Recyclable and highly active cationic 2,2′-bipyridyl palladium(II) catalyst for Suzuki cross-coupling reaction in water

Article abstract of DOI:10.1016/j.tetlet.2006.10.127

A water-soluble and air-stable palladium(II)/cationic 2,2′-bipyridyl catalyst is proven to be a recyclable and extremely active catalyst for Suzuki reaction in aqueous and aerobic conditions. The conveniently prepared catalyst showed little loss in the catalytic process of the coupling between 4-bromoacetophenone and phenylboronic acid after five cycles. For the reactions of aryl chlorides, biaryls were formed in high yields under refluxing temperature in the presence of TBAB.

Full text of DOI:10.1016/j.tetlet.2006.10.127

Tetrahedron Letters 47 (2006) 9267–9270
Recyclable and highly active cationic 2,20-bipyridyl
palladium(II) catalyst for Suzuki cross-coupling reaction in water
Wei-Yi Wu, Shao-Nung Chen and Fu-Yu Tsai*
Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 106, Taiwan
Received 20 July 2006; revised 19 October 2006; accepted 25 October 2006
Abstract—A water-soluble and air-stable palladium(II)/cationic 2,20-bipyridyl catalyst is proven to be a recyclable and extremely
active catalyst for Suzuki reaction in aqueous and aerobic conditions. The conveniently prepared catalyst showed little loss in
the catalytic process of the coupling between 4-bromoacetophenone and phenylboronic acid after five cycles. For the reactions
of aryl chlorides, biaryls were formed in high yields under refluxing temperature in the presence of TBAB.
Ó 2006 Elsevier Ltd. All rights reserved.
Suzuki cross-coupling reaction is one of the most impor-
tant tools for the synthesis of unsymmetrical biaryls,1
which are widely found in the organic compounds used
in agrochemicals, pharmaceutics, natural products,
liquid crystalline materials, and conducting polymers.1e,2
The advantage of the Suzuki cross-coupling reaction is
that both reactants of aryl halides and arylboronic acids
can tolerate various functional groups. This coupling
reaction is usually performed in mixed organic/H2O sol-
vents. To reduce the consumption of organic solvent,
the employment of water-soluble catalysts in aqueous
systems has been paid much attention for the advanta-
ges of environmental friendly, inflammable, cheap, and
recyclable features.3 Recently, a large variety of auxil-
iary ligands and palladium catalysts, such as phosphine
ligands,3d,4 di(2-pyridyl)methylamine,5 palladacycles,6
Pd/C,7 catalysts in the mixture of H2O–surfactants,8
ligand-free palladium salts,9 and microwave-promoted
reactions,10 have been developed in order to enable the
Suzuki reaction to be performed in neat water to meet
the purpose of green chemistry. However, there are only
few catalysts with a high efficiency on the coupling of
aryl chlorides with arylboronic acids in water under aer-
obic conditions.5,6a–d This is a severe limitation, as from
the viewpoint of economics, the use of cheaper aryl chlo-
rides is more suitable for industrial processes. To expand
this scope, we prepare a new water-soluble cationic 2,20-
bipyridyl ligand and its palladium complex, which is
used to perform as a recyclable and highly active cata-
lyst for the coupling of aryl bromides and chlorides with
arylboronic acids into biaryls in water.
The precursor 4,40-bis(bromomethyl)-2,20-bipyridine, 1,
was prepared according to the published method.11
Treatment of 1 (0.5 g, 1.5 mmol) with an excess of
Me3N (50% aqueous solution, 20 mL) in dichlorometh-
ane at room temperature for 24 h resulted in the forma-
tion of a clear solution. The resulting mixture was
freeze-dried to give the cationic 2,20-bipyridyl ligand, 2,
in a quantitative yield (Scheme 1).12 Because 2 is soluble
in water at room temperature, it is feasible to prepare the
catalyst by mixing the equal molar amounts of 2 and
dichlorodiammine palladium, Pd(NH3)2Cl2, in water di-
rectly. The catalyst is stable in air, even in the solution.
