Efficient pyridylbenzamidine ligands for palladium-catalyzed Suzuki-Miyaura reaction

Article abstract of DOI:10.1002/aoc.2913

A series of pyridylbenzamidine ligands were applied in palladium-catalyzed Suzuki-Miyaura reactions and the effect of ligand on catalytic properties was evaluated. Under the optimization conditions, the bulky and electron-donating nitrogen donor ligands were successfully used to catalyze the reaction of a variety of aryl bromides and aryl chlorides with arylboronic acid, giving the desired products in moderate to high yields. Copyright

Full text of DOI:10.1002/aoc.2913

Full Paper
Received: 4 June 2012
Revised: 27 July 2012
Accepted: 27 July 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2913
Efficient pyridylbenzamidine ligands for
palladium-catalyzed Suzuki–Miyaura reaction
Ying-Tang Huang, Xiao Tang, Yi Yang, Dong-Sheng Shen*, Cheng Tan and
Feng-Shou Liu*
A series of pyridylbenzamidine ligands were applied in palladium-catalyzed Suzuki–Miyaura reactions and the effect of ligand
on catalytic properties was evaluated. Under the optimization conditions, the bulky and electron-donating nitrogen donor
ligands were successfully used to catalyze the reaction of a variety of aryl bromides and aryl chlorides with arylboronic acid,
giving the desired products in moderate to high yields. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: Suzuki–Miyaura reaction; pyridylbenzamidine ligand; aryl bromide; aryl chloride
coupling partners because the activation of aryl chlorides is much
more difficult than aryl bromides and iodides. To search for new
Introduction
Palladium-catalyzed cross-coupling reactions are now widely
recognized as the most versatile tools for carbon–carbon bond
formation and are widely used in organic synthesis.[1–21] In
2010, the Nobel Prize for Chemistry was awarded to R. F. Heck,
Ei-ichi Negishi and A. Suzuki, who have achieved excellent
progress in this field.[22] Among the palladium-catalyzed cross-
coupling reactions, the Suzuki–Miyaura reaction is now becoming
a very powerful tool in synthetic methodologies, particularly for
convenient formation of biaryl compounds, owing to the high
stability and wide range of functional group tolerance of the
reactants and products. Many palladium complexes have been
used to promote the Suzuki–Miyaura cross-coupling reaction,
while phosphine ligands have commonly proved to be very
efficient and allowed the use of sterically hindered aryl bromide
substrates and even aryl chlorides at low catalyst loadings and
relatively low reaction temperatures.[23–29] However, these phos-
phine ligands are often sensitive to air and moisture, and require
air-free handling in order to minimize ligand oxidation, limiting
their further practical utilization. Therefore, phosphine-free ligands
have attracted great attention in recent years.[30–42]
catalysts that exhibit high activity and stability with a broad range
of substrates in the coupling reaction, as part of our ongoing
research interest in cross-coupling with phosphine-free
ligands,[60–62] we herein report a series of pyridylbenzamidine
ligands (Fig. 1) as phosphine-free ligands for Suzuki–Miyaura
reaction under aerobic conditions.
Experimental
Materials and Methods
All the chemical reagents (AR grade) were purchased from
commercial resources and used without further purification.
NMR spectra were recorded on a Bruker 300 MHz spectrometer
using CDCl3 as the solvent with tetramethylsilane (TMS) as an
internal standard. Mass spectral data were recorded on an
Acquity UPLC-Q-Tof Micro MS detector. Elemental analysis was
done using a Vario EL III instrument (Elementar Analysen Systeme
Gmbh, Germany).
The X-ray diffraction data of the single crystal of L3PdCl2 was
obtained with o-2θ scan mode on a Bruker SMART 1000 CCD
diffractiometer with graphite-monochromated Mo Ka radiation
(l = 0.71073 ) at 110 K. The structure was solved using direct
methods, and refinement with full-matrix least squares on F2
was performed with the SHELXTL program package.[63] The abso-
lute structure was determined based on differences in Friedel
pairs included in the dataset. All non-hydrogen atoms were
refined anisotropically. The data collection and structure
refinement parameters are summarized in Table 1.
