An efficient and simple ligand from phthalandione for palladium-catalyzed Suzuki reaction in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2013.11.039

An efficient and simple ligand derived from phthalandione was used for palladium catalyzed Suzuki coupling reaction in water/ethanol (V/V = 2/1) under aerobic conditions. The reaction exhibited a high catalytic efficiency even with lower Pd loading (0.002 mol %). In this work, the catalyst could be successfully used in coupling reaction between various aryl halides with phenylboronic acid in excellent yields with high turnover number (TON) (the maximal TON was up to 49,000 for the reaction of bromobenzene with phenylboronic acid). Moreover, this new ligand had been elucidated by ¹H NMR, ¹³C NMR and X-ray crystal diffraction.

Full text of DOI:10.1016/j.tetlet.2013.11.039

Tetrahedron Letters 55 (2014) 415–418
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and simple ligand from phthalandione
for palladium-catalyzed Suzuki reaction in aqueous media
Haiyang Liu a,b, Hailong Liu a, Ruixiang Li a, Hua Chen a,
⇑
a Key Lab of Green Chemistry and Technology, Ministry of Education, The Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu,
Sichuan 610064, China
b Advanced Materials Institute, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2013
Revised 1 November 2013
Accepted 12 November 2013
Available online 19 November 2013
An efficient and simple ligand derived from phthalandione was used for palladium catalyzed Suzuki
coupling reaction in water/ethanol (V/V = 2/1) under aerobic conditions. The reaction exhibited a high
catalytic efficiency even with lower Pd loading (0.002 mol %). In this work, the catalyst could be success-
fully used in coupling reaction between various aryl halides with phenylboronic acid in excellent yields
with high turnover number (TON) (the maximal TON was up to 49,000 for the reaction of bromobenzene
with phenylboronic acid). Moreover, this new ligand had been elucidated by 1H NMR, 13C NMR and X-ray
crystal diffraction.
Keywords:
Suzuki–Miyaura reaction
Palladium catalyst
Aryl bromides
Ó 2013 Elsevier Ltd. All rights reserved.
Phthalandione
Introduction
nomical, and environmentally friendly catalytic system remains a
challenging task.
The palladium catalyzed Suzuki–Miyaura reaction is one of the
most powerful and convenient approaches for the synthesis of
biaryl derivatives that are structural elements of numerous natural
products, agrochemicals, pharmaceuticals, and polymers.1–3 The
most commonly used reaction protocol utilizes organic solvents
in the presence of an inorganic base, a palladium catalyst precur-
sor, and a ligand that coordinates to the palladium center to stabi-
lize the catalyst. Among all the influencing factors, the ligand plays
a pivotal role in the successful execution of the coupling reaction,
because the activity and selectivity of the catalyst depend on the
steric and electronic properties of the ligand attached to the Pd me-
tal. In the traditional Suzuki–Miyaura reactions, the electron-rich
phosphine ligands were generally employed to improve the cata-
lytic performance.4 Since phosphine ligands are often water- and
air-sensitive,5,6 catalysis under phosphine-free conditions is still
a challenge of high importance. Then, a number of phosphine-free
ligands for the Suzuki–Miyaura reaction had been reported, such
as N-heterocylic carbenes,7,8 diimines,9,10 diaminos,11,12 and
N,O-ligands.13–15 On the other hand, the classic Suzuki–Miyaura
reaction was often carried out in organic media, such as
DMF,16,17 THF,18,19 dioxane,20 toluene,21 CH3CN,22 and metha-
nol,16,23–25 which was contrary to the idea of green chemistry.
From these standpoints, the development of efficient, stable, eco-
To the best of our knowledge, there are few papers about using
amide as ligands for the Suzuki–Miyaura reaction.26 Herein, we
would like to report an efficient, convenient, and environmentally
friendly protocol for the Suzuki–Miyaura reaction of aryl bromides
with arylboronic acids in aqueous media. The synthetic route of the
phthalandione derivative ligand (PDL) can be clearly seen in
Scheme 1. The new ligand had been elucidated by 1H NMR, 13C
NMR, and X-ray crystal diffraction (Scheme 2).
