Factorial design evaluation of the Suzuki cross-coupling reaction using a magnetically recoverable palladium catalyst

Article abstract of DOI:10.1016/j.tetlet.2017.01.046

A magnetically recoverable catalyst [Fe₃O₄@SiO₂-AEAPTMS-Pd(II)] was prepared, fully characterized and had its catalytic activity evaluated on the Suzuki cross-coupling reaction under microwave irradiation. The reaction conditions for the synthesis of biaryl compounds was optimized in two stages - an initial fractional design 2⁴, in which the parameters reaction time, temperature, solvent and catalyst loading were evaluated, followed by a Doehlert design. The factorial design proved to be a viable approach for obtaining the optimal reaction conditions based on a relatively small number of experiments. Additionally, the biaryl derivatives synthesized by this method were obtained with good to excellent yields (71–96%) and the recovery and reuse of the palladium catalyst was also evaluated.

Full text of DOI:10.1016/j.tetlet.2017.01.046

Accepted Manuscript
Factorial Design Evaluation of the Suzuki Cross-Coupling Reaction Using a
Magnetically Recoverable Palladium Catalyst
Raíza R.G. Guerra, Felipe C.P. Martins, Carolina G.S. Lima, Ricardo H.
Gonçalves, Edson R. Leite, Edenir R. Pereira-Filho, Ricardo S. Schwab
PII:
S0040-4039(17)30066-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.046
TETL 48549
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 November 2016
7 January 2017
13 January 2017
Please cite this article as: Guerra, R.R.G., Martins, F.C.P., Lima, C.G.S., Gonçalves, R.H., Leite, E.R., Pereira-
Filho, E.R., Schwab, R.S., Factorial Design Evaluation of the Suzuki Cross-Coupling Reaction Using a Magnetically
Recoverable Palladium Catalyst, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.046
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Factorial Design Evaluation of the Suzuki Cross- Leave this area blank for abstract info.
Coupling Reaction Using a Magnetically Recoverable
Palladium
Raíza R. G. Guerra, Felipe C. P. Martins, Carolina G. S. Lima, Ricardo H. Gonçalves, Edson R. Leite, Edenir
R. Pereira-Filho, Ricardo S. Schwab*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Factorial Design Evaluation of the Suzuki Cross-Coupling Reaction Using a
Magnetically Recoverable Palladium Catalyst
Raíza R. G. Guerra, Felipe C. P. Martins, Carolina G. S. Lima, Ricardo H. Gonçalves, Edson R. Leite,
Edenir R. Pereira-Filho, Ricardo S. Schwab∗
Centre of Excellence for Research in Sustainable Chemistry (CERSusChem), Departamento de Química, Universidade Federal de São Carlos – UFSCar,
Rodovia Washington Luís, km 235 - SP-310, São Carlos, São Paulo, 13565-905, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A magnetically recoverable catalyst [Fe3O4@SiO2-AEAPTMS-Pd(II)] was prepared, fully
characterized and had its catalytic activity evaluated on the Suzuki cross-coupling reaction under
microwave irradiation. The reaction conditions for the synthesis of biaryl compounds was
optimized in two stages - an initial fractional design 24, in which the parameters reaction time,
temperature, solvent and catalyst loading were evaluated, followed by a Doehlert design. The
factorial design proved to be a viable approach for obtaining the optimal reaction conditions
based on a relatively small number of experiments. Additionally, the biaryl derivatives
synthesized by this method were obtained with good to excellent yields (71 to 96%) and the
recovery and reuse of the palladium catalyst was also evaluated.
Available online
Keywords:
Factorial Design;
Suzuki Cross-Coupling;
Heterogeneous Catalysts;
Magnetic Nanoparticles;
2009 Elsevier Ltd. All rights reserved.
———
∗Corresponding author. Tel.: +55 16 33518081; e-mail: rschwab@ufscar.br (R.S. Schwab)

2
Tetrahedron
1. Introduction
Catalytic reactions play an important key role in organic
synthesis, since they allow the improvement of methods that are
used to prepare highly-valuable organic compounds.1 Following
this lead, several research groups have dedicated their efforts to
develop more environmentally-benign catalysts for a wide range
of organic transformations.2 Literature surveys show that
heterogeneous catalysts take a prominent place in this field,
mainly due to some particular features such as easy recoverability
and reusability.3 In this sense, iron oxide magnetic nanoparticles
(MNPs) have emerged as an important class of materials for the
immobilization of new catalysts owing to their large surface area,
high chemical stability, high saturation magnetization values, and
both low cost and toxicity.4 More importantly, MNPs fill the gap
between homogeneous and heterogeneous catalysis5 in terms of
activity, selectivity and removal from the reaction medium, since
the separation of these types of materials can be easily achieved
by using an external magnetic field. Consequently, the generation
of residue is minimized, thereby contributing to the development
of greener synthetic protocols.6 Magnetite (Fe3O4) is among the
most studied MNPs as supports, mainly due to its super-
paramagnetic properties, biological compatibility7 and a wide
variety of synthetic methods for its preparation which leads to
different morphologies and size distributions.8 The palladium-
catalyzed Suzuki cross-coupling reaction constitutes a very
powerful approach for the formation of new C-C bonds.9 This
methodology is used to synthesize a wide range of products,
namely biaryl moieties, which can be found in a great number of
biologically active compounds, such as valsartan, felbinac and
imatinib, among others.10
Scheme 1. General design of experiments.
