Suzuki-Miyaura cross-coupling of potassium organoborates with 6-sulfonate benzimidazoles using microwave irradiation

Article abstract of DOI:10.1002/jhet.1109

This article focuses on the utility of organotrifluoroborate salts as coupling partners for Suzuki-Miyaura cross-coupling with 4-nitro-6-triflyl benzimidazoles using microwave irradiation. The C-C bond formation at the 6-position of the electron-rich 1-,4

Full text of DOI:10.1002/jhet.1109

E166
Suzuki–Miyaura Cross-Coupling of Potassium Organoborates with 6-Sulfonate
Vol 50
Benzimidazoles Using Microwave Irradiation
*
Prashi Jain, Shuyan Yi, and Patrick Thomas Flaherty
School of Pharmacy, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne
University, Pittsburgh, Pennsylvania, United States
*
E-mail: flahertyp@duq.edu
Received September 2, 2010
DOI 10.1002/jhet.1109
Published online 18 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
This article focuses on the utility of organotrifluoroborate salts as coupling partners for Suzuki–Miyaura
cross-coupling with 4-nitro-6-triflyl benzimidazoles using microwave irradiation. The C–C bond formation at
the 6-position of the electron-rich 1-,4-,6-trisubstituted benzimidazole core is challenging and was not achievable
via Kumada, Negishi, Stille, or Heck coupling strategies. Yields of 37–70% could be obtained via palladium
coupling strategies utilizing potassium benzyl trifluoroborates as the organometallic coupling partner.
J Heterocyclic Chem., 50, E166 (2013).
INTRODUCTION
species in one pot [7]. Reviews on the utility of potassium
trifluoroborate salts are available [1,5,6,8,9].
Palladium-catalyzed carbon–carbon bond forming reac-
tions are a central tenet of modern synthetic organic chemis-
try. Various methods currently exist for palladium-catalyzed
formation of C–C bonds [1,2]. The Suzuki–Miyaura cross-
coupling reaction[3] has numerous advantages including mild
reaction conditions, functional group tolerance, low toxicity,
and the ready availability of organoboron compounds [1].
Boronic acid, boronate esters, and organoboranes have been
employed as coupling partners for Suzuki–Miyaura cross-
coupling reactions. However, limitations still exist such as
difficulty in purification, indeterminate stoichiometry, air
and moisture instability of boronic acids, and cost [4].
In contrast, potassium trifluoroborate salts are air-stable
and moisture-stable crystalline solids. Potassium organotri-
fluoroborates show greater nucleophilicity than their
corresponding organoboranes or boronic acid derivatives
[4,5]. They are less prone to protodeboronate during cross-
coupling reactions even at elevated temperatures. NMR
studies established that fluoride/hydroxyl exchange on the
organotrifluoroborates existed. This discovery resulted in
cross-coupling reaction protocols, where water and a base
were used as essential components for the success of the
reaction. Trifluoroborate can be viewed as a protected
boronic acid, producing intermediates analogous to those
generated by traditional boronic acid precursors in a palla-
dium-coupling reactions [6]. Potassium trifluoroborate salts
can be easily prepared by boration of a substituted benzyl
bromide or by transmetallation from an organomagnesium
The benzimidazole nucleus is an important heterocycle
because of its broad range of pharmacological activities
and high thermal stability [10]. It is a component of several
antifungal, antiulcer, and antibacterial agents and has
recently been reported as a scaffold for kinase inhibitors
[11–13]. Although the benzimidazole core has demonstrated
both utility and future potential, functionalization on the
benzimidazole scaffold is challenging. Functionalization at
the 1-, 2-, and 3-positions are reported and structurally tracta-
ble [14,10]. Functionalization at the 5-position or 6-position
of benzimidazole is less fully explored [15]. There is need
for organometallic couplings on the benzimidazole core.
As a part of our continuing interest in 6-hydroxy-derived
1,4-disubstituted benzimidazoles [16], we sought efficient
ways to functionalize the 6-hydroxy substituent of the
benzimidazole core to the corresponding 6-carbon analogues.
Carbon–carbon bond forming reactions of sp3-hybridized
organoboranes with sp2 or aromatic hybridized triflates or
bromides have been reported previously by the Molander
group [17]. There are no reported methods for the cross-
coupling of benzimidazoles at the 6-position. The electrophi-
licity of a trisubstituted benzimidazole core is significantly
reduced because of the electron-rich nature of the imidazole
moiety that makes coupling at the 6-position difficult. The
presence of a nitro group at 4-position of a benzimidazole
scaffold was anticipated to reduce the electron-rich nature
of the imidazole ring and the known greater nucleophilicity
of the potassium trifluoroborate compared with the
© 2013 HeteroCorporation

February 2013
Suzuki-Miyaura Cross Coupling of Potassium Oraganoborates with 6-Sulfonate
Benzimidazoles Using Microwave Irradiation
E167
corresponding boronic acid, suggested the potential utility of
this strategy, and provided a point for structural elaboration
found to be relevant to kinase inhibition [16]. Novel functiona-
lization of 1-,4-,6-trisubstituted benzimidazoles at 6-position
using Suzuki–Miyaura cross-coupling conditions is presented.
giving poor or no conversion. Thus, Suzuki–Miyaura
cross-coupling on the electron-rich benzimidazole core was
conceivable (Scheme 2) but had not yet been reduced to
the level of practical utility.