Results and discussion
We initially tested the reaction of phenylboronic acid with
4-bromo anisole in 3 mL aqueous media (Vwater/Vethanol, 2/1) as a
model reaction under 80 °C in the presence of 0.1 mol % PdCl2
and 2 equiv K3PO4 as a base in 2 h. The desired products were
obtained in good yield (98%). Then, we enlarged the S/C up to
5000 (Pd loading = 0.02 mol %) to optimize the reaction conditions
in the model reaction, including the effect of base, solvents, the
reaction time, and Pd loadings.
As known, the base plays an important role in this reaction.27
The effects of various inorganic and organic bases on the Suzuki–
Miyaura reaction were investigated (Table 1). Among the bases
screened for their influence on the yields of the model reaction,
the use of stronger inorganic bases gave the desired product in
high yield. Organic bases, such as Et3N, Dicyclohexylamine, and
DMAP, were also tested, but the results were not good (Table 1,
⇑
Corresponding author. Tel./fax: +86 28 85142904.
E-mail address: scuhchen@163.com (H. Chen).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.039

416
H. Liu et al. / Tetrahedron Letters 55 (2014) 415–418
Table 1
The effect of base on the Suzuki–Miyaura reactiona
H
N
DCM
O
O
+
N
O
NH2
O
O
O
Yieldb (%)
Scheme 1. The synthetic route of PDL.
Entry
Base
Pd loading (mol %)
1
2
3
4
5
6
7
8
K3PO3
KOH
KHCO3
K2CO3
NaOH
NaHCO3
Na2CO3
NaOAc
Cs2CO3
Et3N
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
92
99
82
91
93
79
91
76
95
46
37
18
entries 10–12). Among the bases employed, KOH was found to be
the best in the present protocol (Table 1, entry 2).
The choice of solvent was also important in the Suzuki–Miyaura
reaction. In order to investigate this effect, we screened different
solvents with the model reaction. As was evidenced from Table 2,
the reaction in pure water afforded 4-methylbiphenyl in a low
yield after 2 h (entry 7). However, the addition of appropriate
amounts of polar organic solvents (such as DMF, THF, Dioxane,
MeOH, i-PrOH, and EtOH) into water led to an increase in the activ-
ity, and better yield was obtained. From the results in Table 2, it
could be seen clearly that the mixture of water and ethanol (V/V,
2/1) was the best media for this catalyst system (Table 2, entry
9). These results suggested that the proper ratio of water and eth-
anol played the key role in the model reaction with the probable
reason of the good solubility of two substrates in these mixed
solvents.28
9
10
11
12
DMAP
Dicyclohexylamine
a
Reaction conditions: 4-bromo anisole (0.5 mmol), phenylboronic acid
(0.75 mmol), base (1.0 mmol), solvent (3.0 mL), 80 °C, 2 h, n (ligand)/n (Pd) = 2.
b
Isolated yield.
Table 2
Suzuki-Miyaura reaction employing virous solventsa
Considering hydrolysis and ionization of PDL in alkaline solu-
tion to some extent, we illustrated the effect of diisopropylamine
(DIPA, L-02) and phthalandione (L-03) to the process of the cou-
pling reaction and carried out the related study in the model reac-
tion. These results were shown in Table 3. It was found that L-02
had a little effect on response to the cross-coupling reaction with
higher Pd-loading (0.1 mol %) while L-03 could promote the model
reaction to some extent with the same Pd-loading. It was notewor-
thy that the catalytic reactions proceeded fast in the co-solvent
solution containing active palladium species, which was stable
without the formation of Pd-black (Table 3, entry 4), while Pd-
black formed significantly within 4 h using L-02 or L-03 as ligand
in the model reaction. It indicated that PDL could prevent the
aggregation of Pd-nano particle to Pd-black and stabilize the Pd-
nano particle more efficiently than L-02 and L-03. As can be seen
from the results of Table 3 and the above discussion, PDL was
proved to be an effective ligand in the palladium catalyzed Suzuki
reaction.