It is a trend that phosphine-free ligands which are easily
available, and are moisture and air stable, are in heavy demand in
the palladium-catalyzed Suzuki–Miyaura reactions of aryl halides
with arylboronic acids. In particular, nitrogen donor ligands and
their palladium complexes have shown excellent catalytic activity
because of their strong s-donating abilities.[43] For example,
Kirchner and co-workers found that the b-diimine ligands
exhibited moderate activity towards aryl bromides.[44] A family of
benzimidazolium–pyrazole palladium complexes developed by
Andy Hor turned out to be excellent for Suzuki–Miyaura reaction
and other types of cross-coupling reactions under homogeneous
conditions.[45] Moreover, nitrogen ligands bearing pyridine as a
strong coordination donor and labile group gave superior catalytic
performance in other carbon–carbon- and carbon–nitrogen-
forming reactions.[46–59] Generally, aryl bromides are usually
employed as coupling substrates in the above protocols. However,
the more inexpensive aryl chlorides have been rarely used as
*
Correspondence to: Feng-Shou Liu, Dong-Sheng Shen, School of Chemistry and
Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, Guang
Dong, 528458, China. E-mail: fengshou2004@126.com(F.-S. Liu); sds8@163.com
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Zhongshan, Guang Dong 528458, China
Appl. Organometal. Chem. 2012, 26, 701–706
Copyright © 2012 John Wiley & Sons, Ltd.

Y.-T. Huang et al.
L1: R1=Ph, R2=H, R3=H;
H
the filtrate. After recrystallization of the product from ethanol, 2,6-
iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-;Py (L3) was obtained as light-yellow
crystals. Yield 45%; m.p. 165ꢀC. EI-MS (m/z) 372 [M]+; 279
[Mꢁ C5H5N2]+.1H NMR (300 MHz, CDCl3), d (ppm): 7.95 (br, 1H,
pyridyl a-H), 7.57–6.78 (m, 10H, pyridyl and phenyl protons), 2.99
(m, 2H, CH(CH3)2), 2.47 (s, 3H, CH3), 0.96 (d, J = 6.9 Hz, 12H, CH
(CH3)2). 13C NMR (75 MHz, CDCl3), d (ppm): 166.74 (C ;N), 157.78
(2-Cpy), 146.22 (6-Cpy), 143.95 (CAr-;N), 136.91(4-Cpy), 134.49 (CAr-;
CH3), 131.64 (CAr-;CH(CH3)2), 129.15 (CAr), 128.69 (CAr), 127.59 (CAr),
127.05 (CAr), 123.43 (5-Cpy), 122.61(3-Cpy), 27.98 (CH(CH3)2), 24.11
(CH(CH3)2), 22.49 (CAr-;CH3).
R1
N
L2: R1=p-CH3OC6H4, R2=H, R3=H;
L3: R1=p-CH3C6H4, R2=H, R3=H;
L4: R1=Ph, R2=H, R3=NO2;
N
N
R3
L5: R1=p-CH3C6H4, R2=CH3, R3=H;
L6: R1=Ph, R2=CH3, R3=H;
R2
Figure 1. Structure of pyridylbenzamidine ligands.
