An efficient microwave-assisted suzuki reaction using a new pyridine-pyrazole/Pd(II) species as catalyst in aqueous media

Article abstract of DOI:10.3390/molecules18021602

A new pyridine-pyrazole N-N ligand has been conveniently synthesized and characterized by ¹H-, ¹³C-NMR, IR spectroscopies, HRMS and X-ray single-crystal crystallography analyses. The ligand adds to palladium(II) under basic conditions to give high yields of an air-stable and water-soluble complex that was fully characterized by NMR and HRMS. The complex was investigated as a catalyst for the Suzuki reaction in aqueous media under microwave irradiation. The compound proved to be an effective catalyst.

Full text of DOI:10.3390/molecules18021602

Molecules 2013, 18, 1602-1612; doi:10.3390/molecules18021602
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient Microwave-Assisted Suzuki Reaction using a New
Pyridine-Pyrazole/Pd(II) Species as Catalyst in Aqueous Media
Liqun Shen *, Suyu Huang, Yuanmei Nie and Fuhou Lei *
Key Laboratory of Development and Application of Forest Chemicals of Guangxi, College of Chemistry
and Chemical Engineering, Guangxi University for Nationalities, Nanning, 530006, China
*
Authors to whom correspondence should be addressed; E-Mails: liqunshen@126.com (L.S.);
leifuhou@163.com (F.L.); Tel./Fax: +86-771-326-0558 (L.S.).
Received: 27 December 2012; in revised form: 21 January 2013 / Accepted: 22 January 2013 /
Published: 25 January 2013
Abstract: A new pyridine-pyrazole N–N ligand has been conveniently synthesized and
1
13
characterized by H-, C-NMR, IR spectroscopies, HRMS and X-ray single-crystal
crystallography analyses. The ligand adds to palladium(II) under basic conditions to give
high yields of an air-stable and water-soluble complex that was fully characterized by
NMR and HRMS. The complex was investigated as a catalyst for the Suzuki reaction in
aqueous media under microwave irradiation. The compound proved to be an effective catalyst.
Keywords: Suzuki coupling; pyridine-pyrazole; palladium; aqueous media
1
. Introduction
In the past three decades, the palladium-catalyzed Suzuki reaction of aryl halides with aryl boronic
acids has been one of the most important and efficient methods for the formation of unsymmetrical
biaryl compounds [1,2], which are extensively found in a range of natural products [3],
pharmaceuticals [4], ligands [5], herbicides and advanced materials [6]. Modern techniques have been
developed in order to enable simpler, faster and cheaper versions of already known chemical
transformations to meet the purposes of Green Chemistry [7]. Recently, the use of aqueous phases
including water and water/organic mixtures as solvents for the Suzuki reaction has also received
considerable attention, as water is cheap, environmental friendly, inflammable, and allows simple
separation and catalyst recycling [8,9]. For these reasons, much effort has been directed to perform the
Suzuki coupling in neat water. Casalnuovo [10] was the first to demonstrate that the palladium-

