Environmentally friendly synthesis of biaryls: Suzuki reaction of aryl bromides in water at low catalyst loadings

Article abstract of DOI:10.1016/j.tetlet.2005.10.158

Pd(DPPF)Cl₂ is shown to be an extremely active catalyst for the Suzuki reaction of aryl bromides in water. This green procedure provides biaryls in excellent yields and high turnover numbers (TONs) (TONs up to 870,000 for the reaction of 1-bromo-4-nitrobenzene and phenylboronic acid). A small amount of PEG-2000 also allows the recycling of the palladium catalyst for three times without any significant loss of catalytic activity.

Full text of DOI:10.1016/j.tetlet.2005.10.158

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 197–200
Environmentally friendly synthesis of biaryls: Suzuki reaction
of aryl bromides in water at low catalyst loadings
Nan Jiang and Arthur J. Ragauskas*
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
Received 29 September 2005; revised 27 October 2005; accepted 28 October 2005
Available online 16 November 2005
Abstract—Pd(DPPF)Cl2 is shown to be an extremely active catalyst for the Suzuki reaction of aryl bromides in water. This green
procedure provides biaryls in excellent yields and high turnover numbers (TONs) (TONs up to 870,000 for the reaction of 1-bromo-
4-nitrobenzene and phenylboronic acid). A small amount of PEG-2000 also allows the recycling of the palladium catalyst for three
times without any significant loss of catalytic activity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Transition-metal-catalyzed cross-coupling reactions are
extremely useful synthetic tools for carbon–carbon bond
formation.1 The Suzuki reaction,2 palladium-catalyzed
cross-coupling of aryl boronic acids and aryl halides,
has become an attractive standard process for the syn-
thesis of biaryls, which have a diverse spectrum of appli-
cations, ranging from pharmaceuticals to materials
science.3 Consequently, much attention has been direc-
ted toward improving the Suzuki reaction by designing
various new ligands and palladium-precursors, such as
bulky electron-rich phosphine ligands,4 N-heterocyclic
carbenes,5 and palladacycles,6 to accomplish efficient
coupling of inexpensive and unreactive aryl bromides
and chlorides. However, most of these ligands and
palladium precursors are expensive, which significantly
limits their industrial applications. Therefore, the devel-
opment of efficient catalytic systems consisting of eco-
nomical catalysts, bases, and solvents remains a highly
desirable goal.
0.1 mol% Pd/C (10%)
MeO
Br PhB(OH)
+
2
Ph
OMe
K2CO3, H2O, 60 ˚C
31%, 30 min
Scheme 1.
Table 1. Optimizing the reaction conditions for Suzuki coupling of
PhB(OH)2 and 4-bromoanisole in watera
Entry Pd (mol %)
T (ꢁC)b Time
Convnc/
yieldd (%)
(h)
1
2
3
4
5
6
7
8e
9f
10f
10% Pd/C (0.1)
Pd(OAc)2 (0.1)
60
60
60
60
60
0.5
0.5
0.5
0.5
0.5
0.5
0.5
40/31
19/—
12/—
62/50
74/61
88/85
100/98
Pd(MeCN)2Cl2 (0.1)
Pd(PPh3)2Cl2 (0.1)
Pd(DPPE)Cl2 (0.1)
Pd(DPPF)Cl2 (0.1)
Pd(DPPF)Cl2 (0.1)
Pd(DPPF)Cl2 (0.1)
Pd(DPPF)Cl2 (0.01)
60
80
80
110
0.5+0.5 100/95
3
In addition, intensive efforts have been directed to
reduce or eliminate the use of flammable, hazardous,
and nonrenewable organic solvents in the Green chemis-
try focus area.7 While a variety of environmentally
benign media, such as ionic liquids, fluorous solvents,
98/96
82/78
Pd(DPPF)Cl2 (0.001) 110
48
a 5 mmol 4-Bromoanisole, 5.5 mmol PhB(OH)2, 10 mmol K2CO3,
2 mL H2O, Pd catalyst, DPPE = 1,2-bis(diphenylphosphino)ethane,
and DPPF = 1,10-bis(diphenylphosphino)ferrocene.
b Oil bath temperature.
c Determined by 1H NMR of the crude product mixture.
d Isolated yield by flash chromatography.
e 5 mmol 4-Bromoanisole, 5.5 mmol PhB(OH)2, and 10 mmol K2CO3
were added after 0.5 h stirring for the initial run.
f 5 mmol 4-Bromoanisole, 7 mmol PhB(OH)2, and 10 mmol K2CO3
were used.
Keywords: Suzuki reaction; Biaryls; Turnover number; Green
chemistry.
*
Corresponding author. Tel.: +1 404 894 9701; fax: +1 404 894
4778; e-mail: arthur.ragauskas@chemistry.gatech.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.158