The catalyst Fe3O4@SiO2-AEAPTMS-Pd(II) 1 was prepared
following the steps described in Scheme 2. Initially, the
magnetite microspheres were prepared through a solvothermal
method,18 followed by a silica-coating step using the well-known
Stöber
method.19.
Next,
the
amino
ligand
N-[3-
was
(trimethoxysilyl)propyl]ethylenediamine
(AEAPTMS)
anchored onto the surface of Fe3O4@SiO2 in anhydrous toluene
under reflux for 24 h. The obtained Fe3O4@SiO2-AEAPTMS
powder was then treated with palladium acetate in
tetrahydrofuran (THF) under N2 atmosphere, at room temperature
for 5 h, to generate the Fe3O4@SiO2-AEAPTMS-Pd(II) catalyst
1. The catalyst was fully characterized by a variety of analytical
techniques e.g. x-ray diffraction (XRD), transmission electron
microscopy with energy-dispersive x-ray spectroscopy (TEM-
EDX), scanning electron microscopy (SEM), X-ray
photoelectron spectroscopy (XPS), elemental analysis (EA),
inductively coupled plasma optical emission spectrometry (ICP-
OES) and vibrating sample magnetometer (VSM).
Considering that the Suzuki-Miyaura reaction has been widely
applied as an important tool in organic synthesis, there has been a
growing interest in and accordingly the development of greener,
more sustainable approaches to chemistry.11 In this way, several
new magnetically recoverable palladium-based catalysts have
been developed in the last few years and extensively applied in
batch,12 and more recently, in flow processes.13
It is well known that most organic reactions are optimized in a
univariate approach, being performed one variable at a time.
However, according to Leardi,14 “…this approach would be valid
only if the variables to be optimized would be totally independent
from each other”, which is certainly not the case for most
reactions. In this way, it can be assumed that during the
optimization of the reaction conditions, the interaction among the
different factors being evaluated is highly relevant and can
contribute to the obtainment of the best conditions with fewer
experiments. Thus, the optimization in a multivariate approach
enables the development of mathematical models that can be
used to predict the response for any possible setting, even
untested regions. Although the experimental design15 can reduce
the number of reactions, thereby reducing the generation of waste
and increasing the quality of information that can be obtained,
and this approach being already very common in industry, only a
few reports from academic groups on this sort of chemistry have
been disclosed using this tool.16
Scheme 2. Preparation of catalyst Fe3O4@SiO2- AEAPTMS-Pd(II).
We have started our characterization studies by evaluating the
crystalline structure of the Fe3O4 microspheres and the
Fe3O4@SiO2-AEAPTMS-Pd(II) catalyst 1 by X-ray diffraction
(XRD). The high angle X-ray diffraction pattern of Fe3O4
microspheres (black line in Figure S1 in the ESI) showed the
typical peaks of the spinel structure of magnetite (2 = 30.1,
35.4, 43.1, 53.5, 57.0, 62.6), while the diffractogram of the final
catalyst showed an additional broad peak around (2 =23.3),
related to the presence of amorphous silica in the sample. In
addition, no characteristic peaks of the palladium nanoparticles
were observed, which may be a result of the presence of well-
dispersed small particles of the palladium species, or to the
presence of a non-crystalline palladium phase.20 However, the
presence of Pd on the catalyst was confirmed by TEM-EDX (see
Figure S2 in the ESI). Additionally, the exact concentration of Pd
was determined by ICP-OES and the obtained valued was 1.3
wt%.
Bearing these factors in mind, and continuing our ongoing
research into the development of greener methodologies,17 in this
paper we report the synthesis of a novel magnetically recoverable
Fe3O4@SiO2-AEAPTMS-Pd(II) catalyst for the Suzuki cross-
coupling reaction under microwave irradiation via a multivariate
approach using factorial design (Scheme 1).
Aiming to investigate the morphology and size distribution of
both the support and the final catalyst, TEM and SEM analyses
were conducted (see Figure S3 in the ESI). The SEM images
show that the obtained Fe3O4 microspheres (Figure S3a) are
spherically shaped and a detailed statistical particle count

3
4
5
0.6 (+1)
0.06 (-1)
0.6 (+1)
0.06 (-1)
0.6 (+1)
0.06 (-1)
0.6 (+1)
0.06 (-1)
0.6 (+1)
0.06 (-1)
0.6 (+1)
0.06 (-1)
0.6 (+1)
100 (+1)
25 (-1)
30 (-1)
120 (+1)
120 (+1)
120 (+1)
120 (+1)
30 (-1)
H2O (-1)
H2O (-1)
51
0
revealed an average size of 227 28 nm (Figure S3b). The TEM
image of Fe3O4@SiO2 (Figure S3c) confirms the formation of
core/shell-structured magnetic silica microspheres with a shell
thicknesses of approximately 51,4 5,9 nm. As for the final
catalyst, it was possible to notice the presence non-uniformly
distributed Pd nanoparticles, with a mean diameter range
9.03 1,23 nm in the surface of the catalyst (Figure S3e) (See the
ESI for further details).