Under established conditions [17], when triflate 3 and the
commercially available potassium benzyl trifluoroborate salt
4a were treated with cesium carbonate, THF, water, and
palladium catalyst at reflux (68ꢀC) for 24 h, the reaction
did not proceed to completion and the coupled product could
not be isolated. When the reaction was heated using micro-
wave irradiation at 100ꢀC for 20 min, the reaction proceeded
and the product 5a was isolated in 20% yield. Unreacted
starting material 3 was recovered with 50% efficiency.
Optimization of the reaction time and temperature under
microwave irradiation provided improved yield with substi-
tuted benzyl analogues. The utility of microwave heating in
facilitating palladium coupling reactions is believed to result
from achieving higher internal temperatures (110ꢀC for
microwave compared with 66ꢀC on the bench top) and a
resultant acceleration of the rate of reaction.
Non-commercially available potassium benzyl trifluoro-
borates 4b–e were synthesized from the corresponding
halides 6b–d in acceptable yield. A one-pot procedure
was pursued to permit isolation of the more stable benzyl
trifluoroborate salt rather than utilizing the unstable
trivalent organoboron species. The precursor halides were
treated with Mg metal in dry diethylether under argon to
yield the Grignard reagent, followed directly by boron
exchange with trimethoxyborane to give the intermediate
trivalent organoboron species, and followed by final
treatment with KHF2 to produce the stable substituted
potassium benzyl trifluoroborates 4b–e [27]. Conversion
to the Grignard species 7b–d was assayed with anhydrous
diphenyl acetic acid as a titrant and 1,10-phenanthroline as
an indicator [28]. Grignard reagent 7e was commercially
available. Electron-withdrawing groups on the benzyl ring
provide moderate to good yield with this three-step reaction
sequence (24%), whereas electron-donating groups such as
4-OMe give a lower yield (20%). The synthesis of the
substituted potassium benzyl trifluoroborates examined is
presented in Scheme 3.
RESULTS AND DISCUSSION
We have reported aryl hetero bond formation at 6-position
of benzimidazole in the development of CDK5 [18] and
MEK5 [16] inhibitors. To complete our structure activity
relationship studies of these series, we wanted to explore
carbon analogues at the 6-position. There is no reported liter-
ature method for the C–C bond formation of benzimidazoles
at the 6-position. Synthesis of common intermediate 1 was
previously described and proceeded well [19]. Compound 1
was subjected to demethylation in 48% HBr at 120ꢀC for
2.5 h with microwave irradiation. Compound 2 was then
treated with 4-nitrophenyl trifluoromethanesulfonate and po-
tassium carbonate at room temperature to generate the triflate
3 in 87% yield. This synthetic route is presented in Scheme 1.
Attempted triflate ester formation utilizing triflic anhydride
and pyridine resulted in lower yield and lower purity. Other
sulfonyl-leaving groups have also been prepared and exam-
ined, but triflates were the only reactive members of the sulfo-
nyl family identified. Early attempts to couple triflate 3 with
different nucleophiles are summarized in Table 1.
Initial Fe(acac)3 catalyzed cross-coupling with EtMgBr
as the organometallic coupling partner [20] did not proceed.
Ni(0)-catalyzed Kumada coupling [21] utilizing Ni(dppp)
Cl2 and PhCH2MgBr as the organometallic coupling
partner also failed. Attempts at Stille coupling [22] with
tributyl(3-Me-2-butenyl)tin as the organometallic coupling
partner also failed. Negishi [23] cross-coupling with
PhCH2ZnBr as the organometallic coupling partner with a
variety of palladium ligands gave a complicated mixture
with inseparable products. Heck coupling [24] with ethyl
methacrylate at 120ꢀC using microwave irradiation also
did not provide any conversion to the product.
Failure of the aforementioned methods prompted us to
explore a Suzuki–Miyaura cross-coupling strategy employ-
ing the very nucleophillic potassium benzyltrifluoroborates.
It is established [17,25,26] that potassium benzyltrifluorobo-
rates can react with aryl triflates generating a C–C bond.
Previously electron-rich aryl triflates were identified as
All substituted potassium benzyl trifluoroborate salts
were subjected to Suzuki–Miyaura cross-coupling using
microwave irradiation with the common intermediate 3 to
generate compounds 5a–e in 50–70% isolated yield. The
Scheme 1. Preparation of common intermediates.
Journal of Heterocyclic Chemistry
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P. Jain, S. Yi, and P. T. Flaherty
Vol 50
Table 1
Attempted coupling strategies with 3.
