A convergent approach to the total synthesis of telmisartan via a Suzuki cross-coupling reaction between two functionalized benzimidazoles

Article abstract of DOI:10.1021/jo5025333

A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.

Full text of DOI:10.1021/jo5025333

Note
pubs.acs.org/joc
A Convergent Approach to the Total Synthesis of Telmisartan via a
Suzuki Cross-Coupling Reaction between Two Functionalized
Benzimidazoles
Alex D. Martin, Ali R. Siamaki, Katherine Belecki,* and B. Frank Gupton*
Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University,
Richmond, Virginia 23284, United States
S
* Supporting Information
ABSTRACT: A direct and efficient total synthesis has been
developed for telmisartan, a widely prescribed treatment for
hypertension. This approach brings together two function-
alized benzimidazoles using a high-yielding Suzuki reaction
that can be catalyzed by either a homogeneous palladium
source or graphene-supported palladium nanoparticles. The
ability to perform the cross-coupling reaction was facilitated by
the regio-controlled preparation of the 2-bromo-1-methyl-
benzimidazole precursor. This convergent approach provides
telmisartan in an overall yield of 72% while circumventing
many issues associated with previously reported processes.
Scheme 1. Original Synthesis of Telmisartan
elmisartan (1) is a potent angiotensin II receptor
T
antagonist used in the treatment of essential hyper-
tension.1−3 It is one of the most efficacious drugs in its class,
boasting the longest half-life, a high protein binding affinity, and
a low daily dosage.4,5 The drug is currently marketed under the
brand name of Micardis and provides additional benefits against
vascular and renal damage caused by diabetes and cardiovas-
cular disease.6−8
Previously reported syntheses of telmisartan, including the
commercial process, invariably rely on the sequential formation
of the two benzimidazole moieties through cyclization of
appropriately substituted aniline precursors. The high temper-
atures and extreme pH conditions required by this strategy
result in lower yields and significant byproduct formation.
Given the recent loss of telmisartan patent protection in the
US, taking a fresh look at the construction of this widely
prescribed drug is a timely and relevant endeavor. We now
report a fundamentally different approach based on a Pd-
catalyzed coupling of two structurally distinct benzimidazole
units. Our synthetic scheme is more convergent and higher
yielding than recently reported efforts, reaching telmisartan in
an overall yield of 72% in comparison to the previously
reported highest yield of 50%.9
The original synthesis of telmisartan was developed by Ries
et al. in 199310 (Scheme 1), beginning with the stepwise
construction of the central benzimidazole ring from 4-amino-3-
methylbenzoic acid methyl ester (2). Saponification of the
resulting substituted benzimidazole 4 was followed by
condensation with N-methyl-1,2-phenylenediamine (5) using
polyphosphoric acid at elevated temperature (150 °C) to afford
the functionalized dibenzimidazole 6. Alkylation of the latter
with 4′-(bromomethyl)-2-biphenylcarboxylic acid tert-butyl
ester (7) followed by hydrolysis of the resulting ester provided
telmisartan in 21% overall yield over eight linear steps.
The elevated temperature and acidic conditions required
during the second cyclization step adversely impact both
product yield and purity, a major drawback of this original route
that has not been addressed in subsequent process improve-
ments to this basic method.9,11−13 In a recent report, the
cyclocondensation of an aromatic aldehyde with o-phenyl-
enediamine was explored as an alternative path to the
Received: November 5, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo5025333
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The Journal of Organic Chemistry
Note
a
dibenzimidazole moiety; however, this process still suffers from
a rather low overall yield.14 Other groups have taken advantage
of cross-coupling reactions to build a formylated biphenyl
fragment, avoiding the intricate and low-yielding preparation of
7 used in the original synthesis by substituting a reductive
amination approach for the alkylation step.15−17 Bypassing this
alkylation reaction is no longer necessary because affordable
analogs of bromide 7 are now commercially available. Notably,
none of these modifications represent a significant departure
from the original synthetic strategy nor have they remedied the
major shortcomings associated with the formation of the
dibenzimidazole component of the molecule.
