The Suzuki cross-coupling reaction in pure water catalyzed by ligandless palladium using polyethylene glycol derivatives as surfactant

Article abstract of DOI:10.1002/aoc.3018

The results of a ligandless Pd(OAc)₂-catalyzed Suzuki-Miyaura coupling experiment are presented. It was found that the use of polyethylene glycol phosphonium salts (PEG-quat) as surfactant resulted in very rapid reactions of aryl halides with phenylboronic acids in pure water. Moreover, aryl chlorides such as 4-nitrochlorobenezene reacted quantitatively with phenylboronic acid under optimized conditions. Copyright

Full text of DOI:10.1002/aoc.3018

Letter to the Editor
Received: 29 March 2013
Revised: 28 April 2013
Accepted: 2 May 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3018
The Suzuki cross-coupling reaction in pure
water catalyzed by ligandless palladium using
polyethylene glycol derivatives as surfactant
Liu Xianga, Zhao Xiaohuab and Lu Minga*
The results of a ligandless Pd(OAc)2-catalyzed Suzuki–Miyaura coupling experiment are presented. It was found that the use of
polyethylene glycol phosphonium salts (PEG-quat) as surfactant resulted in very rapid reactions of aryl halides with
phenylboronic acids in pure water. Moreover, aryl chlorides such as 4-nitrochlorobenezene reacted quantitatively with
phenylboronic acid under optimized conditions. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: Suzuki–Miyaura coupling; ligandless palladium; PEG-quat; surfactant
agent in pure water in the absence of added ligand (Scheme 1).
Notably, the Suzuki–Miyaura C-C coupling of aryl halides
Introduction
Over the past few years, the notion of doing transition-metal-
catalyzed organic synthesis in environmentally benign media,
including the Suzuki–Miyaura reaction, has been an area of
intense interest.[1–4] Traditionally, Suzuki coupling reactions have
been catalyzed by palladium complexes with phosphine[5–8]
or N-heterocyclic carbine (NHC) ligands in organic solvent.[9–13]
In most cases, the reactions are oxygen sensitive and rather
expensive due to the physical characteristic of the ligands.
Thus industrial application of the Suzuki reaction – the standard
methodology for the synthesis of biaryl units – remains challeng-
ing. One approach that circumvents the issue is the use of a
ligandless palladium catalyst, for which a large number of
strategies have been developed.[14–19] More importantly, the
‘ligand-free’ catalytic system makes it possible to carry out the
Suzuki reaction under an aerobic atmosphere and/or in aqueous
media. Compared to organic solvents, water is safe, abundant,
non-toxic and inexpensive. Hence research on the application of
water as a benign and sustainable alternative to organic solvents
has become a highly active field, addressing upcoming require-
ments in synthesis and catalysis. To date, there are a large number
of protocols for the Suzuki reaction in water, including the
addition of organic co-solvent,[20,21] amphiphile surfactant[22–24]
and/or the use of water-soluble catalyst.[25,26] Among these, the
application of phase-transfer complex (PTC)-mediated Suzuki–
Miyaura cross-coupling reactions has recently become an area
of interest, not just for the sake of providing a micellar environ-
ment within which low solubility of substrates in water and
catalysts may readily interact, but for facilitating catalyst recovery
by separating the water phase as well. To the best of our knowl-
edge, there have been only a few examples of Suzuki–Miyaura
C-C coupling in pure water catalyzed by ligandless palladium
catalyst.[27,28]
with phenylboronic acids in the presence of PEG800
–
triphenylphosphonium bromide salts afforded as good or better
results both in terms of yields and reaction rates. It is noted that
ultrafiltration could lead to recovery of the surfactants.[29]
Experimental
General Information
1H NMR spectra and 31P NMR spectra were recorded on a Bruker
DRX500 (500 MHz) instrument. Analysis by gas chromatography
(GC) was performed on an Agilent GC-6820 instrument. All other
chemicals (AR grade) were commercially available and used
without further purification. All products are known compounds
and were identified by 1H NMR or compared with those reported
in the literature.
