides gave the
expected biaryl derivatives in high yield (Table 4, entry 9). As far
Although the reason for the difference in catalyst activity is not
clear, it might be caused by the high concentration of leached Pd
in the reaction mixture. Firstly, the oxygen atom on 18-crown-6
could bind to the palladium adsorbed on the active carbon
support and remove it from the solution. Secondly, 18-crown-6
could help to stabilize Pd in solution. Therefore, the function of
18-crown-6 is similar to the phase transfer catalyst and ligands
in the reaction.
Generally, base is an important factor in the cross-coupling
reaction.[33] Various bases were evaluated for the model cross-
coupling reaction of 4-bromonitrobenzene with phenylboronic
acid. The results are summarized in Table 2 and show that
K2CO3 (Table 2, entry 1) gave better results than other bases
(Table 2, entries 2–6). Therefore, K2CO3 was selected as the
effective base in this catalytic system.
Further investigations were carried out to examine the
influence of the solvent on the same model reaction. The
results are summarized in Table 3. Both methanol and 50%
methanol aqueous solution (Table 3, entries 1 and 2) gave
satisfactory yields; 50% methanol aqueous solution gave an
Table 2. Effect of base on the Suzuki reactiona
Entry
Base
Time (h)
Yield (%)b
1
2
3
4
5
6
K2CO3
Na2CO3
NaOH
1
1
1
1
1
2
98
89
46
52
63
25
NaHCO3
Cs2CO3
Et3N
aReaction conditions: 4-bromonitrobenzene (0.5mmol), phenylboronic acid (0.6mmol), 10wt% Pd/C(2mol%, 0.01 mmol ), base (1.0mmol), 18-crown-6
(0.5mmol), 50% methanol (4ml), 45ꢀC.
bIsolated yield.
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Suzuki reaction Promoted by 18–crown–6
Table 3. Effect of different solvents on the Suzuki reactiona
Entry
Solvent
MeOH
Time (h)
Yield (%)
1
2
3
4
5
6
3
94b
98b
5c
33c
22c
28c
50%MeOH
H2O
1
12
6
Dioxane
Acetone
DMF
6
6
aReaction conditions: 4-bromonitrobenzene (0.5mmol), phenylboronic acid (0.6mmol), 10wt% Pd/C(2mol%, 0.01mmol ), 18-crown-6 (0.5mmol), K2CO3
(1.0mmol), solvent (4ml), 45ꢀC.
bIsolated yield.
cNot completed.
Table 4. Pd/C-catalyzed Suzuki–Miyaura cross-coupling between aryl bromides and arylboronic acidsa
Entry
R1
R2
Time (h)b
Yield (%)c
1
4-NO2
H
H
H
H
1
99
98
97
97
99
99
98
91
91
96
95
94
92
91
88
98
92
84
86
34d
22d
26d
90e
28f
2
4-CHO
1
3
4-OMe
2
4
3-OMe, 4-OMe
4-NO2
4
5
3-OMe, 4-OMe
3-OMe, 4-OMe
3-OMe, 4-OMe
3-OMe, 4-OMe
3-OMe, 4-OMe
4-CF3
0.5
0.5
1
6
4-CHO
7
4-OMe
8
3,4-OCH2O-
2-NO2, 4-OMe
4-NO2
3
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3
4-CHO
4-CF3
3
4-OMe
4-CF3
5
3-OMe, 4-OMe
3,4-OCH2O-
2-NO2, 4-OMe
4-NO2
4-CF3
8
4-CF3
8
4-CF3
8
2-Me, 5-Me
2-Me, 5-Me
2-Me, 5-Me
2-Me, 5-Me
2-Me, 5-Me
4-CF3
2
4-OMe
3
3-OMe, 4-OMe
3,4-OCH2O-
4-NO2
5
5
6
4-NO2
3
4-CHO
4-CF3
3
4-NO2
4-CF3
3
4-NO2
4-CF3
3
aReaction conditions: aryl bromides (0.5 mmol), aryl boronic acid (0.6 mmol), 10 wt% Pd/C (2 mol%, 0.01 mmol), K2CO3 (1.0 mmol), 18-crown-6
(0.5mmol), 50% methanol aqueous solution (4ml), 45ꢀC.
bCompletion time.
cIsolated yield.
dWithout addition of 18-crown-6.
e18-Crown-6 (0.1 equiv.) was added to the mixture with an incubation period of 30 min.
f18-Crown-6 (0.1equiv.) was added to the mixture without an incubation period.