Br
Br
Br Me N
NMe Br
3
3
Me N, H O
3
2
CH Cl , rt, 24h
2
2
N
N
N
N
1
2
Scheme 1.
*
Corresponding author. Fax: +886 2 2731 7174; e-mail: fuyutsai@ntut.edu.tw
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.127

9268
W.-Y. Wu et al. / Tetrahedron Letters 47 (2006) 9267–9270
The recyclability of the coupling reaction of phenyl-
boronic acid with 4-bromoacetophenone using K2CO3 as
a base and 0.1 mol % catalyst was first investigated in
water at 80 °C (Scheme 2). The biaryl product was mon-
itored by GC until the complete consumption of aryl
bromide. The organic product can be directly separated
by filtration, and the aqueous filtrate which contains the
catalyst could be re-used for the next run. It was note-
worthy that the recycled catalyst provided the cross-cou-
pling product over 90% yields in the five runs, although
the extended reaction time to the completion was re-
quired. This is mainly due to the work-ups and succes-
sive dilution of the catalyst. The employment of
various bases such as KOH, K3PO4, and KOAc gave
similar results. It was found that the use of neutral
PdCl2(bpy) gave only a 49% yield under the comparable
reaction conditions, suggesting the ionic nature of the
catalyst could be crucial to the reaction.
K2CO3 as the base afforded the product in a 99% yield
within 3 h (entry 1). However, only 43% yield was ob-
tained when Pd(NH3)2Cl2 was used as the catalyst under
the similar conditions (entry 2), indicating that the use
with ligand 2 is crucial. As expected, a longer reaction
time was required while using 2-substituted aryl
bromides (entries 3 and 6) due to the steric reason. In
contrast, the reactions of 4-bromoaniline and 4-bromo-
phenol in entries 4 and 7 were faster than that of bromo-
benzene. This is attributed to their better solubility in
aqueous media. A lower loading of catalyst (0.001
mol %) for the reaction of 4-bromophenol with various
arylboronic acids has also been studied (entries 8 and
10–12). The reaction for coupling between 4-bromophe-
nol and phenylboronic acid in water with the use of
0.0005 mol % of the catalyst showed TOF up to
81,000 hꢀ1, which was substantially higher than the pub-
lished data5b,6e (entry 9). In addition, the use of 2-bro-
mophenol with
a lower loading of the catalyst
The variation of aryl bromides was also investigated and
the data are collected in Table 1. The reaction of bromo-
benzene and 4-acetylbenzeneboronic acid with
0.1 mol % catalyst in water under air at 100 °C using
(0.001 mol %) gave the product in a nearly quantitative
yield after the reaction was stirred at 100 °C for 18 h
(entry 13). In the cases of bromopyridines, the rate of
3-bromopyridine is much higher than that of 2-bromo-
Pd(NH ) Cl / 2 (0.1 mol%)
3 2
2
COMe
+
COMe
B(OH)
2
Br
o
H O, K CO , 80 C
2
2
3
First cycle:
0.5h, 99%
Second cycle: 1h, 99%
Third cycle: 1.5h, 97%
Fourth cycle: 3h, 94%
Fifth cycle:
6h, 92%
Scheme 2.