Table 1. Crystallographic data for L3PdCl2
Complex
L3PdCl2
Synthesis of 2,6-iPr2C6H3-;N ;C(Ph)-;NH-;(5-CH3-;Py) (L6)
Formula
C25H29Cl2N3Pd
548.81
2,6-iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-(5-;CH3-;Py) (L6) was synthe-
sized according to the method described above as light-yellow
crystals. Yield 68%; m.p. 166ꢀC.1H NMR (300 MHz, CDCl3), d (ppm)
[isomer ratio of 4.9:1] major isomer: 7.95 (br, 1H, pyridyl a-H),
7.57–6.78 (m, 10H, pyridyl and phenyl protons), 2.99 (m, 2H, CH
(CH3)2), 2.47 (s, 3H, CH3), 0.96 (d, J = 6.9 Hz, 12H, CH(CH3)2). Minor
isomer: 7.95 (br, 1H, pyridyl a-H), 7.66–6.92 (m, 10H, pyridyl and
phenyl protons), 3.16 (m, 2H, CH(CH3)2), 2.47 (s, 3H, CH3), 1.26 (d,
J = 6.9 Hz, 12H, CH(CH3)2). 13C NMR (75 MHz, CDCl3), d (ppm) major
isomer: 166.74 (C ;N), 157.78 (2-Cpy), 146.22 (6-Cpy), 143.95 (CAr-;N),
136.91(4-Cpy), 134.49 (CAr-;CH3), 131.64 (CAr-;CH(CH3)2), 129.15 (CAr),
128.69 (CAr), 127.59 (CAr), 127.05 (CAr), 123.43 (5-Cpy), 122.61(3-Cpy),
27.98 (CH(CH3)2), 24.11(CH(CH3)2), 22.49 (CAr-;CH3). Minor isomer:
166.74 (C ;N), 157.78 (2-Cpy), 146.22 (6-Cpy), 143.95 (CAr-;N), 136.91
(4-Cpy), 134.49 (CAr-;CH3), 131.64 (CAr-;CH(CH3)2), 129.15 (CAr),
128.69 (CAr), 127.59 (CAr), 127.05 (CAr), 123.43 (5-Cpy), 122.61(3-Cpy),
29.03 (CH(CH3)2), 24.42 (CH(CH3)2), 22.58 (CAr-;CH3). EI-MS (m/z):
372 [M]+; 265 [Mꢁ C6H8N2]+. Elemental anal. Calc. for C25H29N3: C,
80.82; H, 7.87; N, 11.31. Found: C, 80.77; H, 7.82; N, 11.24%.
Formula weight
Crystal color; Form
Crystal size (mm)
Crystal system
Space group
T (K)
Yellow block
0.15 ꢂ 0.15 ꢂ 0.24
Orthorhombic
P212121
110 (2)
a(Å)
b(Å)
12.6883(19)
13.254(2)
14.200(2)
2388.0(6)
1.526
c(Å)
V(Å3)
Dcalc (mg m–3
)
F (000)
1120
Z
4
m(mm- 1
)
1.018
θ range for data collection (ꢀ)
Reflections collected
Rint
2.1 – 27.1
12 123
0.034
Data/ parameters
Goodness-of-fit
R1/wR2[I>2s(I)]
5174/297
1.07
Synthesis of [2,6-iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-;Py]PdCl2 (L3PdCl2)
0.030/0.059
0.039/0.062
R1/wR2(all data)
A suspension of PdCl2 (177 mg, 1 mmol) in acetonitrile (20 ml)
was refluxed until a clear solution of Pd(MeCN)2Cl2 was formed.
When cooling to room temperature, L3 (371 mg, 1.0 mmol) was
then added and stirred for another 12 h. After the solvent was
concentrated to ~5 ml, 20 ml hexane was added and an orange
solid was obtained. Washed with hexane (2 ꢂ 10 ml) and dried
under vacuum, the orange palladium complex was received in
96% yield; m.p. 288ꢀC. ESI-MS (m/z): [M + Na]+ 571;[M ꢁ Cl]+ 514;
[M ꢁ 2Cl]+ 476, 479, 474. 1H NMR (300 MHz, CDCl3), d (ppm):
9.56 (s, 1H, pyridyl a-H), 8.33–6.02 (m, 10H, pyridyl and phenyl
protons), 2.87 (m, 2H, CH(CH3)2), 2.32 (s, 3H, CH3), 1.03(d, J = 6.7
Hz, 12H, CH(CH3)2). 13C NMR (75 MHz, CDCl3), d (ppm): 163.81
(C ;N), 149.68 (2-Cpy), 145.85 (6-Cpy), 140.52 (CAr-;N), 138.19 (4-Cpy),
133.52 (CAr-;CH3), 129.68 (CAr-;CH(CH3)2), 129.30 (CAr), 128.88 (CAr),
127.53 (CAr), 123.54 (CAr), 123.10 (CAr), 119.01 (5-Cpy), 116.96 (3-Cpy),
28.34 (CH(CH3)2), 25.42 (CH(CH3)2), 22.68 (CAr-;CH3). Elemental anal.
Calc. for C25H29Cl2N3Pd: C, 54.71; H, 5.33; N, 7.66. Found. C: 54.63;
H, 5.26; N, 7.51.
