Microwave-assisted C-C coupling reaction using polymer-supported electron-rich oxime palladacycles in aqueous condition

Article abstract of DOI:10.1016/j.tetlet.2017.05.080

Previously reported polymer-supported oxime palladacycle catalyst has shown effective catalytic activity in the Suzuki coupling reaction. In this work, the effect of microwave on reaction rate and induction period was examined by comparing them with the conventional heating. Undoubtedly, microwave heating effectively enhanced the catalytic performance in the Suzuki reaction. In-depth observation of the kinetic profiles revealed that the microwave irradiation not only reduced the overall reaction time but also significantly decreased the induction period to less than 3?min. Finally, the performance of the catalyst in water, coupling of potassium phenyltrifluoroborate and aryl bromides, and recyclability were also examined.

Full text of DOI:10.1016/j.tetlet.2017.05.080

Tetrahedron Letters 58 (2017) 2670–2674
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted C-C coupling reaction using polymer-supported
electron-rich oxime palladacycles in aqueous condition
Sung-Jun Park a,c, Hong-Jun Cho a,c, Sang-Myung Lee b, Yoon-Sik Lee a,
⇑
a School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
b Department of Chemical Engineering, Kangwon National University, Kangwon-Do 200-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously reported polymer-supported oxime palladacycle catalyst has shown effective catalytic activity
in the Suzuki coupling reaction. In this work, the effect of microwave on reaction rate and induction per-
iod was examined by comparing them with the conventional heating. Undoubtedly, microwave heating
effectively enhanced the catalytic performance in the Suzuki reaction. In-depth observation of the kinetic
profiles revealed that the microwave irradiation not only reduced the overall reaction time but also sig-
nificantly decreased the induction period to less than 3 min. Finally, the performance of the catalyst in
water, coupling of potassium phenyltrifluoroborate and aryl bromides, and recyclability were also
examined.
Received 11 April 2017
Revised 22 May 2017
Accepted 23 May 2017
Available online 24 May 2017
Keywords:
Microwave
Suzuki coupling reaction
Oxime palladacycle
Polymer-supported catalyst
Induction period
Ó 2017 Elsevier Ltd. All rights reserved.
Introduction
was revealed, and the highly active heterogeneous oxime pallada-
cycle catalyst could be developed for the Suzuki coupling reaction.
Since palladacycles were introduced with unprecedented cat-
alytic performance for the Heck and Suzuki coupling reactions by
Herrmann and Beller,1,2 various palladacycles have been developed
that are more thermally stable and not sensitive to air and mois-
ture with efficient catalytic activity. Among them, oxime pallada-
cycles have been proved to be highly active palladium (Pd)
catalysts for various coupling reactions such as Suzuki-Miyaura,
Mizoroki-Heck, Stille, Sonogashira, and Ullmann-type reactions
by the pioneering works of the Nájera group.3–5
Using magnetic nanoparticles as solid supports,14,15 various
heterogeneous oxime palladacycle catalysts have been developed
in order to meet the major concerns of easy work up and recycla-
bility. However, the heterogeneous oxime palladacycles as a
catalyst precursor contain inherent issues to be solved for efficient
C-C coupling reactions.
The main issue is unfavorable reaction kinetics due to the solid-
liquid biphasic system.16 This obstacle requires higher reaction
temperature and longer reaction time, compared to homogeneous
systems. Furthermore, another significant issue delaying the reac-
tion time is the presence of an induction period of palladacycles
observed in the first run of C-C coupling reactions.17–19 The induc-
tion period have been explained by the slow transformation of Pd
precatalyst into an active form in the cross-coupling reactions.20 To
address this inherent problems, we here utilize the microwave
irradiation technique to shorten the reaction time in the Suzuki
coupling reaction with the three-alkoxy-substituted oxime pal-
ladacycle resin. The instantaneous ‘‘flash heating” by microwave
irradiation has been proven to be effective in the solid-phase C-C
coupling reactions.21,22 In this study, we evaluate the catalytic
activity of three-alkoxy-substituted oxime palladacycle resin for
the Suzuki coupling reaction in water system under microwave
irradiation. Through analysis of the kinetic profiles of the Suzuki
coupling reaction, we demonstrate the effect of the microwave
irradiation on the reaction kinetics and especially, the induction
With increasing catalyst recovery issue for green process,6–8
highly active oxime palladacycles have been converted into reusa-
ble catalytic systems. As a result of such efforts, Corma group
developed reusable oxime palladacycles anchored on different type
of supports, such as SiO2, ionic liquid, and polymers, for C-C cou-
pling reactions in water.9 Najera group used Kaiser oxime resin
to prepare heterogeneous oxime palladacycle, which showed effi-
cient catalytic activity in the Suzuki and Heck reactions.10–12 We
previously reported on a three-alkoxy-substituted oxime pallada-
cycle immobilized polystyrene resin (Fig. 1).13 By changing the
electron-richness of the oxime ligand, the relationship between
the electron-richness of the oxime ligand and the catalytic activity
⇑
Corresponding author.
E-mail address: yslee@snu.ac.kr (Y.-S. Lee).
These authors contributed equally to this work.
c
http://dx.doi.org/10.1016/j.tetlet.2017.05.080
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

