Pd/Nb2O5: Efficient supported palladium heterogeneous catalyst in the production of key intermediates for the synthesis of 'sartans' via the Suzuki reaction

Article abstract of DOI:10.1016/j.tetlet.2011.12.076

Pd/Nb₂O₅ was prepared, characterized and tested in Suzuki-Miyaura cross-coupling reactions under ligand-free conditions. High yields and selectivities were observed within short reaction times and very low palladium loadings.

Full text of DOI:10.1016/j.tetlet.2011.12.076

Tetrahedron Letters 53 (2012) 1089–1093
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd/Nb2O5: efficient supported palladium heterogeneous catalyst
in the production of key intermediates for the synthesis of ‘sartans’
via the Suzuki reaction
Gizelda O.D. Estrada a, Ana Luiza P. Blanco a, Joaquim F.M. da Silva b, Christian G. Alonso c,
Nádia R.C. Fernandes-Machado c, Lucio Cardozo-Filho c, Rodrigo O.M.A. de Souza a,
Leandro S.M. e Miranda a,
⇑
a Instituto de Química, Universidade Federal do Rio de Janeiro, Avenida Athos da Silveira Ramos 149, CT Bloco A 641, Cidade Universitária, Rio de Janeiro, CEP 21941-909, Brazil
b Instituto de Química, Universidade Federal do Rio de Janeiro, Rua Hélio de Almeida 40, Pólo de Xistoquímica Prof. Claudio Costa Neto, PXQMed, Cidade Universitária, Rio de Janeiro,
CEP 21941-614, Brazil
c Departamento de Engenharia Química, Universidade Estadual de Maringá, Avenida Colombo 5790, Bloco D90, Jardim Universitário, Maringá, Paraná, CEP 87020-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd/Nb2O5 was prepared, characterized and tested in Suzuki–Miyaura cross-coupling reactions under
ligand-free conditions. High yields and selectivities were observed within short reaction times and very
low palladium loadings.
Received 28 November 2011
Revised 17 December 2011
Accepted 19 December 2011
Available online 29 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Heterogeneous palladium catalyst
Solid-supported palladium
Suzuki–Miyaura cross-coupling
Ligand-free
Microwave irradiation
Introduction
tion, a major challenge lies in separating the product from the
expensive catalyst and as a consequence its recovery, leaving the
Transition metal-catalyzed reactions, especially palladium cata-
lyzed cross-coupling reactions, since their development in the 70’s
became a very important protocol with versatile application in
organic synthesis. Among these reactions the Suzuki–Miyaura
reaction is a prominent exponent. It consists of the Pd-catalyzed
reaction between an organoboron reagent and an organic halide
and has, undoubtedly, become the most important approach in
the synthesis of biaryls which can find innumerous applications
in the synthesis of natural products,1 pharmaceutical intermedi-
ates,2 pesticides3 and covalent organic frameworks (COFs).4 The
low toxicity associated with the organoboron compounds, the mild
reaction conditions and the availability and ease of preparation of
the organoboron coupling partner is behind its high acceptance in
the chemical synthetic community.5
large scale production expensive and difficult. As an alternative, solid
supported Pd catalysts have been developed for several cross-cou-
pling reactions, allowing the catalyst’s recovery and recycle and en-
abling the production of palladium free products which avoids the
need to purge the residual transition metal from the final active phar-
maceutical ingredients (API) product.8–12 In this context, heteroge-
neous catalytic systems present advantages to homogeneous
systems since lower levels of residual metals on the final product is
observed and is usually performed in the absence of ligands such as
organic phosphines which make these systems cheaper and greener.
In the scope of the Suzuki–Miyaura cross-coupling reactions,
the reaction involving substituted phenylboronic acids and 2-halo-
benzonitriles is an important transformation in the context of the
synthesis of important API,2 for this scaffold is present in building
blocks of GABA a2/3 agonists and the angiotensin II inhibitors for
the treatment of hypertension known as the ‘Sartan’ family (Fig. 1).
