Amide as an efficient ligand in the palladium-catalyzed Suzuki coupling reaction in water/ethanol under aerobic conditions

Article abstract of DOI:10.1016/j.cclet.2010.12.048

Amide, which is derived from proline and is inexpensive and air-stable, has been synthesized and characterized by ¹H NMR, ¹³C NMR, and MS. It was found to be an efficient ligand in the palladium-catalyzed Suzuki cross-coupling reaction. In the Pd/amide catalytic system, aryl bromides can be coupled with phenylboronic acid in ethanol/water (1:2; v/v) in excellent yields even with a low Pd loading of 0.01 mol%. Moreover, the scope of the reaction is broad, and a wide variety of functional groups are tolerant.

Full text of DOI:10.1016/j.cclet.2010.12.048

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 738–740
www.elsevier.com/locate/cclet
Amide as an efficient ligand in the palladium-catalyzed Suzuki
coupling reaction in water/ethanol under aerobic conditions
*
Hai Yang Liu, Kun Wang, Hai Yan Fu, Mao Lin Yuan, Hua Chen , Rui Xiang Li
Key Lab of Green Chemistry and Technology, Ministry of Education, the Institute of Homogeneous Catalysis,
College of Chemistry, Sichuan University, Chengdu 610064, China
Received 15 October 2010
Abstract
Amide, which is derived from proline and is inexpensive and air-stable, has been synthesized and characterized by 1H NMR, 13
C
NMR, and MS. It was found to be an efficient ligand in the palladium-catalyzed Suzuki cross-coupling reaction. In the Pd/amide
catalytic system, aryl bromides can be coupled with phenylboronic acid in ethanol/water (1:2; v/v) in excellent yields even with a
low Pd loading of 0.01 mol%. Moreover, the scope of the reaction is broad, and a wide variety of functional groups are tolerant.
# 2011 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Suzuki cross-coupling; Palladium catalyst; Aryl bromides; Amide; Water
In the past two decades, the palladium-catalyzed Suzukicross-coupling reaction of aryl halides with arylboronic acids
has evolved into one of the most valuable synthetic processes to form biaryls [1–4]. Phosphine-based ligands have been
widely used for the palladium-catalyzed coupling reaction [5–8]. However, most of these phosphines are sensitive to air
and moisture and they are also expensive and toxic. Therefore, a few phosphine-free ligands, such asN-heterocylic
carbenes [9–12], diimines [13], diaminos [14], N,N,N-ligands [15], O,N,N,O-ligands [16] and N,N,O-ligands [17] have
been studied for the Suzuki reaction. To the best of our knowledge, there are few papers about using amide as ligands for
the Suzuki cross-coupling reaction. Herein, we report a new kind of ligands, which is derived from proline (compound1),
for Suzuki cross-coupling reaction in water and ethanol under aerobic conditions. Our synthetic route can be clearly seen
in Scheme 1 [18,19]. The new ligand (compound 3) has been elucidated by 1H NMR, 13C NMR and MS [20].
1. Experimental
1H and 13C 400 MHz spectra were recorded on a Bruker spectrometer using CDCl3 as solvent and tetramethylsilane
[TMS] as internal standard in all cases. Melting points were determined on a Thomas–Hoover capillary melting point
apparatus. High-resolution mass spectra were recorded on a Q-TOF mass spectrometry (Waters) equipped with
Z-spray ionization source. The isolation of pure products was carried out via Silica gel column (Silica gel 300–400
mesh). Aryl halides were used directly as obtained commercially without any process.
* Corresponding author.
E-mail address: scuhchen@163.com (H. Chen).
1001-8417/$ – see front matter # 2011 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.048

