M. Waheed, N. Ahmed / Tetrahedron Letters 57 (2016) 3785–3789
3787
Table 2
Table 4
Optimization of base and solventsa
Suzuki–Miyaura reaction of aryl chlorides with arylboronic acid
Cl
O
L1
Pd(OAc)2,
B(OH)2
O
H2O, K2CO3, 80 °C, 5h
H
B(OH)2
Pd(OAc)2, L1
H
R
R
R = H, CHO, COCH3, OH, NH2
OCH3, CN, and Chalcone
Base, solvent, reflux
Br
O
H
O
Entry
Base
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
K2CO3
NaHCO3
Na2CO3
K2CO3
K2CO3
K2CO3
THF
DMF
Acetone
MeOH
EtOH
H2O
2
2
2
1.5
2
60
45
53
84
88
94c
1
3,
75%
, 60%
2, 80%
O
O
1
Ph
Ph
4,
7,
70%
CN
65%
a
Reagents and conditions: 4-bromobenzaldehyde (1.0 mmol), phenylboronic
acid (1.2 mmol), base (2.0 mmol), solvent 5 ml, 0.1 mol% of Pd(OAc)2/L1.
b
Isolated yield,
At 80 °C.
c
OH
O
NH2
6,
60%
9, 55%
10,
50%
aReagents and conditions: aryl chloride (1.0 mmol), phenylboronic acid (1.2 mmol),
base (2.0 mmol), water 5 ml, 1 mol% of Pd(OAc)2/L1.
Table 3
Suzuki–Miyaura reaction of aryl bromide/iodide with arylboronic acida
X
Ph
L1
Pd(OAc)2,
B(OH)2
Ph
H2O, K2CO3, 80 °C 1-2h
R
R
which gave the corresponding coupled products in good yield
(Table 3, compounds 4–10). An excellent yield was obtained when
activated electron-poor aryl halides such as 4-bromobenzalde-
hyde, and 4-bromoacetophenone were treated with phenylboronic
acid in water at 80 °C (Table 3, compounds 2, 3). And moderate
yield was obtained with deactivated electron rich aryl bromide
such as 4-bromophenol, 4-bromoaniline, coupled with phenyl-
boronic acid (Table 3, compounds 9, 10). Similarly, we have also
carried out a series of reactions using aryl chlorides with phenyl-
boronic acid in the presence of Pd(OAc)2/L1 in water at 80 °C
(Table 4).
R = H, CHO, COCH3, OH, NH2
OCH3, CN, and Chalcone
X = Br, I
O
O
H
1, 90%(Br),
2, 94% (Br)
3,
92% (Br)
92%(I)
O
CN
O
O
Ph
Under Suzuki–Miyaura reaction condition, novel ligands are
equally good for aryl chloride substrate with arylboronic acid
under aqueous medium. However, the coupling of aryl chlorides
with phenylboronic acid required a long reaction time and more
catalyst loading (1.0 mol%) which gave a moderate to good yield
at 80 °C in 5 h as compared to the aryl bromide/iodide due to the
stability of C–Cl bond.
OH
6, 80% (Br)
5,
4
80%(Br),
82%(I)
, 88%
(Br)
O
O
OH
8,
Ph
Ph
7,
90% (Br)
75%(Br)
The scope of our protocol was studied with a diverse range of
aryl chlorides. We observed that the deactivated electron rich aryl
halide gave moderate yields. However, the activated electron-poor
group gave good yield. Activated aryl chlorides such as 4-
chlorobenzaldehyde, 4-chloroacetophenone, and chloro-chalcone
in water at 80 °C gave good yields (Table 4, compounds 2, 3, 4,
and 5), whereas other inactivated aryl chlorides such as 4-
chloroaniline and 4-chlorophenol gave moderate yield (Table 4,
compounds 9, 10).
OH
NH2
9, 70%(Br),
74%(I)
10, 68%(Br),
70%(I)
a
Reagents and conditions: aryl halide (1.0 mmol), phenylboronic acid
(1.2 mmol), base (2.0 mmol), water 5 ml, 0.1 mol% of Pd(OAc)2/L1.
We have successfully reused and cycled the catalyst Pd(OAc)2/
L1 system in the cross-coupling of 4-bromobenzaldehyde and
phenylboronic acid (Table 5). The reaction was carried out in water
at 80 °C. After cooling to room temperature, the organic products
were extracted by ethyl acetate, and the aqueous phase was then
transferred to a new reaction flask, and the aqueous phase was
used for the next reaction. It was observed that the 0.1 mol% Pd
(OAc)2/L1 system could be reused by three cycles and the yield sig-
nificantly dropped for the fourth cycle.
We also used the ligands in the Mizoroki–Heck cross-coupling
reactions under aqueous medium with tetra butyl ammonium bro-
mide as an additive.27 First, we optimized the reactions conditions
using of 4-bromoacetophenone and styrene and 0.3 mol% Pd
(OAc)2/L1 catalyst system (Table 6).
Under optimized reaction conditions, we have carried out the
reactions using many substrates with arylboronic acid.26 Generally,
it was observed that aryl bromides having electron donating
groups were less reactive than aryl bromides having electron with-
drawing group in the Suzuki–Miyaura cross-coupling reactions. An
excellent yield was obtained for 4-bromobenzaldehyde coupled
with phenylboronic acid in the presence of 0.1 mol% Pd(OAc)2/L1
with two equivalent of K2CO3 to give near quantitative yield of
biphenyl-4-carbaldehyde 2. We have also studied the coupling of
substituted aryl bromides with arylboronic acid, for example, 5-
bromo-2-methoxybenzonitrile, 5-bromo-2-hydroxy acetophe-
none, and some derivatives of chalcones with phenylboronic acid