Table 1. Suzuki coupling of aryl bromides and arylboronic acids in watera
Entry
Ar1–Br
Ar2–B(OH)2
[Pd] (mol %)
Time (h)
Yieldc (%)
TON
990
1
BrC6H5
BrC6H5
4-MeC(O)C6H4B(OH)2
4-MeC(O)C6H4B(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3
3
24
2
12
24
1
99
43
86
86
75
2b
3
430
860
860
750
400
2-Bromomesitylene
4-BrC6H4NH2
4-BrC6H4OMe
2-BrC6H4OMe
4-BrC6H4OH
4
5
6
7
PhB(OH)2
PhB(OH)2
(40)
99
990
8
9
4-BrC6H4OH
4-BrC6H4OH
4-BrC6H4OH
4-BrC6H4OH
4-BrC6H4OH
2-BrC6H4OH
2-Bromopyridine
3-Bromopyridine
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COMe
4-BrC6H4COOH
4-BrC6H4COOH
4-BrC6H4CF3
PhB(OH)2
PhB(OH)2
0.001
0.0005
0.001
0.001
0.001
0.001
0.1
1
2
99
81
(95)
64
(92)
(99)
(31)
(77)
94
99
84
60
84
99000
162000
95,000
64,000
92,000
99,000
310
770
9400
99,000
8400
60,000
8400
99,000
9700
99,000
97,000
395,000
990
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-MeOC6H4B(OH)2
4-FC6H4B(OH)2
4-MeC(O)C6H4B(OH)2
4-MeC(O)C6H4B(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
4-MeOC6H4B(OH)2
4-MeOC6H4B(OH)2
4-FC6H4B(OH)2
4-FC6H4B(OH)2
4-MeC(O)C6H4B(OH)2
4-MeC(O)C6H4B(OH)2
PhB(OH)2
24
1
20
18
22
6
1
3
1
3
1
3
1
3
1
5
12
0.1
0.01
0.001
0.01
0.001
0.01
0.001
0.01
0.001
0.001
0.0002
0.1
99
(97)
(99)
(97)
(79)
99
PhB(OH)2
PhB(OH)2
a Reaction conditions: aryl bromide (1 mmol), arylboronic acid (1.3 mmol), K2CO3 (2 mmol), H2O (3 mL), 100 °C in air.
b Pd(NH3)2Cl2 was used in the absence of ligand 2.
c GC yields using n-hexadecane as internal standard based on aryl bromides, isolated yields are given in parentheses.

W.-Y. Wu et al. / Tetrahedron Letters 47 (2006) 9267–9270
Table 2. Suzuki coupling of aryl chlorides and arylboronic acids in watera
9269
Entry
Ar1–Cl
Ar2–B(OH)2
[Pd] (mol %)
T (°C)
Time (h)
Yieldc (%)
1
2
3b
4b
5
6
7
8
9b
10
11b
12b
13b
14b
15b
16b
17b
18b
4-ClC6H4NO2
4-ClC6H4NO2
4-ClC6H4NO2
4-ClC6H4NO2
4-ClC6H4NO2
4-ClC6H4NO2
4-ClC6H4NO2
2-ClC6H4NO2
4-ClC6H4COMe
4-ClC6H4COMe
4-ClC6H4COMe
4-ClC6H4COMe
4-ClC6H4COMe
2-ClC6H4COMe
4-ClC6H4CN
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
4-MeOC6H4B(OH)2
4-FC6H4B(OH)2
4-MeC(O)C6H4B(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
4-MeOC6H4B(OH)2
4-FC6H4B(OH)2
4-MeC(O)C6H4B(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
0.5
0.1
0.1
0.01
0.5
0.5
0.5
0.5
1
0.01
1
1
1
1
100
140
140
140
100
100
100
100
140
140
140
140
140
140
140
140
140
140
3
12
12
24
8
99
70
99
70
(97)
(97)
(92)
(95)
99
81
99
99
(99)
(98)
99
98
50
6
4
12
6
12
12
7
5
18
24
7
48
9
1
1
1
1
2-ClC6H4CN
Chlorobenzene
2-ClC6H4OH
4-MeOC6H4B(OH)2
4-MeC(O)C6H4B(OH)2
(99)
a Reaction conditions: aryl chloride (1 mmol), arylboronic acid (1.3 mmol), K2CO3 (2 mmol), TBAB (0.5 mmol), H2O (3 mL).
b 1 mmol TBAB is used as additive.
c GC yields using n-hexadecane as internal standard based on aryl chlorides. Isolated yields are given in parentheses.