Entry
Solvent
Pd loading (mol %)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
DMF
THF
Dioxane
i-PrOH
MeOH
EtOH
H2O
H2O/MeOH (2:1)
H2O/EtOH (2:1)
H2O/i-PrOH (2:1)
H2O/Dioxane (2:1)
H2O/THF (2:1)
H2O/DMF (2:1)
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
4
4
4
4
4
4
4
2
2
2
2
2
2
81
62
86
71
89
82
46
91
99
87
94
79
92
9
10
11
12
13
a
Reaction conditions: 4-bromo anisole (0.5 mmol), phenylboronic acid
(0.75 mmol), base (1.0 mmol), solvent (3.0 mL), 80 °C, 2 h, n (ligand)/n (Pd) = 2.
b
Isolated yield.
Under the optimized reaction conditions (water/ethanol, KOH,
80 °C, 0.002 mol % catalyst), we subsequently investigated the cou-
pling reaction using different aryl halides and hetero-aryl halides
with phenylboronic acid and the data were collected in Table 4.
In particular, high catalytic activity was observed in the reaction
Scheme 2. ORTEP drawing for two PDL units with 30% probability ellipsoids, showing the atomic numbering scheme. Symmetry transformation for N1_3, N2_3, O2_3, O3_3,
C5_3, C11_3, C12_3, C13_3: ꢀx, ꢀy, ꢀz. The two PDL units are linked by hydrogen bonds labeled using dashed lines.

H. Liu et al. / Tetrahedron Letters 55 (2014) 415–418
417
Table 3
The effect of phthalandione and diisopropylamine on the Suzuki reactiona
B
Entry
1
Ligand
Pd loading (mol %)
0.1
Temp(°C)/Time(h)
Yieldb (%)
34
TON
340
Pd-black formationc
No ligand
80/4
Yes
2
3
0.1
0.1
80/4
80/4
52
71
520
710
Yes
Yes
No
4
0.002
80/0.5
98
49,000
a
b
c
Reaction conditions: 4-bromo anisole (0.5 mmol), phenylboronic acid (0.75 mmol), KOH (1.0 mmol), solvent (3.0 mL, Vwater/Vethanol = 2/1), 80 °C, n (ligand)/n (Pd) = 2.
Isolated yield.
After 2 h, Pd black appeared (yes or no).
Table 4
Table 4 (continued)
Suzuki–Miyaura reactiona of phenylboronic acid and various aryl halides in water/
ethanol
Entry
Ar-X
Pd loading (mol %)
0.002
Time(h)
2
Yieldb,c (%)
88
16
17
18
0.002
0.01
4
4
92d
91
Entry
Ar-X
Pd loading (mol %)
0.002
Time(h)
0.5
Yieldb,c (%)
1
2
3
4
98
98
98
98
0.002
0.5
19
20
0.01
0.01
4
4
94
96
0.002
0.5
0.002
0.5
21
22
0.05
0.1
4
84
5
6
7
0.002
0.002
0.002
0.5
0.5
1
95
98
89
10
23e
a
Reaction conditions: aryl halide (0.5 mmol), phenylboronic acid (0.75 mmol),
KOH (1.0 mmol), solvent (3.0 mL, Vwater/Vethanol = 2/1), 80 °C, n (ligand)/n (Pd) = 2.
b
Isolated yield.
Yields were of average of two runs.
The product is 1,4-terphenyl.
Time = 10 h, 100 °C, Pd black appeared.
c
d
e
8
9
0.002
0.002
0.5
0.5
98
98
of substituted bromobenzenes with phenylboronic acid. Consider-
ing the model reaction of phenylboronic acid with 4-bromo
anisole, for example, when 0.002 mol % Pd loading was used, the
yield of desired products was up to 98% (Table 4, entry 4). To the
best of our knowledge, this is a good result in the system using
phosphine-free ligands in the presence of 0.002 mol % catalyst in
mixed solvents.29 In our system, the reaction was found to afford
good to excellent yield for the desired product with different elec-
tron-withdrawing and electron-donating aryl bromides. Due to the
steric hindrance of 2-BrC6H4Me, 2-bromo-m-xylene, and 2-bromo-
p-xylene, the desired products were obtained in medium yield (en-
tries 7, 15, and 16). We also investigated the reaction of heteroaryl
bromides and aryl chlorides. The target products of aryl–heteroaryl
were also obtained in good yields (Table 4, entries 18–21) when we
extended the reaction time. Unfortunately, the coupling of aryl
chlorides with phenylboronic acid did not perform as well as aryl
bromides, even we when raised the Pd loading up to 0.1 mol %
and prolonged the reaction time to 10 h (entry 22).