It is worth to emphasize that these ‘Sartan’ family of drugs rep-
resent one of the most important blockbuster drugs for the phar-
maceutical industry.
However most of the procedures found in the literature for these
couplings are performed with Pd complexes or active Pd complexes
generated in situ by adding P and/or N ligands.6,7 Many of these li-
gands are expensive, toxic, and sensitive to air and moisture. In addi-
However some problems are encountered in this palladium cat-
alyzed reactions of halobenzonitriles and phenylboronic acids such
⇑
Corresponding author.
E-mail address: leandrosoter@iq.ufrj.br (L.S.M. e Miranda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.076

1090
G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 1089–1093
R1
CN
α
GABA 2/3 agonists
R2
CN
B(OH)2
R2
CN
F
F
X
R1
R1
N
O
N
HN
N
N
N
O
O
O
N
HN
N
N
CN
O
N
N
O
Cl
HO
Candesartan
Losartan
N
HN
N
N
N
N
N
HN
N
N
N
HN
N
N
N
N
O
COOH
N
N
O
O
Tasorsartan
Irbesartan
Valsartan
Figure 1. ‘Sartan’ family.
as dehalogenation of the nitrile substrate, homocoupling and pro-
todeboration, leading to a decreased yield of the desired prod-
uct.2,13 In addition, it should be noted that hydrolysis of nitriles
may be mediated by metal.14
Herein, we report the development of a new heterogeneous pal-
ladium catalyst, which performed the Suzuki–Miyaura reaction in
high yields, with turnover numbers (TON) up to 105. In addition,
dehalogenation and hydrolysis were not detected. In the present
work, we report this heterogeneous catalyst in the reaction
between 2-bromobenzonitrile (1) and phenylboronic acid (2)/tol-
ylboronic acid MIDA ester (4), where the corresponding product,
40-methyl-biphenyl-3-carbonitrile (5), is used as key intermediate
in the synthesis of ‘Sartan’ family.
A few recent reports showed simple and efficient protocols for
PdCl2-ligandless and additive-free Suzuki–Miyaura cross-coupling
reactions of aryl bromides with arylboronic acids in aqueous sys-
tems at room temperature in short reaction times, affording the
corresponding cross-coupling products in excellent yields.15,16
Although homogeneous palladium catalysts have proven to be
highly efficient, it is difficult to recover them from the reaction
crude, which represents high cost and contamination in the prod-
uct for the pharmaceutical industry.17,18 Therefore, several hetero-
geneous catalysts have been developed to improve alternative
desirables from industrial.19
at room temperature for 18 h. Catalytic precursor was heated at
55 °C at reduced pressure in a rotating evaporator and dried in
an oven at 90 °C/24 h. The real content of impregnated noble metal
(Pd) was determined by X-ray fluorescence analysis (XRF). The XRF
result shows that the Pd real content is similar to the nominal con-
sidered in the preparation method of the catalyst (PN). The palla-
dium real content was determined to be 1.03 (% w/w).
Thermogravimetry and Differential Thermal Analysis (TG/DTA)
were applied to determine possible structural changes as a result
of thermal treatments of raw material and catalytic precursors in
a temperature range between 20 and 1000 °C. TG/DTA curves for
HY-340 sample without treatment are shown in Figure 2. The
observed 20% mass loss between 25 °C and 300 °C is attributed
to the dehydration of HY-340, agreeing with the material chemical
analysis informed by the supplier. The DTA curve shows two peaks,
an exothermic one with maximum at temperature of 97 °C related
to the mass loss observed in the corresponding TG curve, and an
endothermic one with maximum at 556 °C corresponding to the
0.4
100
98
0.3
0.2
0.1
0.0
-0.1
-0.2
96
94
92
90
Results and discussion
Catalyst preparation and characterization
88
86
84
Sample of the niobium pentoxide (referred to as N) was ob-
tained from niobic acid HY-340, after washing with deionized
water followed by drying at 90 °C/72 h and calcination in a furnace
at 500 °C/5 h.