6
25 (-1)
H2O (-1)
0
7
100 (+1)
100 (+1)
25 (-1)
H2O (-1)
83
69
0
8
H2O (-1)
9
EtOH (+1)
EtOH (+1)
EtOH (+1)
EtOH (+1)
EtOH (+1)
EtOH (+1)
EtOH (+1)
EtOH (+1)
10
11
12
13
14
15
16
25 (-1)
30 (-1)
0
100 (+1)
100 (+1)
25 (-1)
30 (-1)
52
68
0
In addition, the catalyst 1 was also analysed by XPS in order
to determine the oxidation state of the palladium species present
in the material. The XPS elemental survey scans of the surface of
the fresh catalyst 1 (see Figure S4a in the ESI) showed peaks
ascribed to silicon (Si), carbon (C), palladium (Pd), nitrogen (N)
and oxygen (O). A closer look at the Pd3d region reveals the
presence of two peaks at 337.43 (3d5/2) and 342.62 (3d3/2),
attributed to Pd(II), and other two peaks at 335.84 (3d5/2) and
339.97 (3d3/2), assigned to Pd(0). The intensities of the peaks
clearly indicate that the palladium species are present
predominantly in +2 oxidation state (88%) with a lower content
of Pd(0). Then, magnetic properties of the synthesized materials
were evaluated by VSM at room temperature. The magnetization
curves for Fe3O4 and Fe3O4@SiO2-AEAPTMS-Pd(II) are
presented in Figure S5 in the ESI; the values of saturation
magnetization for the Fe3O4 microspheres and the Fe3O4@SiO2-
AEAPTMS-Pd(II) were 29.2 and 7.85 emu/g respectively. The
significant decrease in the saturation magnetization is due to the
formation of the thick silica layer over the surface of the
magnetic microspheres, with its further functionalization with the
organic ligand and the Pd salt. It is worth mentioning that the
magnetic curves show no hysteresis for both two samples,
suggesting that both Fe3O4 and Fe3O4@SiO2-AEAPTMS-Pd(II)
catalyst exhibit superparamagnetic behavior, thus being easily
dispersed and recovered from reaction medium with the aid of a
magnetic field.
30 (-1)
120 (+1)
120 (+1)
120 (+1)
120 (+1)
25 (-1)
5
100 (+1)
100 (+1)
81
81
[a] Unless otherwise specified, all the reactions were performed with phenylboronic acid (1,5 mmol) 2a,
4-iodoanisol (1.0 mmol) 3a, Fe3O4@SiO2-AEAPTMS-Pd(II) 1 and K2CO3 (1.5 mmol) in the presence
of solvent (10 mL) in a 2 necked round bottom flask. (-1 low and +1 high levels). Yields were
[b]
[c]
determined through CG-MS.
These preliminaries experiments, which were performed using a
full factorial design (24), indicated that the most important
variables were temperature, time and their interaction. The other
variables presented negligible effects in the studied range.
Posteriorly, a Doehlert design22 was performed to further study
the variables that showed to exert important effects, as well as
variables that are known to influence the Suzuki Cross-coupling
reaction.
Table 2. Doehlert design results for the optimization of Suzuki cross-
coupling reactions. Coded levels (-1 and +1) are in parenthesis.[a]
Entry
1
Time (min)
6.0 (0)
Base
Power (W)
40 (0)
Yield (%)[b]
KOH (-0.12)
KOH (-0.12)
KOH (-0.12)
KOH (-0.12)
Na2CO3 (1.0)
K2CO3 (0.6)
KOH (-0.12)
Et3N (-1.0)
92
90
94
83
51
88
69
0
2
6.0 (0)
40 (0)
3
6.0 (0)
40 (0)
4
11.0 (1.0)
8.5 (0.5)
8.5 (0.5)
1.0 (-1.0)
3.5 (-0.5)
3.5 (-0.5)
8.5 (0.5)
8.5 (0.5)
8.5 (0.5)
3.5 (-0.5)
6.0 (0)
40 (0)
Having the catalyst fully characterized in hand, we moved to
evaluate its catalytic activity in the Suzuki reaction and study
how different parameters could affect its outcome by using
factorial design. In that way, the reaction between phenyl boronic
acid 2a and 4-iodoanisol 3a was chosen as a model reaction for
the optimization studies (Scheme 3) and a series of experiments
were performed using a multivariate approach.