pyridine (entry 14 and 15). As for the aryl bromides
bearing electron-withdrawing groups, the loading of cat-
alyst can also be reduced to 0.001 mol % and good to
high yields were obtained in a short reaction time (entry
17, 19, 21, and 23–24). Since 4-bromobenzoic acid is sol-
uble in basic aqueous media the loading of catalyst was
further reduced to 0.0002 mol %, we found that a 79%
yield was obtained in 5 h corresponding to a TON:
395,000 (entry 25). The longer reaction time for the cou-
pling of 4-bromobenzotrifluoride with phenylboronic
acid was probably due to its poor solubility (entry 26).
sponding products in excellent yields (entries 5–8).
Different substituted chloroacetophenones were trans-
formed efficiently into the corresponding biaryls with
1 mol % catalyst (entry 9 and 11–14). High TON: 8100
was obtained by using 0.01 mol % catalyst for the reac-
tion of 4-chloroacetophenone with phenylboronic acid
(entry 10). Other activated aryl chlorides, such as 4-
and 2-chlorobenzonitriles, were coupled efficiently with
phenylboronic acid using 1 mol % catalyst (entries 15–
16). Finally, we studied the reactivity of unactivated aryl
chlorides and we observed that chlorobenzene gave a
moderate yield after 48 h (entry 17). 2-Chlorophenols,
due to good solubility in water, afforded an excellent
yield after 9 h at 140 °C (entry 18).
Apparently, the solubility of aryl bromides is to affect
the reaction rates. 4-Bromophenol and 4-bromobenzoic
acid that are soluble in the basic aqueous phase, thus
facilitate the oxidative addition (entries 9 and 25).
In summary, a water-soluble Pd(II)/cationic 2,20-bipyr-
idyl catalyst is developed. This exhibits recyclability
and a high efficiency for the coupling of activated and
deactivated aryl bromides and chlorides with various
arylboronic acids in water under aerobic conditions.
This environmental friendly procedure using water as
the solvent makes it potentially for industrial applica-
tions. The further studies of other organic carbon–
carbon bond formations catalyzed by this system are
currently under investigation.
The reactivity of aryl chlorides was also studied. The
reaction of 4-chloronitrobenzene with phenylboronic
acid at 100 °C in the presence of 0.5 mol % of catalyst
gave no product after 1 day. To circumvent this prob-
lem, tetra-n-butylammonium bromide (TBAB) was
employed as an additive, and the results are shown
in Table 2.
In the presence of 50 mol % TBAB the coupling of 4-
chloronitrobenzene with phenylboronic acid resulted in
the formation of cross-coupling product in a 99% GC
yield in 3 h with 0.5 mol % catalyst at 100 °C (entry 1).
It was found that the amount of addition of TBAB is
crucial in the cross-coupling reaction of aryl chlorides
and arylboronic acids. When the reaction temperature
was elevated to 140 °C, a better result was obtained with
the use of 100 mol % of additive (entries 2–3). In the
similar fashion, the loading of catalyst could be reduced
to 0.01 mol % giving 4-nitrobiphenyl in a 70% yield
(entry 4). Furthermore, 4- and 2-Chloronitrobenzenes
could also react with electron-rich and electron-poor
arylboronic acids in water at 100 °C to afford the corre-
Acknowledgements
The research was financially supported by the National
Science Council of Taiwan (NSC94-2113-M-027-002).
We gratefully thank Professor Kou-Yuan Hwa for her
helpful suggestion.
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NMR (D2O): d 3.16 (s, 18H), 5.07 (s, 4H), 7.65 (d,
J = 5.1 Hz, 2H), 8.24 (s, 2H), 8.75 (d, J = 5.1 Hz, 2H); 13
C
NMR (acetone-d): d 52.1 (6C), 66.6 (2C), 124.2 (2C), 126.8
(2C), 136.5 (2C), 148.6 (2C), 153.7 (2C); FAB-MS: m/z:
379, 381 [M+ꢀBr] (calcd: 379, 381).