Preparation of PEG800–Triphenylphosphonium Bromide Salts
(PEG800-quat)
The synthetic pathway for the polyethylene glycol phosphonium
salts is depicted in Scheme 1. To the solution of PEG800 (0.1 mol)
and pyridine (0.1 mol) in 150 ml toluene, SOCl2 (0.2 mol)
was added slowly. The mixture was then refluxed for about 5 h.
*
Correspondence to: Lu Ming, Nanjing University of Science and Technology,
College of Chemical Engineering, Nanjing, Jiangsu, China. E-mail:
luming302@126.com
a Nanjing University of Science and Technology, College of Chemical Engineer-
ing, Nanjing, Jiangsu, China
In this communication, we wish to report a new protocol for
the palladium-catalyzed Suzuki reaction of aryl halides based on
the concept of PEG800–phosphonium salts as phase-transfer
b Jiangsu University, School of Materials Science and Engineering, Zhenjiang,
Jiangsu, China
Appl. Organometal. Chem. (2013)
Copyright © 2013 John Wiley & Sons, Ltd.

L. Xiang et al.
X
Pd(OAc)2, K2CO3
H2O/PEG-quat
B(OH)2
R2
+
R1
R2
R1
SOCl2/pyridine
toluene
NaBr
HO
O
n
Cl
O
n
O
OH
Br
O
Cl
PR3
Br R3P
O
n
Br
O
n
O
PR3 Br
O
PEG-quat
Scheme 1. polyethylene glycol phosphonium salts (PEG-quat) for Suzuki cross-coupling reaction in H2O as surfactant
After that, the solution was filtered. The residue was
dissolved in dichloromethane (DCM) and treated with acti-
vated alumina. The procedure was repeated twice. The
solution was filtered again and the solvent removed to give
ClÀPEG800ClÀ. To the ClÀPEG800ClÀ prepared above, NaBr
(0.6 mol) was added and the mixture was heated to 120ꢀC
for 12 h. After cooling, DCM was added, the solution was
filtered, and the solvent was removed to obtain
BrÀPEG800BrÀ. Finally, the above BrÀPEG800BrÀ (1.0 mol) and
triphenylphosphine (1.0 equiv.) were heated to 70ꢀC for
3 days. The residue was washed with petroÀleum ether at
that the phosphonium ion was formed in accordance with
the literature.[30]
General Procedure for the Suzuki Reactions
All Suzuki reactions were carried out without an inert atmosphere.
A mixture of aryl halide (1.0 mmol), arylboronic acid (1.2 mmol),
K2CO3 (2.0 mmol), Pd(OAc)2 (1.5% mmol) and polyethylene glycol
phosphonium salts (PEG-quat, 0.6 mmol) in H2O (2ml) was allowed
to react in a sealed tube at 80ꢀC. The reaction mixtures were
extracted three times with methyl tert-butyl ether. The solvent
was concentrated under vacuum and the product was isolated by
short chromatography on a silica gel (200–300 mesh) column.
60–80ꢀC and dried under vacuum to give Br Ph+3P–PEG800
–
P+Ph3BrÀ. The catalyst was characterized by 31P NMR (CDCl3),
which shows a peak at 25.10 ppm. This observation suggests
Table 1. Suzuki reactions of bromobenzene and p-methoxyben-zeneboronic acid in aqueous mediaa
Entry
PTC
PTC (equiv.)
