An efficient and recyclable thermoregulated phosphine-palladium catalyst for the carbonylative Suzuki coupling of aryl halides with arylboronic acids in water

Article abstract of DOI:10.1016/j.catcom.2015.08.008

An efficient protocol has been developed for the carbonylative Suzuki coupling of aryl halides using the thermoregulated phosphine-palladium as a reusable catalyst in pure water. This protocol was applied to a wide variety of hindered and functionalized aryl iodides and bromides with arylboronic acids, to afford the desired biaryl ketones in good to high yields. The palladium catalyst was easily recovered in the aqueous phase and reused up to eight cycles without a significant decrease in its activity.

Full text of DOI:10.1016/j.catcom.2015.08.008

An efficient and recyclable thermoregulated phosphine-palladium catalyst for
the carbonylative Suzuki coupling of aryl halides with arylboronic acids in
water
Yuanping Hao, Jingyang Jiang, Yanhua Wang, Zilin Jin
PII:
DOI:
Reference:
S1566-7367(15)30042-X
doi: 10.1016/j.catcom.2015.08.008
CATCOM 4405
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
18 July 2015
5 August 2015
6 August 2015
Please cite this article as: Yuanping Hao, Jingyang Jiang, Yanhua Wang, Zilin Jin,
An efficient and recyclable thermoregulated phosphine-palladium catalyst for the car-
bonylative Suzuki coupling of aryl halides with arylboronic acids in water, Catalysis
Communications (2015), doi: 10.1016/j.catcom.2015.08.008
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ACCEPTED MANUSCRIPT
An efficient and recyclable thermoregulated phosphine-palladium catalyst for the
carbonylative Suzuki coupling of aryl halides with arylboronic acids in water
Yuanping Hao, Jingyang Jiang,* Yanhua Wang, and Zilin Jin
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, China
E-mail: jyjiang@dlut.edu.cn
Abstract:
An efficient protocol has been developed for the carbonylative Suzuki coupling of
aryl halides using the thermoregulated phosphine-palladium as a reusable catalyst in
pure water. This protocol was applied to a wide variety of hindered and functionalized
aryl iodides and bromides with arylboronic acids, to afford the desired biaryl ketones
in good to high yields. The palladium catalyst was easily recovered in the aqueous
phase and reused up to eight cycles without a significant decrease in its activity.
Keywords:
carbonylation, Suzuki coupling, palladium, thermoregulated phosphine, water
1.Introduction
Biaryl ketones are important building blocks in numerous natural products,
pharmaceuticals, photosensitizers, and advanced organic materials [1-6]. Among
many well-documented synthetic strategies [7,8], the palladium-catalyzed
carbonylative Suzuki coupling of aryl-X compounds, carbon monoxide, and
arylboronic acids is a powerful and convenient tool for the synthesis of biaryl ketones
[9,10], due to that boronic acids are generally nontoxic and air- and moisture-stable

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[11]. Therefore, many efforts have been devoted to the advancement of this
transformation over the past few decades [12-16]. However, the vast majority of the
work has been carried out in organic solvents (e.g. toluene, anisole). Only a handful of
reports on the carbonylative Suzuki coupling reaction focus on the use of
environmentally benign solvents, such as aqueous solvent [17-19], and polyethylene
glycol (PEG) [20]. Among them, the use of water as a promising medium to replace
organic solvents has attracted increasing attention for reasons of economy, safety and
environmental concerns [21,22]. To this end, there is still considerable room for
progress toward efficient catalytic systems for the carbonylative Suzuki coupling
reaction in water. Although water-based catalytic system can facilitate
catalyst/product separation and catalyst reuse, most of organic substrates are insoluble
in water, resulting in poor reactivity. To solve this problem, many attempts have been
made, such as adding organic co-solvents or phase transfer agents, and so on [23].
A water/organic biphasic system termed thermoregulated phase transfer catalysis
(TRPTC) offers an attractive alternative approach which can combine the advantages
of homogeneous catalysis for reactivity and heterogeneous catalysis for catalyst
recovery [24-28]. In a typical TRPTC process, a suitable organic solvent is necessary
as a co-solvent for the efficient aqueous/organic biphasic catalysis. To date, a limited
number of reports exist on pure water-based thermoregulated biphasic catalytic
reactions. Our group has previously developed a type of phosphine ligands containing
PEG moieties (Ph2P(CH2CH2O)nCH3) possessing the capability of phase-transferring
between aqueous phase and organic phase based on the cloud point (Cp) as a nonionic