Molecules 2013, 18
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catalyzed cross-coupling reactions could be carried out in aqueous solvents catalyzed by
TPPMS/Pd(OAc) , and since then, other hydrophilic ligands for aqueous-phase Suzuki cross-coupling
2
reactions have been developed [11]. Recently the application of nitrogen-based ligands systems, such
as Schiff bases, guanidine, aryloximes, arylimines, has also been found to produce highly active
catalysts for Suzuki reaction in water [12–17]. Nowadays, microwave heating has been widely
exploited in organic synthesis and its advantages over traditional heating lay in the reduction in
reaction time from hours to minutes [18,19]. In addition, microwave heating is generally able to reduce
side reactions, increase yields and improve reproducibility [20]. Microwave-assisted Suzuki reactions
can be considered today as an efficient synthetic methodology [21–25].
To the best of our knowledge, Pd(II) complexes with the pyridine-pyrazole ligand have been examined
for cytotoxic activity and few investigations have been carried out on their catalytic activity [26–28]. In
this paper, we report carboxylated water-soluble pyridine-pyrazole ligands as supporting ligands for
the Suzuki reaction in water and in aqueous phases in conjunction with microwave heating.
2
. Results and Discussion
2
.1. Synthesis and Characterization of the Ligand and Complee
The synthetic pathway for compounds 3 and 4 was shown in Scheme 1. 5-Hydroxy-1-pyridin-2-yl-
H-pyrazole-3-carboxylic acid methyl ester (1) was easily synthesized by the reaction of
-hydrazinopyridine and dimethyl acetylenedicarboxylate (DMADC), with subsequent cyclization in
1
2
methanolic NaOCH solution.
3
Scheme 1. Synthesis of pyridine-pyrazole ligand 3 and the Pd(II) complex 4.
CH I/K CO
3
1
, DMADC, CH OH
3
2
3
OH
OCH3
N
NHNH2
N
acetone
N
2, CH ONa, CH OH
N
N
3
3
1
N
2
N
COOCH3
COOCH3
LiOH/H O
K PdCl
2 4
2
OCH3
OCH3
N
CH OH/H O
N
N
3
2
N
N
Pd
Cl
N
Cl
4
COOH
COOH
3
The alkylation of 2 with iodomethane provided 5-methoxy-1-pyridin-2-yl-1H-pyrazole-3-
carboxylic acid methyl ester (2). Compound 2 was hydrolyzed with LiOH in methanol at room
temperature to afford 5-methoxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (3) bearing a
1
13
carboxylic acid group. Compound 3 has been characterized by H-NMR, C-NMR, IR and high
resolution mass spectrometry (HRMS). The solid-state structure has been established by X-ray
single-crystal crystallography [29] (Figure 1). The reaction of a methanol solution of ligand 3 with an
2 4
equimolar amount of an aqueous solution of K PdCl produced the palladium(II) complex (4) in 81%

Molecules 2013, 18
1604
yield as yellow crystals. The mononuclear complex with a pyridine-pyrazole N,N-chelate has been
characterized by IR, UV/vis (Figure 2), NMR and high resolution mass spectrometry.
Figure 1. The molecular structure of the compound 3 with atom-numbering scheme,
displacement ellipsoids are drawn at the 30% probability level.
Figure 2. (a) UV-vis spectra of K
2
PdCl
4
in water; (b) UV-vis spectra of complex 4 in water.
1.0
0.8
0.6
0.4
0.2
0.0
a K PdCl4
2
a
b complex 4
b
200
300
400
Wavelength (nm)
We now observe the interaction of K PdCl with the ligand 3 by UV/vis spectroscopy. In Figure 2,
2
4
as can be seen, the spectrum of K
2
PdCl
4
displays one major absorption band at 208 nm, that changes
upon addition of ligand 3 (195 and 294 nm). This change in the UV/vis spectrum can be attributed to
the coordination of Pd(II) to the ligand 3 [30].
2
.2. Catalysis of the Suzuki Reaction
As a starting point for the development of our microwave-promoted methodology, the Suzuki
reaction were performed using a scientific microwave apparatus [31], working on a 1 mmol scale in a
0 mL sealed glass vessel. The Suzuki reaction of different types of aryl halides using complex 4 as
1
catalyst was then investigated under microwave irradiation. Initially, in order to optimize the reaction
conditions, we employed the coupling reaction of 4'-bromoacetophenone with phenylboronic acid in
water/ethanol as a model reaction to investigate the effect of different bases on the reaction.
Water/ethanol as solvent facilitates solvation of the aryl halide in neat water [32]. For this purpose, this
reaction was performed using different bases in the presence of 0.1 mol% of complex 4 as catalyst.