5
40 (0)
6
70 (0.817)
40 (0)
7
8
40 (0)
9
Cs2CO3 (-0.52)
Et3N (-1.0)
10 (-0.817)
40 (0)
38
2
10
11
12
13
14
15
16
17
Cs2CO3 (-0.52)
Cs2CO3 (-0.52)
Na2CO3 (1.0)
Na3PO4 (0.68)
K2CO3 (0.6)
K3PO4 (-0.84)
Na2CO3 (1.0)
10 (-0.817)
10 (-0.817)
40 (0)
90
87
23
2
10 (-0.817)
70 (0.817)
70 (0.817)
70 (0.817)
Scheme 3. Suzuki cross-coupling reaction between phenyl boronic acid
and 4-iodoanisol.
3.5 (-0.5)
6.0 (0)
90
86
80
11.0 (1.0)
The first stage of the optimization involved an experimental
design, which can be used as a powerful tool for identifying the
most important variables among many others. Based on literature
survey, four experimental factors (solvent, time, temperature and
catalyst loading), were selected for testing (Table 1).21
[a] Unless otherwise specified, all the reactions were performed with phenylboronic acid (1,5 mmol)
2a, 4-iodoanisol (1.0 mmol) 3a, Fe3O4@SiO2-AEAPTMS -Pd(II) (0.06 mol%) 1 and base (1.5 mmol) in
the presence of solvent (1,5 mL) under microwave irradiation. [b] Yields for isolated products.
In this context, microwave irradiation has been pointed in the
last decades as one of the most efficient and sustainable energy
sources, since it allows to reduce the reaction time, to improve
the reaction yields and the product purity, when compared to
experiments involving conventional heating.23 Despite of the
controversy surrounding microwave-induced reactions, they have
been widely used in organic synthesis.24 Therefore, we have
decided to use a microwave reactor in this stage of the study, and
the microwave power was considered a factor, rather than
temperature. Time and type of base were the other evaluated
experimental factors (Table 2). With the factorial design
performed (second stage), 10 coefficients were calculated: b0
(intercept or constant), b1, b2 and b3 (linear coefficients for
Table 1. Full factorial design and results for the optimization of Suzuki cross-
coupling reactions. Coded levels (-1 and +1) are in parenthesis.[a]
Catalyst loading
(mol%)[b]
0.06 (-1)
Yield
(%)[c]
0
Entry
T (oC)
Time
Solvent
1
2
3
25 (-1)
25 (-1)
30 (-1)
30 (-1)
30 (-1)
H2O (-1)
H2O (-1)
H2O (-1)
0.6 (+1)
0
0.06 (-1)
100 (+1)
32

4
Tetrahedron
variables 1, 2 and 3), b11, b22 and 33 (quadratic coefficient for
As may be seen from Figure 1, the factors time and power
variables 1, 2 and 3) and its interactions b12, b13 and b23.
were not significant and, therefore, can be fixed in a more
economic condition (at lower the levels, for instance). With the
optimal conditions in hands, that is, catalyst loading (0.06
mol%), base (KOH) solvent (EtOH), time (6 min.) and
microwave irradiation power (40 W), we have extended the
protocol to a broader range of aryl iodides and boronic acids, in
order to evaluate the scope and limitations of this approach
(Table 3). Initially, a set of reactions was performed with phenyl
boronic acid and different aryl iodides (entries 1–10). In most
cases, excellent yields were achieved. However, it could be
observed that steric effects exerted some influence during the
cross-coupling reactions; substituents attached to the para and
meta-positions of the aryl iodides furnished better yields (Table
3, entries 1 and 5) than the same substituents in the ortho position
(entries 4 and 6). On the other hand, the electron-donating (Table
3, entries 1, 5 and 7) and electron-withdrawing (entries 9 and 10)
nature of the groups attached to the para and meta positions or
the aromatic ring did not exert any influence on the yield.
Additionally, 4-bromoanisol could also be used to generate the
product, albeit with a lower yield when compared with 4-
iodoanisol (entries 3 vs 1). In another set of experiments, we
promoted the coupling changing the boronic acid component and,
once again, the products were formed with high yields (entries
11–18). Moreover, our protocol also allowed the Suzuki cross-
The significance of these coefficients was verified using
analysis of variance (Anova) and only two coefficients were
significant at a 95% of confidence level. The proposed model
was expressed by eqn (1).
……………(1)
As can be observed in this equation, only the quadratic
coefficient for the type of base was significant (b22). A surface
response was generated and the best conditions (for high yields)
were obtained when KOH was used as a base (Figure 1).
coupling of
a heteroaromatic boronic acid, providing the
Figure 1. Response surface plot of the yield vs the two independent factors
corresponding product in excellent yield (entry 17).
time and base.