The Pd/Nb2O5 1% (PN) catalyst was prepared by wet impregna-
tion method from alcoholic solution of PdCl2. The corresponding
salt solution was added to wetted Nb2O5 (Nb2O5/deionized H2O ra-
tio equals to 1 g/1.5 cm3), maintaining the mixture under agitation
82
-0.3
80
-0.4
0
100 200 300 400 500 600 700 800 900 1000
Temperature (°C)
Figure 2. Thermal analysis results for HY-340.

G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 1089–1093
1091
structural change from the amorphous phase to the hexagonal
crystalline Nb2O5 phase, in agreement with the diffractograms of
the HY-340 and Nb2O5 samples in Figure 3.
HY-340
Nb2O5
PN
Figure 3 shows TG/DTA curves for the support (Nb2O5) and the
precursor of the PN catalyst, dried at 90 °C/24 h and before calcina-
tion. These materials show similar behavior regarding shape and
intensity and have a total mass loss around 1% each. The DTA
curves of Nb2O5 and PN did not present any thermal transition,
which indicates that the phase transition was complete during
HY-340 calcination and that the material crystallinity is not altered
at the interval of 25 and 1000 °C.
The crystallinity of calcined catalyst (PN), Nb2O5 used as support
and the niobia precursor (HY-340) were evaluated by X-ray diffrac-
tion (XRD), which are presented in Figure 4. The non-crystalline
starting material (HY-340) turns into crystalline niobium pentoxide
hexagonal phase (diffraction peaks from JCPDS card # 28-0317)
after treatment. Catalyst sample did not present diffraction lines
corresponding to the impregnated oxides, which might be related
to the small particles or to amorphous feature of the oxides. In addi-
tion, the XRD profile of the catalyst (ON) does not show change of
crystallinity compared to pure support (Nb2O5).
The measures of specific surface area, pore volume and pore aver-
age diameter were realized by Textural Analysis (BET) from adsorp-
tion/desorption isotherm of N2 at ꢀ196.15 °C with samples
previously submitted to N2 flow and in situ heating at 90 °C (HY-
340) and 200 °C (calcined support and catalyst). The results of tex-
tural analysis of the materials are summarized in Table 1. HY-340
presented type IV isotherm, characteristic of mesoporous solids
with condensation due to narrow, crack-shaped pores while Nb2O5
showed type III isotherm, characteristic of non-porous or macropo-
rous solids. The difference between isotherms of the starting mate-
rial and the catalyst support is due to the phase change during
calcination, in agreement with TG/DTA and XRD analyses.
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
2θ (°)
Figure 4. X-ray diffractograms for starting material, support and catalyst.
Table 1
Textural analysis by N2 adsorption/desorption isotherms at ꢀ196 °C
Catalyst
HY-340
N
PN
Specific surf. area (m2/g)
aExternal surf. area (m2/g)
aMicro-pore surf. area (m2/g)
Pore total volume (cm3/g)
aMicro-pore volume (cm3/g)
Pore average diameter (Å)
187
174
13
0.18
0.004
38
31
31
—
0.09
—
27.8
27.8
—
0.09
—
114
129
a
Calculate by t-method from Boer standard isotherms.
-workers15 employed water—N,N-dimethylformamide (DMF) mix-
ture (1:1), and very recently, Qiu and co-workers16 studied the ef-
fect of aqueous ethanol systems.