198
N. Jiang, A. J. Ragauskas / Tetrahedron Letters 47 (2006) 197–200
supercritical fluids, and PEGs, have been promoted as
replacements to volatile organic compounds (VOCs),8
water represents one of the most economically and envi-
ronmentally viable options.9 The use of water as the
reaction solvent has several benefits, including low cost,
improved safety, and abundance. Furthermore, phase
separation is easier because most organic compounds
are lipophilic and can be easily separated from the aque-
ous phase. To date, aqueous Suzuki coupling reactions
have been largely limited to couplings of aryl iodides
and activated aryl bromides.10 In continuation of our
interest in minimizing the consumption of depletive re-
sources for sustainable chemistry and environmental
benefits, we herein report a highly efficient Suzuki reac-
tion of aryl bromides and arylboronic acids at low cata-
lyst loading in water. Furthermore, we demonstrate that
a 20% aqueous PEG-2000 solution can be used as the
reaction media for the recycling and reuse of the palla-
dium catalyst.
The initial investigation started with the coupling of
phenylboronic acid and 4-bromoanisole, an electron-
rich and therefore unreactive aryl bromide, as our test
substrate. In the presence of 0.1 mol % palladium char-
coal (10%) under nitrogen atmosphere in water at 60 ꢁC,
4-methoxybiphenyl was obtained in 40% conversion and
31% isolated yield after 30 min stirring (Scheme 1).
Further efforts were then focused on screening differ-
ent palladium catalysts and optimizing the reaction
condition. Five other palladium catalysts, Pd(OAc)2,
Pd(MeCN)2Cl2, Pd(PPh3)Cl2, Pd(DPPE)Cl2, and Pd-
(DPPF)Cl2 were tested, respectively, and the results
are summarized in Table 1. Among the three phos-
phine-ligand-free palladium catalysts, only Pd/C (10%)
gave reasonable conversion. Very low conversions were
obtained by Pd(OAc)2 or Pd(MeCN)2Cl2 (less than 20%,
Table 1, entries 2 and 3). The use of Pd(PPh3)Cl2,
Pd(DPPE)Cl2, or Pd(DPPF)Cl2 gave mild to good con-
Table 2. Suzuki coupling of arylbromides and arylboronic acids in watera
Entry
1
Aryl halides
Arylboronic acids
Product
Ph
Ph
Ph
Yieldb (%)
99
Br
B(OH)2
2
3
93
97
99
98
87
85
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
Br
Br
4
F3C
Br
F3C
Ph
Ph
Ph
5
MeO
O2N
Br
Br
MeO
O2N
6c
7d
Br
Ph
8
9
93
89
B(OH)2
B(OH)2
N
S
Br
Br
N
Ph
Ph
S
O
O
10
11
96
92
Br
B(OH)2
Ph
B(OH)2
MeO
Br
Br
OMe
12d
13d
81
88
B(OH)2
MeO
Br
B(OH)2
B(OH)2
OMe
14d
—
Br
a 5 mmol Aryl bromide, 5.5 mmol arylboronic acid, 10 mmol K2CO3, 2 mL H2O, and 0.1 mol% Pd(DPPF)Cl2, oil bath temperature at 80 ꢁC, and 1 h
(not optimized).
b Isolated yield by flash chromatography.
c 5 mmol 4-Bromo-1-nitrobenzene, 7 mmol PhB(OH)2, and 10 mmol K2CO3, 2 mL H2O, and 0.0001 mol % Pd(DPPF)Cl2, 110 ꢁC, 48 h.
d Oil bath temperature at 110 ꢁC, 4 h.