Molecules 2013, 18
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Using a microwave power of 60 W, we ramped the temperature from 25 °C to 120 °C, and then held it
at 120 °C for 2 min. The results are summarized in Table 1. The best results were obtained using KOH
as the base (Table 1, entries 1–4), other bases, such as K PO , K CO and Et N were slightly less
3
4
2
3
3
efficient. We next investigated the effect of different solvents for the same reaction (Table 1, 5–8). As
can be seen in Table 1, the best result was obtained using aqueous EtOH/H O as the solvent (Table 1),
2
2
+
perhaps, attributable to the better solubility of the reagents and easier reduction of Pd to Pd(0).
Table 1. Optimization of base and solvent for Suzuki cross-coupling reaction under
a
microwave irradiation .
B(OH)2
0.1 % complex 4
Br +
o
1
20 C, MW, 2 min
O
O
b
Entry
Base
KOH
PO
Solvent
Conversion (%)
1
2
3
4
5
6
7
8
EtOH/H
EtOH/H
2
O
O
99
K
3
4
2
95.2
96.0
92.3
90.9
85.4
94.5
85.0
K CO3
2
EtOH/H O
2
Et N
3
EtOH/H O
2
KOH
KOH
KOH
KOH
DMF/H O
2
DMAC/H O
2
MeCN/H O
2
H O
2
a
Reaction conditions: 1 mmol 4'-bromoacetophenone, 1.3 mmol phenylboronic, 2 mmol base, 2 mL solvent
(
EtOH/H O = 1:1; MeCN/H O = 1:1; DMF/H O = 1:1; DMA/H O = 1:1), Microwave irradiation = 60 W.
2
2
2
2
b
and 0.1 mol% complex 4. DMF = N,N-Dimethylformamide; DMAC = N,N-Dimethylacetamide; Determined
by HPLC analysis.
Under the above optimized conditions, complex 4 was applicable to a wide range of aryl bromides,
iodides, and less reactive aryl chlorides and the results are summarized in Table 2. Generally, the
catalyst was very effective when electron poor or electron-rich aryl bromides were used (Table 2, entry
1
–7). From Table 2, it can be seen that the electronic and steric characters of the aryl bromides have an
effect on the Suzuki reactions under the optimized conditions. For this purpose we applied 2-, 3-, and
-bromobenzaldehyde under the optimized reaction conditions (Table 2, entries 1–3). The Suzuki
reaction of 4-bromobenzaldehyde was complete and gave excellent yields. Sterically demanding
-bromobenzaldehyde resulted in decreased coupling. The reaction of 4-chlorobromobenzene with
4
2
phenylboronic acid produced mono-substituted 4-chlorobiphenyl (Table 2, entry 8), the result indicates
that the catalytic reaction has a good chemical selectivity. The coupling reaction using
4
-methoxyphenylboronic acid was also performed, the corresponding products are obtained in good
yields (Table 2, entry 14–26). We also investigated the scope of this method on aryl chlorides, and
found that the conversion of activated aryl chloride was up to 89.0% (Table 2, entry 26) and
unactivated aryl chlorides gave moderate yields.

Molecules 2013, 18
Table 2. Suzuki coupling of aryl halides and aryl boronic acids in H O/EtOH using
1606
2
a
complex 4 under optimized reaction conditions under microwave irradiation .
B(OH)2
0
.1 % complex 4
X
+
Y
KOH, H O/EtOH
Y
Z
Z
2
o
1
20 C, MW, 2 min
b
Entry
X
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Y
4-CHO
3-CHO
2-CHO
4-OMe
4-CH3
4-OH
4-COMe
4-Cl
Z
H
H
H
H
H
H
H
H
H
H
H
H
H
Yield (%)
90.3
85.1
80.3
86.7
82.4
93
1
2
3
4
5
6
7
8
9
92.6
90.8
86.7
91.3
63.8
75.5
88.3
92.7
87.7
83.5
88.1
85.3
93.2
93.0
91.2
90.8
92.7
67.2
78.4
89.0
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
H
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
H
2-COOH
4-NO2
4-CHO
3-CHO
2-CHO
4-OMe
4-CH3
4-OH
4-COMe
4-Cl
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
H
Cl
Cl
Cl
H
2-COOH
4-NO2
a
Reaction conditions: 1 mmol 4'-bromoacetophenone, 1.3 mmol phenylboronic, 2 mmol KOH, 2 mL solvent
b
(
EtOH/H O = 1:1), Microwave irradiation = 60 W, and 0.1 mol% complex 4; Isolated yield after
2
purification by column chromatography.
2
.3. Catalyst Recycling
The potential recyclability of the catalysts derived from the pyridine-pyrazole/Pd system was
examined using the model cross-coupling of 4-bromoacetophenone with phenylboronic acid. The
reaction was carried out in 1:1 H O/CH CH OH under microwave irradiation for 2 min. After
2
3
2
extracting the products with dichloromethane the yields were determined by HPLC. The resulting
aqueous solution was recharged with the same substrates for the next cycle. It was shown that the
catalytic solution could be reused for third cycles, and by the fifth cycle, the yield had dropped to 21%
(
Table 3).