To verify the scope of these methodologies using heterogeneous
palladium catalysts, we decided to run a comparative study be-
tween the Pd/Nb2O5 synthesized by our group and the commercial
available palladium catalysts such as Pd/C 10 wt %, Pd/CaCO3
5 wt % and Pd/BaSO4 5 wt %, for the model reaction between 2-bro-
mobenzonitrile (1) and phenylboronic acid (2). The results ob-
tained are summarized in Table 2.20
It can be observed that a slight decrease in the catalyst (PN) spe-
cific surface area as a result of a small increase in the average pore
diameter, however without influence on the total pore volume. It is
noteworthy that the analysis of both, catalyst and support,
revealed type III isotherms (not shown).
Application on Suzuki reactions
Recently, works reported the use of fast and efficient protocols
for PdCl2-catalyzed ligand-free Suzuki–Miyaura reactions in aque-
ous systems at room temperature. For example, Liu and co
As shown in Table 2, the results obtained for the Suzuki–Miya-
ura reaction using supported palladium catalysts in DMF/Water
0.4
0.4
(a)100
(b)100
98
98
0.3
0.3
96
96
0.2
0.2
94
94
0.1
0.1
92
90
88
86
84
82
80
92
90
88
86
84
82
80
0.0
0.0
-0.1
-0.2
-0.3
-0.4
-0.1
-0.2
-0.3
-0.4
0
100 200 300 400 500 600 700 800 900 1000
Temperature (°C)
0
100 200 300 400 500 600 700 800 900 1000
Temperature (°C)
Figure 3. Thermal analysis results for (a) Nb2O5 and (b) PN.

1092
G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 1089–1093
Table 2
Table 3
Optimization of the reaction conditions: investigation of the influence of supported
palladium catalysts, temperature and reaction time
Optimization of the reaction conditions: investigation of the influence of catalyst load,
solvent and reaction time under microwave irradiation
Supported Pd Catalyst
Br
B(OH)2
Br
B(OH)2
Pd/Nb2O5
(4.1
μmol of Pd)
+
+
K2CO3
Solvent
K2CO3
DMF/Water (1:1)
Silicon Carbide Plate
CN
CN
CN
CN
(1)
(2)
(3)
(1)
Entry
(2)
(3)
MW,120 oC
Catalysts
Pd/Nb2O5
Temperature
Reaction time
Conversiona (%)
Entry Catalyst loading Solvent
Time (min) Conversiona (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
rt
rt
120 °C
6 min
72 h
6 min
30 min
60 min
24 h
6 min
72 h
6 min
30 min
60 min
24 h
6 min
72 h
6 min
30 min
60 min
24 h
6 min
72 h
6 min
30 min
60 min
24 h
19
56
79
>99
>99
>99
—
17
59
84
99
>99
—
31
35
54
57
>99
—
1
2
3
5
6
7
8
9
10
11
12
14
10%
10%
10%
5%
DMF
10
20
30
73
78
88
58
57
63
DMF/H2O (1:1)b 10
20
30
Pd/C
rt
rt
120 °C
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
10
20
30
10
20
30
10
20
30
>99
>99
>99 (86%)c
>99
>99
>99
82
Pd/CaCO3
Pd/BaSO4
rt
rt
120 °C
1%
15
16
>99
>99
a
Based on CG–MS analysis; Reaction and conditions: 2-bromobenzonitrile (1,
1.0 mmol); phenylboronic acid (2,1.2 mmol); Pd/Nb2O5 1.03 wt %; K2CO3
(1.2 mmol); solvent (2 mL); Microwave Anton Paar, 120 °C.
rt
rt
120 °C
b
Solvent 4 mL.
11
6
30
40
>99
Isolated yield determined by NMR 1H and 13C.
c
with no detection of side-product, such as homocoupling, debro-
mation and nitrile hydrolysis (Table 3; entry 16). This reaction with
ultra-low loading of catalyst leads to a turnover up to 105.