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surfactant, which were shown to be very efficient and versatile thermoregulated
ligands for palladium-catalyzed cross-coupling reactions and cobalt-catalyzed
hydroformylation in water [29-32]. Larpent and co-workers reported the use of a
thermoresponsive PEG-supported dipyridyl ligand in the thermoregulated biphasic
palladium-catalyzed Heck reaction in water [33]. These thermoregulated systems are
based on the inverse temperature dependent solubility of PEG residues in water that
allows the transfer of the catalyst into the organic phase (substrate phase) during the
reaction at high temperature and the separation of the catalyst in the aqueous phase
once cooled to room temperature, and further reuse. Considering the fact that there are
no reports on TRPTC for aqueous carbonylative Suzuki coupling reactions, in this
paper, a thermoregulated phosphine ligand Ph2P(CH2CH2O)nCH3(n ≈ 22) was
employed in palladium-catalyzed carbonylative Suzuki coupling of aryl iodides and
bromides with arylboronic acids using water as a sole solvent.
2. Experimental
2.1 General procedure for the carbonylative Suzuki coupling reaction.
A 75 mL autoclave equipped with a Teflon liner and a magnetic stirrer bar was
charged with Pd(OAc)2 (4.48 mg, 2.0×10-2 mmol), L (46.7 mg, 4.0×10-2 mmol) and
H2O (6 mL) and the mixture was stirred at room temperatures for 0.5 h under N2.
Then iodobenzene (113μL, 1 mmol), phenylboronic acid (134 mg, 1.1 mmol),
Na2CO3 (106 mg, 1 mmol), and n-decane (0.1 mL, GC internal standard) were added.
Once sealed, the autoclave was purged three times with CO, and pressurized to 1 atm
of CO. The reaction mixture was stirred at 100 °C for 2 h. After reaction, the mixture

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was extracted with diethyl ether (3 × 5 mL). The combined organic layer was
concentrated in vacuo and the product was purified by column chromatography.
In the recycling experiment, the aqueous phase containing the catalyst was subjected
to a second run by charging it with the same substrates as mentioned above, and the
reaction performed under the same conditions.
3. Results and discussion
The carbonylative Suzuki coupling of iodobenzene with phenylboronic acid in the
presence of CO (1 atm) in water was chosen as the model reaction and different
parameters were evaluated to optimize the reaction conditions (Table 1). Initially, the
effect of temperature on the carbonlative Suzuki coupling was studied. The results
indicated that the preferred temperature was 100 °C, since a complete conversion of
iodobenzene with 97% selectivity into the desired benzophenone could be obtained
after 2 h (Table 1, entry 3). Further increasing the temperature from 100 °C to 110 °C,
the selectivity of the expected product decreased from 97% to 93% due to the
increased amount of the direct coupling product (Table 1, entry 4). Generally, the base
is an important factor that determines the efficiency of the carbonylative Suzuki
coupling reaction. Here, suitable bases may suppress the rate of transmetallation to
form the Ar-Pd-Ar intermediate and favor the insertion of CO into the Ar-Pd-X
species [9]. Among the bases evaluated, Na2CO3 was found to be superior compared
with other bases (Table 1, entries 5-13). K3PO4 and triethylamine also led to good
product selectivity on decreasing the amount from 2 equiv to 1 equiv (1 equiv, 93-96%
versus 2 equiv, 68-76%, Table 1, entries 10-13). In the case of L/Pd molar ratio study,

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it was found that deviation from the 2:1 ratio resulted in a significantly drop in
activity. Most likely, for lower amounts of ligand, the system is not stable enough to
give a satisfactory conversion (Table 1, entry 14). On the contrary, when higher
amounts of ligand are used, the coordination sphere of the palladium center is likely
too hindered to allow a good activity (Table 1, entry 15). Therefore, the optimized
conditions were obtained as listed in entry 5 (Table 1).
Encouraged by this result, the scope of the reaction with a range of aryl iodides was
explored. As demonstrated in Table 2, the presented method shows high yields up to
93% for electron-donating substituents such as methyl (Table 2, entries 2-4) or
methoxy (Table 2, entries 5-6) on the iodoaryl partner including ortho-substituted
examples. Sterically hindered 1-iodonaphthalene was effectively converted into the
corresponding product in 87% yield (Table 2, entry 7). meta-, para-Fluoro and
chloro-substituted aryl iodides provided the corresponding biaryl ketones, good
partners for further functionalization, in 81-85% yields (Table 2, entries 8-11). Aryl
iodides containing strong electron-withdrawing groups are known to be prone to
undergo noncarbonylative coupling to biaryl byproducts [9,34]. Here, para-nitro and
carbonyl-substituted iodoarenes furnished the desired products in 61% and 68% yields
even under an increased CO pressure of 5 atm, respectively (Table 2, entries 12-13).
Heteroaryl iodide such as 2-iodothiophene was successfully employed in this reaction
to provide the corresponding product in 75% yield (Table 2, entry 14). This aqueous
protocol for the carbonylative Suzuki coupling reaction could also be performed with
more challenging aryl bromides (Table 2, entries 15-17).

