Cyclopalladated complexes of 2-phenylaniline and their catalytic activity in Suzuki and Heck reactions under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2012.03.003

A series of palladium complexes bearing monodentate and bidentate ligands were applied in the Suzuki reaction of aryl halides and the Heck reaction of styrene with phenylboronic acid. The complexes were found to be effective catalysts for these reactions affording the cross-coupled products in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.03.003

Tetrahedron Letters 53 (2012) 2428–2431
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclopalladated complexes of 2-phenylaniline and their catalytic activity
in Suzuki and Heck reactions under mild conditions
⇑
Kazem Karami , Naser Rahimi, Mahlagha Bahrami Shehni
Department of Chemistry, Isfahan University of Technology, Isfahan 84156/83111, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of palladium complexes bearing monodentate and bidentate ligands were applied in the Suzuki
reaction of aryl halides and the Heck reaction of styrene with phenylboronic acid. The complexes were
found to be effective catalysts for these reactions affording the cross-coupled products in moderate to
excellent yields.
Received 13 December 2011
Revised 16 February 2012
Accepted 1 March 2012
Available online 8 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladacycle
Catalytic activity
Suzuki reaction
Heck reaction
The palladium-catalyzed Suzuki cross-coupling is a very useful
and convenient method, especially for the synthesis of various
biaryl compounds1–6 that are found as important structural units
in pharmaceuticals and natural products.7–10 The mild reaction
conditions and the commercial availability of various boronic acids
make this reaction preferable over other Pd-catalyzed cross-
coupling reactions.1–3,11–16 Besides using aryl bromides, there is
great interest in developing catalysts that use aryl chlorides in Su-
zuki reactions.1,17,18 Since the bond strengths of C–Cl and C–Br are
stronger than C–I, the reactivity of aryl bromides and chlorides is
reduced compared with the more active iodides. Thus, despite
being cheaper, more available and practical, aryl bromides and
chlorides often do not react efficiently.19 Furthermore, the Heck
reaction and related chemistry has numerous applications in or-
ganic synthesis,20–25 polymers, dendrimers, fine chemicals and
pharmaceutical intermediates.26–30 Many catalyst systems can be
used to catalyze various frequently used cross-coupling reactions.
In this regard, palladacycles have played an important role due
to their versatility and non-toxicity. Besides phosphorus-
containing complexes, a substantial amount of research has been
undertaken on NC-based complexes. Cyclopalladated complexes
with nitrogen donor atoms have been widely studied due to their
novel and outstanding applications in a vast range of fields such
as organic synthesis,31 insertion reactions,32 as anti-tumor drugs33
and in catalysis.34 The related benzylamine,35 aryl urea,36 sulfili-
mine37 and benzodiazepine38 based palladacycles have also shown
good activity with aryl bromides in C–C coupling reactions.
We have reported the synthesis and characterization of ther-
mal, oxygen and moisture stable palladium complexes containing
a 2-phenylaniline cyclopalladated unit that conveniently formed
six-membered NC palladacycles39 (Fig. 1). Complex 4 was further
studied by X-ray crystallography.39 In this Letter, we report the
application of the palladacycles in Suzuki and Heck reactions. Dur-
ing our research40,41 we have used aryl bromides and chlorides
with phenylboronic acid in the Suzuki reactions and aryl bromides
with styrene in the Heck reaction.
⇑
Corresponding author. Tel.: +98 3113912351; fax: +98 3113912350.
E-mail address: karami@cc.iut.ac.ir (K. Karami).
Figure 1. Palladium complexes used as pre-catalysts.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.03.003