2,6-iPr2C6H3-;N-;C(Ph)-;NH-;Py (L1), 2,6-iPr2C6H3-;N ;C(4-CH3OC6H4)-;
NH-;Py (L2), 2,6-iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-;(4-NO2-;Py) (L4) and
2,6-iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-;(5-CH3-;Py) (L5) were synthesized
according to our previous reports.[64,65]
General Procedure for the Synthesis of Ligand and Palladium
Complex
Synthesis of 2,6-iPr2C6H3-;N ;C(4-CH3C6H4)-;NH-;Py (L3)
p-Toluoyl chloride (1.33 ml, 10 mmol) was slowly added to a vig-
orously stirred solution of 2,6-diisopropylaniline (1.9 ml, 10 mmol)
in CH2Cl2 (45 ml), then triethylamine (1.6 ml, 11 mmol) was added
in one portion and a white precipitate appeared immediately. After
refluxing for 3 h, the precipitate of (C2H5)3N.HCl was filtrated, and a
white solid powder of amide was obtained by evaporating the
solvent. Then excess of thionyl chloride (2.0 ml, 28 mmol) was
added to the amide and the reaction mixtures were stirred for 2 h
at 80ꢀC. The remaining thionyl chloride was distilled off under
reduced pressure to give the imidoyl chloride as a yellow and
slowly solidifying oil. Successively, toluene (40 ml), triethylamine
(1.6 ml, 11 mmol) and 2-aminopyridine (0.94 g, 10 mmol) were
added to the reaction system. The mixtures were heated to reflux
for 24 h under the protection of nitrogen atmosphere. (C2H5)3N.
HCl was removed by filtration and toluene was evaporated from
General Procedure for Suzuki–Miyaura Reaction
In a round-bottom bottle, ligand (1% mmol), PdCl2 (1% mmol),
aryl halides (1 mmol), arylboronic acid (1.2 mmol), K2CO3 (2 mmol)
and 5 ml solvent were added with a magnetic stir bar. The reactants
were heated to the required temperature for the described time.
Then the solvent was removed under reduced pressure. The
residue was diluted with EtOAc (5 ml), followed by extraction twice
(2ꢂ 5 ml) with EtOAc. The organic layer was combined and dried
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Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 701–706

Pyridylbenzamidine Suzuki–Miyaura reaction
with anhydrous Na2SO4, filtered and evaporated under vacuum.
The isolated products were purified by silica-gel column chroma-
tography using petroleum/ethyl acetate as an eluent. All the iso-
Suzuki–Miyaura Cross-Coupling of Aryl Halides with
Arylboronic Acids
In order to investigate the activity of the pyridylbenzamidine
ligands (L1–6), 4-chlorobenzonitrile and phenylboronic acid were
selected as coupling partners in the presence of 1 mol% ligand
and 1 mol% PdCl2 in the model reaction (Table 2). The experiments
were carried out under aerobic conditions at 110ꢀC for 4 h utilizing
K2CO3 as a base in DMF/H2O.
1
lated desired biaryl products were characterized by H and 13C
NMR and comparison of the melting points with the literature data.
Results and Discussion
Synthesis and characterization of palladium complex
As illustrated in Table 2, the steric and electronic substituents on
the ligand played an important role in catalytic ability. Among the
ligands investigated, L1, with the phenyl group on R1, showed
moderate efficiency and provided the coupling product in 79%
yield (Table 2, run 1). Meanwhile, L2 and L3, with an anisole and
p-toluoyl group on R1, were found to be more efficient ligands
and afforded the coupling product in 86% and 84% yield, respec-
tively (Table 2, runs 2 and 3). The results suggested that the increase
in the electron-donating properties of the ligand would lead to an
increase in the rate of oxidative addition and stabilization of the
palladium species; even these substituents were far away from
the coordinated imine nitrogen atom. Comparatively, L4, with an
electron-withdrawing nitro group on the pyridyl ring in the R3 posi-
tion, was much less active under the same conditions (67% yield),
which indicated that the decreased electron density of the pyridyl
ring caused by the nitro group might lead to the instability and
low catalytic activity of the in situ formed palladium complex.