Organometallic coupling partner
Catalyst/ligand
Solvent
Temperature (ꢀC)/time (h)
Result
(CH3)2CHCH2MgBr
CH3CH2MgBr
PhCH2MgBr
Tributyl(3-Me-2-butenyl)tin
PhCH2ZnBr
Fe(acac)3
Fe[Salen] complex
Ni(dppp)Cl2
Pd(PPh3)4, LiCl
Pd2dba3
THF/NMP
THF
THF
Dioxane
THF
THF
THF
THF
THF
DMF
23, 2
23, 3
NR
NR
NR
CM
CM
CM
CM
CM
CM
NR
23, 20
101, 7
68, 20
68, 20
68, 20
68, 20
68, 20
120, 2
Pd(dppf)Cl2ÁCH2Cl2
Pd(PPh3)4
Pd(OAc)2 and Xantphos
Pd(OAc)2 and DPEphos
(PPh3)2•PdCl2 NaHCO3
Ethyl methacrylate
NR = no reaction, CM = complicated mixture, no clear evidence of product
EXPERIMENTAL
2-F substituted benzyl analogue 4c generated a lower yield
due to electron-withdrawing effects or perhaps due to steric
hindrance (Table 2).
All solvents and reagents were used as received unless noted
otherwise. Tetrahydrofuran (THF) was distilled from Na-benzo-
phenone ketyl radical under a blanket of argon prior to use. All
reactions were conducted in dry glassware and under an atmo-
sphere of argon unless otherwise noted. Microwave reactions
were conducted in sealed tube and utilized a multimode Milestone
Start apparatus for irradiation with power and control parameters
as noted. Melting points were determined on a MelTemp appara-
tus and are uncorrected. All proton NMR spectra were obtained
with 500 or 400 MHz Oxford spectrospin cryostat, controlled by
a Bruker Avance system, and were acquired using Bruker Top-
spin 2.0 acquisition software. Acquired FIDs were analyzed using
MestReC 3.2. Elemental analyses were conducted by Atlantic
Microlabs and are Æ0.4 of theoretical. All HRMS mass spectral
analyses were conducted at Duquesne University with a nano
ESI chip cube TOF HRMS and are Æ0.004 of theoretical. All
1H NMR spectra were taken in CDCl3 unless otherwise noted
and are reported as parts per million relative to TMS as an internal
standard. Coupling values are reported in hertz.
1-Isopropyl-4-nitro-1H-benzo[d]imidazol-6-ol (2). 1-Isopropyl-
6-methoxy-4-nitro-1H-benzo[d]imidazole (1.00 g, 4.25 mmol) and
48% HBr (20 mL) were added to a 50 mL microwave tube. The
mixture was subjected to microwave irradiation (350 W) to maintain
120ꢀC for 2.5 h. After cooling, solvent was removed on the rotavap.
The resulting yellow solid was dissolved in minimum amount of
water. Saturated NaHCO3 (aq) was added until pH = 6. The mixture
was filtered and the yellow solid was collected and washed with
water then dried under high vacuum (150 mm) to afford 0.92 g (97%)
of the desired compound 2. Rf 0.36 (CH2Cl2/MeOH/NH4OH
100 : 10 : 0.1). mp 206–207ꢀC. 1H NMR (DMSO-d6): d 10.16 (s,
1H), 8.45 (s, 1H), 7.51 (d, J= 2.0 Hz, 1H), 7.40 (d, J=2.0Hz, 1H),
4.68–4.75 (m, 1H), 1.50 (d, J= 6.8 Hz, 6H). Anal. Calcd. for
C10H11N3O3: 0.131 HBr: C, 51.81; H, 4.84; N, 18.12; O, 21.70.
Found: C, 51.84; H, 4.73; N, 18.07.
Another common intermediate 8 was also explored.
Compound 9 was treated with hydrobromic acid for 2.5 h
at 120ꢀC in microwave to yield 10 in 86% yield. Triflate
8 was prepared from 10 with 4-nitrophenyl trifluoromethane-
sulfonate at 23ꢀC in 87% over 4 h. Triflate 8 underwent
Suzuki–Miyaura cross-coupling with potassium trifluorobo-
rate salt 4a to afford 11 in 17% yields. Yields were consistent
with the isopropyl variant (Schemes 4 and 5).
An attempt [29] to prepare the 6-benzimidazolyl organo-
boron reagent 12 and then couple with an electrophile [30]
to generate 5a is shown in Scheme 6. This strategy was not
successful. A rationale for this lack of reactivity is that the
generated aryl organoborane lacks sufficient nucleophilicity
to couple with a normally very reactive electrophile and
establishes the practical necessity for use of the potassium tri-
fluoroborate in Suzuki–Miyaura couplings with this system.
CONCLUSIONS
Palladium-catalyzed cross-coupling reaction of potas-
sium aryltrifluoroborates with less reactive benzimidazole
triflates is achievable with microwave irradiation. The ad-
vantage of the microwave irradiation method includes
shorter reaction time, fewer side reactions, and higher
product yield, when contrasted against conventionally
heated Suzuki–Miyaura cross-coupling reactions.
Scheme 2. Suzuki–Miyaura cross-coupling using potassium trifluorobo-
1-Isopropyl-4-nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate
(3). Solid K2CO3 (608.1 mg, 4.4 mmol) was added to a solution of
1-isopropyl-4-nitro-1H-benzo[d]imidazol-6-ol (486.7 mg, 2.2 mmol)
and 4-nitrophenyl trifluoromethanesulfonate (656.5 mg, 2.42 mmol)
in 11mL of DMF. This suspension was stirred at 23ꢀC for 2 h.