Molecules 2013, 18
1607
a
Table 3. Recycling of catalyst .
Cycles(n)
Conversion (%)
1
2
3
4
5
b
99
97
86
53
21
a
Reaction conditions: 1 mmol 4'-bromoacetophenone, 1.3 mmol phenylboronic, 2 mmol KOH, 120 °C under
b
microwave irradiation 2 min; Determined by HPLC analysis.
3
. Experimental
.1. General
All chemicals were of reagent grade and used as commercially purchased without further
3
purification. All solvents were purified according to standard procedures. Melting points were
determined using a WRS-1B apparatus and were uncorrected. The IR spectra were recorded in the
−
1
1
range of 400–4000 cm with a Magna 550 FT-IR spectrometer using KBr pellets. The H and
1
3
C-NMR spectra were recorded on a Bruker AV600 spectrometer. High resolution mass (HRMS)
spectra were obtained in ESI mode on a Finnigan MAT95XP HRMS system (Thermo Electron
Corporation). HPLC analysis of the target compound was performed on a C18 reversed-phase column
(5 µm, 200 × 4.6 mm) using water-methanol (20:80, v/v) as the mobile phase at a flow rate of 0.8 mL/min.
Microwave reactions were carried out in a Biotage Initiator 60.
3.2. Synthesis and Characterization
5
-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid methyl ester (1) [33]. Dimethyl
acetylenedicarboxylate (7.5 mL, 61 mmoL) in methanol (15 mL) was added dropwise to a solution of
-pyridylhydrazine (6.0 g, 55 mmoL) in methanol (60 mL), and the mixture was stirred for 6.0 h at 0 °C.
2
Sodium methoxide (4.6 g, 85.1 mmoL) was then added and stirring was continued for 30 min at 70 °C.
After cooling, and quenched with water. The reaction mixture was filtered and washed with cold
methanol, and dried in vacuo to give a white solid. Yield: 8.9 g (77.4%). M.p.: 142.2–143.0 °C;
1
3
H-NMR (600 MHz, CDCl ) δ 3.95 (s, 3H), 6.10 (s, 1H), 7.27–7.31 (m, 1H), 7.91–7.98 (m, 1H), 8.11
1
3
(
dd, J = 5.0, 4.2 Hz, 1H), 8.31–8.36 (m, 1H), 12.83(s, 1H). ppm. C-NMR (151 MHz, CDCl
3
) δ 52.4,
+
9
0.3, 111.3, 121.6, 140.4, 144.5, 145.4, 154.2, 157.1, 162.8 ppm; HRMS (M+H ) calcd. for
C H N O 220.0722, found 220.0726. IR (KBr): 3471, 3030, 2957, 1744, 1612, 1588, 1452, 1254,
1
0
10
3
3
−
1
7
75 cm .
5-Methoxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid methyl ester (2). Potassium carbonate (1.23 g,
9.91 mmoL) was added to stirred solution of 1-(pyridin-2-yl)-5-hydroxy-1H-pyrazole-3-carboxylicacid
methyl ester (1, 0.65 g, 2.97 mmoL) in acetone (25 mL) at 50 °C, methyl iodide (0.4 mL) was added
under argon. The mixture allowed to be stirred at 50 °C for 12 h, the reaction mixture was filtered and
3
extracted with CHCl three times, after evaporating the organic layers under pressure, the residue was
purified by chromatography on silica gel to give a pale white solid. Yield: 0.53 g (76.6%). M.p.:
1
1
08.7–116.6 °C; H-NMR (600 MHz, CDCl
3
) δ 3.94 (s, 3H), 4.00 (s, 3H), 6.26 (s, 1H), 7.28–7.31
1
3
(
m, 1H), 7.75–7.77 (m, 1H), 7.83–7.84 (m, 1H), 8.53–8.59 (m, 1H) ppm. C-NMR (151 MHz, CDCl
3
)
+
δ 52.2, 59.7, 88.5, 117.8, 122.8, 138.5, 143.5, 148.7, 151.0, 156.8, 162.8 ppm; HRMS (M+H ) calcd.