Besides the electronic effect, the steric properties of the substitu-
ents on the ligand also exhibited a profound effect on catalytic
activity. For instance, L5 and L6, with the methyl group in the R2
position, which is adjacent to the coordinated pyridyl nitrogen
The pyridylbenzamidine ligands were easily prepared in moderate
yield. Moreover, reaction of L3 with Pd(MeCN)2Cl2 afforded the
corresponding L3PdCl2 in high yield. A great advantage of the
described palladium complex is that it is a thermally robust orange
solid that is stable towards air both in the solid state and in solution.
It can therefore be exposed to air without decomposition. A single
crystal of the complex suitable for X-ray diffraction was grown from
CH2Cl2/hexane solution at ambient temperature. A diagram of the
molecular structure is presented in Fig. 2 along with selected bond
lengths and bond angles. As seen from Fig. 2, the expected
complex shows the formation of a six-membered chelate ring with
a proton at the central nitrogen atom; the palladium center adopts
a slightly distorted square planar coordination geometry (the sum
of the angles around the palladium atom is ~362ꢀ). The C6–N3
and C5–N3 bond lengths are 1.378(4) and 1.392(4) Å, respectively.
This is similar to typical C(sp2)–N(sp2) single and double bond
lengths, which indicates rather significant delocalization in the
complex. Similar to the related Pd(II) 1,2,4-triphenyl-1,3,5-triazapen-
tadiene complexes,[66] the six-membered chelate ring of L3PdCl2 is
not exactly planar but distorted in a boat conformation. Moreover,
the aryl ring on the aniline moiety is approximately perpendicular
to the chelate ring, with a dihedral angle of ~86ꢀ, which can be
explained by steric repulsion of the bulky substituted 2,6-diisopropyl
group on the aniline and p-toluoyl backbone, and thus will provide
effective protection of the metal center in the cross-coupling.
Table 2. Ligand screening on Suzuki–Miyaura cross-coupling reaction
Run
R
L or LPdCl2 Pd (mol%)a T (ꢀC) t (h) Yield (%)a
1
CN
CN
L1
L2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
6
79
86
84
85
67
90
92
82
48
56
51
57
44
78
85
79
2
3
4b
CN
L3
CN
L3PdCl2
L4
5
CN
6
CN
L5
7
CN
L6
8
CN
None
L1
9
CHO
CHO
CHO
10
L2
11
L3
12b CHO
L3PdCl2
L4
13
14
15
16
CHO
CHO
CHO
CHO
L5
L6
None
Reaction conditions: 4-Chloronitrobenzene (1 mmol), phenylboronic
acid (1.2 mmol), K2CO3 (2.0 mmol), DMF: H2O=4ml: 1 ml, reaction
time is 6 hours, under aerobic atmosphere. The molar ratio of
Ligand and Pd is 1:1.
Figure 2. Molecular structure of L3PdCl2 depicted with 50% displacement
ellipsoids and with carbon-bound hydrogen atoms omitted. Selected bond
lengths (Å) and angles (ꢀ): C6–N3 1.378(4), C5–N3 1.392(4), C6–N2 1.288(4),
C5–N1 1.337(4), Pd–N1 2.021(2), Pd–N2 2.050(2), Pd–Cl1 2.2993(8), Pd–Cl2
2.3031(8), N1–Pd–N2 88.10(9), N1–Pd–Cl1 178.62(7), N1–Pd–Cl2 91.13(7),
N2–Pd–Cl1 92.85(7), N2–Pd–Cl2 (2) 177.80(7), Cl1–Pd–Cl2 87.87(3).
aIsolated yield.
bThe palladium complex is used.
Appl. Organometal. Chem. 2012, 26, 701–706
Copyright © 2012 John Wiley & Sons, Ltd.
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Y.-T. Huang et al.
atom, showed the corresponding biphenyls in 90% and 92% yield,
respectively (Table 2, runs 6 and 7). Apparently, the increased steric
bulk on the ligands facilitates the reductive elimination process in
the catalytic cycle.[67] It is noteworthy that the palladium complex
of L3PdCl2 was also effective for this cross-coupling reaction,
giving a product of 85% yield (Table 2, run 4), which was compara-
tive to the case of in situ complex formation (Table 2, run 3). To fur-
ther reveal the role of the pyridylbenzamidine ligands to promote
the reaction, cross-coupling was conducted in the absence of
ligands for comparison. The result showed that a moderate yield
of 82% was obtained in the presence of 1 mol% of PdCl2, which
was much less than that of L6/PdCl2 system (Table 2, run 8). More-
over, the catalytic properties of these ligands were explored by
screening another reaction between 4-chlorobenzaldehyde and
phenylboronic acid. The results provided guidelines showing that
L6 was the best choice for the coupling (Table 2, runs 9–16).