Table 3. Suzuki cross-coupling reaction catalyzed by Fe3O4@SiO2-APPTS-Pd(II) under microwave irradiation.[a]
Entry
RB(OH)2
R1
Product
Yield (%)[b]
Entry
RB(OH)2
R1
Product
Yield (%)[b]
1
H
4-OMe
94
10
H
4-NO2
96
2[c]
H
H
4-OMe
4-OMe
ND[e]
11
12
4-OMe
2-OMe
H
H
92
92
3[d]
74
4
5
6
H
H
H
2-OMe
3-Me
71
87
80
13
14
15
4-Me
4-COMe
4-NO2
H
H
H
91
93
95
2-Me

5
7
8
H
H
4-NH2
96
95
16
17
3-C
l
H
H
85
95
H
9
H
3-CF3
84
18
H
96
[a] Unless otherwise specified, all the reactions were performed with boronic acid (1.5 mmol) 2a-i, aryl halide (1.0 mmol) 3a-i, Fe3O4@SiO2-AEAPTMS-Pd(II) (0.06 mol%) 1, KOH (1.5 mmol), EtOH (1,5 mL)
[b]
[c]
[d]
[e]
under
microwave
irradiation
(40
W)
for
6
min.
Yields
for
isolated
products.
Without
base.
4-bromoanisol
was
used.
Not
detected
The development of economic and environmentally friendly
methods is one of our prime concerns. These concepts have
prompted us to further improve our protocol and perform an
evaluation of the recyclability of the catalyst. The Suzuki cross-
coupling reaction between phenyl boronic acid 2a and 4-
iodoanisol 3a was chosen as a model for the recycling test. After
the completion of reaction, the catalyst 1 was readily separated
from the reaction mixture employing an external magnet, washed
with water and ethanol and reused for the next cycles. The results
(Figure 2) have indicated that the catalyst can be recycled up to
three cycles with a small drop in the product yield.
3a was carried out in presence of the commercially available 3-
mercaptopropyl-functionalized silica (SiO2-SH) as a selective
palladium scavenger with a molar ratio of scavenger 5:Pd of 33.
In this case, the presence of an excess of SiO2-SH lead to a
complete loss in the catalytic activity, with no product formation
being verifiable by thin layer chromatography (TLC).
MW, 40 W, 6 min
0,06 mol% cat. 1
KOH, EtOH
I
B(OH)2
OMe
+
X
MeO
SiO2
SH
4a
:SH-SBA-15 (1:33): 0 %
3a
2a
5
cat.1
Scheme 4. Solid phase poisoning test
.
Based on this result, we infer that our heterogeneous catalyst
may be acting simply as a reservoir of leached palladium, with
the catalyst becoming soluble during the oxidative addition step
and redeposited on the surface after the reductive elimination
step, similar to the mechanisms described in the previous
reports.11d,25g,27 However, the magnetic nature of the catalyst
significantly improves the recovery of the palladium species from
the reaction medium. This result was confirmed by the ICP-OES
analysis of the reaction medium, which showed no detectable
amount of Pd after the removal of the catalyst.
Figure 2. Recyclability of the prepared catalyst Fe3O4@SiO2-AEAPTMS-
Pd(II) catalyst 1 for the Suzuki cross-coupling reaction of phenyl boronic acid
2a with 4-iodoanisol 3a under MW irradiation.
TEM and XPS analyses were then used to evaluate the
recycled catalyst after the 1st reaction cycle. The TEM images
(see Figure S6 in the ESI) demonstrated that the morphology of
Fe3O4@SiO2-AEAPTMS-Pd(II) did not change after one reaction
cycle when compared to the fresh catalyst. However, it is
noteworthy that the Pd nanoparticles were now randomly
deposited on the silica layer and had both their amount and size
increased (from 9 nm in the fresh catalyst to 30 nm, Figure S6).
This result was also confirmed by XPS (see Figure S7 in the
ESI), since the intensities of the two peaks at 335.12 (3d5/2) and
339.69 (3d3/2) clearly indicated a significant increase in the
content of Pd(0) (36%) after the first cycle. However, most of the
palladium species are still present predominantly in the +2
oxidation state [peaks at 337.79 (3d5/2) and 342.97 (3d3/2), 64%].
2. Conclusions
In summary, we have described the synthesis and
characterization of a novel Fe3O4@SiO2-AEAPTMS-Pd(II). The
optimization of the Suzuki cross-coupling reaction using this
catalyst was conducted through a factorial design; in the first
stage, two factors (temperature and time) and their interaction
were identified using a full factorial design as the most important
variables. During the second stage, the optimal conditions for the
Suzuki cross-coupling were obtained using the Doehlert matrix.
The analysis of the responses obtained in the second stage
showed that the nature of the base strongly influences the yield,
with KOH being the one that afforded the better yield. Other
factors such as time and microwave power were not significant
and were fixed in more economic conditions. The optimized
protocol could be applied to a wide range of substrates, and the
products were obtained with yields ranging from 71 to 96%
under microwave irradiation in only 6 minutes of reaction.
Moreover, owing to its magnetic behavior, the nanocatalyst could
be easily recovered and reused for three times with only a small
loss of its catalytic activity. The use of a scavenger (SH-SBA-15)
allowed us to conclude that the immobilized palladium catalyzed
the reaction in a dissolution and redeposition way.