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Further investigation of the scope of this catalytic system was carried out for the
carbonylative Suzuki coupling reaction between different aryl iodides and other
arylboronic acids (Table 3). Under the applied reaction conditions, the reaction of
methyl-, methoxy-, fluoro-, and cyano-substituted arylboronic acids with various aryl
iodides proceeded smoothly, to give the expected biaryl ketones in 71-92% yields.
4,4’-Difluorobenzophenone, a key intermediate in the synthesis of denagliptin used
for the treatment of Type Ⅱdiabetes [35], was produced in 84% yield (Table 3, entry
13). It was also desirable to expand the scope of the method for heterocyclic boronic
acids. Thus, 2-thiopheneboronic acid reacted with iodobenzene and 4-iodotoluene,
and the desired heteroaryl ketones were obtained in 79% and 71% yields, respectively
(Table 3, entries 4 and 7).
Next, the reactivity and selectivity of dihalobenzenes were also investigated (Scheme
1). Under low CO pressure (1 atm), 1,4-diiodobenzene reacted at 100 °C to give
mainly compound 1 in 61% selectivity, which results from the combination of
carbonylative coupling and direct coupling (Table 4, entry 1). Higher CO pressure and
lower temperature induced the selectivity formation of the diketone, which is
important intermediate for advanced functional materials [2,3], but with rather low
activity (Table 4, entry 3). In the case of 4-bromoiodobenzene, under 5 atm of CO
pressure, the corresponding diketone was obtained with 87% selectivity (Table 4,
entry 4).
In addition, under the reaction conditions used for aryl bromides,
1,2-diphenylethanone was obtained in 72% yield in the carbonylative coupling of

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benzyl chloride with phenylboronic acid. Further investigation on the scope of the
aqueous carbonylative coupling reaction is underway in our laboratory.
In order to evaluate the recyclability of the catalyst, the reusability experiments were
carried out for the model reaction under the optimized conditions. According to the
unique feature of thermoregulated biphasic catalysis, the catalysts would recover their
water solubility and return into the aqueous phase via cooling to room temperature.
Then the product was simply extracted with diethyl ether, and the aqueous solution
containing recycled catalyst was directly reused in the next run by adding fresh
substrates. The palladium catalyst could be recycled effectively in eight cycles (Fig.
1). The total leaching of Pd into the organic phase after eight times was observed to be
5.7 wt.% by inductively coupled plasma atomic emission spectroscopic (ICP-AES)
analysis (see Supplementary data).
4. Conclusions
In summary, the thermoregulated system has been successfully applied to
palladium-catalyzed carbonylative Suzuki coupling of aryl iodides and bromides with
arylboronic acids in pure water for the first time. This system tolerates a variety of
functional groups on both coupling partners, and the corresponding biaryl ketones
were obtained in 61%-93% yields. 1,4-Dihalobenzene can also undergo successive
carbonylative Suzuki coupling reactions. Notably, the catalytic system is based on
environmentally benign solvent and can be recycled up to eight times.
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Fig. 1

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Scheme 1
Table 1. Thermoregulated phosphine-palladium catalyzed carbonylative Suzuki coupling of
iodobenzene with phenylboronic acida.
B(OH)2
O
I
Pd(OAc)2/L
base, H2O
Temp. (°C)
80
+
CO
(1 atm)
+
+
Entry
1
Base (equiv)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (1)
K2CO3 (1)
Conversionb (%)
Selectivityc (%)
89
99
98
97
93
99
96
95
99
99
68
96
76
93
95d
98e
2
90
96
3
100
100
100
100
99
4
110
5
100
6
100
7
Cs2CO3 (1)
NaHCO3 (1)
NaOAc (1)
K3PO4·3H2O (2)
K3PO4·3H2O (1)
Et3N (2)
100
98
8
100
77
9
100
49
10
11
12
13
14
15
100
100
99
100
100
100
100
76
Et3N (1)
100
Na2CO3 (1)
100
Na2CO3 (1)
100
88
a Reaction conditions: iodobenzene (1.0 mmol), phenylboronic acid (1.1 mmol), Pd(OAc)2 (2.0
mol%), L/Pd = 2:1 (molar ratio), H2O (6 mL), CO (1 atm), 2 h. Each entry is the result of two
tests.
b
Conversion was determined by GC on the basis of iodobenzene using n-decane as internal
standard.
c Selectivity for carbonylated product, diphenyl accounts for the balance.
d L/Pd = 1:1 (molar ratio).
e L/Pd = 4:1 (molar ratio).