Table 1. Bromination of 1-Methylbenzimidazole
b
b
b
entry
solvent
8
8b
di- and tribromination
1
2
3
4
5
DCM
DMF
MeOH
Et2O
0
0
0
0
0
100
92
88
73
0
8
12
27
0
THF
100
93
c
d
6
THF
0
0
This convergent synthesis of telmisartan entails the assembly
of three major subunits: two differentially substituted
benzimidazole derivatives and a biphenyl-2-carboxylic acid
synthon (Scheme 2). Our strategy provides for the use of a
a
b
11 (0.76 mmol), NBS (2.3 mmol), 4 mL of solvent. % Conversions
determined by GC-MS. Reaction ran under reflux for 1 h. Isolated
c
d
yield.
at the 2-position and was an essential element of our
convergent strategy. Although compound 8 is available
commercially, the cost is prohibitive. This procedure provides
an effective and affordable route to 8, and it is likely that this
strategy will find utility in the preparation of other
benzimidazole adducts in the future.
Scheme 2. Retrosynthetic Analysis of Telmisartan
In order to establish the necessary precursors for a Suzuki-
based approach to the dibenzimidazole core of telmisartan, we
elected to prepare the trifluoroborate salt 9 starting from
commercially available 4-bromo-2-methyl-6-nitroaniline (12).
Compound 12 could be easily converted to benzimidazole 14
in a single step. This reductive cyclization, provoked by
introducing n-butyraldehyde (13) in the presence of sodium
dithionite,14 produced 14 in 97% isolated yield (Scheme 3).
Scheme 3. Synthesis of Compound 9
Suzuki cross-coupling reaction to form a new carbon−carbon
bond between advanced isolated intermediates. The lack of a
convenient and economical preparation of bromobenz-
imidazole 8 has apparently precluded consideration of this
approach until now. The biphenyl moiety is introduced via
direct N-alkylation with commercially available methyl 4′-
bromomethyl-biphenyl-2-carboxylate (10), followed by a
saponification to the desired carboxylic acid. This approach
provides a more efficient assembly of the target molecule, while
avoiding the harsh reaction conditions associated with the
previous synthetic methods.
Initial efforts focused on preparation of 8, a strategic element
in the Suzuki coupling reaction. Starting with commercially
available 1-methylbenzimidazole (11), we were able to identify
reaction conditions to selectively brominate the imidazole ring
with N-bromosuccinimide (NBS). While benzimidazoles can be
susceptible to bromination at multiple sites18 resulting in the
formation of a mixture of mono-, di-, and tribrominated
byproducts, our major challenge was to identify conditions by
which bromination could be achieved exclusively at the 2-
position in high yield. A solvent screen of microwave-assisted
reactions revealed that dichloromethane (DCM), methanol,
dimethylformamide (DMF), and diethyl ether yield mainly
undesired mixtures of byproducts (Table 1, entries 1−4), but
tetrahydrofuran (THF) affords essentially complete conversion
to the desired product (entry 5). Similar selectivity trends were
observed during solvent screening under conventional reaction
conditions (Supporting Information, Table S1), and we were
able to achieve an isolated yield of 93% with the THF under
reflux conditions. To our knowledge, this is the first example of
a selective and scalable bromination of 1-methylbenzimidazole
This approach represents a significant improvement over the
originally reported method: benzimidazole formation can be
completed in a single step, compared to the problematic three-
step sequence (amidation, reduction, and cyclization) of Ries et
al.10 Moreover, sodium dithionite provides an effective and
inexpensive alternative to the palladium catalyst typically used
for reduction of the nitro group. Avoiding palladium in this case
is particularly beneficial, as the aryl bromide is susceptible to
dehalogenation under Pd-catalyzed hydrogenation conditions.19
Benzimidazole 14 was then converted to the trifluoroborate
salt 9 in two steps with no isolated intermediate. We chose to
introduce the boron species as the pinacol ester.20 The reaction
of 6-bromo-4-methyl-2-propylbenzimidazole (14) and diboron
15 (2 equiv) at 100 °C for 5 h in the presence of PdCl2dppf (5
mol %) led to the formation of the desired boronic acid pinacol
ester. We converted this pinacol boronate directly to the
corresponding trifluoroborate salt,21 as trifluoroborates tend to
be significantly more reactive toward Suzuki cross-coupling
reactions.22−24 The yield from this two-step process is 90%
from benzimidazole 14. Isolation of trifluoroborate 9 is
straightforward, as it can be precipitated out of the reaction
mixture in pure form.