Several authors have argued that the real active catalytic
species in the Suzuki reaction are resulting from leached
palladium species from the catalyst, that return to the support at
the end of the reaction.25 In this view, the authors have suggested
a (quasi)homogeneous mechanism in which the heterogeneous
catalyst seems to be simply a reservoir of leached palladium. In
this context, different experiments have been applied to answer
this question, including (1) hot-filtration, (2) three-phase and (3)
solid poisoning test. To gain more insights into which type of
catalysis is operating in our reaction system, we performed a
solid phase poisoning test (Scheme 4). Under optimized
conditions and following a previously reported protocol,26 the
cross-coupling between phenyl boronic acid 2a and 4-iodoanisole
Acknowledgments

6
Tetrahedron
Luo, J.; Wei, Y. Catal. Sci. Technol. 2013, 3, 235-243. (e)
Rosario-Amorin, D.; Wang, X.; Gaboyard, M.; Clérac, R.; Nlate,
S.; Heuzé, K. Chem. Eur. J. 2009, 15, 12636-12643. (f) Karimi,
B.; Mansouria, F.; Valib, H. Green Chem. 2014, 16, 2587-2596.
(g) Ghotbinejad, M.; Khosropour, A. R.; Mohammadpoor-Baltork,
I.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. J. Mol.
Catal. A: Chem. 2014, 385, 78-84. (h) Firouzabadi, H.; Iranpoor,
N.; Gholinejad, M.; Akbaria, S.; Jeddi N. RSC Adv. 2014, 4,
17060-17070. (i) Martínez-Olid, F.; Andrés, R.; de Jesús, E.;
Flores, J. C.; Gómez-Sal, P.; Heuzé, K.; Vellutini, L. Dalton
Trans. 2016, 45, 11633-11638.
We gratefully acknowledge the São Paulo Research Foundation
and GlaxoSmithKline FAPESP/GSK (2014/50249-8), FAPESP
(2013/06558-3) and Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq). R. R. G. Garcia and C. G. S.
Lima thank Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (CAPES) for their fellowships. The authors are
also grateful to Analítica and Thermo Scientific for the loan of
ICP-OES.
13. Rehm, T. H.; Bogdan, A.; Hofmann, C.; Lo b, P.; Shifrina, Z. B.;
Morgan, D. G.; Bronstein, L. M. ACS Appl. Mater. Interfaces
2015, 7, 27254- 27261.
14. Leardi, R. Analytica Chimica Acta 2009, 652, 161-172.
15. (a) Lundstedt, T.; Seifert, E.; Abramo, L.; Thelin, B.; Nystrom, A.;
Pettersen, J.; Bergman, R. Chemometr. Intell. Lab. 1998, 42, 3-40.
(b) Teófilo, R. F.; Ferreira, M. M. C. Quim. Nova 2006, 29, 338-
350.
16. (a) Arabi, M.; Ghaedi, M.; Ostovan, A.; Tashkhourian, J.;
Asadallahzadeh, H. Ultrason. Sonochem. 2016, 33, 67-76. (b)
Guervenou, J.; Giamarchi, P.; Coulouarn, C.; Guerda, M.; Le Lez,
C.; Oboyet, T. Chemometr. Intell. Lab. 2002, 63, 81-89. (c)
Carlson, R.; Simonsen, G.; Descomps, A.; Carlson, J. E. Org.
Process Res. Dev. 2012, 16, 1371-1377. (d) Naeimi, H.;
Nejadshafieea, V.; Masoumb, S. RSC Adv. 2015, 5, 15006-15016.
17. (a) Lima, C. G. S.; Silva, S.; Gonçalves, R. H.; Leite, E. R.;
Schwab, R. S.; Corrêa, A. G.; Paixão, M. W. ChemCatChem 2014,
6, 3455-3463. (b) Salman, S. M.; Narayanaperumal, S.; Schwab,
R. S.; Bender, C. R.; Rodrigues, O. E. D.; Dornelles, L. RSC Adv.
2012, 2, 8478-8482. (c) Corrêa, A. G.; Paixão, M. W.; Schwab, R.
S. Curr. Org. Synth. 2015, 12, 675-695.
References and notes
1. (a) Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H.
Adv. Synth. Catal. 2011, 353,1825-1864. (b) Braga, A. L.; Lüdtke,
D. S.; Schneider, P. H.; Andrade, L. H.; Paixão, M. W. Quim.
Nova. 2013, 36, 1591-1599. (c) Grunes, J.; Zhu, J.; Somorjai, G.
A. Chem. Commun. 2003, 2257-2260. (d) Douglas, J. J.; Sevrin,
M. J.; Stephenson, C. R. J. Org. Process Res. Dev. 2016, 20,
1134-1447. (e) Rothenberg G. in Catalysis: Concepts and Green
Applications, 1st ed., Wiley-VCH, Weinheim, 2008. (f) Fürstner,
A. Angew. Chem. Int. Ed. 2014, 53, 8587-8598.
2. (a) Sheldon, R. A. Chem. Commun. 2008, 3352-3365. (b) Cheng,
T.; Zhang, D.; Li, H.; Liu, G.; Green Chem. 2014, 16, 3401-3427.