Appl. Organometal. Chem. (2012)
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W. Chu et al.
as we know, aryl boronic acids bearing electron-withdrawing
groups usually shows lower reactivity in the Suzuki reaction.[25,34]
Very few papers, to the best of our knowledge, have reported
that high yields were achieved with arylboronic acids bearing
strong electron-withdrawing groups. In this catalytic system,
4-(trifluoromethyl)phenylboronic acid coupled with various aryl
bromides bearing electron-withdrawing groups and electron-
donating groups gave high yields (Table 4, entries 10–15). For
example, 4-(trifluoromethyl)phenylboronic acid reacted with
4-bromonitrobenzene to afford the product in 98% yield in
3 h (Table 4, entry 10). However, the Suzuki reaction between
4-bromonitrobenzene and 4-(trifluoromethyl)phenylboronic acid
did not go to completion without the addition of 18-crown-6
(Table 4, entry 21). Steric hindrance of the ortho-substituted
arylboronic acids did not affect the reaction progress in this
system. 2,5-Dimethylphenylboronic acid coupled with various aryl
bromides in high yields (Table 4, entries 16–19). For example,
2,5-dimethylphenylboronic acid reacted with 4-bromonitrobenzene
to afford the product in 98% yield in 2 h (Table 4, entry 16). By
contrast, only 34% yield was achieved without the addition of
18-crown-6 (Table 4, entry 20). In addition, we tried to carry out
the Suzuki coupling of aryl chlorides with phenylboronic acid in
this system. Unfortunately, no desired product was obtained when
4-chloronitrobenzene was coupled with phenylboronic acid at
80 ꢀC using a catalyst loading of 5 mol%.
From the standpoint of green chemistry, low loading of
additive would be desirable. Simeone has reported an efficient
system catalyzed by palladium on carbon and the amount of
ligand can be significantly decreased by incorporating an incuba-
tion period.[25] Thus we designed experiments whereby low
levels of 18-crown-6 (0.1equiv.) are added to the reaction mixture
after a short incubation period. We were surprised to find that the
reaction between 4-bromonitrobenzene and 4-(trifluoromethyl)
phenylboronic acid proceeded quite efficiently to afford the
product in 90% yield with only 0.1 equiv. of 18-crown-6 added
to the reaction mixture after an incubation time of 30 min
(Table 4, entry 23). On the other hand, only 28% yield was
achieved without incubation time (Table 4, entry 24).
summarized in Table 5 and show that Pd/C could be recycled
five times without loss of activity. After the fifth run, Pd/C was
filtered through a 0.45 mm filter and the filtrates were analyzed
by inductively coupled plasma (ICP) for palladium. ICP analysis
showed that less than 1 ppm leached Pd existed in the filtrate
after catalyst removal. These results show that after the reaction
was completed almost all the dissolved palladium species can
redeposit on the support, and be easily separated from the
reaction mixture, which is consistent with the reports by Chen
and coworkers.[22]
In conclusion, we have developed a mild and efficient protocol
for Pd/C-catalyzed Suzuki–Miyaura cross-coupling reaction. The
addition of 18-crown-6 can promote the reaction. The method
allows for the preparation of a wide variety of biaryl derivatives
with excellent yields. Furthermore, the Pd/C catalyst could be
recycled five times without loss of activity.
Experimental
General Information
Unless otherwise stated, all the reactions were carried out in air.
All aryl bromide and arylboronic acids were purchased from
Aladdin, Alfa, and used without purification. Pd/C was purchased
from Kaida Chemical Co. Ltd. The bases and solvents were
purchased from Kermel Chemical Co. Ltd. NMR spectra were
recorded on a Bruker Avance 400 spectrometer. Chemical shifts
are reported in ppm relative to TMS. The Pd analysis was per-
formed by ICP-MS (Thermo Electron, XSeries II). All products were
isolated by short chromatography on a silica gel (200–300 mesh)
column using petroleum ether (60–90 ꢀC).
General Procedure for the Suzuki–Miyaura
Cross-Coupling Reaction
Aryl bromide (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3
(1.0 mmol ,138 mg), 10 wt% Pd/C(0.01 mmol, 24 mg), 18-crown-6
(0.5 mmol, 132 mg) and MeOH (2 ml) and H2O (2 ml) were added
to a test tube, and the reaction mixture was stirred at 45 ꢀC in air.
After a certain period, the reaction mixture was diluted with H2O
We next examined the reuse of Pd/C in the coupling of
4-bromonitrobenzene with phenylboronic acid. The results are
a
Table 5. Pd/C as the catalyst recycled times experiment
Entry
Run
Time (h)b
Yield (%)c
1
2
3
4
5
1
2
3
4
5
1
1
1
1
1
99
97
98
98
97
aReaction conditions: 4-bromonitrobenzene (0.5mmol), phenylboronic acid (0.6mmol), K2CO3 (1.0mmol), 10 wt% Pd/C(2mol%, 0.01mmol), 18-crown-6
(0.5mmol) and 50% MeOH (4ml), 45ꢀ.
bCompletion time.
cIsolated yield.
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Suzuki reaction Promoted by 18–crown–6
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(10 ml) and EtOAc (10 ml) and passed through a membrane filter.
The filtrate was separated into two layers and the aqueous layer
was extracted with EtOAc (2 Â 10 ml). The combined organic
layers were washed with brine (10 ml), dried over MgSO4, and
concentrated in vacuo. The crude product was purified by
column chromatography on silica gel using petroleum ether to
afford pure product. All of the isolated products were gave
1
satisfactory H NMR data (see supporting information).
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Acknowledgments
We are grateful for financial support from the Research Project of
the Education Department of Heilongjiang Province of China (No.
12511383).
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