B
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Note
Most of the previous telmisartan syntheses employed a
common strategy in which the dibenzimidazole moiety was
prepared first, followed by the installation of the biphenyl
group. However, we chose to alkylate benzimidazole 9 prior to
the Suzuki reaction in order to avoid an observed side reaction
between 8 and 9.25 The N-alkylation of 9 with bromide 10 was
carried out in DMSO under basic reaction conditions (Scheme
4). Notably, we found it necessary to pretreat 9 with potassium
currently underway. Other homogeneous catalyst systems were
screened; however, PdCl2dppf proved to be the most effective
(Supporting Information, Table S3).
In related work, we have recently developed a method to
produce highly active Pd nanoparticles supported on graphene
(Pd/G).28 These materials demonstrate remarkable catalytic
activity and recyclability in a wide range of Suzuki cross-
coupling reactions. Thus, we were interested in evaluating this
catalyst system for the key step of our telmisartan synthesis.
Preliminary experiments using just 2 mol % of Pd/G under
microwave irradiation conditions led to the formation of the
desired product with 76% isolated yield (Table 2, entry 4). The
palladium content in this final product was lower than that of a
sample from the corresponding homogeneous reaction,
although both samples are below the USP limits for
pharmaceuticals (Supporting Information, Table S4). Further-
more, the catalyst was recycled for two further reactions under
the same conditions without appreciable reduction in isolated
yield. We are currently evaluating the use of this catalyst system
for optimization of both batch and continuous processes for the
assembly of telmisartan.
Scheme 4. One-Pot Synthesis of Compound 16
A concise and convergent synthesis of the antihypertensive
drug telmisartan has been achieved (Scheme 5). With an overall
tert-butoxide to avoid the formation of unwanted Williamson
ether byproducts. Furthermore, we developed reaction
conditions to telescope saponification of the methyl ester
with the alkylation step, achieving a 93% yield of 16 over these
two chemical steps.
Scheme 5. Convergent Synthesis of Telmisartan
The final coupling reaction of 16 with 8 was carried out
under Suzuki cross-coupling reaction conditions26,27 using
PdCl2dppf with KOH in a H2O/EtOH solvent system. Under
atmospheric reflux conditions, the reaction afforded telmisartan
in a low to moderate yield (Table 2, entries 1 and 2). In order
a
Table 2. Suzuki Cross-Coupling To Form Telmisartan
b
entry
catalyst
conditions
reflux, 15 h
1
(%)
36
1
2
PdCl2dppf (2 mol %)
PdCl2dppf (10 mol %)
PdCl2dppf (2 mol %)
Pd/G (2 mol %)
reflux, 15 h
55
89
76
yield of 72%, our strategy represents a significant improvement
over the highest yield reported previously9 (50%). Our
approach features an efficient Pd-catalyzed Suzuki reaction
between two intact benzimidazole moieties as the final reaction
step, enabled by the development of a regioselective
bromination of 1-methylbenzimidazole. In addition, the harsh
reaction conditions that have plagued the commercial route
have been avoided and, with only four isolated intermediates in
the longest linear sequence, the number of unit operations has
been greatly reduced. Our synthetic route also illustrates the
potential of graphene-supported Pd nanoparticles (Pd/G) as an
alternative catalytic source for cross-coupling reactions. Finally,
our strategy has a very efficient endgame, as each step to
assemble telmisartan from the key synthons is high-yielding
(83% over the final three steps, from trifluoroborate 9). From a
broader perspective, dibenzimidazoles represent an important
class of pharmacophores, and this report describes a selective
and straightforward method for the preparation of these
privileged structures.