(c) Ranu, B. C.; Saha, A.; Dey, R. Curr. Opin. Drug Discov.
Devel. 2010, 13, 658-668. (d) Holzwarth, M. S.; Plietker, B.
ChemCatChem 2013, 5, 1650-1679.
3. (a) Copéret, C.; Chabanas, M.; Saint-Arroman, R. P.; Basset, J.-M.
Angew. Chem. Int. Ed. 2003, 42, 156-181. (b) Wang, Z.; Chen, G.;
Ding, K. Chem. Rev. 2009, 109, 322-359. (c) Astruc, D.; Lu, F.;
Aranzaes, J. R. Angew. Chem. Int. Ed. 2005, 44, 7852-7872. (d)
Trindade, A. F.; Gois, P. M. P.; Alfonso, C. A. M. Chem. Rev.
2009, 109, 418-514.
4. (a) Gubin, S. P.; Koksharov, Y. A.; Khomutov, G. B.; Yurkov, G.
Y. Russ. Chem. Rev. 2005, 74, 489-520. (b) Polshettiwar, V.;
Luque, R.; Fihri, A.; Zhu, H.; Bouhrara, M.; Basset, J.-M. Chem.
Rev. 2011, 111, 3036-3075. (c) Wang, D.; Astruc, D. Chem. Rev.
2014, 114, 6949-6985. (d) Baig, R. B. N.; Nadagoudab, M. N.;
Varma, R. S. Coord. Chem. Rev. 2015, 287, 137-156. (e) Lim, C.
W.; Lee, I. S. Nano Today, 2010, 5, 412-434. (f) Mrówczyński,
R.; Nan, A.; Liebscher, J. RSC Adv. 2014, 4, 5927-5952.
18. Sun, J.; Yu, G.; Liu, L.; Li, Z.; Kan, Q.; Huo, Q.; Guan, J. Catal.
Sci. Technol. 2014, 4, 1246-1252.
19. Li, W.; Deng, Y.; Wu, Z.; Qian, X.; Yang, J.; Wang, Y.; Gu, D.;
Zhang, F.; Tu, B.; Zhao, D. J. Am. Chem. Soc. 2011, 133, 15830-
15833.
20. Li, P.; Wang, L.; Zhang, L.; Wang, G.-W. Adv. Synth. Catal.
2012, 354, 1307-1318.
21. (a) Zhang, L.; Wang, L.; Li, H.; Li, P. Synth. Commun. 2008, 38
1498-1511. (b) Zhang, Q.; Su, H.; Luo, J.; Wei, Y. Catal. Sci.
Technol. 2013, 3, 235-243. (c) Le. X.; Dong, Z.; Jin, Z.; Wang, Q.;
Ma, J. Catal. Commun. 2014, 53, 47-52.
22. Ferreira, S. L. C.; dos Santos, W. N. L.; Quintella, C. M.; Neto, B.
B.; Bosque-Sendra, J. M.; Talanta 2004, 63, 1061-1067.
23. (a) Baig, R. B.; Varma, R. S. Chem. Soc. Rev. 2012, 41, 1559-
1584. (b) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250-
6284.
24. (a) Gawande, M. B.; Shelke, S. N.; Radek, Z.; Varma, R. S. Acc.
Chem. Rev. 2014, 47, 1338-1348. (b) Rathia, A. K.; Gawande, M.
B.; Zboril, R.; Varma, R. S. Coord. Chem. Rev.2015, 291, 68-94.
(c) Horikoshi, S.; Serpone, N. Catal. Sci. Technol. 2014, 4, 1197-
1210. (d) Kappe, C.O.; Pieber, B.; Dallinger, D. Angew. Chem.
Int. Ed. 2013, 52, 1088-1094. (e) Dudley, G. B.; Stiegman, A. E.;
Rosana, M. R. Angew. Chem. Int. Ed. 2013, 52, 7918-7923.
25. (a) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285-
3288. (b) Vries, J. G. Dalton Trans. 2006, 421-429. (c) Zhao, F.;
Bhanage, B. M.; Shirai, M.; Arai, M. Chem. Eur. J. 2000, 6 843-
848. (d) Bhanage, B. M.; Shirai, M.; Arai, M. J. Mol. Catal. A:
Chem. 1999, 145, 69-74. (e) Reetz, M. T.; Westermann, E. Angew.
Chem. Int. Ed. 2000, 39, 165-168. (f) Reetz, M. T.; Helbig, W.;
Quasier, S. A.; Stimming, U.; Breuer, N.; Vogel, R. Science 1995,
267, 367-369. (g) Thathagar, M. B.; Ten Elshof, J. E.; Rothenberg,
G. Angew. Chem. Int. Ed. 2006, 45, 2886-2890. (h) Gaikwad, A.
V.; Holuigue, A.; Thathagar, M. B.; ten Elhof, J. E.; Rothenberg,
G. Chem. Eur. J. 2007, 13, 6908-6913.
5. (a) Shylesh, S.; Schünemann, V.; Thiel, W. R. Angew. Chem. Int.