S.-J. Park et al. / Tetrahedron Letters 58 (2017) 2670–2674
2671
Table 1
Effect of solvent conditions in Suzuki coupling reaction of 4-bromoanisole with
phenylboronic acid.a
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
H2O
DMF
2
1
8
20
10
80
74
88
84
H2O/DMF (1:3)
H2O/DMF (1:2)
H2O/DMF (2:3)
H2O/DMF (1:1)
H2O/DMF (3:2)
H2O/DMF (2:1)
H2O/DMF (3:1)
Fig. 1. Structure of polymer-supported electron-rich oxime palladacycle catalyst.
period, compared to the conventional heating. Furthermore, the
activity of the resin catalyst is examined during recycling and
other cross-coupling reaction of aryl bromides with
phenyltrifluoroborate.
a
Conditions: 4-bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime
palladacycle resin (1 mol%), Cs2CO3 (1.5 mmol) in various solvent systems (v/v,
3 mL), 50 °C for 15 min at 40 W.
b
GC yields.
Results and discussion
The three-alkoxy-substituted oxime palladacycle resin was pre-
pared as described in the previous paper.13 The final Pd catalyst
resin was obtained by treating the three-alkoxy-substituted oxime
resin with Li2PdCl4 and NaOAc at room temperature for 12 h (Pd
loading level: 0.146 mmol gÀ1). The Suzuki coupling reaction of
4-bromoanisole with phenylboronic acid was carried out to opti-
mize the reaction condition under microwave irradiation (40 W,
50 °C, 15 min) using the three-alkoxy-substituted oxime pallada-
cycle resin. Heating mechanism of the microwave is directly
related with dielectric molecules, and water is a suitable solvent.
However, chloromethyl polystyrene (CM PS) resin is not compati-
ble with water, and polar aprotic solvents such as DMF, NMP, or
DMSO is required for swelling.23 Moreover, it was proved in the
previous work that delicate balance of the solvents is required in
the heterogeneous catalytic system that uses inorganic base.
Therefore, H2O/DMF mixtures of different ratios were tested as a
solvent (Table 1). The H2O/DMF mixtures with over 50% H2O were
compatible for the Suzuki coupling reaction under microwave irra-
diation, while only H2O or DMF solvent system was unfavorable.
Among them, the H2O/DMF (2:1) mixture gave better yield than
1:1 mixture which was the optimum solvent condition for the con-
ventional heating system.13
The solvent screening results could be explained by the differ-
ence in the dielectric constant of water (80) and DMF (38). Higher
dielectric constant means more efficient heating by microwave
irradiation, so solvents with higher H2O ratios (entries 7–9 in
Table 1) gave higher yields than the ones with lower H2O ratios
(entries 3–5 in Table 1). Under microwave condition, the H2O con-
tent seemed more critical for the optimal reaction, while DMF
affected the swelling of the polymer catalyst. Overall, H2O/DMF
(2:1) was chosen as the optimized solvent system, which was used
in base screening (Table 2). Inorganic bases exhibited affordable
performances except for CH3COONa, and an organic base triethy-
lamine, was not suitable. Based on the optimization results,
K2CO3 as a base and H2O/DMF (2:1) mixture as a solvent were used
for the following Suzuki coupling reactions under microwave
irradiation.
Table 2
Effect of various bases in Suzuki coupling reaction of 4-bromoanisole with phenyl-
boronic acid.a
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
Na2CO3
K3PO4
Na3PO4
KOH
NaOH
CH3CHOONa
Trimethylamine
88
93
69
74
83
91
84
3
31
a
Conditions: 4-bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime
palladacycle resin (1 mol%), various bases (1.5 mmol) in H2O/DMF (2:1, v/v, 3 mL),
50 °C for 15 min at 40 W.
b
GC yields.
2-bromothiopene and 2-bromopyridine with phenylboronic acid
gave hetero biaryl compounds which is of interest in the pharma-
ceutical industry.24 Due to the potential coordinating feature of the
heterocyclic substrate to the Pd center,25 the Suzuki coupling reac-
tion of hetero aryl bromides did not proceed well under microwave
irradiation as much as that of aryl bromides (entries 11–12 in
Table 3). To confirm the advantage of microwave heating over con-
ventional heating, we terminated the reactions in 20 min at the
same temperature (50 °C). As shown in in Table 3 (entries 1 and
13), the microwave heating converted the substrate into the corre-
sponding biaryl compound much more efficiently than the conven-
tional heating system.
For in-depth comparison study between the microwave and the
conventional heating systems, we analyzed the kinetic profiles of
the Suzuki coupling reaction by measuring the coupling yields at
designated reaction time points (Fig. 2). Under the conventional
heating system, the overall reaction time was around 60 min,
and the induction period was observed as 20 min, which is similar
to the one reported by Nájera group.5 Other palladacycle catalysts,
including cyclopalladated imine catalyst and phosphapalladacycle,
showed an induction period of 1 h in homogeneous system.17–19 In
contrast, the three-alkoxy-substituted oxime resin under micro-
wave heating exhibited a negligible induction time (<3 min) and
reached a plateau in 15 min with over 93% yield. Taken together,
the microwave heating accelerated the catalytic activity as well
as dramatically reduced the induction period for efficient Suzuki
coupling reactions.
The Suzuki coupling reactions were performed with various aryl
halides and phenylboronic acid using the three-alkoxy-substituted
oxime resin under microwave irradiation in a sealed vessel
(Table 3). Overall reaction time was fixed to 30 min, which was
much shorter compared to the 2 h reaction of the previous report.
Regardless of activated or deactivated substrates, almost all aryl
bromides were converted to the corresponding biaryl compounds
in excellent yields under mild condition (50 °C), whereas 2-phenyl-
naphthalene required higher reaction temperature to obtain high
yield (entries 1–6 in Table 3).
With regard to its application in green process, we investigated
the applicability of the oxime palladacycle catalyst under micro-
wave condition for the Suzuki coupling in water. Since only traces
of the product was obtained in pure water from the preliminary
Aryl chloride substrates gave low yields even under higher tem-
perature (entries 7–10 in Table 3). The Suzuki coupling reactions of