c
3
cd
,
μw 150 °C, 30 min
μw 150 °C, 20 min
4
a
8 (0.19 mmol), KOH (0.57 mmol), 4 mL of H2O/EtOH (1:1
b
c
mixture). Isolated yield. Reactions were carried out under microwave
irradiation at 150 °C, generating a pressure of 18 atm inside the
microwave tube. Pd/G catalyst was recycled an additional 2 times
d
affording 68% and 62% isolated yields, respectively.
to achieve higher temperatures with this same solvent system,
reactions were then run under elevated pressure using
microwave heating. Using this strategy, reaction times were
significantly reduced, and isolated yields showed some
improvement. We then applied a factorial design of experiment
approach in order to identify the set of reaction parameters that
would maximize yield while minimizing catalyst loading (Table
S2). Optimized Suzuki reaction conditions (Table 2, entry 3)
generated telmisartan in 89% isolated yield using only 2 mol %
catalyst. We expect that similar results can be achieved under
elevated pressures with conventional heating; these studies are
C
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The Journal of Organic Chemistry
Note
(86.7 mg, 89% yield). 1H NMR (CDCl3) δ 8.41 (d, 1H), 8.04 (d, 1H),
7.00−7.52 (m, 12H), 5.43(s, 2H), 3.76 (s, 3H), 3.16 (t, 2H), 2.73 (s,
2H), 2.02 (m, 2H), 1.18 (t, 3H); 13C NMR (CDCl3) δ 172.9, 158.2,
155.7, 145.2, 144.5, 143.3, 142.7, 137.2, 136.2, 135.6, 135.3, 132.1,
131.9, 131.0, 130.6, 130.4, 129.0, 128.8, 125.2, 124.9, 124.8, 123.5,
121.4, 113.0, 111.0, 50.5, 33.5, 31.7, 24.1, 18.6, 15.8; HRMS (ESI-
QTOF): m/z Calcd for C33H30O2N4 + H+: 515.2447, found:
515.2468.
Procedure for Preparation of Pd Nanoparticles Supported
on Graphene (Pd/G). Pd nanoparticles supported on graphene (Pd/
G) was prepared according to the procedure developed previously.28
Graphite oxide (100 mg) and the palladium nitrate (194 μL of 10 wt
% in 10 wt % HNO3, 99.999%) were sonicated in deionized water until
a yellow dispersion was obtained. The solution was placed inside a
conventional microwave after adding 100 μL of the reducing agent
hydrazine hydrate. The microwave oven (Emerson MW8119SB) was
then operated at full power (1000 W), 2.45 GHz, in 30 s cycles (on for
10 s, off, and stirring for 20 s) for a total irradiation time of 60 s. The
yellow solution of Pd nitrate-graphite oxide changed to a black color
indicating the completion of the chemical reduction to graphene. The
Pd/G nanoparticles were separated by using an Eppendorf 5804
centrifuge operated at 5000 rpm for 15 min and dried overnight under
vacuum.