The next investigation in this study was to compare efficient
catalytic system assisted microwaves between the Pd/Nb2O5 and
the commercial available palladium catalysts, such as Pd/C
10 wt %, Pd/CaCO3 5 wt % and Pd/BaSO4 5 wt % (Table 4). The re-
sults indicated that Pd/Nb2O5 is more efficient than the other het-
erogeneous palladium catalysts in the short reaction times,
affording the desired coupled product in high yield.
a
Based on CG–MS analysis; Reaction and conditions: 2-bromobenzonitrile (1,
0.5 mmol), phenylboronic acid (2, 0.75 mmol), K2CO3 (1.0 mmol), supported palla-
dium catalyst (0.44 mg of Pd), DMF/water (2 mL/2 mL).
(1:1) system at room temperature do not lead to high conversions
of the desired product, and the maximum conversions were
achieved using Pd/Nb2O5 (entries 1 and 2). Notably, the complete
reaction was achieved under heating in 30 min with Pd/Nb2O5 (en-
try 4), and all the reactions carried out at 120 °C in 24 h provided
high conversions (entries 6, 12, 18 and 24).
The protocol reported by Liu and co-workers16 for PdCl2-cata-
lyzed Suzuki reaction between 2-bromobenzonitrile (1) and phen-
ylboronic acid (2) at room temperature in DMF/Water (1:1) gave
the product in 99% yield in 6 min, showing that this cross-coupling
reaction by homogeneous palladium catalysis is more efficient
than by heterogeneous palladium processes under the same reac-
tion conditions. However, the use of homogeneous Pd catalysts in
industry is not preferred.19 This way, the Pd/Nb2O5 catalyst shows
a promising alternative in the application of heterogeneous Pd-cat-
alyzed coupling reactions.
We also decided to perform the Suzuki–Miyaura reaction be-
tween 2-bromobenzonitrile (1) and phenylboronic acid (2) at
120 °C under microwave irradiation. The first microwave-assisted
reaction was conducted in 6 minutes with the same amount of cat-
alyst and reagents previously tested on silica carbide plate, giving
complete conversion (>99%).
Table 4
Influence of palladium catalysts and reaction time under microwave irradiation
Supported Pd catalysts
(1,8 mol of Pd)
Br
B(OH)2
μ
+
K2CO3
Ethanol/Water (1 : 1)
MW, 120 o
CN
CN
(1)
(2)
(3)
C
Entry
Catalysts
Pd/C
Time (min)
Conversion (%)a
1
2
3
4
5
6
7
8
9
10
20
30
10
20
30
10
20
30
10
20
30
74
>99
>99
70
99
>99
59
Pd/CaCO3
Pd/BaSO4
Pd/Nb2O5
To demonstrate the scope of Pd/Nb2O5 catalyst in the Suzuki–
Miyaura coupling reaction under microwave irradiation, low cata-
lyst loadings, binary systems with water, reaction time, and low
stoichiometry considering the economic advantages, were exam-
ined and results obtained are presented in Table 3.
80
>99
>99
>99
>99
10
11
12
As shown in Table 3, excellent performances were observed
with Ethanol/Water mixture in the short reaction times, where
high yield of the cross-coupling product in only 30 min of reaction
with 1.7 ꢁ 10ꢀ7 mol of Pd was achieved with complete selectivity,
a
Based on CG–MS analysis; Reaction and conditions: 2-bromobenzonitrile (1,
1.0 mmol); phenylboronic acid (2, 1.2 mmol); supported palladium catalyst
(0.19 mg of Pd); K2CO3 (1.2 mmol); ethanol/water (2 mL/2 mL); Microwave Anton
Paar, 120 °C.

G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 1089–1093
1093
Table 5
Acknowledgment
Suzuki–Miyaura reaction between 2-bromobenzonitrile (1) and tolylboronic acid
MIDA ester (4)
We thank CAPES, CNPq, FAPERJ and FINEP for financial support.
O
O
N
Supplementary data
B
Br
Pd/Nb2O5
O
+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.076.
K2CO3
O
CN
CN
(1)
(4)
(5)
Ethanol/Water (1:1)
MW 120 o
C
References and notes
Entry
Reaction time (min)
Conversiona (%)
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