T (h)
Conversionb
(%)
Yieldc
(%)
1
—
None
0.6
0.6
0.6
0.6
0.2
0.4
0.8
1.0
0.6
0.6
0.6
0.6
24
8
<5
60
70
90
95
60
83
93
91
82
90
93
88
Trace
50
62
85
92
53
72
90
86
78
85
87
85
2
TBAB
3
PEG800
8
4
PEG800–TBPBd
PEG800–TPPBe
PEG800–TPPB
PEG800–TPPB
PEG800–TPPB
PEG800–TPPB
PEG200–TPPB
PEG600–TPPB
PEG2000–TPPB
PEG6000–TPPB
1.5
1.5
8
5
6
7
8
8
1.5
1.5
1.5
1.5
1.5
1.5
9
10
11
12
13
aReaction conditions: bromobenzene (1.0 mmol), p-methoxy-benzeneboronic acid (1.2 mmol), K2CO3 (2.0 mmol), Pd(OAc)2 (1.5% mmol);
surfactant in H2O (2 ml) at 80ꢀC (external).
bDetermined by GC analysis, with biphenyl as an internal standard.
cIsolated yield.
dPEG800–tributylphosphonium bromide.
ePEG800–triphenylphosphonium bromide.
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Appl. Organometal. Chem. (2013)

The Suzuki cross-coupling reaction in pure water
Besides PEG800–TPPB, we also tried to use other types, such as
PEG200–TPPB, PEG600–TPPB, PEG2000–TPPB and PEG6000–TPPB as
phase-transfer catalyst in the reaction. PEG800–TPPB demon-
strated the best performance (Table 1, entries 10–13).
It is known that many parameters are very important factors for
determining the efficiency of the Suzuki–Miyaura C-C coupling
reaction. Therefore, optimization studies were also performed to
determine how bases, temperature and the amount of Pd(OAc)2
affect the coupling reaction of bromobenzene and p-metho-
xybenzeneboronic acid in water. As demonstrated in Table 2, the
best yield was not obtained until the Suzuki reaction was carried
out at 80ꢀC in H2O in the presence of PEG800–TPPB (0.6 equiv.)
using K2CO3 (2.0 equiv.) as base and 1.5 mmol% Pd(OAc)2.
Under the above conditions, the scope of the catalytic system
was explored with a range of aryl halides and arylboronic acid. It
was found that both the electron-rich and electron-deficient aryl
bromides delivered the desired products with high yields in a
short time of about 1.5 h. Furthermore, the catalytic system could
tolerate a broad range of functional groups, such as CHO, NO2,
NH2 and OH (Table 3, entries 5–8). As expected, aryl iodides as
the substrate could also afford excellent yields (Table 3, entries
1–3). These results are consistent with the well-established
trend in the traditional Suzuki reaction using palladium derivative
as catalyst. It is well known that the use of aryl chlorides as
substrates has proven difficult because of the high bonding
energy of C-Cl,[5] but is highly desirable in view of the wide diver-
sity, ready availability and low cost of aryl chlorides. Hence there
is considerable significance in the development of a new catalyst
and system which can efficiently promote the coupling reactions
of aryl chlorides. Encouraged by these results, we attempted to
study the reaction activity between aryl chlorides and arylboronic
acid in water. Gratifyingly, the desired product was obtained
almost quantitatively when the activated 4-nitrochlorobenzene
was employed as the Suzuki coupling partner. DABCO (1, 4-
diazabicyclo[2.2.2]octane) was found to be a superior base
for these reactions. With other aryl chlorides such as 4-
methoxychlorobenzene the reaction was not satisfactory (Table 3,
entry 11). We further applied this reaction system to substituted
aryl chloride. As shown in Table 3, these relatively mild conditions
could successfully be applied to electron-deficient substrates in
Results and Discussion
The Suzuki reaction of bromobenzene and p-methoxybenzene-
boronic acid as a model reaction in aqueous media were initially
carried out in the presence and absence of phase transfer
complexes using Pd(OAc)2 as catalyst. The result demonstrated
that the reaction proceeded very slowly and the conversion of
bromobenzene was no more than 5% after 24 h in the absence
of any surfactant (Table 1, entry 1). There is very reason to suspect
that not all surfactants would be equally effective in metal-
catalyzed cross-couplings. Bu4NBr (TBAB)[31–33] and PEGs[34–36] have
been shown to enhance the rate of Suzuki reaction greatly in con-
ventional organic solvents. In comparison with the activity of TBAB
or PEG800 as surfactant for the Suzuki reaction in pure water, such
types of PEG800–phosphonium salts are most useful for the conver-
sion of bromobenzene (Table 1, entries 2–5). It is noteworthy that
PEGs are an important class of phase-transfer catalyst and have
been studied extensively for Suzuki–Miyaura cross-coupling reac-
tions owing to their low cost, lack of toxicity and high degree of
stability in work reaction systems. The results demonstrated the
fact that they attach easily to insoluble solid substrates and could
promote reactions efficiently through reduction of Pd(II) to Pd(0).