Procedure for Suzuki Cross-Coupling Reaction Using Pd/G
and Recycling the Heterogeneous Catalyst. 2-Bromo-1-methyl-
benzimidazole 8 (20 mg, 0.094 mmol) was dissolved in a mixture of 2
mL of H2O/EtOH (1:1) and placed in a 10 mL microwave tube. To
this were added 16 (48.8 mg, 0.099 mmol) and potassium hydroxide
(21.3 mg, 0.38 mmol). The palladium on graphene catalyst (Pd/G)
(2.5 mg, 1.9 μmol) was then added, and the tube was sealed and
heated under microwave irradiation (250 W, 2.45 MHz) at 150 °C for
20 min. Upon the completion of the reaction period, the reaction
mixture was diluted with 2 mL of 10 mg/mL KOH in EtOH and
centrifuged to remove the solid catalyst. The EtOH/KOH washing
was repeated twice to ensure the complete dissolution of the product
from the surface of the catalyst. The solution was decanted, and the
solvent was partially concentrated in vacuo. After adjusting the pH of
the remaining solution to 4 using AcOH, the precipitated telmisartan
product was isolated by filtration and dried in the oven (76% isolated
yield). In the case of recycling the Pd/G nanoparticles, the solid
catalyst was removed by centrifugation and added to the next reaction
mixture using fresh reagents as indicated above. The reaction solution
was heated in the microwave at 150 °C for 20 min and the same
purification was applied, affording telmisartan with an isolated yield of
68% and 62% in the second and third reactions, respectively.
EXPERIMENTAL SECTION
■
2-Bromo-1-methylbenzimidazole (8). 1-Methylbenzimidazole
(11) (5.0 g, 37.8 mmol) and N-bromosuccinimide (20.2 g, 113.5
mmol) in 200 mL of THF were heated under reflux for 1 h. The
solvent was removed by a rotary evaporator, and the residue was
1
recrystallized from EtOAc yielding 8 (7.4 g, 93%) as a white solid. H
NMR (DMSO-d6) δ 7.77 (d, 1H), 7.65 (d, 1H), 7.39 (m, 2H), 3.86 (s,
3H); 13C NMR (DMSO-d6) δ 138.2, 135.4, 131.5, 124.8, 124.7, 117.0,
112.3, 33.0; HRMS (ESI-QTOF): m/z Calcd for C8H7N2Br + H+:
210.9871; found: 210.9862.
6-Bromo-4-methyl-2-propylbenzimidazole (14). n-Butyralde-
hyde (13) (3.1 mL, 34.6 mmol) was added to a 250 mL flask
containing 4-bromo-2-methyl-6-nitroaniline (12) (4.0 g, 17.3 mmol)
and sodium dithionite (18.1 g, 103.9 mmol) in 80 mL of 50% MeOH
in H2O. The reaction was stirred at reflux for 5 h. The methanol was
removed via rotary evaporator. To the remaining aqueous solution, an
additional 40 mL of water were added and the mixture was extracted
using EtOAc (3 × 80 mL). The organic layer was dried using
magnesium sulfate. After filtration, the organic layer was removed via
rotary evaporator and the resulting solid was dried in the oven
1
producing 13 as a white solid (4.3 g, 97%). H NMR (DMSO-d6) δ
7.47 (s, 1H), 7.08 (s, 1H), 2.77 (t, 2H), 2.47 (s, 3H), 1.79 (m, 2H),
0.95 (t, 3H); 13C NMR (DMSO-d6) δ 155.7, 124.0, 113.1, 30.5, 20.9,
16.4, 13.6; HRMS (ESI-QTOF): m/z Calcd for C11H13N2Br + H+:
253.0340; found: 253.0323.
Potassium (4-Methyl-2-propyl-benzimidazol-6-yl) Trifluoro-
borate (9). 6-Bromo-4-methyl-2-propylbenzimidazole (14) (2.0 g, 7.9
mmol) and bis(pinacolato) diboron (15) (4.0 g, 15.8 mmol) were
added to a flask along with KOAc (2.3 g, 23.7 mmol) and PdCl2dppf
(289 mg, 0.4 mmol). DMSO (20 mL) was added, and the flask was
evacuated and placed under nitrogen. The solution was heated at 100
°C for 5 h. The reaction mixture was cooled followed by the addition
of 80 mL of H2O and extracted with EtOAc (3 × 100 mL). The
organic layer was combined and concentrated by rotary evaporation.