[()TD$FIG]
H.Y. Liu et al. / Chinese Chemical Letters 22 (2011) 738–740
739
O
O
O
COOH
NH
COOMe
COOEt
N
H
a
b
N
H
N
N
O
3
1
2
Scheme 1. Reagents and conditions (a) (1) MeOH, K2CO3, RT, 0.5 h; (2) ClCOOEt, 0 8C, 12 h; (b) DMF, BuOK, 3-NH2-C6H4OMe, 140 8C, 30 min
(75–80%).
All reactions were performed under aerobic conditions. In the first step, the referred solution
(CPd = 1.0 ꢀ 10ꢁ4 mmol/mL, CLigand = 2.0 ꢀ 10ꢁ4 mmol/mL, water as solvent) was prepared. A single-necked ground
tube (rinner = 1.2 cm, L = 17.5 cm) equipped with a magnetic stir bar was charged with 1.0 mmol of aryl halides,
1.5 mmol of phenylboronic acid and 2 mmol base under aerobic conditions. Then, 1.0 mL referred solution and 2.0 mL
water and 1.5 mL ethanol was added into the tube. The reaction mixture was stirred in oil bath with pre-arranged
temperature for appropriate reaction time. After the reaction was completed, 3 mL water was added, and the aqueous
phase was extracted with EtOAc (8 mL ꢀ3). The organic phase was dried over anhydrous Na2SO4 and concentrated
under reduced pressure after filtered. The residue was then purified by column chromatography on silica gel column.
2. Results and discussion
We initially tested the reaction of phenylboronic acid with 4-bromoanisole as a model reaction in EtOH/H2O (1:2;
v/v) in the presence of ligand and PdCl2 (Scheme 2). The effects of various inorganic and organic bases on the Suzuki
cross-coupling reaction were investigated. Among them, K3PO4 and Cs2CO3 are effective for the reaction.
Considering the high-cost of Cs2CO3, we chose the mild base K3PO4 in all the subsequent reaction.
The temperature ranging from 25 8C to 90 8C was screened for the suitable reaction temperature in the presence of
0.01 mol % PdCl2 and 0.02 mol% ligand. The GC yield of 4-MeOC6H4-Ph was only 7% in 10 h at room temperature,
and increased significantly with the temperature rising. When the temperature rose up to 80 8C, the GC yield was
increased to 99% while only 26% yield can be obtained in the absence of ligand in 1 h.
Under the optimized condition with PdCl2 (0.01 mol%), ligand (0.02 mol%), K3PO4 (2 equiv) in 4.5 mL EtOH/
H2O mixture, we examined the cross-coupling reaction of a wide range of phenylboronic acid with various aryl
halides, and the results were summarized in Table 1.
In the above Pd-catalyzed Suzuki cross-coupling system, the Suzuki reaction was found to afford good to excellent
yield for the desired product. For example, in the presence of 0.01 mol% PdCl2 and 0.02 mol% ligand, an excellent
conversion (97%) and high TON (9700) for the substrate 4-BrC6H4OMe was obtained at 80 8C in 1 h, and a moderate
yield (58%) still could be obtained even the Pd-loading was reduced to 0.001 mol%. As can be seen from Table 1
(entries 1–12), various aryl bromides with electron rich or deficient group were converted efficiently to the target
products in good to excellent yields within 1 h. In spite of the hindrance of 2-BrC6H4Me, 2-BrC6H4NO2 and 2-bromo-
m-xylene, a good yield of desired products was still obtained (Table 1, entries 6, 9, and 12). The coupling of
phenylboronic acid with heteroaryl bromides, such as 3-bromopyridine, 3-bromoquinoline and 5-bromopyrimidine
was also investigated. The target products were also obtained in good yields (Table 1, entries 13–15) and high TONs
(8100, 9500 and 9400) were obtained when the reaction temperature was elevated to 90 8C (refluxed temperature) and
the time was prolonged to 6 h. The coupling reaction of phenylboronic acid with activated aryl chloride such as
4-ClC6H4NO2 and 4-ClC6H4CF3 was carried out with 0.5 mol% catalyst loading. But the yield was only 52% and 39%
(Table 1, entries 16 and 17) respectively, even though the Pd-loading was raised and the reaction temperature was
elevated to 90 8C and the reaction time was prolonged to 20 h.
[()TD$FIG]
B(OH)
Br
2
PdCl
2
O
+
temp, 2 eq
base
O
Scheme 2. The model reaction in EtOH/H2O.

740
H.Y. Liu et al. / Chinese Chemical Letters 22 (2011) 738–740
Table 1
PdCl
2
The coupling reaction of aryl halides with phenylboronic acid in water/ethanol ArX þ Ph ꢁ BðOHÞ2H
ꢁ!
ArꢁPh X ¼ Br; Cl.
4
O=EtOH;
K PO
3
2
Entry
Ar–X
Pd loadings (mol%)
Temp. (%)/time (h)
Yield (%)b
TON
9800
1
2
BrC6H5
0.01
0.01
0.001
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.5
80/1
80/1
80/20
80/1
80/1
80/1
80/1
80/1
80/1
80/1
80/1
90/1
90/6
90/6
90/6
90/20
90/20
98
97
58
97
98
94
98
98
92
97
96
89
81
95
94
52
39
4-BrC6H4OMe
4-BrC6H4OMe
3-BrC6H4OMe
4-BrC6H4Me
9700
58,000
9700
9800
9400
9800
9800
9200
9700
9600
8900
8100
9500
9400
104
3
4
5
6
2-BrC6H4Me
7
4-BrC6H4CF3
4-BrC6H4NO2
2-BrC6H4NO2
4-BrC6H4COMe
4-BrC6H4CHO
2-Bromo-m-xylene
3-Bromopyridine
3-Bromoquinoline
5-Bromopyrimidine
4-ClC6H4NO2
4-ClC6H4CF3
8
9
10
11
12
13
14
15
16
17
0.5
78
Reaction conditions: n(L)/n(Pd) = 2, aryl halide (1.0 mmol), phenyl boronic (1.5 mmol), K3PO4 (2.0 mmol), H2O (3.0 mL), and ethanol (1.5 mL).
b
Isolated yield.
In conclusion, we have successfully synthesized and characterized a novel ligand derived from proline, which has
been shown to be highly effective in the Suzuki cross-coupling reaction of phenylboronic acid with different
substituted bromobenzenes and heteroaryl bromides under aerobic conditions in EtOH/H2O (1:2; v/v).
Acknowledgment
We would like to gratefully acknowledge the Analytical and Testing Center of Sichuan University for providing the
spectroscopic data.
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[20] Selected analytical data for amide ligand: mp 178–181 8C; 1H NMR (400 MHz, CDCl3): d 3.2 (m, 2H, CH2), 1.9 (m, 2H, CH2), 2.2 (m, 2H,
CH2), 4.6 (m, 1H, CH), 3.9 (s, 6H, OCH3–OCH3), 6.3 (m, 1H, CONH), 9.4 (m, 1H, CONH), 6.8–7.3 (m, 8H, ArH–ArH); 13C NMR (400 MHz,
CDCl3): d 169.79, 160.23, 160.07, 155.51, 139.57, 139.53, 129.64, 129.48, 112.39, 112.08, 110.13, 109.31, 106.15, 105.26, 60.96, 55.28,
55.26, 46.68, 27.23, and 25.28; HRMS Calcd. for C20H23N3O4: 370.1760 [M]+, found: 370.1689.