K. Karami et al. / Tetrahedron Letters 53 (2012) 2428–2431
2429
Table 1
Pd(0), and hence a facile entry to the catalytic cycle. The reaction
did not proceed in benzene. After optimizing the solvent, the
reaction was run with two different substrates, 4-bromoanisole
and 2-bromobenzaldehyde, in order to optimize the base (Tables
3 and 4). Among the bases employed, K2CO3, K3PO4Á3H2O and
Na2CO3, Na2CO3 (Table 2) and K3PO4Á3H2O (Tables 3 and 4) were
found to be the best. The third factor to be optimized was the reac-
tion time. A shorter reaction time had a positive effect on the
reaction of 4-bromoanisole with phenylboronic acid (Table 3, entry
3) which may be due to the prevention of homocoupling. In con-
trast, two reactions were negatively affected by this change and
the catalytic activity decreased (Tables 2 and 4, entry 3). Decreas-
ing the temperature of the reactions, led to different catalytic activ-
ity. As the temperature was lowered, there was no decrease in the
reaction yield for the reaction of bromobenzene with phenylbo-
ronic acid (Table 2, entry 4). Moreover, utilizing Na2CO3 instead
Effect of solvents on the Suzuki reaction of bromobenzene with phenylboronic acida
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
3
3
3
3
6
6
6
6
MeOH
THF
Acetone
Benzene
MeOH
THF
100
22
27
3
38
3
Acetone
Benzene
11
0
a
Reaction conditions: bromobenzene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst (0.01 mmol), Na2CO3 (1.5 mmol), solvent (6 mL), 1 h, 65 °C.
of K2CO3 showed no effect on the reaction, as the anion, CO32À
,
which contributes to the catalytic cycle, is the same. The catalytic
activity in two other reactions (Tables 3 and 4, entry 4) was
reduced, however. The optimized conditions for the reaction of
bromobenzene with phenylboronic acid were Na2CO3 as base,
MeOH as solvent, 1 h as the reaction time, and room temperature.
The study was pursued to test catalysts 2, 4–8 using these condi-
tions which resulted in diverse yields. The catalysts with mono-
dentate ligands (2–4) were the best in all reactions and exhibited
better catalytic reactivity than complexes with bidentate ligands
(5–8). Also, the catalytic activity of 6 was lower than that of 7 in
all the reactions in this work. This may be due to the fact that Pd(II)
in palladacycles with five-membered rings is difficult to reduce to
Pd(0). The best conditions for the reactions of 4-bromoanisole and
2-bromobenzaldehyde with phenylboronic acid were the same as
those for the reaction of bromobenzene with phenylboronic acid,
except for differences in the reaction times, which are shown in
Tables 3 and 4.
Table 2
Effect of catalyst, base, temperature and time on the Suzuki reaction of bromobenzene
with phenylboronic acida
Entry
Catalyst
Base
Temp/time
Yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
2
4
5
6
7
8
K2CO3
65 °C/1 h
65 °C/1 h
65 °C/30 min
rt/1 h
rt/1 h
rt/1 h
rt/1 h
rt/1 h
rt/1 h
rt/1 h
100
99
86
100
100
100
36
12
76
55
K3PO4Á3H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
10
Using the optimized reaction conditions, complex 4 was applied
to a representative range of aryl chlorides (Table 5). The activated
electron-deficient substrate, 4-chlorobenzaldehyde coupled with
phenylboronic acid to give a relatively high yield of product (entry
1). Unexpectedly, the reaction of 4-nitrochlorobenzene failed to
give a high yield (entry 2). Chlorobenzene was also coupled with
phenylboronic acid to afford a high yield of biphenyl (entry 3).
The deactivated electron-rich aryl chlorides, 4-chlorotoluene and
4-chloroaniline were poor substrates (entries 4 and 5). It can be in-
ferred that the electronic effects of the substituents on the aryl
chlorides had significant influence on the reaction and electron-
withdrawing substituents were more appropriate for the coupling.
In all the reactions of aryl bromides and chlorides, particularly
when complexes 2–4 were applied, the suspension color turned
a
Reaction conditions: bromobenzene (0.5 mmol), phenylboronic acid
(0.75 mmol), catalyst (0.01 mmol), base (1.5 mmol), MeOH (6 mL).
The reaction conditions such as the solvent and base, reaction
temperature and time were optimized. Initially, the effectiveness
of different solvents such as MeOH, THF, acetone and benzene were
tested with palladacycles 3 and 6 in the Suzuki reaction.42 The cou-
pling of bromobenzene with phenylboronic acid in the presence of
0.01 mmol of 3 or 6, 1.5 mmol of Na2CO3 as the base and a reaction
time of one hour and temperature of 65 °C were chosen as initial
conditions to optimize the reaction (Table 1).
MeOH proved to be the best solvent and this may be due to the
better solubility of the reagents and easier reduction of Pd(II) to
Table 3
Effect of base, catalyst, temperature and time on the Suzuki reaction of 4-bromoanisole with phenylboronic acida
Entry
Catalyst
Base
Temp/time
Yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
2
4
5
6
7
8
K2CO3
65 °C/1 h
65 °C/1 h
65 °C/30 min
rt/30 min
65 °C/30 min
65 °C/30 min
65 °C/30 min
65 °C/30 min
65 °C/30 min
65 °C/30 min
89
90
92
85
89
98
31
20
71
35
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
10
a
Reaction conditions: 4-bromoanisole (0.5 mmol), phenylboronic acid (0.75 mmol), catalyst (0.01 mmol), base (1.5 mmol), MeOH (6 mL).