The resulting residue was then taken up in THF (32 mL) and
combined with a solution of potassium bifluoride (3.1 g, 39.5 mmol)
in H2O (8 mL). The combined solution was stirred at room
temperature for 5 h. Upon removal of the THF, the precipitate was
filtered and rinsed using EtOAc, yielding 9 as a white solid (2.0 g,
90%). 1H NMR (DMSO-d6) δ 7.36 (s, 1H), 7.25 (s, 1H), 3.01 (t, 2H),
2.48 (s, 3H), 1.85 (m, 2H), 0.94 (t, 3H); 13C NMR (DMSO-d6) δ
152.5, 130.7, 129.3, 121.4, 113.0, 28.5, 21.0, 17.1, 14.0; HRMS (ESI-
QTOF): m/z Calcd for C11H13N2BF3K + H+: 281.0839, found:
281.0826.
Potassium (1-(2′-Carboxy-[1,1′-biphenyl]-4-yl)-4-methyl-2-
propyl-benzimidazole-6-yl) Trifluoroborate (16). Compound 9
(2.0 g, 7.1 mmol) was added to a solution of KOtBu (2.4 g, 21 mmol)
in DMSO (20 mL) and stirred for 30 min at room temperature.
Compound 10 (2.2 g, 7.1 mmol) was then added to the reaction
mixture and stirred for 2 h at room temperature. A solution of 2 g of
KOH (35 mmol) in H2O (80 mL) was then added to the reaction
mixture and stirred for an additional 5 h at room temperature. The
solution was adjusted to pH 4 using AcOH, producing a white
precipitate. The precipitated material was filtered, rinsed with THF,
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data and additional scheme and tables. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
1
and then dried, yielding a white solid (3.2 g, 93% yield). H NMR
■
(DMSO-d6) δ 7.22−7.72 (m, 10H), 5.80 (s, 2H), 3.19 (t, 2H), 2.54 (s,
3H), 1.76 (m, 2H), 0.96 (t, 3H); 13C NMR (DMSO-d6) δ 170.2,
152.8, 141.2, 141.0, 134.8, 132.2, 131.6, 131.2, 129.8, 129.5, 129.4,
128.1, 126.9, 122.2, 112.1, 47.4, 27.3, 21.5, 17.1, 14.1; HRMS (ESI-
QTOF): m/z Calcd for C25H23O2N2BF3K + H+: 491.1520, found:
491.1513.
Telmisartan (1). 2-Bromo-1-methyl-benzimidazole 8 (40 mg, 0.19
mmol) and 16 (97.6 mg, 0.20 mmol) were combined with KOH (31.9
mg, 0.57 mmol) and 2 mol % PdCl2dppf (2.8 mg, 0.004 mmol) in a
1:1 mixture of H2O and EtOH (4 mL). The solution was heated using
microwave irradiation, in a sealed tube, with stirring for 30 min at 150
°C. Temperature was monitored using an IR temperature sensor. The
solution was filtered through Celite. To the filtrate, 10 mL of H2O
were added, and the pH was adjusted to 4 using AcOH. The resulting
precipitate was filtered and dried in an oven producing telmisartan
Corresponding Authors
*E-mail: kbelecki@vcu.edu.
*E-mail: bfgupton@vcu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Corning Inc., Altria Group Inc., and
Virginia Commonwealth University for their support of this
project. We would also like to thank Kendra Brinkley for
supplying the Pd/G catalyst and Conrad Roos for assistance in
the preparation of stockpiled intermediates.
D
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REFERENCES
■
(1) Wienen, W.; Hauel, N.; Van Meel, J. C. A.; Narr, B.; Ries, U.;
Entzeroth, M. Br. J. Pharmacol. 1993, 110, 245−252.
(2) Battershill, A. J.; Scott, L. J. Drugs 2006, 66, 51−83.
(3) McClellan, K. J.; Markham, A. Drugs 1998, 56, 1039−1044.
(4) Cernes, R.; Mashavi, M.; Zimlichman, R. Vasc. Health Risk
Manag. 2011, 7, 749−759.