Molecules 2013, 18
1608
for C H N O 234.0878, found 234.0880. IR (KBr): 3159, 3086, 2947, 1737, 1595, 1564, 1480,
1
1
12
3
3
−1
1
473, 1230, 1067, 754 cm .
5
-Methoxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (3). Lithium hydroxide (190 mg, 4.5 mmoL)
was added to a solution of 1-(pyridin-2-yl)-5-methyl ether-1H-pyrazole -3-carboxylic acid methyl ester
2, 0.35 g, 1.5 mmoL) in methanol (18 mL) and water (3 mL),The mixture was stirred at room
(
temperature for 12 h. After completion of the reaction, extracted with chloroform (3 × 15 mL), and
evaporating the organic layers under reduced pressure, the residue recrystallised from absolute ethyl
1
alcohol to obtain the white product. Yield: 0.24 g (73%). M.p.: 201.1–203.5 °C; H-NMR (600 MHz,
DMSO) δ 3.96 (s, 3H), 6.33 (s, 1H), 7.46 (ddd, J = 7.5, 4.9, 0.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 8.02
1
3
(
td, J = 7.8, 1.9 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 12.93 (s, 1H) ppm. C-NMR (151 MHz,
+
DMSO) δ 59.6, 88.4, 118.0, 123.4, 139.1, 143.6, 148.6, 150.3, 156.3, 163.0 ppm; HRMS (M+H )
calcd. for C H N O 220.0722, found 220.0726. IR (KBr): 3444, 3134, 3114, 2997, 1701, 1604,
1
0
10
3
3
−1
1
574, 1484, 1439, 1242, 793 cm .
Palladium(II) complex 4. An aqueous solution (4 mL) of K
2
4
[PdCl ] (66.3 mg, 0.2 mmoL) was added
dropwise to a stirred methanol solution (20 mL) of ligand 3 (43.7 g, 0.2 mmol) at room temperature [34].
During the addition a solid product precipitated immediately from the reaction mixture. Stirring was
continued for 30 min. The stable yellow complex was filtered off, washed with cold water, and dried;
1
6
8.3 mg yield (83.3%), m.p. > 300 °C; H-NMR (600 MHz, DMSO) δ 3.95 (s, 3H), 6.32 (s, 1H), 7.47
(
m, 1H), 7.67 (d, J = 8.2 Hz, 1H), 8.00 (m, 1H), 8.55 (d, J = 4.9 Hz, 1H), 12.93 (s, 1H) ppm.
1
3
C-NMR (151 MHz, DMSO) δ 59.5, 88.4, 118.2, 123.4, 139.2, 143.6, 148.7, 150.2, 156.4, 163.1 ppm;
+
HRMS (M+H ) calcd. for C10
H
10
C N
l2 3
O
3
Pd 395.9056, found 395.9055. IR (KBr): 3430, 3110, 2936,
−1
1
664, 1609, 1584, 1511, 1487, 1317, 771, 469 cm .
3
.3. Crystallography
A suitable crystal was obtained from an ethanol solution by slow evaporation. Diffraction
a
experiments for 3 was carried out on with Mo K radiation (λ = 0.71073 Å) using a Bruker SMART
APEX CCD diffractometer at 296 K. Raw frame data were integrated with the SAINT program. The
structures were solved by direct methods which gave the positions of all non-hydrogen atoms and
2
refined with full-matrix least-squares on F using SHELXS-97 and SHELXL-97 [35]. The hydrogen
atoms were set in the calculated positions and refined by riding model. The crystallographic and
refinement data of 3 is listed in Table 4.
3
.4. General Procedure for Aqueous Suzuki Coupling Reactions
Into a 10 mL glass vial were placed aryl halide (1.0 mmol), phenylboronic acid (1.2 mmol), base
(
2 mmol), complex 4 (0.4 mg, 0.001 mmol), ethanol (1 mL), water (1 mL), and a magnetic stir bar.
The vessel was sealed by capping with a Teflon septum fitted in an aluminum crimp top and placed
into the microwave cavity. Microwave irradiation of 60 W was used, the temperature being ramped
from room temperature to 120 °C. Once 120 °C was reached, the reaction mixture was held at this
temperature for 2 min. After the mixture was allowed to cool to room temperature, the reaction vessel