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S.-J. Park et al. / Tetrahedron Letters 58 (2017) 2670–2674
Table 3
Suzuki coupling reaction of various aryl halides with phenylboronic acid.a
Entry
1
Substrate
Temp (°C)
Yield (%)b
97c
50
2
50
97
3
4
5
50
50
50
99
96
99
6
100
97
Fig. 2. Comparison of reaction profiles of the Suzuki coupling reactions of 4-
bromoanisole with phenylboronic acid using microwave heating (40 W, 50 °C) and
oil bath heating (50 °C).
7
100
100
100
100
21
53
20
34
8
Table 4
9
Suzuki coupling reaction of various aryl halides and phenylboronic acid in water,
using TBAB (1 mmol).a
10
11
12
70
70
35
66
Entry
1
Substrate
Temp (°C)
Yield (%)b
95
13
50
3
70
dConventional heating in H2O/DMF (1:1, v/v).
2
70
92
a
Conditions: aryl halides (1 mmol), phenylboronic acid (1.2 mmol), oxime pal-
ladacycle resin (1 mol%), K2CO3 (1.5 mmol) in H2O/DMF (2:1, v/v, 3 mL), 30 min at
40 W.
b
Isolated yields by column chromatography.
Reaction time: 20 min.
3
4
5
70
70
70
97
95
96
c
test, tetra-n-butylammonium bromide (TBAB) was used as a phase
transfer catalyst, and K2CO3 was selected as a base for the Suzuki
coupling reaction in water (Table 1S in Supporting Information).
As shown in Table 4 (entries 1–5), the Suzuki coupling reaction
of aryl bromides with phenylboronic acid smoothly afforded the
desired biaryls in high yields (over 92%) in 30 min at 70 °C, indicat-
ing that the three-alkoxy-substituted oxime palladacycle resin is
working well under microwave condition for the Suzuki coupling
reaction in water. For chloride substrates, the catalyst under micro-
wave condition in water/TBAB system provided better catalytic
performance in the Suzuki coupling reaction than those of previous
water/DMF system (entries 6–7 in Table 4).
6
7
100
100
62
88
a
Conditions: aryl halides (1 mmol), phenylboronic acid (1.2 mmol), oxime pal-
ladacycle resin (1 mol%), base (1.5 mmol), TBAB (1 mmol) in H2O (3 mL), 30 min at
40 W.
b
GC yields.