(5) Burnier, M.; Brunner, H. R. Lancet 2000, 355, 637−645.
(6) Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.;
Desai, P.; Pravenec, M.; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W.
Hypertension 2004, 43, 993−1002.
(7) Benndorf, R. A.; Rudolph, T.; Appel, D.; Schwedhelm, E.; Maas,
R.; Schulze, F.; Silberhorn, E.; Boger, R. H. Metab., Clin. Exp. 2006, 55,
1159−1164.
(8) Mann, J. F. E.; Schmieder, R. E.; McQueen, M.; Dyal, L.;
Schumacher, H.; Pogue, J.; Wang, X.; Maggioni, A.; Budaj, A.;
Chaithiraphan, S.; Dickstein, K.; Keltai, M.; Metasarinne, K.; Oto, A.;
̈
Parkhomenko, A.; Piegas, L. S.; Svendsen, T. L.; Teo, K. K.; Yusuf, S.
Lancet 2008, 372, 547−553.
(9) Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu,
Y.; Venkatraman, S.; Bhattacharya, A.; Mathad, V. T. Org. Process Res.
Dev. 2007, 11, 81−85.
(10) Ries, U. J.; Mihm, G.; Narr, B.; Hasselbach, K. M.; Wittneben,
H.; Entzeroth, M.; Van Meel, J. C. A.; Wienen, W.; Hauel, N. H. J.
Med. Chem. 1993, 36, 4040−4051.
(11) Hauel, N.; Dach, R.; Heitger, H.; Meyer, O. U.S. Patent 2004,
0236113A1.
(12) Kankan, R. N.; Rao, D. R.; Srinivas, P. L.; Ravikumar, P. U.K.
Patent 2005, GB2414019A.
(13) Rao, C. H.; Naresh, T.; Satyanarayana, K.; Reddy, B. R.; Reddy,
G. M. Synth. Commun. 2010, 40, 530−534.
(14) Wang, P.; Zheng, G.; Wang, Y.; Wang, X.; Wei, H.; Xiang, W.
Tetrahedron 2012, 68, 2509−2512.
(15) Goosen, L. J.; Knauben, T. J. Org. Chem. 2008, 73, 8631−8634.
(16) Kumar, A. S.; Ghosh, S.; Mehta, G. N.; Soundararajan, R.;
Sarma, P. S. R.; Bhima, K. Synth. Commun. 2009, 39, 4149−4157.
(17) Kumar, A. S.; Ghosh, S.; Mehta, G. N. Beilstein J. Org. Chem.
2010, 6, No. 25.
(18) Mistry, A. G.; Smith, K. Tetrahedron Lett. 1986, 27, 1051−1054.
(19) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102,
4009−4091.
(20) Velaparthi, U.; Wittman, M.; Liu, P.; Carboni, J. M.; Lee, F. Y.;
Attar, R.; Balimane, P.; Clarke, W.; Sinz, M. W.; Hurlburt, W.; Patel,
K.; Discenza, L.; Kim, S.; Gottardis, M.; Greer, A.; Li, A.; Saulnier, M.;
Yang, Z.; Zimmermann, K.; Trainor, G.; Vyas, D. J. Med. Chem. 2008,
51, 5897−5900.
(21) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007,
9, 757−760.
(22) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302−
4314.
(23) Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2003, 4313−4327.
(24) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973−980.
(25) Displacement of the bromide on benzimidazole 8 by the
nucleophilic nitrogen of 9 was observed to compete with the desired
Suzuki coupling between 8 and 9. See Scheme S1.
(26) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483.
(27) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419−2440.
(28) Siamaki, A. R.; Khder, A. E. R. S.; Abdelsayed, V.; El-Shall, M. S.;
Gupton, B. F. J. Catal. 2011, 279, 1−11.
E
DOI: 10.1021/jo5025333
J. Org. Chem. XXXX, XXX, XXX−XXX