Salicylaldehyde-stabilized palladium nanoparticles for highly efficient suzuki-miyaura reaction at room temperature

Article abstract of DOI:10.1246/cl.190051

Pd-catalyzed Suzuki-Miyaura cross-coupling reactions promoted by simple and commercial salicylaldehyde-based ligands were investigated. The effect of the ligands was evaluated and the reaction conditions were optimized. Moreover, the physical nature of the palladium was determined by TEM analysis and poison tests. It demonstrated that this catalytic system can be reused for ten consecutive runs and showed excellent activities toward aryl bromides with arylboronic acids at room temperature in air.

Full text of DOI:10.1246/cl.190051

Advance Publication Cover Page
Salicylaldehyde-Stabilized Palladium Nanoparticles for Highly Efficient Suzuki-Miyaura
Reaction at Room Temperature
Zhen Zhou,* Gao Cao, and Ning Liu
Advance Publication on the web April 17, 2019
doi:10.1246/cl.190051
©
2019 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the
Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance
Publication manuscripts.

1
Salicylaldehyde-Stabilized Palladium Nanoparticles for Highly Efficient Suzuki-Miyaura Reaction
at Room Temperature
1
,2
1,2
1,2
Zhen Zhou,* Gao Cao, and Ning Liu
1
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, Guangdong 528458, China
2
Guangdong Cosmetics Engineering & Technology Research Center, Zhongshan, Guangdong 528458, China
E-mail: zhouzhen@gdpu.edu.cn
1
2
3
4
5
6
7
8
9
0
Pd-catalyzed Suzuki-Miyaura cross-coupling reactions
promoted by simple and commercial salicylaldehyde-based
ligands were investigated. The effect of the ligands was
evaluated and the reaction conditions were optimized.
Moreover, the physical nature of the palladium was
determined by TEM analysis and poison tests. It
demonstrated that this catalytic system can be reused for ten
consecutive runs and showed excellent activities toward the
aryl bromides with arylboronic acids at room temperature in
air.
1
50 Scheme 1. Salicylaldehyde and its different derivatives as ligand for
5
1
Suzuki-Miyaura reaction.
1
1
1
2
Keywords: Salicylaldehydes, Suzuki-Miyaura reaction,
Pd nanoparticles
52
Keep this in mind, we were interested in developing
catalytic system that could perform the Suzuki-Miyaura
cross-coupling at ambient temperature in air. The key to the
success was the generation of catalytic Pd(0) species
quickly under mild reactions, which required a weak
5
5
5
5
3
4
5
6
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
The Pd-catalyzed Suzuki-Miyaura cross-coupling
reaction has been received considerable attention in the
construction of biaryls, which are common motifs found in
1
,2
57 coordinated environment around the palladium. On the
natural products, pharmaceuticals and materials. Generally,
the ligands and precatalysts played significant influence on
the catalytic efficiency and selectivity in the homogeneous
5
5
8
9
contrary, a steric bulk ligand is essential to stabilize the Pd(0)
intermediate. Moreover, the electronic nature of the ligand
1
,2
60 would directly influence the oxidative addition and the
reaction. Over the past decades, the development of well-
defined palladium complexes with sterically demanding and
strong σ-donor ligands, such as phosphine and N-
heterocyclic carbenes (NHCs), have been well established
as the most powerful choice in Pd-catalyzed cross-coupling
6
6
6
6
1
2
3
4
reductive elimination processes. With these factors in mind,
we envisioned that the weak coordinated oxygen-based
salicylaldehydes (Scheme 1) could allow a new modular and
systematic way to tune the steric as well as electronic effect
1
,2
65 onto the Pd NPs. Moreover, salicylaldehydes behave several
reactions.
6
6
6
7
advantages such as commercial availability and
inexpensiveness for applications. Herein, we report
On the other hand, the involvement of Pd nanoparticles
(NPs) has emerged as an alternative strategy in Suzuki-
3
68 salicylaldehydes/PdCl
2
catalytic systems for the synthesis of
Miyaura cross-coupling reaction over the past few years.
6
7
7
7
9
0
1
2
biaryls under mild reaction conditions.