The reaction mixture was diluted with CH2Cl2 (250 mL) and then
filtered. The filtrate was washed with water (100 mL Â 4) and
brine and dried over sodium sulfate. Evaporation of the solvent
gave a yellow oil, which was then subjected to silica gel column
rate salts.
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February 2013
Suzuki-Miyaura Cross Coupling of Potassium Oraganoborates with 6-Sulfonate
Benzimidazoles Using Microwave Irradiation
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Scheme 3. Synthesis of substituted potassium benzyltrifluoroborates.
Table 2
Synthetic route for compounds 5a–e.
Triflate
R-BF3K
Product
Isolated yield (%)
37a
3
3
70b
3
3
3
38b
58b
50b
a1.1 equiv R-BF3K, 1.5 equiv Cs2CO3, THF/H2O (1/0.1), 0.1 equiv PdCl2(dppf)•CH2Cl2, MW, 100ꢀC, 1 ~ 2.5 h.
b3.0 equiv Cs2CO3.
Journal of Heterocyclic Chemistry
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P. Jain, S. Yi, and P. T. Flaherty
Vol 50
Scheme 4. N-1-Cyclopentyl benzimidazole analogues.
Scheme 5. Synthetic strategies for N-1-cyclopentyl benzimidazole
J= 6.75 Hz, 6H). Anal. Calcd. for C17H17N3O2: C, 69.14; H, 5.80; N,
analogues.
14.23. Found: C, 68.97; H, 5.80; N, 14.23.
Potassium (3-chlorobenzyl)trifluoroborate (4b).
A dry
single-neck round bottom flask with a nitrogen inlet was
charged with trimethoxyborate (780.0 mg, 7.5 mmol) and in
10 mL of THF. The solution was cooled to À78 ꢀC, and (3-
chlorobenzyl)magnesium chloride 0.85 M in THF (5.9 mL,
5 mmol) was added dropwise over 15 min. The mixture was
stirred at À78ꢀC for 1 h and then allowed to warm to room
temperature over 1 h. The resulting white slurry was cooled to
0ꢀC, and MeOH (5 mL) was added dropwise over 5 min. Then
the nitrogen inlet was removed and a 4.5 M aqueous solution of
KHF2 (6.5 mL, 30 mmol) was added dropwise at 0ꢀC. After the
addition, the mixture was stirred at 0ꢀC for 1 h. The mixture
was concentrated and azeotroped with toluene three times at
60ꢀC on the rotavap to remove residual water and then dried
under high vacuum overnight to afford a white solid. This solid
was broken into a fine powder with a spatula and suspended in
10 mL of acetone on rotavap with rotation at atmosphere
pressure for 5 min at 40ꢀC. The suspension was filtered through
Celite. Acetone (5 mL) was added to the remaining solid in the
flask, and the procedure was repeated two more times. The
combined filtrates were concentrated under vacuum. The solid
obtained was suspended in 4 mL of Et2O and filtered, and the
collected solid was washed with an additional 4 mL of aliquots
of Et2O, then dried under high vacuum to afford 747.0 mg of
chromatography (Hex/EA/TEA 1 : 1 : 0.005) to afford 673.0 mg of
the triflate 3 (87%). Rf 0.42 (CH2Cl2/MeOH/NH4OH 100 : 5 : 0.1).
1
mp 129.5–130.5ꢀC. H NMR (DMSO-d6): d 8.33 (s, 1H), 8.08
(d, J = 2.2 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 4.71 (m, J = 6.71 Hz,
1H), 1.70 (d, J = 6.77Hz, 6H). Anal. Calcd. for C11H10F3N3O5S:
C, 37.40; H, 2.85; N, 11.89. Found: C, 37.43; H, 2.79; N, 11.84.
6-Benzyl-1-isopropyl-4-nitro-1H-benzo[d]imidazole (5a).
A
dry microwave tube with a stir bar was charged with 1-isopropyl-
4-nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate
(353.0 mg, 1.0 mmol), potassium benzyltrifluoroborate (198.0 mg,
1.0 mmol), Cs2CO3 (488.7 mg, 1.50 mmol), and PdCl2(dppf)•CH2Cl2
(81.66 mg, 0.1 mmol). The microwave tube was capped with a
rubber septum and underwent three vacuum/N2 purge cycles.
Degassed deionized water (0.7 mL) and THF (7 mL) were added via
syringe. The rubber septum was quickly removed and replaced with
the microwave tube cap. The mixture was subjected to microwave
irradiation at 250 W to maintain 110ꢀC for 1.5 h. After cooling to
room temperature, the mixture was filtered through Celite. The
filtrate was extracted with EA. The combined extracts were washed
with 5 mL brine and dried over magnesium sulfate. Filtration then
evaporation of the solvent under reduced pressure gave a brown
solid, which was subjected to silica gel column chromatography
(Hex/EA/TEA 1 : 1 : 0.005) to afford 70.0 mg of the desired product
in 5a (32%). Rf 0.4 (CH2Cl2/MeOH/NH4OH 100 : 5 : 0.1). mp 106–
106.5ꢀC. 1H NMR (CDCl3): d 8.18 (s, 1H), 8.05 (d, J=1.26Hz 1H),
7.52 (d, J= 0.93 Hz, 1H), 7.34 (m, 2H), 7.27 (m, 1H), 7.22 (d,
J= 7.16 Hz, 2H), 4.64 (m, J= 6.75 Hz, 1H), 4.21 (s, 2H), 1.63 (d,
the desired salt (64%). 1H NMR (DMSO-d6):
d 7.05(t,
J = 27.6 Hz 1H), 6.96 (s, 1H), 6.89–6.92 (m, 2H), 1.44 (br, 2H).
