2
P. Vishnuvardhan Reddy et al. / Polyhedron xxx (2016) xxx–xxx
Table 1
2. Experimental
Optimization of reaction conditions.a
B(OH)2
2.1. Materials and instrumentations
Br
Catalyst 1 (0.5 mol %)
Solvent , Base, 60 oC, 4 h
N
All reagents were commercial grade materials and were used
without further purification. All solvents were dried and distilled
by standard methods. Purification of products was carried out by
column chromatography using commercial column chromatogra-
phy grade silica gel (60–120 mesh) purchased from s. d. fine-chem-
icals Ltd. using mixture of ethyl acetate and hexane as eluting
solvent. All synthesized compounds were characterized and com-
pared with the literature reports. The 1H NMR and 13C NMR spectra
were recorded on a Bruker-Avance (300 MHz), and Varian-Inova
(500 MHz) spectrophotometer using CDCl3 solvent, and TMS as
the internal standard.
N
Entry
Solvent
Base
Yield (%)b
1
2
3
4
5
6
7
8
DMF
DMA
DMSO
MeoH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Na2CO3
Cs2CO3
K3PO4
K3PO4
0
0
0
70
86
96e
80
84
80
79
77
70
EtOH
EtOH/H2O (1:2)
MeOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
9
10
11c
12
d
2.2. Experimental procedure for the Suzuki cross coupling reaction of
heteroaryl bromides
a
The reactions were carried out with 3-bromopyridine (1 mmol), phenylboronic
acid (1.5 mmol), base (2 eq) and catalyst (0.5 mol%) in 3 mL of solvent at 60 °C for
4 h.
b
The reaction vessel was charged with heteroaryl bromides
(1.0 mmol), arylboronic acid (1.2 mmol), K3PO4Á7H2O (1.5 mmol),
and the catalyst 1 (0.5 mol%) in EtOH/H2O (1:2, v/v 3 mL). The reac-
tion mixture was heated at 60 °C in air and the progress of the
reaction was monitored by TLC. At the end of the reaction, the reac-
tion mixture was diluted with water (20 mL) and then extracted
with EtOAc (2 Â 20 mL). The combined organic layers were washed
with brine (10 mL) and then dried over anhydrous Na2SO4. After
removal of the solvent, the crude product was purified by flash
chromatography over silica gel using ethyl acetate/hexane as an
eluent to afford the pure product.
Isolated yields.
Catalyst loading 0.3 mol%.
Reaction at 40 °C.
Optimized condition: 1:2, v/v EtOH/H2O; 3 mL K3PO4.
c
d
e
entry 11) or lowering the temperature (40 °C, Table 1, entry 12)
resulted in poor yield of the coupling product. Thus, the optimized
conditions for the coupling reaction are 0.5 mol% of palladium
complex, (2.0 equiv) K3PO4 in 3 mL of EtOH/H2O (1:2, v/v) at
60 °C for 4 h (96%, Table 1, entry 6).
The scope of the reaction was extended to various structurally
diverse heteroaryl bromides using the optimized reaction condi-
tions and the results are summarized in Table 2. The reaction of
the phenylboronic acid with electron-deficient heteroaryl bromides
such as 3-bromopyridine, 2-bromopyridine, 3-bromoquinoline,
4-bromoisoquinoline, 5-bromopyrimidine and 2-bromopyrazine
(Table 2, 3a-3f) proceeded smoothly to afford the corresponding
coupling products in excellent yields. Similarly, the reaction carried
out with electron-rich heteroaryl bromide like 2-bromothiophene
(Table 2, 3g) produced the desired product in 88% yield. Further-
more, electron donating and electron withdrawing heteroaryl
bromides such as 2-bromo-6-methylpyridine and 5-bromo-2-
nitropyridine (Table 2, 3h, and 2i) also reacted well with phenyl-
boronic acid and the corresponding products were obtained in
96% and 85% yield, respectively.
3. Results and discussion
In the initial screening of Suzuki cross-coupling reactions,
phenylboronic acid (1.0 mmol) and 3-bromopyridine (1.5 mmol)
were selected to examine the catalytic activity of carboxy amido/
carbene ligated palladium complex (II) (Fig 1). The optimization
studies were conducted using various base and solvents at 60 °C,
and the results are tabulated in Table 1. Remarkably, the reaction
did not proceed in polar aprotic solvents like DMF, DMSO and
DMA (Table 1, entries 1–3). However, the use of polar protic
solvents like MeOH and EtOH afforded good yields of the desired
product, namely, 3-phenylpyridine (Table 1, entries 4 & 5). Further
improvement in the product yield was observed using 1:2, v/v
EtOH/H2O mixture (Table 1, entry 6).
In the screening study of bases, it was observed that K3PO4 is
the best suitable base (Table 1, entry 6) although, carbonate bases
like K2CO3, Na2CO3 and Cs2CO3 also gave good results (Table 1,
entries 8–10). Lowering the catalyst loading (0.3 mol%, Table 1,
Table 2
Suzuki coupling reaction of phenylboronic acid with heteroarylbromides.a
1
Catalyst (0.5 mol %)
ArB(OH)2
Het-Ar-Br
Ar-Ar-Het
3
K3PO4, H2O/EtOH
2
60 oC, 4 h
Entry
Heteroarylbromides (2)
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
3-bromopyridine
2-bromopyridine
3-bromoquinoline
4-bromoisoquinoline
5-bromopyrimidine
2-bromopyrazole
3-bromothiphene
2-metyl-6-bromopyridine
3-bromo5-nitropyridine
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
91
89
87
95
86
88
86
96
O
Pd N
N
N
O
a
The reactions were carried out with hetroaryl bromides (1 mmol), phenyl-
boronic acid (1.5 mmol), K3PO4 (2 eq) and catalyst (0.5 mol%) in 3 mL of EtOH/H2O
at 60 °C for 4 h.
b
Isolated yields.
Fig. 1. Structure of carboxyamido/carbene palladium complex (II).