Compared with homogenous catalysis with conventional
palladium complexes, the physical properties of the
nanoscale dimension of palladium particles exhibited
intrinsically large surface area, and allowed for highly
Initially, we have studied the efficiency of
salicylaldehyde and its derivatives (Scheme 1, L1–5) in
Suzuki-Miyaura reaction using 4-bromochlorobenzene (1.0
3
73 mmol) and phenylboronic acid (1.2 mmol) as model
accessible surface-bound catalytic sites. Nevertheless, the
7
7
7
7
7
7
4
5
6
7
8
9
substrates. The reaction was carried out in the cosolvent of
Pd NPs tend to be aggregated with the loss of catalytic
activities due to their high surface energy. To prevent the
generation of palladium black, the development of ligands
for their excellent stabilization of the Pd NPs, has
dramatically increased the efficiency of the cross-coupling
reactons. As consequence, a variety of ligands, such as
ethanol and water (10:1; 6 mL) utilizing K CO as base at
2
3
room temperature in air. As illustrated in Table 1, all these
five catalytic systems showed the almost quantitative yields
in the presence of 0.01 mol% of PdCl (Table 1, entries 1–5).
2
Subsequently, we chose 4-bromotoluene as a less reactive
4
5,6
6,7
8,9
80 substrate instead. As summarized in Table 1 (entries 7–11),
amines, thiols,
palladacycles,
ionic liquids, and
1
0,11,12
81 the steric and electronic ability of the ligands exhibited
bidentate NHCs
have been developed. Despite the
8
8
2
3
profound effect on the catalytic efficiency under the same
reaction conditions. Among the salicylaldehyde ligands
impressive recent improvements in this topic, the cross-
coupling still suffers from some shortcomings, such as high
o
84 evaluated, the electron rich and bulky 3,5-di-tert-butyl-
reaction temperature (80–140 C), or relative high palladium
8
8
5
6
salicylaldehyde (L3) gave the best result (73%, Table 1;
entry 9). However, the presence of electron withdrawing
loading (0.5–2.5 mol%). The reaction took place at room
temperature at a low palladium (0.01 mol%) generally led to
8
,11,13
87 group (–Cl) at ortho and para position of the salicylaldehyde
low reactivity even no conversion.
Furthermore,
8
8
9
9
8
9
0
1
significantly diminished the yields of the cross coupling
products (Table 1, entries 10–11). The super efficient
catalytic systems in this study highlighted that the weak
O,O-based ligand would led to a rapid formation of low-
multiple synthetic steps were necessary for the accessible of
the desired ligands, which limited their large scale
application.

2
1
2
3
4
5
6
7
valent active intermediate. These observation also implied
that the sterically bulky ligands is indispensible, which
might enable the stabilization of the Pd(0) species and favor
24 of the inorganic base, which subsequently accelerated the
25 transmetalation of the catalytic process.
26 With the preliminary results in hand, the effect of base
27 was then explored since the nature of base played significant
28 role on the transmetalation. The results evidently showed
29 that base is essential for the coupling reactions since no
30 coupling product was obtained in the absence of base
31 (Table1, entry 33). Optimization of the base for the reaction
1
5
1
2,14
the reductive elimination.
In comparison, much lower
yields were observed in the absence of ligand, which further
demonstrated the stabilization of the palladium center by
oxygen-based ligand (Table 1, entries 6 & 12).
a
8
Table 1. Optimization of the Suzuki-Miyaura cross-coupling reaction.
3
3
3
3
3
2
3
4
5
6
was evaluated by using K CO , Na CO , NaHCO3,
2 3 2 3
CH COONa, NaOH, KOH and NEt . It was found that
3
3
K CO was the best choice for this system (Table1, entry
2
3
17). Thus, a general condition consisting of 0.01 mol%
PdCl , L3 as ligand, and K CO as base was established for
2
2
3
Yield
37 Suzuki-Miyaura cross-coupling in ethanol/water at room
Entry Ligand
R
Solvent
Base
(%)
3
8
temperature under aerobic condition.
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
-
L1
L2
L3
L4
L5
-
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
Cl
Cl
Cl
Cl
Cl
Cl
EtOH/H
2
2
2
2
2
2
2
2
2
2
2
2
2
O (10:1)
K
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
99
99
99
85
99
62
65
71
73
52
68
44
20
18
19
82
89
74
54
38
Trace
—
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (10:1)
O (1:10)
39 Table 2.
Suzuki-Miyaura cross-coupling reaction of various aryl
a
40 bromides with phenylboronic acid.