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Table 2. Carbonylative Suzuki coupling of various aryl halides with phenylboronic acida.
O
B(OH)2
X
Pd(OAc)2/L
R1
R1
X = I/Br
+ CO +
Na2CO3 (1.0 equiv)
H2O, 100 °C
Entry
R1
X
I
P(CO) (atm) Time (h) Product
Yieldb (%)
93
O
1
-
1
2
O
O
2
3
4-Me
3-Me
I
I
1
1
5
7
90
88
O
4
5
6
2-Me
I
I
I
1
1
1
10
5
91
93
66
O
4-OMe
2-OMe
MeO
O
12
OMe
O
7
1-Iodonaph
-
1
10
87
O
O
8
9
4-F
3-F
I
I
1
1
8
84
82
F
F
10
O
10
11
12
13
4-Cl
I
I
I
I
1
1
5
5
8
8
3
9
85
81
61
68
Cl
Cl
O
3-Cl
O
4-NO2
4-CO2Me
O2N
O
MeO2C
O
14
2-Iodothiophene
-
5
10
75
S
O
15
16
1-Bromonaph
4-COMe
-
5
5
20
20
73
71
O
Br
MeOC

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O
17
4-CHO
Br
5
20
69
OHC
a Reaction conditions: aryl halide (1 mmol), phenylboronic acid (1.1 mmol), Pd(OAc)2 (2 mol%), L
(4 mol%), Na2CO3 (1 equiv), H2O (6 mL), 100 °C.
b Isolated yields.
Table 3. Carbonylative Suzuki coupling of various aryl iodides with arylboronic acidsa.
O
B(OH)2
I
Pd(OAc)2/L
R1
R1
R2
R2
+ CO +
Na2CO3(1.0 equiv)
H2O, 100 °C
Entry
1
R1
R2
Time (h) Product
Yieldb (%)
87
O
-
4-F
6
F
O
2
3
-
-
4-CN
4-Me
7
81
90
CN
O
7
O
4
-
2-Thiophene
6
79
S
O
5
6
4-Me
4-Me
4-F
6
91
92
F
O
4-Me
15
O
7
8
9
4-Me
2-Me
2-Me
2-Thiophene
4-CN
7
71
87
76
S
O
6
CN
O
4-Me
13
O
10
11
12
4-OMe
4-OMe
4-OMe
4-F
6
6
7
86
80
83
MeO
MeO
MeO
F
O
4-CN
4-Me
CN
O
O
13
14
15
4-F
4-F
4-F
4-F
8
7
8
84
F
F
F
O
4-CO2Me
2-Iodothiophene
73 c
76 c
MeO2C
O
O
S
S
F
16
2-Iodothiophene
4-OMe
8
85 c
OMe
a Reaction conditions: aryl halide (1 mmol), arylboronic acids (1.1 mmol), Pd(OAc)2 (2 mol%), L

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(4 mol%), Na2CO3 (1 equiv), H2O (6 mL), CO (1 atm), 100 °C.
b Isolated yields.
c CO (5 atm).
Table 4. Carbonylative Suzuki coupling of 1,4-dihalobenzenesa.
Entry
X
Temp.
(°C)
100
100
80
P(CO)
(atm)
1
8
8
5
Time
(h)
6
4
36
30
Conv.b (%) Selet.b of Selet.b of Selet.b of
1
2
3
1
2
3
4
I
I
I
Br
100
100
100
100
63
42
7
22
58
93 (81)
88
15
0
0
100
12
0
a Reaction conditions: 1,4-dihalobenzene (1 mmol), phenylboronic acid (2.2 mmol), Pd(OAc)2 (2
mol%), L (4 mol%), Na2CO3 (2 equiv), H2O (6 mL).
b Conversions of 1,4-dihalobenzenes and selectivities of 1-3 was determined by GC-MS; the value
in parentheses refers to isolated yields of the corresponding product.

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Table 1. Thermoregulated phosphine-palladium catalyzed carbonylative Suzuki coupling of
iodobenzene with phenylboronic acida.
Table 2. Carbonylative Suzuki coupling of aryl halides with phenylboronic acida.
Table 3. Carbonylative Suzuki coupling of aryl iodides with arylboronic acidsa.
Table 4. Carbonylative Suzuki coupling of 1,4-dihalobenzenesa.
Scheme 1. Carbonylative Suzuki coupling of 1,4-dihalobenzenes.
Fig. 1. Catalyst reusability study. Reaction conditions: iodobenzene (1 mmol), phenylboronic
acid (1.1 mmol), Pd(OAc)2 (2 mol%), L/Pd = 2:1 (molar ratio), Na2CO3 (1 equiv), H2O (6 mL),
CO (1 atm), 100 °C, 2 h, isolated yield.

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Graphical abstract

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Highlights
The carbonylative Suzuki coupling reaction was carried out in pure water.
Thermoregulated phosphine-palladium catalyst was used.
The catalyst exhibited high catalytic activity for the synthesis of biaryl ketones.
Both aryl halides (I,Br) and benzyl chloride were suitable substrates.
The palladium catalyst can be simply recovered and efficiently reused up to 8 runs.