6-(3-Chlorobenzyl)-1-isopropyl-4-nitro-1H-benzo[d]imidazole
(5b).
A 10 mL dry microwave reactor tube with a stir bar
was charged with 1-isopropyl-4-nitro-1H-benzo[d]imidazol-6-yl
trifluoromethanesulfonate (176.6 mg, 0.50 mmol), potassium
(3-chlorobenzyl)trifluoroborate (137.5 mg, 0.59 mmol), Cs2CO3
(485.7 mg, 1.50 mmol), and PdCl2(dppf)•CH2Cl2 (41.0 mg,
0.05 mmol). The microwave reactor tube was capped with a
rubber septum, evacuated and underwent three vacuum/N2
purge cycles. Degassed deionized water (0.5 mL) and THF
(5 mL) were added via syringe. The rubber septum was quickly
removed and replaced with the microwave reactor tube cap,
Scheme 6. Alternate Suzuki–Miyaura cross-coupling strategy.
Journal of Heterocyclic Chemistry
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February 2013
Suzuki-Miyaura Cross Coupling of Potassium Oraganoborates with 6-Sulfonate
Benzimidazoles Using Microwave Irradiation
E171
and the mixture was subjected to microwave irradiation at 100ꢀC
for 2.5 h. After cooling to room temperature, the mixture was
filtered through Celite. The filtrate was extracted with EA. The
combined extracts were washed with brine and dried over
magnesium sulfate. Filtration and then evaporation of the
solvent gave a brown solid, which was subjected to silica gel
column chromatography (Hex/EA/TEA 1 : 1 : 0.005) to afford
673.0 mg of 5b (70%). Rf 0.37 (CH2Cl2/MeOH/NH4OH
100 : 5 : 0.1). mp 136.7–137.1ꢀC. 1H NMR (CDCl3): d 8.18
(s, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.23 (m, 2H), 7.18 (s, 1H),
7.09 (d, J = 7.5 Hz, 1H), 4.61–4.67 (m, 1H), 4.16 (s, 2H), 1.63
(d, J = 7.0 Hz, 6H). Anal. Calcd. for C17H16ClN3O2: C, 61.91;
H, 4.89; Cl, 10.75; N, 12.74; O, 9.70. Found: C, 62.20; H,
4.91; N, 12.59.
(s, 2H), 1.63 (d, J = 6.8Hz, 6H). Anal. Calcd. for C17H16FN3O2:
C, 65.17; H, 5.15; F, 6.06; N, 13.41; O, 10.21 Found: C, 64.98;
H, 5.16; N, 13.33.
Potassium (4-fluorobenzyl)trifluoroborate (4d).
A dry
single-neck round bottom flask with a nitrogen inlet was
charged with trimethoxyborate (780.0 mg, 7.5 mmol) and 10 mL
of THF. The solution was cooled to À78ꢀC, and
(4-fluorobenzyl) magnesium chloride 0.75 M in THF (6.7 mL,
5 mmol) was added dropwise over 15 min. The mixture was
stirred at À78ꢀC for 1 h and then allowed to warm to room
temperature over 1 h. The resulting white slurry was cooled to
0ꢀC, and MeOH (5 mL) was added dropwise over 5 min. Then
the nitrogen inlet was removed, and 4.5 M aqueous solution of
KHF2 (6.5 mL, 30 mmol) was added dropwise at 0ꢀC. After
addition, the mixture was stirred at 0ꢀC for 1 h. The mixture
was concentrated and azeotroped with toluene three times at
60ꢀC on the rotavap to remove residual water and then dried
under high vacuum overnight to afford a white solid. The solid
was broken into a fine powder with a spatula and then
suspended in 10 mL acetone on rotavap with rotation at
atmosphere pressure for 5 min at 40ꢀC. The suspension was
filtered through Celite. Acetone (5 mL) was added to the
remaining solid in the flask, and the procedure was repeated two
more times. The combined filtrate was concentrated under
vacuum. The solid obtained was suspended in 10 mL of Et2O,
then filtered, and the collected solid was washed with 10 mL of
Et2O and dried under high vacuum to afford 399.6 mg of 4d
(37%). 1H NMR (DMSO-d6): d 6.94–6.97 (m, 2H), 6.81–6.84
(m, 2H), 1.41 (br, 2H).