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
2
2
2
2
2
O (1:5)
O (1:3)
O (1:1)
O (3:1)
O (5:1)
EtOH
MeOH
H
2
O
EtOAc
DMF
THF
DMA
DCM
K
2
K
2
K
2
K
2
—
—
—
Trace
33
16
12
85
35
12
—
EtOH/H
2
2
2
2
2
2
2
O (3:1)
Na
NaHCO
CH COONa
2 3
CO
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
EtOH/H
O (3:1)
O (3:1)
O (3:1)
O (3:1)
O (3:1)
O (3:1)
3
3
NaOH
KOH
NEt
3
—
a
9
0
1
2
Reaction conditions: aryl bromides (1 mmol), phenylboronic acid (1.2
1
1
1
mmol), base (2.0 mmol), solvent (6 ml); under aerobic atmosphere at
room temperature for 2 h. The molar ratio of ligand (0.01 mol%) and
a
4
4
4
1
2
3
Reaction conditions: aryl bromides (1 mmol), phenylboronic acid (1.2
CO (2.0 mmol), EtOH:H O (6 ml, 3:1); under aerobic
atmosphere at room temperature for 2 h. The molar ratio of L3 (0.01
PdCl
2
(0.01 mol%) is 1:1. Isolated yields.
mmol), K
2
3
2
1
1
1
1
1
1
1
2
2
2
2
3
4
5
6
7
8
9
0
1
2
3
Encouraged by these results, we ran further
44 mol%) and PdCl (0.01 mol%) is 1:1. Isolated yields.
2
optimization of the reaction conditions in the presence of
L3/PdCl . The reaction was screened under different
2
45
Under the optimized conditions established, the scopes
solvents using K CO as base at room temperature for 2 h
2
3
46 and limitations of Suzuki-Miyaura cross-coupling were
(Table 1; entries 9 & 13–26). It was found that the polar
protic solvents such as methanol and ethanol gave the
coupling product in good yields while the pure water
resulted in trace mount of product (Table 1; entries 19–21).
To our pleasure, using ethanol and water as co-solvent
4
4
4
5
5
7
8
9
0
1
investigated. As list in Table 2 & 3, the catalytic system in
this study exhibited that the catalyst system was very
efficient for the cross-coupling reaction of a wide range of
aryl bromides and different substituted phenylboronic acids.
Various substituted aryl bromides, bearing either
(EtOH:H O, 3:1) led to the highest yield of 89% (Table 1,
2
52 electron-deficient groups or electron-rich groups, such as –
entry 17). Probably, the water would promote the solubility
5
3
CN, –NO , –CHO, –COCH , –Cl, –F, –CF , –CH , –OCH ,
2
3
3
3
3

3
1
2
3
4
were compatible and provided the corresponding products in
moderate to excellent yields. Generally, it was observed that
aryl bromides with electron withdrawing donating groups
were more efficient than that of electron donating groups.
17 on cross-coupling transformation, giving the biaryls in
18 satisfactory yields (Table 2, entries 3ae vs 3af, 3al vs 3am,
19 3an vs 3ao). Nevertheless, when the heteroaryl bromide of
20 3-pyridyl bromide was used as substrate, it gave much
2
1
inferior yields of 3aj & 4bj in the yield of 16% & 37%
5
6
Table 3.
Suzuki-Miyaura cross-coupling reaction of various aryl
a
22 (Table 2 & 3), respectively. Probably, the nitrogen atom on
bromides with different arylboronic acids.
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
heteroaryl might poison the catalytic center, and make this
catalytic procedure less favorable.
To further expand the scope and applicability of this
reaction, we continued to investigate the effect of
substitution on arylboronic acids. As can be seen in Table 3,
it revealed that 4-methylphenylboronic acid underwent
reaction smoothly with kinds of activating and deactivating
substituted aryl bromides (Table3, entries 4bb – 4bp). To
our delight, the coupling reaction of 2-tolylboronic acid also
gave satisfied yields (Table3, entries 4ca – 4cp), which
demonstrated that the hemilabile ligand would allow a
flexible environment and subsequently promote the
transmetalation process when sterically arylboronic acid
1
2,14
involvement.
Moreover, the reactions with less
nucleophilic of 4-chlorophenylboronic acid underwent
smoothly when the reaction was conducted at room
temperature (Table 3, entries 4db – 4dp).
4
4
4
0
1
2
Figure 1. Comparison of the kinetics of this catalytic system in the
Suzuki-Miyaura cross-coupling reaction with and without added
triphenylphosphine/mercury.
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
To gain more information, kinetic experiments were
then investigated under the standard reaction conditions. As
can be seen in the kinetic profile, it is highlighted a rapid
initiation process occurred, and a high GC yield of 64% was
achieved at the beginning of the first 2 minutes. To probe
the physical nature of palladium involvement the reaction,
some poison tests were conducted. It is well-known that
triphenylphosphine as well as mercury could bind strongly
to heterogenous metal centres, thereby blocking access of
10,11,16
the substrate to the active site.