Based on the ligand screening, L6 was chosen as the most
effective ligand in the following Suzuki–Miyaura cross-coupling
reactions of different aryl halides with arylboronic acids. With
the optimal reaction conditions in hand, we checked the scope
of the aryl bromides by conducting a series of experiments. As
seen from Table 3, the activated 4-bromonitrobenzene was
coupled smoothly with phenylboronic acid in only 0.5 h, giving
the corresponding product in almost a quantitative yield of
98% at room temperature under aerobic conditions (Table 3,
run 1). However, 4-bromochlorobenzene just delivered its
coupling product in a lower yield of 76% at room temperature
(Table 3, run 2). Meanwhile, reduced yields were also observed
with other unactivated electron-rich aryl bromide under the
same reaction conditions (Table 3, runs 3–5). To our delight, as
the temperature increased to 60ꢀC, most of the substrates includ-
ing activated and deactivated aryl bromides were all successfully
transformed to the desired products in quantitative yields within
2 h. For instance, 4-bromoanisole gave its product in 95% yield
(Table 3, run 11). The more hindered electronic candidates, such
as 1-bromonaphthalene, 2-bromoaniline and 2-bromotoluene,
also produced satisfactory yields (Table 3, runs 13–15). However,
the bulky substituted 2-bromomesitylene gave a much lower
yield of 48% at 60ꢀC in 24 h due to its steric hindrance and low
reactivity (Table 3, run 19).
Table 3. Suzuki–Miyaura cros s-coupling reaction of aryl bromides with arylboronic acid
Run
Ar-;Br
4-O2NPhBr
ArB(OH)2
PhB(OH)2
Product
Pd (mol%)
T (ꢀC)
t (h)
Yield (%)a
1
4-O2NPh-;Ph
1
RT
RT
RT
RT
RT
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
90
60
60
60
0.5
4
98
76
64
60
61
98
97
94
90
18
95
80
99
80
96
92
20
5
2
4-ClPhBr
PhB(OH)2
4-ClPh-;Ph
1
3
4-CH3PhBr
4–CH3OPhBr
NaphtylBr
PhB(OH)2
4-CH3Ph-;Ph
1
6
4
PhB(OH)2
4-CH3OPh-;Ph
Naphtyl-;Ph
1
4
5
PhB(OH)2
1
6
6
4-ClPhBr
PhB(OH)2
4-ClPh-;Ph
1
2
7
4-CH3PhBr
4-CH3PhBr
4-CH3PhBr
4-CH3PhBr
4-CH3OPhBr
4-tBuPhBr
PhB(OH)2
4-CH3Ph-;Ph
1
2
8
PhB(OH)2
4-CH3Ph-;Ph
0.5
0.1
0.01
1
2
9
PhB(OH)2
4-CH3Ph-;Ph
2
10
11
12
13
14b
15
16
17
18
19
20
21
22
23
24
PhB(OH)2
4-CH3Ph-;Ph
2
PhB(OH)2
4-CH3OPh-;Ph
4-tBuPh-;Ph
2
PhB(OH)2
1
4
NaphtylBr
PhB(OH)2
Naphtyl-;Ph
1
2
2-NH2PhBr
2-CH3PhBr
2-CH3PhBr
2-CH3PhBr
2-CH3PhBr
2,4,6-trimethylphBr
4-CH3OPhBr
4-tBuPhBr
PhB(OH)2
2-NH2Ph-;Ph
1
4
PhB(OH)2
2-CH3Ph-;Ph
1
2
PhB(OH)2
2-CH3Ph-;Ph
0.5
0.1
0.01
1
2
PhB(OH)2
2-CH3Ph-;Ph
2
PhB(OH)2
2-CH3Ph-;Ph
2
PhB(OH)2
2,4,6-trimethylph-;Ph
4-CH3Oph-;20-CH3Ph
4-tBuPh-;20-CH3Ph
4-CH3Ph-;40-ClPh
4-CH3OCPh-;40-ClPh
4-OHCPh-;40-ClPh
24
2
48
98
99
93
98
97
2-CH3PhB(OH)2
2-CH3PhB(OH)2
4-ClPhb(OH)2
4-ClPhB(OH)2
4-ClPhB(OH)2
1
1
2
4-CH3PhBr
4-CH3OCPhBr
4-OHCPhBr
1
2
1
2
1
2
Reaction conditions: ArBr (1.0 mmol), ArB(OH)2 (1.2 mmol), K2CO3 (2.0 mmol), DMF: H2O = 4 ml: 1 ml, under aerobic atmosphere. The molar ratio of
Ligand (1 mol%) and Pd (1 mol%) is 1:1.