Thus the surfactants perform a dual role in these aqueous Suzuki
reactions. First, they provide a strong micellar effect, and second
they act as a stabilizer for Pd nanocluster formation. As shown in
Table 1, the use of triphenylphosphonium bromide (TPPB) is
advantageous compared with tributylphosphonium bromide
(TBPB) due to the issues related to stability, toxicity and handling
of the corresponding phosphines which are used as a precursors
for the synthesis of these catalysts.
When the reactions were performed with PEG800–TPPB as phase-
transfer catalyst, the conversion increased to 60% in a shorter time
(8 h) when only 0.2 equiv. PEG800–TPPB were used (Table 1, entry 6).
The conversion increased with the amount of PEG800–TPPB and
reached a maximum (95%) with 0.6 equiv. (Table 1, entry 5).
However, under the same conditions, the conversion was not
enhanced significantly with further addition. In fact, the presence
of surfactants in amounts far exceeding the critical micelle concen-
tration could lead to the formation of complex systems, such as
gels, which are not desirable as media for reactions.
Table 2. Effect of bases and temperature for the Suzuki cross-coupling reactiona
Entry
Base
Temperature (ꢀC)
Conversionb (%)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
NaOAc
KOH
80
80
60
75
92
95
20
85
93
1.5
1.5
1.5
1.5
3.0
1.5
1.5
50
70
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
80
85
80
92
RT
<10
81
60
110
90
aReaction conditions: bromobenzene (1.0 mmol), p-methoxy-benzeneboronic acid (1.2 mmol), base (2.0 mmol), Pd(OAc)2 (1.5% mmol), PEG800
–
TPPB (0.6 mmol), H2O (2 ml).
bDetermined by GC analysis, with biphenyl as an internal standard.
cIsolated yield.
Appl. Organometal. Chem. (2013)
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L. Xiang et al.
Table 3. Suzuki coupling reaction of various aryl halides with arylboronic acidsa
Entry
X
R1
R2
Conversionb (%)
Time (h)
Yieldc (%)
1
I
H
4-OCH3
100
100
100
96
0.5
0.5
0.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
8
98
97
2
I
4-CH3
4-NO2
2-OH
4-F
4-OCH3
3
I
4-OCH3
98
4
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
4-OCH3
92
5
4-OCH3
96
93
6
2-F, 4-OCH3
4-CHO
2-CHO
3-NO2, 4-OH
2-NH2
H
H
H
H
H
H
H
H
H
H
H
H
100
99
95
7
95
8
98
92
9
100
95
96
10
11
12
13
14
15
16
17
90
2-OH
96
90
4-NO2
4-NO2
4-OMe
H
70
65a
95d
30d
55d
85d
80d
>98
40
8
12
12
8
60
2-NO2
4-CN
93
87
8
aReaction conditions: aryl halide (1.0 mmol), arylboronic acids (1.2 equiv.), K2CO3 (2.0 equiv.), Pd(OAc)2 (1.5% mmol); PEG800–TPPB (0.6 mmol) in
H2O at 80ꢀC (external).
bDetermined by GC analysis, with biphenyl as an internal standard.
cIsolated yield.
dDABCO as base.
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