Thus, the PPh and Hg
a
3
7
8
9
0
Reaction conditions: aryl bromides (1 mmol), arylboronic acids (1.2
poisoning test were performed on representative reactions of
4-bromochlorobenzene (1.0 mmol) and phenylboronic acid
(1.2 mmol) under the optimized reaction conditions. As
shown in Figure 1, the reaction was thoroughly shut down
mmol), K
atmosphere at room temperature for 2 h. The molar ratio of L3 (0.01
mol%) and PdCl (0.01 mol%) is 1:1. Isolated yields.
2 3 2
CO (2.0 mmol), EtOH:H O (6 ml, 3:1); under aerobic
1
2
when 1 equiv (relative to Pd) PPh was added. Besides, the
3
1
1
1
1
1
1
1
2
3
4
5
6
For instance, the 4-bromobenzaldehyde and 4-
bromochlorobenzene afford nearly quantitative yields
(Table 2, entries 3ac & 3ae). Comparably, the substrates
with methyl or methoxy groups resulted in moderate yields
(Table 2, entries 3al – 3ao). Moreover, the substitutions on
para- and meta- position on showed measurable influence
Hg poisoning test was also positive (ca. 10% yield was
obtained). In contrast, the kinetics of this catalytic system in
Suzuki cross-coupling without added PPh or Hg indicates
3
that the reaction yield up to 90% within 30 min. These tests
suggest the involvement of a heterogeneous catalytic
process.

4
3
3
3
4
4
4
4
4
4
7
8
9
0
1
2
3
4
5
conditions, the present catalytic system demonstrated
excellent catalytic activity with very low palladium loading
of 0.01 mol% at room temperature in air. Moreover, the
TEM analysis and poison tests revealed the heterogenous
nature of the palladium species. The catalytic system was
recycled up to ten times with small decrease in its activity.
This study highlighted that the bulk weak ligands played
significant role on the stabilization of the palladium NPs
generated in-situ, and rapid initiated the transformation.
1
46
This work was supported by the Programs of GDPU
4
7 (No. 2017KQNCX110, 2014KQNCX144) and Program of
2
3
Figure 2. TEM micrograph and size distribution of in-situ generated
Pd NPs during Suzuki-Miyaura cross-coupling.
48 TCMBGP (No. 20191196)
4
5
9
0
Supporting
http://dx.doi.org/10.1246/cl.******.
Information
is
available
on
4
5
6
7
8
9
0
1
2
3
4
5
In this circumstance, we considered that Pd(0) NPs are
formed from PdCl in the presence of L3, wherein L3 acts as
2
both ligand and stabilizer. In order to further clarify the real
catalytic species in Suzuki cross-coupling reaction,
transmission electron microscope (TEM) was used for the
analysis of the distribution and size of Pd NPs. As illustrated
in Figure 2, the TEM analysis indicated that nano-Pd
particles were generated as dark spherical dots and
dispersed well with an average particle sized around of 3–7
nm. These results demonstrated that the in-situ formed Pd
NPs are supposed to be the key catalytic species in this
catalytic system.
51 References and Notes
5
2
3
1
G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem.
Rev. 2011, 32, 563.
5
54
2
a) D. Roy, Y. Uozumi, Adv. Synth. Catal. 2017, 360, 602. b) J. S.
Ouyang, Y. F. Li, F. D. Huang, D. D. Lu, F. S. Liu,
ChemCatChem 2018, 10, 371. c) T. Hoshi, Y. Shishido, A.
Suzuki, Y. Sasaki, H. Hagiwara, T. Suzuki, Chem. Lett. 2018, 47,
780.
a) J. D. Scholten, B. C. Leal, J. Dupont, ACS Catal. 2012, 2, 184.
b) B. Karimi, F. Mansouri, H. M. Mirzaei, ChemCatChem 2015,
7, 1736. c) N. Oger, F. X. Filpin, ChemCatChem 2016, 8, 1998.
a) E. Ramirez, S. Jansat, K. Philippot, P. Lecante, M. Gomez, A.
M. Masdeu-Bulto´, B. Chaudret, J. Org. Chem. 2004, 689, 4601.
b) R. Bhaskar, H. Joshi, A. K. Sharma, A. K. Singh, ACS Appl.