aIsolated yield.
bUnder nitrogen atmosphere.
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Appl. Organometal. Chem. 2012, 26, 701–706

Pyridylbenzamidine Suzuki–Miyaura reaction
The reaction conducted with a lower catalytic loading was also
explored. It was shown that the catalytic system was still effec-
tively able to convert substrates such as 4-bromotoluene and
2-bromotoluene into the corresponding product in excellent
yield when the catalyst loading was decreased to 0.5 mol%
(Table 3, runs 8 and 16). It is important to note that a high yield
of 90% was received in the case of 4-bromotoluene as substrate
at 0.1 mol% palladium (Table 3, run 9). In contrast, the cross-
coupling of 2-bromotoluene with phenylboronic acid resulted
in remarkably lower yields (20%) at 0.1 mol% palladium loading,
which suggest that steric demanding substrates require higher
catalytic loading to achieve satisfactory yields. Moreover, very
low activities were investigated when the catalyst was decreased
to 0.01 mol% (Table 3, runs 10 and 18).
Based on the successful couplings of most bromide substrates
with phenylboronic acid, other arylboronic acids such as
2-methylphenylboronic acid and 4-chlorophenylboronic acid were
introduced as coupling partners. Under the effective L6/PdCl2
catalytic system, aryl bromides with electron-donating functional
groups, 4-bromoanisole (Table 3, run 20), together with 1-bromo-
4-tert-butylbenzene (Table 3, run 21), were coupled very successfully
with 2-methylphenylboronic acid in almost quantitative yields.
Moreover, some representative types of aryl bromides also provided
their coupling products with 4-chlorophenylboronic acid in high
yields (Table 3, runs 22–24).
chlorides were tested in the presence of L6 and the results are
listed in Table 4. Temperature and reaction times consumed in
the couplings of the aryl chlorides were much higher and longer,
mainly resulting from the commonly recognized hard activation
of inert aryl chlorides. As depicted, aryl chlorides with electron-
withdrawing groups, such as 4-chloronitrobenzene (Table 4, run
1), 2- and 4-chlorobenzonitriles (Table 4, runs 2 and 4) proceeded
at 110ꢀC to give their products in more than 90% yield in 4–6 h.
Meanwhile, 4-chlorobenzaldehyde also yielded the product in
85% at the same reaction temperature (Table 4, run 6). However,
the analogous activated substrate 2-chloronitrobenzene (Table 4,
run 8) gave a much lower yield of 56%. We carefully checked
the reaction and found that dehalogenation and homocoupling
of 2-chloronitrobenzene occurred during the process and side
products were detected. In addition, the low transformation yield
of 4-chloroacetophenone was mainly due to its dehalogenation
in the reaction (Table 4, run 9, 26% yield).[69,70] Nevertheless,
activated aryl chlorides were much easier to couple with aryl-
boronic acids. For example, 4-chlorobenzaldehyde underwent
coupling with 4-chlorophenylboronic acid, 2-methylphenylboro-
nic acid and 4-methylphenylboronic acid in 89%, 91% and 96%
yield, respectively (Table 4, runs 10–12). Moreover, it is notewor-
thy that 2-chlorobenzonitrile could couple with 4-methylphenyl-
boronic acid to proceed to conversion at 71% yield to provide
an important intermediate of the synthesis of the sartan family,
which is an active ingredient in antihypertensive drugs (Table 4,
run 13). On the other hand, cross-coupling between deactivated
aryl chlorides and arylboronic acids also afforded moderate yields.