S.-J. Park et al. / Tetrahedron Letters 58 (2017) 2670–2674
2673
Table 5
Table 6
Suzuki coupling reaction of various aryl bromides and potassium
Reusability test of oxime palladacycle resins in the Suzuki coupling reaction of 4-
phenyltrifluoroborate.a
bromoanisole and phenylboronic acid.a
Entry
1
Substrate
Yield (%)b
90
Yield (%)b
1st cycle
94
2nd cycle
96
3rd cycle
95
4th cycle
95
5th cycle
95
2
3
60
91
a
Conditions: 4-bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime
palladacycle resin (1 mol%), K2CO3 (1.5 mmol) in H2O/DMF (2:1, v/v, 3 mL), 50 °C for
30 min at 40 W.
b
GC yields.
4
5
93
66
pling reaction under microwave condition and recyclable up to 5
times without any decrease in the coupling yield.
Conclusion
6
97
In summary, we evaluated the performance of three-alkoxy-
substituted oxime palladacycle resin as a heterogeneous Pd cata-
lyst for the microwave-assisted Suzuki coupling reaction. The resin
catalyst provided high yield of biaryl compounds in 30 min under
microwave irradiation. The microwave heating system increased
the catalytic activity as well as dramatically reduced the induction
period of the resin catalyst, completing the Suzuki coupling reac-
tion of 4-bromoanisole with phenylboronic acid in 20 min. The cat-
alyst was successfully applied to the Suzuki coupling reaction in
organic solvent-free system and C-C coupling reaction with organ-
otrifluoroborate under microwave condition. Furthermore, the cat-
alyst was reused for the Suzuki coupling reaction in excellent yield
(>94%) up to 5 cycles without any loss of catalytic activity.
a
Conditions: aryl halides (1 mmol), potassium phenyltrifluoroborate (1.2 mmol),
oxime palladacycle resin (1 mol%), Na2CO3 (1.5 mmol) in H2O/DMF (2:1, v/v, 3 mL),
80 °C for 30 min at 40 W.
b
GC yields.
Organotrifluoroborates are one of the boronic acid alternatives
in the C-C coupling reaction due to their air/moisture stability, easy
purification, and long shelf life. But they are generally known to be
less reactive than boronic acids for C-C coupling reactions.26 To
extend the application of the catalyst under microwave irradiation,
the catalytic activity for the coupling of potassium phenyltrifluo-
roborate with aryl bromides was also examined at 80 °C for
30 min, after optimization of the reaction conditions (Table 2S in
Supporting Information).
Although higher temperature was required, the coupling effi-
ciencies of phenyltrifluoroborate with aryl bromides using Na2CO3
in H2O/DMF (2:1) were similar to those of phenylboronic acid with
aryl bromides, including heteroaryl bromides (Table 5). This result
proved that the three-alkoxy-substituted oxime palladacycle resin
is favorable for the C-C coupling of organotrifluoroborate under
microwave condition.
Since the recovery and the reusability of the catalyst are one of
the major concerns in industrial and pharmaceutical application,
the reusability of the three-alkoxy-substituted oxime palladacycle
resin was tested for the Suzuki coupling reaction of 4-bro-
moanisole with phenylboronic acid in H2O/DMF (2:1) under micro-
wave condition. After 30 min, the catalyst was recovered and dried
for the subsequent reactions. During 5 cycles, the catalyst under
microwave condition afforded high yields (>94%) of the desired
biaryl product without any loss of catalytic activity (Table 6). The
recovered catalyst was tested after each cycle by ICP-AES, which
revealed that the Pd loadings were 0.13–0.14 mmol gÀ1, indicating
that no significant leaching of Pd occurred. FE-SEM images showed
that no deformation of occurred on the catalyst after each cycle,
and EDX analysis confirmed the presence of Pd on the catalyst
(Supporting Information).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.05.
080.
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