10
11
12
0.002
0.002
0.002
1
91
97
96
0.5
0.5
13
14
0.002
0.002
0.5
0.5
97
97
15
0.002
2
79

418
H. Liu et al. / Tetrahedron Letters 55 (2014) 415–418
In summary, we have successfully developed a palladium cata-
Acknowledgments
lyzed Suzuki–Miyaura reaction using amide derived from phtha-
landione as a ligand in aqueous media under aerobic conditions.
The low-cost ligand and the environment friendly procedure make
it potential for the application.
We thank the advice of Dr. Youwei Yao’s group (Graduate
School at Shenzhen, Tsinghua University) and Analytical and Test-
ing Center of Sichuan University for characterization support.
Supplementary data
Experimental
Supplementary data (including general experiment details,
NMR and X-ray crystal diffraction data of PDL, and 1H NMR spectra
of all products listed in Table 4) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.11.039.
All aryl halides and arylboronic acids were purchased from en-
ergy chemical. Other chemicals were purchased from commercial
sources without any process. NMR spectroscopy was performed
on a Brucker advance II 400 spectrometer operating at 400 MHz
(1H NMR) and 100 MHz (13C NMR) with CDCl3 as the solvent and
TMS as internal standard. Melting points were determined on a
Thomas–Hoover capillary melting point apparatus. The isolation
of pure products was carried out via column (Silica gel 200–300
mesh).
References and notes
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Synthesis of PDL
592.5 mg (4 mmol) of o-phthalic anhydride was dissolved in
40 mL CH2Cl2, and 2.2 mL diisopropylamine (16 mmol) was
added dropwise under ice-water bath. After the end of addition,
the mixture was stirred at room temperature for 8 h. The solvent
was removed under reduced pressure and the residue was puri-
fied by recrystallization (EtOAc/Cyclohexane = 1:1). Finally, a
white crystal (1.28 g) was obtained, yield: 91%. mp: 183–184 °C.
1H NMR (400 MHz, CDCl3): d 0.92 (d, J = 6.54 Hz, 3H, CH3), 1.09
(d, J = 6.53 Hz, 3H, CH3), 1.19 (d, J = 6.48 Hz, 12H, CH3), 1.47 (m,
6H, CH3), 3.24 (m, 2H, CH), 3.45 (m, 1H, CH), 3.64 (m, 1H, CH),
7.06 (m, 1H, ArH), 7.32 (m, 2H, ArH), 7.86 (d, J = 7.00 Hz, 1H,
ArH) ppm; 13C NMR (100 MHz, CDCl3): d 18.18 (4C,CH3), 19.09
(1C, CH3), 19.39 (1C, CH3), 19.45 (1C, CH3), 19.67 (1C, CH3),
124.67 (1C, Ar), 126.26 (1C, Ar), 128.34 (1C, Ar), 128.66 (1C, Ar),
134.86 (1C, Ar), 138.38 (1C, Ar), 170.63 (1C, –CO–), 170.71 (1C,
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h
ꢀ
ꢁ
i
ꢀ
ꢁ
2
w ¼ 1= s2 F2o þ ð0:0741PÞ
,
s = sin(h)/k, and P ¼ F2o þ 2Fc2 =3.
Atomic scattering factors were taken from International Tables
for X-ray crystallography.32
Crystallographic data reported in this Letter have been depos-
ited with Cambridge Crystallographic Data Centre as supplemen-
tary publication No. CCDC-(945352). Copies of the data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; or deposit@ccdc.cam.ac.uk. Selected crystallographic data
and structure determination parameters for the complex are
shown in supporting information.
32. J. A. Ibers and W. C. Hamilton. International Tables for X-ray Crystallography,
Vol. IV, Kynoch Press, Birmingham, 1974.