Molecules 2013, 18
1609
was opened and the contents poured into a separating funnel. Water and dichloromethane (30 mL of
each) were added, and the organic material was extracted and removed. After further extraction of the
aqueous layer with dichloromethane, combining of the organic washings and drying over MgSO , the
4
dichloromethane was removed in vacuo, leaving the crude product. The crude material was flash
chromatographed on a silica gel column. All of the compounds have been characterized by comparing
1
H-NMR with the values found in the literature [35–41].
Table 4. Crystal data and refinement details for 3.
Compound reference
Empirical formula
Formula weight
Crystal system
3
C
10 5 3 3
H N O
215.17
Monoclinic
Space group
P2(1)/n
Unit cell dimensions
a =7.144(3) Å, α =90.00;
b = 8.093(4)Å, β = 95.6380(10);
c = 16.662(3)Å, γ = 90.00
3
Volume
958.6(6)Å
Z
4
3
Density(calculated)
Absorption coefficient
F(000)
1.491 g/cm
−
1
0.115 mm
440
3
Crystal size
0.27 × 0.25 × 0.22 mm
Theta range for data collection (°) 2.46–25.00 °
Reflections collected
4745
Completeness to θmax
Data/restraints/parameters
0.993
1678/0/146
0.917
2
Goodness-of-fit on F
a,b
Final R indices [I > 2σ(I)]
R = 0.0612，wR = 0.1673
1 2
R indices (all data)
R = 0.0940，wR = 0.2057
1 2
−
3
Largest diff. peak and hole
0.309 and −0.294e Å
a
b
2
o
2 2
2 2 1/2
2
2
2
o
2
2 −1
R
1
= ∑||F
o
|-|F
c
||/∑|F
o
|; wR
2
= [∑w(F
-F
c
) /∑w(F
o
) ] , w = [ (F
o
) + (0.1(max(0, F
) + 2F
c
)/3) ] .
3.5. Recycling of Catalyst
Into a 10 mL glass vial were placed 4-bromoacetophenone (1.0 mmol), phenylboronic acid
1.2 mmol), KOH (2 mmol), complex 4 (0.4 mg, 0.001 mmol), ethanol (1 mL), water (1 mL), and a
(
magnetic stir bar. The reaction mixtures were run at 120 °C for 2 min under microwave irradiation.
After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the
contents poured into a separating funnel. Diethyl ether (5 mL × 2) was added. The aqueous phase was
transferred to another glass vial for the next reaction cycle. The yields were determined by HPLC.
4
. Conclusions
In summary, a new and efficient catalyst system for microwave-mediated Suzuki coupling reaction
was developed. To the best of our knowledge this is the first report of pyridine-pyrazole/Pd(II)

Molecules 2013, 18
1610
complexes for catalysis of Suzuki reaction. The reactions were performed under microwave irradiation
in water/EtOH co-solvent system and have shown the application of this to the synthesis of a number
of biaryls. The method has the advantage of rapid reaction times, no need for anaerobic conditions and
use of a nontoxic solvent. The catalysts could be used for up to five cycles. The methodology is a good
synthetic route for biaryl synthesis.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/2/1602/s1.
Acknowledgments
This work was supported by National Natural Science Foundation of China (No. 21062002), the
Scientific Research Program of Guangxi University for Nationalities (Project No. 2010QD018).
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1.
2.
3.
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Markham, A.; Goa, K.L. Valsartan. A review of its pharmacology and therapeutic use in essential
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through selective and sequential Suzuki palladium-catalyzed cross-coupling reactions. Chem. Mater.
2
005, 17, 5538–5549.
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8.
9.
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Sample Availability: Samples of most compounds are available from the authors.
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