Ed. 2010, 49, 3428-3459. (b) Schätz, A.; Reiser, O.; Stark, J.
Chem. Eur. J. 2010, 16, 8950-8967.
6. (a) Baig R. B. N.; Varma, R. S. Chem. Commun. 2013, 49, 752-
770. (b) Rossi, L. M.; Costa, N. J. S.; Silva, F. P.; Wojcieszak, R.
Green Chem. 2014, 16, 2906-2933. (c) Wang, D.; Deraedt, C.;
Ruiz, J.; Astruc, D. Acc. Chem. Res. 2015, 48, 1871-1880.
7. (a) Hao, B. R.; Xing, R.; Xu, Z.; Hao, Y.; Gao, S.; Sun, S. Adv.
Mater. 2010, 22, 2729-2742. (b) Baeza, A.; Guillena, G.; Ramón,
D. J. ChemCatChem 2016, 8, 49-67. (c) Sharma, R. K.; Dutta, S.;
Sharma, S.; Zboril, R.; Varma, R. S.; Gawande, M. B. Green.
Chem. 2016, 18, 3184-3209.
8. (a) Faraji, M.; Yamini, Y.; Rezaee, M.; J. Iran. Chem. Soc. 2010,
7, 1-37. (b) Rossi, L. M.; Garcia, M. A. S.; Vono, L. L. R. J. Braz.
Chem. Soc. 2012, 23, 1959-1971. (c) Laurent, S.; Forge, D.; Port,
M.; Roch, A.; Robic, C.; Elst, L. V.; Muller, R. N. Chem. Rev.
2008, 108, 2064-2110.
9. (a) Maluenda, I.; Navarro, O. Molecules, 2015, 20, 7528-7557. (b)
Polshettiwar, V.; Decottignies, A.; Len, C.; Fihri, A.;
ChemSusChem 2010, 3, 502-522. (c) Molnár, A. Chem. Rev. 2011,
111, 2251-2320.
10. Sun, J.; Yu, G.; Liu, L.; Li, Z.; Kan, Q.; Huo, Q. J. Guan, Catal.
Sci. Technol. 2014, 4, 1246-1252.
11. (a) Karimi, B.; Mansouri, F.; Mirzaei, H. M.; ChemCatChem
2015, 7, 1736-1789. (b) S. Paul, Islam, Md. M.; Islam, Sk. M.
RSC Adv. 5 (2015) 42193-42221. (c) Phan, N. T. S.; Sluys, M. V.
D.; Jones, C. W. Adv. Synth. Catal. 2006, 348, 609-679. (d)
Pagliaro, M.; Pandarus, V.; Ciriminna, R.; Béland, F.; Carà, P. D.
ChemCatChem 2012, 4, 432-445. (e) Cantillo, D.; Kappe, C. O.;
ChemCatChem, 2014, 6, 3286-3305. (f) Opanasenko, M.;
Štěpnička, P.; Čejka, J. RSC Adv. 2014, 4, 65137-65162. (g) Das,
P.; Linert, W. Coord. Chem. Rev. 2016, 316, 1-20. (h) Oger, N.;
Felpin, F.-X. ChemCatChem 2016, 8, 1998-2009.
12. (a) Shylesh, S.; Wang, L.; Thiel, W. R. Adv. Synth. Catal. 2010,
352, 425-432. (b) Jin M.-J.; Lee, D.-H. Angew. Chem. Int. Ed.
2010, 49, 1119-1122. (c) Li, W.; Zhang, B.; Li, X.; Zhang, H.;
Zhang, Q. Appl. Catal. A 2013, 459, 65-72. (d) Zhang, Q.; Su, H.;
26. Veise, H.; Hamelian, M.; Hemmati, S. J. Mol. Catal. A: Chem.
2014, 395, 25-33.
27. (a) Chen, J.-S.; Vasiliev, A. N.; Panarello, A. P.; Khinast, J. G.;
Appl. Catal. A 2007, 325, 76-86. (b) Richardson, J. M.; Jones, C.
W.; J. Catal. 2007, 251, 80-93. (c) Gómez-Martínez, M.;
Buxaderas, E.; Pastor, I. M.; Alonso, D. A.; J. Mol. Catal. A:
Chem. 2015, 404-405, 1-7. (d) Dubey, A. V.; Kumar, A. V. RSC
Adv. 2016, 6, 46864-46870.

7
Supplementary Material
Electronic Supplementary Information (ESI) available can be
found, in the online version, at XXX.

8
Tetrahedron
Highlights:
•
•
•
•
A magnetically recoverable Pd(II) catalyst was
prepared and fully characterized.
The reaction conditions were optimized
through a Factorial Design.
The products were obtained with yields ranging
from 71 to 96%.
The catalyst was easily recovered and reused
for three times.