6-(4-Fluorobenzyl)-1-isopropyl-4-nitro-1H-benzo[d]imidazole
(5d). A dry microwave tube with a stir bar was charged with 1-
isopropyl-4-nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate
(176.6 mg, 0.50 mmol), potassium (2-fluorobenzyl)trifluoroborate
(129.6 mg, 0.60 mmol), Cs2CO3 (485.7 mg, 1.50 mmol), and
PdCl2(dppf)•CH2Cl2 (41.0 mg, 0.05 mmol). The microwave
tube was capped with a rubber septum and subjected to three
vacuum/N2 purge cycles. Degassed deionized water (0.5 mL)
and THF (5 mL) were added via syringe. The rubber septum
was quickly removed and replaced with the microwave tube
cap, and the mixture was subjected to microwave irradiation
at 250 W to maintain a temperature of 100ꢀC for 3 h. After
cooling down to room temperature, the mixture was filtered
through Celite. The filtrate was extracted with EA. The
combined extracts were washed with brine and then dried
over magnesium sulfate. Filtration then evaporation of the
solvent gave a brown solid, which was subjected to silica gel
column chromatography (Hex/EA/TEA 1 : 1 : 0.005) to afford
91.0 mg of 5d (58%). Rf 0.42 (CH2Cl2/MeOH/NH4OH
100 : 5 : 0.1). 1H NMR (CDCl3): d 8.18 (s, 1H), 7.99 (d,
J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.15–
7.18 (m, 2H), 6.98–7.03 (m, 2H), 4.62–4.68 (m, 1H), 4.17 (s,
2H), 1.63 (d, J = 8.5 Hz, 6H). HRMS (EI) Calcd. for
C17H16FN3O2: 314.1260. Found 314.1311 [M═H+].
Potassium (2-fluorobenzyl)trifluoroborate (4c).
A dry
single-neck round bottom flask with a nitrogen inlet was
charged with trimethoxyborate (780 mg, 7.5 mmol) and 10 mL of
THF. The solution was cooled to À78ꢀC, and (2-fluorobenzyl)
magnesium chloride 0.74 M in THF (6.8 mL, 5 mmol) was added
dropwise over 15 min. The mixture was stirred at À78ꢀC for 1 h
and then allowed to warm to room temperature over 1 h. The
resulting white slurry was cooled to 0ꢀC, and methanol (5 mL)
was added dropwise over 5 min. Then the nitrogen inlet was
removed, and a 4.5 M aqueous solution of KHF2 (6.5 mL,
30 mmol) was added over 5 min at 0ꢀC. After addition, the
mixture was stirred at 0ꢀC for 1 h. The mixture was concentrated
and azeotroped with toluene three times at 60ꢀC on the rotavap
to remove residual water and then dried under high vacuum
overnight to afford a white solid. The solid was broken into a
fine powder with a spatula and suspended in 10 mL acetone on
rotavap with rotation at atmosphere pressure for 5 min at 40ꢀC.
The suspension was filtered through Celite. Acetone (5 mL) was
added to the remaining solid in the flask, and the procedure was
repeated two more times. Combined filtrates were concentrated
on vacuum. The solid obtained was dissolved into minimal
amount of hot acetone (4 mL), and Et2O (5 mL) was added
dropwise to precipitate the white solid. The mixture was slowly
cooled to room temperature, placed in ice bath for 1 h and then
in the refrigerator for another 2 h. The mixture was filtered, and
the white solid was collected and dried under vacuum to afford
498 mg (46%) of the desired product (4c).
6-(2-Fluorobenzyl)-1-isopropyl-4-nitro-1H-benzo[d]imidazole
(5c). A dry microwave reactor tube with a stir bar was charged with 1-
isopropyl-4-nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate
(212.0mg, 0.60 mmol), potassium (2-fluorobenzyl)trifluoroborate
(155.4mg, 0.72 mmol), Cs2CO3 (586.4 mg, 1.80mmol), and
PdCl2(dppf)•CH2Cl2 (50.0 mg, 0.06 mmol). The microwave
reactor tube was capped with a rubber septum and subjected to
three vacuum/N2 purge cycles. Degassed deionized water
(0.6 mL) and THF (6 mL) were added via syringe. The rubber
septum was quickly removed and replaced with the microwave
reactor tube cap, and the mixture was subjected to microwave
irradiation at 250 W to maintain a temperature of 100ꢀC for 1.5h.
After cooling to room temperature, the mixture was filtered
through Celite. The filtrate was extracted with EA. The combined
extracts were washed with brine and dried over magnesium
sulfate. Filtration and evaporation of the solvent gave a brown
solid, which was subjected to silica gel column chromatography
(Hex/EA/TEA 1 : 1 : 0.005) to afford 72.0mg of 5c (38%). Rf 0.36
(CH2Cl2/MeOH/NH4OH 100 : 5 : 0.1). mp 124.8–125.1ꢀC. 1H
NMR (CDCl3): d 8.16 (s, 1H), 8.03 (s, 1H), 7.58 (s, 1H), 7.18–
1.25 (m, 2H), 7.04–7.11 (m, 2H), 4.62–4.68 (m, 1H), 4.19
Potassium (4-methoxybenzyl)trifluoroborate (4e).
A dry
single-neck round bottom flask with a nitrogen inlet was charged
with trimethoxyborate (0.74mL, 6.5 mmol) and 10mL of THF.
The solution was cooled to À78ꢀC, and (2-fluorobenzyl)
magnesium chloride 0.217 M in THF (20 mL, 4.34 mmol) was
added dropwise over 15 min. The mixture was stirred at À78ꢀC
for 1 h and then allowed to warm to room temperature over 1 h.