For example, the corresponding product of 4-chlorotoluene with
phenylboronic acid was obtained in 52% yield (Table 4, run 14)
while 4-chloroanisole yielded 31% (Table 4, run 15), which might
be ascribed to their obvious low activities of substrate. Moreover,
Inspired by the results derived from the cross-couplings of aryl
bromides with arylboronic acids, we carried out further investiga-
tions on catalytic studies on more challenging aryl chlorides with
arylboronic acids. Aryl chlorides are widely utilized in cross-
coupling reactions owing to their commercial availability but
are notoriously known for difficult activation of the C-;Cl
bond.[67,68] In this study, both activated and deactivated aryl
Table 4. Suzuki–Miyaura cross-coupling reaction of aryl chlorides with phenylboronic acid under aerobic conditions
Run
Ar-;Cl
ArB(OH)2
PhB(OH)2
Product
Pd (mol%)
t (h)
Yield (%)a
1
4-O2NPhCl
2-NCPhCl
4-O2NPh-;Ph
1
1
6
4
95
94
35
92
61
85
67
56
26
89
91
96
71
52
31
2
PhB(OH)2
2-NCPh-;Ph
3
2-NCPhCl
PhB(OH)2
2-NCPh-;Ph
0.5
1
6
4
4-NCPhCl
PhB(OH)2
4-NCPh-;Ph
4
5
4-NCPhCl
PhB(OH)2
4-NCPh-;Ph
0.5
1
6
6
4-OHCPhCl
4-OHCPhCl
2-O2NPhCl
4-CH3OCPhCl
4-OHCPhCl
4-OHCPhCl
4-OHCPhCl
2-NCPhCl
PhB(OH)2
4-OHCPh-;Ph
4-OHCPh-;Ph
2-O2NPh-;Ph
6
7
PhB(OH)2
0.5
1
8
8
PhB(OH)2
6
9
PhB(OH)2
4-CH3OCPh-;Ph
4-OHCPh-;40-ClPh
4-OHCPh-;20-CH3Ph
4-OHCPh-;40-CH3Ph
2-NCPh-;40-CH3Ph
4-CH3-;Ph
1
4
10
11
12
13
14
15
4-ClPhB(OH)2
2-CH3PhB(OH)2
4-CH3PhB(OH)2
4-CH3PhB(OH)2
PhB(OH)2
1
8
1
12
8
1
1
8
4-CH3PhCl
4-CH3OPhCl
1
6
PhB(OH)2
4-CH3-;OPh-;Ph
1
4
Reaction conditions: ArcCl (1.0 mmol), ArB(OH)2 (1.2 mmol), K2CO3 (2.0 mmol), DMF:H2O = 4:1 ml; reaction temperature 110ꢀC, under aerobic
atmosphere. Molar ratio of ligand (1 mol%) to Pd (1 mol%) is 1:1.
aIsolated yield.
Appl. Organometal. Chem. 2012, 26, 701–706
Copyright © 2012 John Wiley & Sons, Ltd.
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Conclusions
A series of pyridylbenzamidine ligands were synthesized and
characterized. The ligands were successfully employed in the pal-
ladium-catalyzed Suzuki–Miyaura reaction. It was shown that the
bulky steric and electron-donating substituents on ligands favored
cross-coupling. In particular, the experimental data shows that the
methyl substituent at the ortho position of the pyridine nitrogen
is facilitated for the cross-coupling reaction. Under optimized
reaction conditions, a significant advance in the efficiency of
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Acknowledgments
The National Natural Science Foundation of China (No. 21004014),
Foundation for Distinguished Young Talents in Higher Education
of Guangdong, China (No. LYM10091) and Key Laboratory of
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Appendix
Crystallographic data for the structural analysis of L3PdCl2 have
been deposited with the Cambridge Crystallographic Data Centre
as CCDC 861946. Copies of this information can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (Fax: +44-1223-336033; e-mail: deposit@ccdc.cam.
ac.uk or http://ccdc.cam.ac.uk), upon request.
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