2430
K. Karami et al. / Tetrahedron Letters 53 (2012) 2428–2431
Table 4
Table 6
Effect of base, catalyst, temperature and time on the Suzuki reaction of 2-
The catalytic activity in the Heck reaction of aryl bromides with styrene using the
bromobenzaldehyde with phenylboronic acida
optimized Suzuki reaction conditionsa
Entry
Catalyst
Base
Temp/time
Yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
2
4
5
6
7
8
K2CO3
65 °C/1 h
65 °C/1 h
65 °C/30 min
rt/1 h
65 °C/1 h
65 °C/1 h
65 °C/1 h
65 °C/1 h
65 °C/1 h
65 °C/1 h
97
99
97
89
96
88
33
24
40
54
Entry
R
Catalyst
Base
Temp/time
Yield (%)
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
1
2
3
o-CHO
H
p-OMe
2
3
4
K3PO4Á3H2O
Na2CO3
K3PO4Á3H2O
65 °C/1 h
rt/1 h
65 °C/30 min
2
0
37
a
Reaction conditions: aryl bromide (0.5 mmol), styrene (0.75 mmol), catalyst
(0.01 mmol), base (1.5 mmol), MeOH (6 mL).
10
a
Table 7
Reaction conditions: 2-bromobenzaldehyde (0.5 mmol), phenylboronic acid
Optimization of the Heck reaction of aryl bromides with styrenea
(0.75 mmol), catalyst (0.01 mmol), base (1.5 mmol), MeOH (6 mL).
black at the beginning of the reactions. Thus, it can be inferred that
the reaction mechanism starts with a pre-dissociation and/or
reduction step in which the Pd(II) source is converted into the
more active and coordinatively unsaturated Pd(0) catalyst.43 This
is followed by oxidative addition of the aryl halide which is often
the rate determining step in cross-coupling catalytic cycles.44 The
high C–Cl bond strength compared with C–Br disfavors oxidative
addition and makes the coupling of such substrates far more chal-
lenging.45 The catalytic cycle is completed by transmetallation, aryl
group transfers from boron to palladium, and a final reduction–
elimination to release the product. Therefore, the relative contribu-
tion of steric and electronic effects is very important, particularly
for less reactive aryl halides.46–48
In comparison with PdCl2, complex 4 showed higher catalytic
activity in the reactions of bromo- and chlorobenzene with phen-
ylboronic acid (Table 5, entries 6 and 7). The rate of coupling for
each of these reactions was lower than that when complex 4 was
used (Table 2, entry 6 and Table 5, entry 3).
The catalytic activity of the palladacycles was also studied in
the Heck reaction49 of the aryl bromides with styrene. The catalytic
activity of 2, 3, and 4 with the optimal conditions obtained from
the Suzuki reaction of aryl bromides with phenylboronic acid were
examined in the Heck reaction of bromobenzene, 4-bromoanisole,
and 2-bromobenzaldehyde with styrene. The results are summa-
rized in Table 6.
Entry
Catalyst
R = Hb (%)
R = p-OMe (%)
R = o-CHO (%)
1
2
3
4
5
6
7
2
3
4
5
6
7
8
7
10
22
2
34
34
0
40
27
29
23
45
0
2
0
3
0
0
0
0
0
a
Reaction conditions: aryl bromides (0.5 mmol), styrene (0.75 mmol), catalyst
(0.01 mmol), K3PO4Á3H2O (1.5 mmol), MeOH (6 mL), 3 h, 65 °C.
b
Na2CO3 (1.5 mmol) was used as the base.
The catalytic activity of 2 (Table 6, entry 1) was negligible and
only a trace amount of product was obtained. In the reaction of
bromobenzene with styrene using catalyst 3 (Table 6, entry 2),
no reaction occurred at room temperature. In addition, there was
low catalytic activity in the reaction of 4-bromoanisole with sty-
rene using catalyst 4 (Table 6, entry 3). As these conditions were
not efficient for the Heck reaction of aryl bromides, different con-
ditions were employed. The time for all the reactions and the tem-
perature for the reaction of bromobenzene with styrene (Table 6,
Table 5
Use of the optimized conditions for the Suzuki reaction of aryl chlorides with phenylboronic acida
Entry
R
Catalyst
Base
Temp/time
Yield (%)
1
2
3
4
5
p-CHO
p-NO2
H
p-Me
p-NH2
H
4
4
4
4
K3PO4Á3H2O
K3PO4Á3H2O
Na2CO3
K3PO4Á3H2O
K3PO4Á3H2O
Na2CO3
65 °C/1 h
65 °C/1 h
rt/1 h
65 °C/30 min
65 °C/30 min
rt/1 h
77
35
74
17
13
20
42
4
6
PdCl2
PdCl2
7b
H
Na2CO3
rt/1 h
a
Reaction conditions: aryl chloride (0.5 mmol), phenylboronic acid (0.75 mmol), catalyst (0.01 mmol), base (1.5 mmol), MeOH (6 mL).
Bromobenzene was used as the aryl halide.
b

K. Karami et al. / Tetrahedron Letters 53 (2012) 2428–2431
2431
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to 3 h, some reactions showed no catalytic activity. In other reac-
tions, low to moderate yields were obtained. Moreover, the lower
yields of the reaction 2-bromobenzaldehyde with styrene can be
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In conclusion, we have developed a new combination of palla-
dacycles with 2-phenylaniline, monodentate and bidentate li-
gands, which proved to be efficient for the Suzuki reactions of
various aryl bromides and chlorides with phenylboronic acid.
However, these palladacycles did not work as efficiently in the
Heck reaction.
31. Ryabov, A. D. Synthesis 1985, 233.
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Acknowledgment
We gratefully thank the Iran National Science Foundation (INSF)
for financial support.
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