N. Jiang, A. J. Ragauskas / Tetrahedron Letters 47 (2006) 197–200
199
versions, and Pd(DPPF)Cl2 was found to be optimal,11
0.1 mol% Pd(DPPF)Cl2
providing 88% conversion and 85% isolated yield (Table
1, entries 4–6). Prolonging reaction times to 12 h, how-
ever, failed to improve the reaction conversion due to
the product 4-methoxybiphenyl solidifying along with
the unreacted 4-bromoanisole.
Br +
PhB(OH)2
2.2 mmol
Ph
20% aqueous PEG-2000 (2 mL)
200% K2CO3, 80 ˚C
2.0 mmol
1st run: 91 % yield
2nd run: 88 % yield
3rd run: 80 % yield
On the other hand, elevating reaction temperature to
80 ꢁC afforded a 100% conversion and 98% isolated
yield (Table 1, entry 7). It is noteworthy that the palla-
dium catalyst was still active at the end of the coupling
reaction. For example, after 30 min stirring for the first
run, addition of one more equivalent of starting sub-
strates to the reaction mixture led to its total conversion
in another 30 min (Table 1, entry 8). Elevating the reac-
tion temperature to 110 ꢁC and reducing the catalyst
loading to 0.01 mol % provided a near quantitative yield
of 4-methoxybiphenyl after 3 h stirring (Table 1, entry
9). Further reducing the catalyst loading to
0.001 mol % led to a lower conversion with a 78% iso-
lated yield (TON = 78,000) after 48 h stirring (Table 1,
entry 10). It should be noted that the choice of
Pd(DPPF)Cl2 as the catalyst precursor was not arbi-
trary, as the weakly electron-donating bidentate triaryl-
phosphine ligand DPPF stabilizes the catalytic center
due to the rigid and blocked conformation of the ferro-
cenyl backbone.12
Scheme 2.
phase-transfer catalysts.15 Thus, a 20% aqueous PEG-
2000 solution was tested as the reaction media for the
cross-coupling of 2-bromotoluene with phenylboronic
acid. After stirring for 1 h, 2-methylbiphenyl was
extracted from the reaction mixture with n-pentane
(3 · 5 mL) and the catalyst was reused for another run
by adding fresh 2-bromotoluene, phenylboronic acid
and potassium carbonate to the reaction media. It is
important to stress that this system was shown to be
readily recyclable for three runs, and the isolated yields
were almost consistent (Scheme 2).
In conclusion, a highly efficient Suzuki coupling reaction
of aryl bromides in water has been achieved. This green
procedure is simple and can be used to generate a wide
range of biphenyls with low palladium loadings. Fur-
thermore, a 20% aqueous PEG-2000 solution as the
reaction media allows this catalytic system to be readily
recyclable for three runs without a significant loss of cat-
alytic activity.
This catalysis13 was then applied to various aryl bro-
mides and arylboronic acids, as summarized in Table
2. The desired biaryls were obtained in excellent yields
(81–99%).14 Thus, aryl bromides, which are electron-
poor, electron-rich, or very sterically hindered, coupled
cleanly with phenylboronic acid (Table 2, entries 1–9).
It is important to stress that the cross-coupling of 1-
bromo-4-nitrobenzene and phenylboronic acid by
0.0001 mol % Pd(DPPF)Cl2 afforded 87% isolated yield
with a TON of 870,000, which, to the best of our knowl-
edge, is the highest TON for Suzuki coupling of aryl
bromides achieved in water (Table 2, entry 6).
Acknowledgements
This project was supported by the National Research
Initiative of the USDA Cooperative State Research,
Education and Extension Service, Grant number 2003-
35504-13620.
References and notes
The catalysis is also tolerant of electronic variation in
the arylboronic acid component, and arylbromides cou-
pled cleanly with electron-poor, electron-rich, or steri-
cally hindered arylboronic acids (Table 2, entries 9–
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cally hindered 2-bromo-m-xylene coupling with 2-tolyl-
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a solution of 4-bromoanisole (935 mg,
5 mmol), phenylboronic acid (667 mg, 5.5 mmol), K2CO3
(1.38 g, 10 mmol), and [1,10-bis(diphenylphosphino)ferro-
cene]dichloro-palladium(II)
complex,
Pd(DPPF)Cl2
(4.0 mg, 0.1 mol %) in 2 mL water was flushed with
nitrogen and capped. The reaction mixture was heated
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