The resultant white slurry was cooled to 0ꢀC, and methanol
(5mL) was added dropwise over 5 min. The nitrogen inlet was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E172
P. Jain, S. Yi, and P. T. Flaherty
Vol 50
removed, and a 4.5 M aqueous solution of KHF2 (5.78 mL,
26mmol) was added at 0ꢀC. After addition, the mixture was
stirred at 0ꢀC for 1 h. The mixture was concentrated and
azeotroped with toluene three times at 60ꢀC on the rotavap to
remove residual water and dried under high vacuum overnight
to afford a white solid. The solid was broken into fine powder
with a spatula and then suspended in 10mL acetone on rotavap
with rotation at atmosphere pressure for 5 min at 40ꢀC. The
suspension was filtered through Celite. Acetone (5mL) was
added to the remaining solid in the flask and the procedure was
repeated two more times. The combined filtrates were
concentrated under vacuum. The solid obtained was dissolved in
minimum amount of hot acetone (4mL), and Et2O (5mL) was
added to precipitate a white solid. The mixture was slowly
cooled to room temperature, placed in ice bath for 1 h and in
refrigerator for another 2 h. The mixture was filtered, and the
white solid was collected and then dried under vacuum to afford
135.0 mg (14%) of the desired product 4e. 1H NMR (DMSO-
d6): d 6.89–6.90 (m, 2H), 6.62–6.64 (m, 2H), 3.65 (s, 3H), 1.37
(br, 2H).
1H NMR (400 MHz, CDCl3): d 8.08 (s, 1H), 7.79 (d, J = 2.32Hz,
1H), 7.23(d, J = 2.3 Hz, 1H), 4.68–4.75 (m, 1H), 3.95 (s, 3H),
2.35–2.30 (m, 2H), 1.83–2.05 (m, 6H). Anal. Calcd. for
C13H15N3O3: C, 59.76; H, 5.79; N, 16.08; O, 18.37. Found:
C,59.88; H, 5.84; N, 16.27.
1-Cyclopentyl-4-nitro-1H-benzo[d]imidazol-6-ol hydrobromide
(10).
A 50 mL microwave reactor tube was charged with 1-
(0.75 g,
cyclopentyl-6-methoxy-4-nitro-1H-benzo[d]imidazole
2.87 mmol) and 48% HBr (10 mL) and subjected to microwave
irradiation at 250 W to maintain a temperature of 120ꢀC
for 2.5 h. The solvent was removed in vacuo. The resultant
yellow solid was dissolved in a minimum amount of water.
Solid Na2CO3 was added in small portions until the pH was 6. The
mixture was filtered, and the yellow solid was collected then washed
with water and dried under high vacuum pump to afford 0.6 g
1
(85.7%) of 10. Rf 0.36 (CH2Cl2/MeOH/NH4OH 100 : 10 : 0.1). H
NMR (400 MHz, DMSO-d6): d 10.12 (s, 1H), 8.40 (s, 1H), 7.51
(d, J= 2.17 Hz, 1H), 7.38 (d, J= 2.21 Hz, 1H), 4.81–4.87 (m, 1H),
2.15–2.21 (m, 2H), 1.70–1.96 (m, 6H). Anal. Calcd. for
C12H13N3O3: 1.175. HBr: C, 42.09; H, 4.17; N, 12.27. Found: C,
42.13; H, 4.33; N, 12.12.
6-(4-Methoxy benzyl)-1-isopropyl-4-nitro-1H-benzo[d]imidazole
(5e). A dry microwave tube with a stir bar was charged with 1-
isopropyl-4-nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate
(176.5 mg, 0.50 mmol), potassium (4-methoxybenzyl)trifluoroborate
(135.0mg, 0.60 mmol), Cs2CO3 (488.73 mg, 1.5mmol), and
PdCl2(dppf)•CH2Cl2 (40.83mg, 0.05 mmol). The microwave tube
was capped with a rubber septum and subjected to vacuum/N2
purge cycles three times. Degassed deionized water (0.5mL) and
THF (5mL) were added via syringe. The rubber septum was
quickly removed and replaced with the microwave tube cap, and
the mixture was subjected to microwave irradiation at 250 W to
maintain a temperature of 110ꢀC for 2.5 h. After cooling down to
room temperature, the mixture was filtered through Celite. The
filtrate was extracted with EA. The combined extracts were
washed with brine and dried over magnesium sulfate. Filtration
and then evaporation of the solvent gave a brown solid, which
was subjected to silica gel column chromatography (Hex/EA/TEA
1 : 1 : 0.005) to afford 80.0 mg of 5e (50%). Rf 0.4 (CH2Cl2/
1-Cyclopentyl-4-nitro-1H-benzo[d]imidazol-6-yl trifluoro-
methanesulfonate (8).
Solid K2CO3 (246.0 mg, 1.78 mmol)
was added to a solution of 1-cyclopentyl-4-nitro-1H-benzo[d]
imidazol-6-ol (220.0 mg, 0.89 mmol) and 4-nitrophenyl
trifluoromethanesulfonate (265.5 mg, 0.979 mmol) in 5mL of
DMF. The suspension was stirred at room temperature for 4 h.