Mater. Interfaces 2017, 9, 2223.
a) P. Singh, A. K. Singh, Dalton Trans. 2017, 46, 10037. b) R.
Bhaskar, A. K. Sharma, M. K. Yadav, A. K. Singh, Dalton Trans.
2017, 46, 15235.
M. P. Singh, F. Saleem, R. S. Pal, A. K. Singh, New J. Chem.
2017, 41, 11342.
5
5
5
5
5
5
6
7
8
9
1
1
1
1
1
1
3
4
60
6
6
6
6
6
6
6
6
6
7
7
7
7
7
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
V. Sable, K. Maindan, A. R. Kapdi, P. S. Shejwalkar, K. Hara,
ACS Omega 2017, 2, 204.
V. Calo`, A. Nacci, A. Monopoli, F. Montingelli, J. Org. Chem.
2005, 70, 6040.
1
1
6
7
Figure 3. Recycling of L3/Pd in Suzuki-Miyaura cross-coupling tested
under optimum conditions.
75
J. Xu, X. Zhai, X. Wu, Y. J. Zhang, Tetrahedron 2015, 71, 1712.
76 10 E. C. Keske, O. V. Zenkina, R. Wang, C. M. Crudden,
7
7
7
8
7
8
9
0
Organometallics 2012, 31, 6215.
M. Charbonneau, G. Addoumieh, P. Oguadinma, A. R.
Schmitzer, Organometallics 2014, 33, 6544.
a) J. B. Ernst, C. Schwermann, G. Yokota, M. Tada, S.
Muratsugu, N. L. Doltsinis, F. Glorius, J. Am. Chem. Soc. 2017,
139, 9144. b) J. M. Asensio, S. Tricard, Y. Coppel, R. Andrés, B.
Chaudret, E. Jesús, Chem. Eur. J. 2017, 23, 13435. c) A. V.
Astakhov, O. V. Khazipov, A. Y. Chernenko, D. V. Pasyukov, A.
S. Kashin, E. G. Gordeev, V. N. Khrustalev, V. M. Chernyshev,
V. P. Ananikov, Organometallics 2017, 36, 1981.
11
12
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
Encouraged by the highly efficient catalytic system
depicted in Table 2 & 3, we further explore its ability to
perform as a recyclable catalyst for potential industrial
applications. For this purpose, the recyclability potential of
L3 stabilized Pd NPs after Suzuki coupling cycle was
checked under optimized conditions. A fresh lot of 4-
81
8
8
8
8
2
3
4
5
bromochlorobenzene, phenylboronic acid and K CO were
2
3
86
added to the reaction vessel after completion of a coupling
reaction cycle. The respective yields after each run are
depicted in Figure 3. Yields of this study by GC indicated
that the catalytic system recycled for 10 consecutive runs
with only 24% decrease in activity. The TEM image of
reused catalyst after the fifth run (ESI, Figure S2) indicates
well dispersibility of Pd NPs without detectable size
increase. These results imply the distinct advantage of this
catalytic system in its good stability and reusability.
87 13 Z. Du, W. Zhou, F. Wang, J. X. Wang, Tetrahedron 2011, 67,
8
8
9
9
9
8
9
0
1
2
4914.
14
a) A. Rühling, K. Schaepe, L. Rakers, B. Vonhören, P. Tegeder,
B. J. Ravoo, F. Glorius, Angew. Chem. Int. Ed. 2016, 55, 5856. b)
A. Ferry, K. Schaepe, P. Tegeder, C. Richter, K. M. Chepiga, B.
J. Ravoo, F. Glorius, ACS Catal. 2015, 5, 5414.
93 15 a) D. D. Lu, X. X. He, F. S. Liu, J. Org. Chem. 2017, 82, 10898.
9
9
9
9
9
4
5
6
7
8
b) M. Beygzadeh, A. Alizadeh, M. M. Khodaei, D. Kordestani,
Catal. Commun. 2013, 32, 86. c) G. Sarmah,; U. Bora,
Tetrahedron Lett. 2015, 56, 2906.
a) S. Tarnowicz, W. Alsalahi, E. Mieczyńska, A. M. Trzeciak,
Tetrahedron 2017, 73, 5605. b) P. Wójcik, L. Sygellou, A.
Gniewek, A. Skarżyńska, A. M. Trzeciak, ChemCatChem 2017,
9, 4397.
16
In summary, a simple and efficient Suzuki-Miyaura
cross-coupling reaction promoted by salicylaldehyde/PdCl2
99
has been developed. Under the optimized reaction 100