Then the reaction mixture was diluted with EA (30 mL) and
filtered. The filtrate was washed with water (20mL Â 5) and brine
and then dried over Na2SO4. Filtration and evaporation of the
solvent gave a yellow oil, which was subjected to silica gel
column chromatography (Hex/EA/TEA 1 : 1 : 0.005) to afford
290.0 mg of triflate 8 (86%). Rf 0.5 (CH2Cl2/MeOH/NH4OH
100 : 5 : 0.1). mp 124–125ꢀC. 1H NMR (400 MHz, CDCl3): d 8.30
(s, 1H), 8.10 (d, J = 2.26 Hz, 1H), 7.74 (d, J = 2.27 Hz, 1H), 4.78–
4.83 (m, 1H), 2.42–2.36 (m, 2H), 1.91–2.05 (m, 6H). Anal. Calcd.
for C13H12F3N3O5S: C, 41.16; H, 3.19; F, 15.03; N, 11.08; O,
21.09; S, 8.45. Found: C, 41.21; H, 3.15; N, 11.08.
1
MeOH/NH4OH 100: 5 : 0.1). H NMR (CDCl3): d 8.16 (s, 1H),
6-Benzyl-1-cyclopentyl-4-nitro-1H-benzo[d]imidazole (11).
A
8.01 (d, J = 1.38 Hz, 1H), 7.50 (d, J = 1.36 Hz, 1H), 7.13 (d,
J = 8.74 Hz, 2H), 6.87 (d, J = 8.71 Hz, 2H), 4.63 (m, 1H), 4.14 (s,
2H), 1.63 (d, J = 6.75 Hz, 6H). HRMS (EI) Calcd. for
C18H19N3O3: 326.1499 [M+ H+]. Found 326.1500 [M+ H+],
348.1317 [M + Na+].
dry microwave tube with a stir bar was charged with 1-cyclopentyl-4-
nitro-1H-benzo[d]imidazol-6-yl trifluoromethanesulfonate (500.0 mg,
1.31 mmol), potassium benzyltrifluoroborate (259.41 mg, 1.31 mmol),
Cs2CO3 (640.23 mg, 1.965 mmol), and PdCl2(dppf)•CH2Cl2
(106.98 mg, 0.131 mmol). The microwave tube was capped with a
rubber septum and subjected to three vacuum/N2 purge cycles.
Degassed deionized water (0.8mL) and THF (8mL) were added
via syringe. The rubber septum was quickly replaced with the
microwave tube cap, and the mixture was subjected to
microwave irradiation at 250 W to maintain 110ꢀC for 1.8 h.
After cooling down to room temperature, the mixture was
filtered through Celite. The filtrate was extracted with EA. The
combined extracts were washed with brine and dried over
magnesium sulfate. Filtration then evaporation of the solvent
gave a brown solid, which was subjected to silica gel column
chromatography (Hex/EA/TEA 1 : 1 : 0.005) to afford 70.0mg of
the desired product (17%). Rf 0.45 (CH2Cl2/MeOH/NH4OH
1-Cyclopentyl-6-methoxy-4-nitro-1H-benzo[d]imidazole (9).
A
500 mL one-neck flask was charged with 5-methoxy-3-nitrobenzene-
1,2-diamine (3.67 g, 20.0 mmol), NaBH(OAc)3 (12.71 g, 60.0 mmol),
THF (60 mL), cyclopentanone (8.948 mL, 100.0 mmol), and formic
acid (2.26 mL, 60.0 mmol). The mixture was stirred overnight. The
solvent was removed in vacuo, and the dark red residue was
dissolved in formic acid (60 mL). Butylated hydroxytoluene
(20 mg) was added, and the mixture was cooled to 0ꢀC.
Concentrated HCl (80 mL) was added, and the mixture was
heated to reflux with a heating mantle. After maintaining reflux
for 25 min, most of the solvent was removed in vacuo at 80ꢀC.
The aqueous solution was neutralized with saturated potassium
carbonate solution to pH 8 and extracted with EA (50 mL Â 4).
The combined extracts were washed with brine and dried over
sodium sulfate. Evaporation of the solvent gave a brown solid,
which was subjected to silica gel column chromatography
(Hex/EA 1 : 1) to afford 2.1 g (40%) of 9 as a yellow solid (40%).
Rf 0.32 (CH2Cl2/MeOH/NH4OH 100 : 10 : 0.1). mp 107–108ꢀC.
1
100 : 5 : 0.1). mp 145–147ꢀC. H NMR (CDCl3): d 8.15 (s, 1H),
8.06 (d, J = 1.41Hz 1H), 7.55(d, J = 1.46Hz, 1H), 7.36 (m, 2H),
7.28 (m, 1H), 7.23 (dd, J = 1.41Hz, J = 8.1 Hz, 2H), 4.75
(m,1H), 4.22 (s, 2H), 2.29–2.36 (m, 2H), 1.85–2.02 (m, 6H).
Anal. Calcd. for C19H19N3O2: C, 71.01; H, 5.96; N, 13.08; O,
9.96. Found: C, 70.83; H, 5.88; N, 13.10.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Suzuki-Miyaura Cross Coupling of Potassium Oraganoborates with 6-Sulfonate
Benzimidazoles Using Microwave Irradiation
E173
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Acknowledgments. The authors would like to thank Tim Fahrenholz
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and NIH (NINDS): 1R15NS057772 and NSF equipment grant for
the NMR (NMR: CHE 0614785).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet