Light Fluorous-tagged traceless one-pot synthesis of benzimidazoles facilitated by Microwave irradiation

Article abstract of DOI:10.2174/138620712800194521

A novel protocol for rapid assemble of benzimidazole framework has been demonstrated. This method incorporated with light fluorous-tag provides a convenient method for diversification of benzimidazoles and for easy purification via fluorous solid-phase extraction (F-SPE) in a parallel manner. The key transformation of this study involves in situ reduction of aromatic nitro compound, amide formation, cyclization and aromatization promoted by microwave irradiation in a one-pot fashion. The strategy is envisaged to be applied for the establishment of drug-like small molecule libraries for high throughput screening.

Full text of DOI:10.2174/138620712800194521

Combinatorial Chemistry & High Throughput Screening, 2012, 15, 411-417
411
Light Fluorous-Tagged Traceless One-Pot Synthesis of Benzimidazoles
Facilitated by Microwave Irradiation
Chih-Chung Tseng, Cheng-Hsun Tasi and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao Tung University, Science Building 2, 1001 Ta Hsueh Road, Hsinchu
300-10, Taiwan
Abstract: A novel protocol for rapid assemble of benzimidazole framework has been demonstrated. This method
incorporated with light fluorous-tag provides a convenient method for diversification of benzimidazoles and for easy
purification via fluorous solid-phase extraction (F-SPE) in a parallel manner. The key transformation of this study
involves in situ reduction of aromatic nitro compound, amide formation, cyclization and aromatization promoted by
microwave irradiation in a one-pot fashion. The strategy is envisaged to be applied for the establishment of drug-like
small molecule libraries for high throughput screening.
Keywords: Benzimidazoles, bioactive heterocycles, fluorous synthesis, F-SPE, microwave chemistry.
INTRODUCTION
Rapidly obtaining of benzimidazole core with diversified
functionality is essential for drug discovery, however
preparation of benzimidazole libraries for biological
screening is still predominated by batch-wise linear synthesis
in solution phase. Although solid-phase synthesis of such
scaffolds has been demonstrated as a combinatorial approach
in this field [8], prolonged reaction time, difficult to
characterize intermediates and limited reaction monitoring
methods are still the most fundamental drawbacks in solid-
phase chemistry due to biphasic reaction matrix.
Benzimidazole heterocycles are pervasively in natural
small
products,
molecule
pharmaceuticals,
dyes,
agrochemicals and functional polymers. Benzimidazoles
exhibit wide spectrum of biological activities such as
antibacterial, antifungal, anti-inflammatory, antiulcer (PPIs),
antiviral and antitumor activities [1, 2]. The versatility in
pharmaceutical activities is probably resulting from their
ambident hydrogen bonding donor-acceptor system and salt
bridge acceptors (quaternized nitrogen atoms).
By contrast, light fluorous-phase technologies offer
homogeneous reaction media for easy reaction monitoring
and intermediates characterization by conventional analytical
methods (e.g. TLC, NMR, MS and HPLC), meanwhile
remaining with phase-tagged advantage for parallel organic
synthesis. Moreover, reaction parameters used in solution
phase are ready to apply in fluorous-phase synthesis with
non- or minimum optimization [9, 10].
This privileged pharmacophore is highly visible in
ligand-based drug design approaches for developing
chemotherapeutics [3]. For instance, AKT inhibitor-IV (Fig.
1) and analogs [4] were developed to block phosphatidyl-
inositol-3-kinase (PI3K)-protein kinase B (AKT) pathway as
a drug discovery strategy to treat human cancer [5, 6]. More
recently, novel CRX4 antagonists consisting in
benzimidazole scaffolds are introduced as potent anti-HIV
agents with sub-nanomolar activity (Fig. 1) [7].
The facile and reliable separation protocols of light
fluorous-tagged compounds over non-fluorous components
iPr
N
NMe
N
N
S
N
Et
N
N
N
Me
I-
N
CXR4 antagonist
AKT inhibitor-IV
Fig. (1). Representative molecules of bioactive benzimidazole scaffolds.
are the most attractive features in order to telescope the
purification procedures in synthetic tasks. The separation
process is generally preformed by using fluorous solid-phase
*Address correspondence to this author at the Department of Applied
Chemistry, National Chiao Tung University, Science Building 2, 1001 Ta
Hsueh Road, Hsinchu 300-10, Taiwan; Tel: +886 (3) 5736007;
E-mail: cmsun@mail.nctu.edu.tw
1875-5402/12 $58.00+.00
© 2012 Bentham Science Publishers

412 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5
Tseng et al.
extraction (F-SPE) cartridge packed with perfluoroalkyl-
modified reverse phase silica gel. Upon loading of the
fluorous-tagged reaction mixture onto an F-SPE cartridge
with minimum volume of DMF or DMSO, non-fluorous
compounds are eluted out and fluorous-tagged components
benzoate 1 was then reacted with a variety of primary amines
through SNAr substitution in CH2Cl2 at ambient temperature for
20 min. After purification by F-SPE, Rf-tagged
aminonitrobenzoates 2 were obtained as clean substances,
which were employed to explore the planned chemistry.
are retained in the cartridge under
a fluorophobic
Our strategy toward the target heterocycles from
aminonitrobenzoates 2 used a domino sequence. It is required
synergically by reduction of the aromatic nitro group to anilines,
in situ coupling with carboxylic acids giving an amide followed
by cyclization into the amide and aromatization. We planned to
employ zinc dust in the presence of carboxylic acids to effect
reduction of nitro compounds and utilized the acids to be the
proton source. The acid may also facilitate amide formation at
the same time. The reduction of nitro group cannot proceed at
all when zinc dust is applied only in refluxing or microwave
condition.
environment (e.g. 80% of MeOH in H2O or 80% of MeCN in
H2O). Due to high affinity of fluorous-tagged components
with the stationary phase of F-SPE, flushing the cartridge
with a fluorophilic mobile phase such as 100% of MeOH,
MeCN or THF delivers clean tagged-compounds [11]. This
protocol can further be extended to apply on fluorous HPLC
(F-HPLC) systems that are potentially to be developed for
establishment of fully automated parallel synthesis in
laboratories [12].
The benzimidazole core is normally prepared by a
multiple-step synthetic sequence starting by condensation of
2-nitroaniline with an aldehyde followed by reductive
cyclization of the aromatic nitro compound to afford the
desired molecules. Tedious purification of intermediates
dramatically restricted the application on high throughput
synthesis. Herein, we report our recent achievement in
developing an efficient traceless fluorous phase-tagged one-
pot synthesis of benzimidazole analogs facilitated by
microwave irradiation. This concept is envisaged to
accumulate sufficient molecular databases within a short
time course for bioassay screening and to telescope drug
discovery process.
To test this scenario, a pilot reaction was conducted by
subjection of Rf-tagged aminonitrobenzoate 2 (R1 = iPr) with
a mixture of zinc dust and acetic acid in MeOH to elaborate
reaction profiles. These initial attempts gave no desired
product regardless the reactions were conducted at room
temperature or under reflux conditions. However, the
reduced product, diamino-benzoate, was obtained when this
mixture was exposed to microwave irradiation at 150oC in a
sealed tube for 15 min, albeit no sequential transformations
were proceeded to afford benzimidazole. This uncompleted
process is probably resulted from easy protonation of the
diamine under the protic solvent system to prevent the amide
formation. To circumvent this adverse outcome, we
employed 1,2-dichloroethane (DCE) to replace MeOH and
acetic acid as an acid source for another attempt. To our
delight, the desired Rf-tagged benzimidazole was produced
under the optimized conditions promoted by microwave
irradiation. Encouraged by this promising result, we next
explored substrate scope and a library of benzimidazoles 4a-
s were rapidly constructed by this method after cleavage of
the Rf-tag by methanolysis (Table 1).
RESULTS AND DISCUSSION
The synthetic efforts embarked on anchoring of
1H,1H,2H,2H-perfluoro-1-decanol (abbreviated as Rf
thereafter in this article) onto 4-fluoro-3-nitrobenzoic acid as
a platform for subsequent chemical manipulations in this
study. The esterification reaction was carried out by using
N,-N’-dicyclohexylcarbodiimide (DCC) as
a
coupling
reagent in the presence of DMAP as a catalyst in CH2Cl2 at
room temperature for 3 hr or under microwave irradiation in
open-vessel condition for 30 min (Scheme 1).
Gratifyingly, wide spectrum of substrate scope with
excellent reaction efficiency has been delineated. It is found
that reaction temperature is highly dependent on the nature
of carboxylic acids. According to reactivity profiles, the
desired one-pot reactions proceeded cleanly at 130oC under
microwave irradiation when strong acid such as
trifluoroacetic acid (pKa = 0.23) was employed, whereas
weak acids (e.g. HOAc, pKa = 4.76 and PhCH2CO2H, pKa =
4.31) participated batches required an elevated reaction
temperature at 170 ~ 200oC to achieve the most optimal
outcomes. By contrast, inferior reaction yields were obtained
when benzoic acids were employed. Rising reaction
The reaction was monitored by TLC and the desired
fluorous-tagged fluoronitrobenzoate 1 was purified by F-SPE
cartridge (FluoroFlash®) based on the aforementioned protocol
[11]. The easy removal of excess reagents and residues has
pronounced well on this approach because these chemicals (i.e.
DCC and N,-N’-dicyclohexylurea) are particularly troublesome
for purification tasks performed in tag-free chemistry. 1H NMR
and ESI-TOF MS spectra (see experimental section) of the Rf-
tagged benzoate 1 revealed a clean separation straight after one
F-SPE operation (experimental section). The Rf-tagged
a) DCC, DMAPcat.,
CH2Cl2, RT, 3 h
or
O
O
NO2
NO2
F
C8F17CH2CH2OH
+
HO
RfO
ꢀW (270 W), 30 min
F
1
Rf = C8F17(CH2)2
Scheme 1. Preparation of master scaffold-the Rf-tagged fluoronitrobenzoate 1. Reagents and conditions: a) DCC (1.2 eq.), DMAP (5 mol%),
CH2Cl2, 23oC 3 h; or ꢀW (270 W), 30 min.

One-Pot Synthesis of Benzimidazoles
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5 413
temperature to 220 ~ 250oC or using polyphosphoric acid
(PPA) as an additive is not effective to such substrates.
EXPERIMENTAL SECTION
General Directions
Table 1. Rapid One-Pot Synthesis of Benzimidazole Library
All reactions were performed under anhydrous conditions
and an atmosphere of nitrogen in flame-dried glassware.
b) R2CO2H, Zn,
RfO2C
NO2
X
YO2C
N
R2
Solvents and reagents: All solvents were distilled before
use. Commercial grade solvents used for chromatography
were distilled before use. Anhydrous THF and Et2O were
distilled from sodium/benzophenone ketyl under nitrogen
immediately prior to use. Anhydrous CH2Cl2 was distilled
from CaH2 immediately prior to use. All reagents were used
as commercially supplied and used without further
purification. Chromatography: Flash chromatography (FC)
was always performed on silica gel (Merck Kieselgel 60 F254
230-400 mesh) according to the method of W.C. Still [13].
Thin Layer Chromatography (TLC) was performed on
Merck aluminium-backed plates pre-coated with silica (0.2
mm, 60 F254) which were visualized either by quenching of
ultraviolet fluorescence (ꢁmax = 254 and 366 nm) or by
charring with 10% KMnO4 in 1M H2SO4 or by charring with
10% Ce(SO4)2 and 15% H2SO4. Microwave-assisted
reaction: All reactions involved microwave irradiation were
performed by a CEM Discover 1® or a Biotage Initiator®
microwave reactors unless otherwise mentioned. Infrared
spectra: These were recorded as thin films, on a Perkin-
Elmer Paragon 1000 Fourier transform spectrometer. Only
selected absorbances (ꢂmax) were reported. 1H NMR spectra:
These were recorded at either 300 MHz on a Bruker DRX-
300 instrument. Chemical shifts (ꢀH) were quoted in parts per
million (ppm), referenced to the appropriate residual solvent
peak. Coupling constants (J) were reported to the nearest 0.5
Hz. 13C NMR spectra: These were recorded at 75 MHz on a
Bruker DRX-300 instrument. Chemical shifts (ꢀC) were
quoted in ppm, referenced to the appropriate residual solvent
peak. Degenerate peaks are suffixed by the number of
carbons. Mass spectra: Low resolution mass spectra (m/z)
were recorded on either a VG platform II or VG AutoSpec
spectrometers, with only molecular ions (M+, MH+, MNa+)
and major peaks being reported with intensities quoted as
percentages of the base peak. High Resolution Mass
Spectrometry (HRMS) measurements are valid to 5ppm.
ꢀw, 15 min
130-200 o
N
C
R1
1 X = F
2a-i X = R1NH
3a-s Y = Rf
4a-s Y = Me
a) R1NH2
c) NaOMe
Entry
R1NH2
R2CO2H
Product
Yield (%)a
1
2
3
4
5
6
nBuNH2
nBuNH2
iBuNH2
iBuNH2
iPrNH2
iPrNH2
CF3CO2H
CH3CO2H
CF3CO2H
CH3CO2H
CF3CO2H
CH3CO2H
O
4a
4b
4c
4d
4e
4f
88
87
93
85
76
90
O
O
7
8
9
iPrNH2
4g
4h
4i
72
84
77
OH
CF3CO2H
NH2
CH3CO2H
CF3CO2H
NH2
NH2
NH2
MeO
10
11
4j
80
81
MeO
MeO
CH3CO2H
4k
O
12
4l
84
NH2
Ph
OH
O
MeO
13
14
15
16
17
4m
4n
4o
4p
4q
79
71
73
76
75
NH2
NH2
Ph
Ph
OH
O
Ph
O
OH
NH2
O
O
OH
O
NH2
NH2
O
S
Ph
OH
General Procedure for Fluorous Solid-Phase Extraction
(F-SPE)
CH3CO2H
O
NH2
Pre-packed fluorous solid-phase extraction (F-SPE)
cartridges were purchased from FLUOROUS Technologies
Inc. and pre-conditioned with 50:50 MeOH:H2O. Crude
reaction mixtures were loaded on the cartridge using DMF
and eluted with 80:20 MeOH:H2O (10 ml) as fluorophobic
solvents followed by using MeOH as fluorophilic eluent.
Compressed air flow was employed in a manner as described
by Curran [14].
O
18
19
4r
4s
72
85
OH
BnNH2
CH3CO2H
Reagents and conditions: a) R1NH2 (5 eq.), CH2Cl2, 23 oC, 30 min; b) R2CO2H (15
eq.), Zn dust (15 eq.), DCE, 130-200 oC, 15 min; c) NaOMe (5 eq.), MeOH, 23 oC, 8 h.
aIsolated yields.
In conclusion, a novel “one-pot” protocol aiming for
rapid preparation of benzimidazole analogs was developed.
By combination the light fluorous phase-tag technology with
our new synthetic approach provides alternative purification
tactics. It is envisaged that this novel strategy delivers an
exquisite concept to be adopted for preparing benzimidazole
analogous by one simple operation in a parallel manner.
Further elaboration of substrate scope and applying this
concept to synthesize of drug-like small molecules are
currently under investigation in our group.
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl 4-
fluoro-3-nitrobenzoate 1
To a stirred solution of 1H,1H,2H,2H-perfluoro-1-
decanol (5 g, 10.8 mmol) in CH2Cl2 (20 mL), 4-fluoro-3-
nitrobenzoic acid (2.39 g, 12.9 mmol), DCC (2.66 g, 12.9
mmol) and DMAP (66.0 mg, 0.54 mmol) were added. The

414 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5
Tseng et al.
Fig. (2). 1H NMR and ESI-TOF MS spectra of Rf-tagged 4-fluoro-3-nitrobenzoate 1.
reaction mixture was irradiated in a microwave reactor at 270 W
for 30 min before it was filtered through a plug of Celite® 501
column and the combined organic layer was concentrated in
vacuo. The mixture was purified by F-SPE cartridge to give Rf-
tagged 4-fluoro-3-nitrobenzoate 1 as a pale yellow oil (6.68 g,
98 %). Examining the obtained substance by 1H NMR and ESI-
TOF MS revealed a pure desired product (Fig. 2).
To
a
methanol solution of the crude Rf-tagged
benzimidazoles 3 was added NaOMe (15.0 eq.) and stirred
for 8 h at room temperature before it was diluted with Et2O
(10 mL), washed with saturated aqueous NH4Cl solution (5
mL), dried over (Na2SO4), filtered and concentrated in
vacuo. The resulting yellow oil was purified by F-SPE
cartridge to afford benzimidazoles 4.
General Method for Preparation of Rf-Tagged 4-(N-
alkylamino)-3-nitrobenzoate 2
Representative Example for Synthesis of Benzimidazole
4fMethyl 1-isopropyl-2-methyl-1H-benzo[d]imidazole-5-
carb-oxylate 4f
Amines were added to a CH2Cl2 solution of Rf-tagged 4-
fluoro-3-nitrobenzoate 1 at RT (5.0 eq.). The reaction
mixture was stirred at such temperature for 30 min before it
was diluted with Et2O (10 mL), washed with saturated
aqueous sodium hydrogen carbonate solution (5 mL), dried
over (Na2SO4), filtered and concentrated in vacuo. The
resulting yellow oil was purified by F-SPE cartridge to
afford Rf-tagged 4-(alkyllamino)-3-nitrobenzoates 2.
Using general one-pot procedure, Rf-tagged 4-
(isopropylamino)-3-nitrobenzoate 2c (50 mg, 0.074 mmol),
HOAc (64 L, 1.118 mmol) and zinc dust (73.2 mg, 1.118
mmol) were used in dichloroethane (10 mL). The mixture
was heated to 200 oC for 15 min under microwave irradiation
affording crude Rf-tagged benzimidazole 3f. A partial of the
resulting crude product (15 mg) was purified by F-SPE and
examined by 1H NMR for the purpose of product
identification (Fig. 2). After methanolysis and purification
by F-SPE, benzimidazole 4f was obtained in a pale yellow
oil (15.6 mg, 90%, starting from nitrobenzoate 2c).
Characterization data is shown below.
Representative Example for Synthesis of Nitrobenzoate
2c
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl 4-
(isopropylamino)-3-nitrobenzoate 2c
Using
general
method,
Rf-tagged
4-fluoro-3-
Methyl 1-butyl-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-car-
boxylate (4a)
nitrobenzoate 1 (105 mg, 0.166 mmol) and isopropyl amine
(68.1 ꢀL, 0.832 mmol) were employed. Purification by F-
SPE cartridge to afford Rf-tagged 4-(isopropylamino)-3-
nitrobenzoate 2c as a yellow oil (105.7 mg, 95 %).
1H NMR (300 MHz, CDCl3): ꢀ 8.58 (d, J = 1.0 Hz, 1H),
8.14 (dd, J = 8.7, 1.5 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 4.32
(t, J = 7.8 Hz, 2H), 3.95 (s, 3H), 1.98-1.82 (m, 2H), 1.51-
1.34 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3): ꢀ 167.3, 142.8, 142.3, 141.2, 138.8, 126.8, 126.3,
124.5, 121.1, 117.5, 110.8, 52.7, 45.7, 32.4, 20.4, 13.9; IR
(cm-1, neat): 2969, 2877, 1712; MS (ESI-MS) m/z: 323
(M+Na+); HRMS calcd for C14H15F3N2O2Na: m/z 323.0983;
Found 323.0984.
General Procedure for “One-Pot” Synthesis of Benzi-
midazoles 4
To a solution of Rf-tagged 4-(alkylamino)-3-nitrobenzoates
2 in Cl2CH2CH2Cl2 (2 mL) in a sealed tube were added
carboxylic acids (15.0 eq.) and zinc dust (15.0 eq.). The mixture
was exposed to microwave irradiation for 15 min before it was
diluted with Et2O (5 mL), filtered through a plug of Celite® 501
column and the combined organic layer was concentrated in
vacuo giving crude Rf-tagged benzimidazoles 3. The crude
product was subjected directly to methanolysis without further
purification unless otherwise indicated.
Methyl 1-butyl-2-methyl-1H-benzo[d]imidazole-5-carboxylate (4b)
1H NMR (300 MHz, CDCl3): ꢀ 8.38 (d, J = 0.9 Hz, 1H),
7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 4.10
(t, J = 7.3 Hz, 2H), 3.94 (s, 3H), 2.62 (s, 3H), 1.83-1.73 (m,
2H), 1.45-1.33 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR

One-Pot Synthesis of Benzimidazoles
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5 415
(75 MHz, CDCl3): ꢀ 168.1, 153.7, 142.6, 138.8, 124.3,
124.1, 121.7, 109.2, 52.4, 44.3, 32.2, 20.5, 14.4, 14.1; IR
(cm-1, neat): 2956, 2817, 1714, 1301; MS (ESI-MS) m/z: 269
(M+Na+); HRMS calcd for C14H18N2O2Na: m/z 269.1266;
Found 269.1267.
1305; MS (ESI-MS) m/z: 353 (M+H+); HRMS calcd for
C20H21N2O4: m/z 353.1501; Found 353.1503.
Methyl 1-isopentyl-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-
carboxylate (4h)
1H NMR (300 MHz, CDCl3): ꢀ 8.57 (d, J = 1.0 Hz, 1H),
Methyl 1-isobutyl-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-
carboxylate (4c)
8.13 (dd, J = 8.7, 1.5 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 4.32
(t, J = 7.9 Hz, 2H), 3.96 (s, 3H), 1.78-1.72 (m, 3H), 1.03 (t, J
= 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): ꢀ 167.3, 144.7,
142.7, 142.2, 141.7, 141.2, 138.7, 127.5, 126.8, 126.3, 125.0,
124.7, 124.5, 121.8, 121.1, 117.5, 113.9, 113.3, 110.652.8,
44.4, 39.1, 26.6, 22.6; IR (cm-1, neat): 2960, 2871, 1720,
1436; MS (ESI-MS) m/z: 337 (M+Na+); HRMS calcd for
C15H17F3N2O2Na: m/z 337.1140; Found 337.1142.
1H NMR (300 MHz, CDCl3): ꢀ 8.58 (d, J = 1.0 Hz, 1H),
8.13 (dd, J = 8.7, 1.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 4.14
(d, J = 7.7 Hz, 2H), 3.96 (s, 3H), 2.35 (dt, J = 7.7, 6.7 Hz,
1H), 0.97 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3): ꢀ
167.3, 143.2, 142.8, 141.1, 139.2, 126.7, 126.3, 124.5, 121.1,
119.7, 117.5, 111.4, 52.9, 52.7, 29.6, 20.4; IR (cm-1, neat):
2969, 2879, 1714, 1519; MS (ESI-MS) m/z: 323 (M+Na+);
HRMS calcd for C14H15F3N2O2Na: m/z 323.0983; Found
323.0980.
Methyl 1-isopentyl-2-methyl-1H-benzo[d]imidazole-5-carboxy-
late (4i)
1H NMR (300 MHz, CDCl3): ꢀ 8.39 (d, J = 1.1 Hz, 1H),
7.98 (dd, J = 8.5, 1.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 4.12
(t, J = 7.7 Hz, 2H), 3.95 (s, 3H), 2.63 (s, 3H), 1.73-1.64 (m,
3H), 1.03 (t, J = 6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): ꢀ
168.1, 153.6, 142.5, 138.7, 124.4, 124.2, 121.7, 109.1, 52.4,
42.9, 38.9, 26.4, 22.8, 14.3; IR (cm-1, neat): 2956, 2865,
1716, 1436; MS (ESI-MS) m/z: 283 (M+Na+); HRMS calcd
for C15H20N2O2Na: m/z 283.1422; Found 283.1424.
Methyl 1-isobutyl-2-methyl-1H-benzo[d]imidazole-5-carboxy-
late (4d)
1H NMR (300 MHz, CDCl3): ꢀ 8.37 (d, J = 1.3 Hz, 1H),
7.95 (dd, J = 8.5, 1.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 3.93
(s, 3H), 3.90 (d, J = 7.6 Hz, 2H), 2.61 (s, 3H), 2.21 (dt, J =
7.6, 6.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H); 13C NMR (75
MHz, CDCl3): ꢀ 168.1, 154.0, 142.5, 139.2, 124.3, 124.0,
121.7, 109.6, 52.4, 51.9, 29.6, 2.6, 20.5, 14.7; IR (cm-1,
neat): 2962, 2871, 1712, 1436; MS (ESI-MS) m/z: 269
(M+Na+); HRMS calcd for C14H18N2O2Na: m/z 269.1266;
Found 269.1268.
Methyl 1-(2-methoxyethyl)-2-(trifluoromethyl)-1H-benzo[d]imi-
dazole-5-Carbo-xylate (4j)
1H NMR (300 MHz, CDCl3): ꢀ 8.57 (d, J = 0.9 Hz, 1H),
8.14 (dd, J = 8.7, 1.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 4.52
(t, J = 5.4 Hz, 2H), 3.97 (s, 3H), 3.76 (t, J = 5.4 Hz, 2H),
3.30 (s, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 167.4, 142.8,
142.3, 140.9, 139.7, 126.8, 126.4, 124.7, 124.2, 121.1, 117.5,
111.9, 71.5, 59.5, 52.7, 45.8; IR (cm-1, neat): 2956, 1720,
1438; MS (ESI-MS) m/z: 325 (M+Na+); HRMS calcd for
C13H13F3N2O3Na: m/z 325.0776; Found 325.0774.
Methyl-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-
carboxylate (4e)
1H NMR (300 MHz, CDCl3): ꢀ 8.57 (d, J = 1.2 Hz, 1H),
8.08 (dd, J = 8.8, 1.5 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 4.94
(septet, J = 6.9 Hz, 1H), 3.95 (s, 3H), 1.71 (d, J = 6.9 Hz,
6H); 13C NMR (75 MHz, CDCl3): ꢀ 167.3, 142.0, 137.2,
126.3, 126.0, 124.8, 121.2, 117.6, 113.2, 52.6, 50.4, 21.7; IR
(cm-1, neat): 2983, 1720, 1527, 1444; MS (ESI-MS) m/z: 309
(M+Na+); HRMS calcd for C13H13F3N2O2Na: m/z 309.0827;
Found 309.0824.
Methyl 1-(2-methoxyethyl)-2-methyl-1H-benzo[d]imidazole-5-
carboxylate (4k)
1H NMR (300 MHz, CDCl3): ꢀ 8.38 (d, J = 1.2 Hz, 1H),
7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 4.29
(t, J = 5.4 Hz, 2H), 3.94 (s, 3H), 3.70 (t, J = 5.4 Hz, 2H),
3.27 (s, 3H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3):
ꢀ168.2, 154.7, 142.7, 138.9, 124.5, 124.1, 121.7, 109.2, 71.1,
59.6, 52.4, 44.6, 14.6; IR (cm-1, neat): 2952, 1712, 1438; MS
(ESI-MS) m/z: 249 (M+H+); HRMS calcd for C13H17N2O3:
m/z 249.1239; Found 249.1238.
Methyl 1-isopropyl-2-methyl-1H-benzo[d]imidazole-5-carboxy-
late (4f)
1H NMR (300 MHz, CDCl3): ꢀ 8.36 (s, 1H), 7.90 (dd, J =
8.6, 1.2 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 4.66 (septet, J =
7.0 Hz, 1H), 3.91 (s, 3H), 2.62 (s, 3H), 1.62 (d, J = 7.0 Hz,
6H); 13C NMR (75 MHz, CDCl3): ꢀ 168.1, 153.2, 143.1,
137.4, 124.0, 123.7, 121.8, 111.0, 52.4, 48.6, 21.7, 15.4; IR
(cm-1, neat): 2981, 1716, 1434; MS (ESI-MS) m/z: 255
(M+Na+); HRMS calcd for C13H16N2O2Na: m/z 255.1109;
Found 255.1107.
Methyl 2-benzyl-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-
carboxylate (4l)
1H NMR (300 MHz, CDCl3): ꢀ 8.48 (d, J = 1.2 Hz, 1H),
7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.35-7.23 (m, 6H), 4.42 (s,
2H), 4.20 (t, J = 5.4 Hz, 2H), 3.96 (s, 3H), 3.46 (t, J = 5.4
Hz, 2H), 3.21 (s, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 168.1,
156.0, 142.6, 139.2, 136.5, 129.3, 129.0, 127.5, 124.6, 124.4,
122.2, 109.6, 71.0, 59.5, 52.5, 44.6, 34.8; IR (cm-1, neat):
2948, 1712, 1438; MS (ESI-MS) m/z: 325 (M+H+); HRMS
calcd for C19H21N2O3: m/z 325.1552; Found 325.1554.
Methyl 2-(benzo[d][1,3]dioxol-5-ylmethyl)-1-isopropyl-1H-benzo
[d]imidazole-5-carboxylate (4g)
1H NMR (300 MHz, CDCl3): ꢀ 8.47 (d, J = 1.1 Hz, 1H),
7.95 (dd, J = 8.6, 1.6 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 6.77-
6.66 (m, 3H), 4.63 (septet, J = 7.0 Hz, 1H), 4.28 (s, 2H),
3.96 (s, 3H), 1.46 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz,
CDCl3): ꢀ 168.1, 154.8, 148.5, 147.0, 143.3, 137.3, 130.2,
123.9, 122.4, 121.7, 111.7, 109.2, 108.9, 101.5, 77.6, 52.5,
48.9, 35.2, 21.6; IR (cm-1, neat): 2981, 2888, 1714, 1488,

416 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5
Tseng et al.
1H NMR (300 MHz, CDCl3): ꢀ 8.50 (d, J = 1.0 Hz, 1H),
7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.20-
6.99 (m, 4H), 4.82 (t, J = 6.5 Hz, 1H), 4.62-4.43 (m, 2H),
3.95 (s, 3H), 3.95 (t, J = 9.4 Hz, 2H), 3.22-3.11 (m, 2H),
2.80-2.73 (m, 1H), 2.71 (s, 3H), 2.26-2.15 (m, 2H), 2.04-
2.00 (m, 1H); 13C NMR (75 MHz, CDCl3): ꢀ 168.1, 155.8,
142.0, 139.3, 136.6, 136.5, 131.0, 130.0, 127.6, 126.8, 124.8,
124.7, 122.8, 109.5, 73.6, 69.2, 52.5, 45.3, 33.8, 29.7, 26.3,
19.5; IR (cm-1, neat): 2950, 2863, 1708, 1299; MS (ESI-MS)
m/z: 365 (M+H+); HRMS calcd for C22H25N2O3: m/z
365.1865; Found 365.1867.
Methyl -(2-methoxyethyl)-2-phenethyl-1H-benzo[d]imidazole-5-
carboxylate (4m)
1H NMR (300 MHz, CDCl3): ꢀ 8.48 (d, J = 1.1 Hz, 1H),
8.00 (dd, J = 8.5, 1.5 Hz, 1H), 7.35-7.24 (m, 6H), 4.19 (t, J =
5.4 Hz, 2H), 3.96 (s, 3H), 3.60 (t, J = 5.4 Hz, 2H), 3.30-3.20
(m, 4H), 3.25 (s, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 168.2,
157.2, 142.7, 141.3, 138.7, 129.0, 128.8, 126.8, 124.6, 124.2,
121.9, 109.4, 71.0, 59.5, 52.5, 44.2, 34.3, 30.0; IR (cm-1,
neat): 2942, 1712, 1616, 1438; MS (ESI-MS) m/z: 339
(M+H+); HRMS calcd for C20H23N2O3: m/z 339.1709; Found
339.1712.
Methyl 1-benzyl-2-methyl-1H-benzo[d]imidazole-5-carboxylate
(4s)
Methyl -(2,2-diphenylethyl)-1-((tetrahydrofuran-2-yl)methyl)-
1H-benzo[d]imi-dazole-5-carboxylate (4n)
1H NMR (300 MHz, CDCl3): ꢀ 8.44 (d, J = 1.0 Hz, 1H),
7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.36-7.25 (m, 4H), 7.07-7.03
(m, 2H), 5.36 (s, 2H), 3.95 (s, 3H), 2.60 (s, 3H); 13C NMR
(75 MHz, CDCl3): ꢀ 168.1, 154.2, 142.7, 139.2, 135.7,
129.5, 128.6, 126.6, 124.7, 121.8, 109.5, 52.5, 47.7, 14.6; IR
(cm-1, neat): 2944, 2844, 1706, 1436; MS (ESI-MS) m/z: 281
(M+H+); HRMS calcd for C17H17N2O2: m/z 281.1290; Found
281.1292.
1H NMR (300 MHz, CDCl3): ꢀ 8.44 (d, J = 1.2 Hz, 1H),
8.00 (dd, J = 8.5, 1.6 Hz, 1H), 7.30-7.18 (m, 11H), 4.93 (t, J
= 7.6 Hz, 1H), 4.01-3.60 (m, 7H), 3.95 (s, 3H), 1.95-1.75 (m,
4H); 13C NMR (75 MHz, CDCl3): ꢀ 168.2, 156.3, 144.2,
142.7, 138.9, 128.9, 128.3, 127.0, 124.5, 124.1, 121.9, 109.8,
78.0, 68.6, 52.4, 50.1, 47.4, 34.5, 29.5, 26.0; IR (cm-1, neat):
2948, 2865, 1712, 1434; MS (ESI-MS) m/z: 441 (M+H+);
HRMS calcd for C28H29N2O3: m/z 441.2178; Found
441.2176.
ACKNOWLEDGEMENT
Methyl -ethyl-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imi-
dazole-5-carboxylate (4o)
The authors wish to thank National Science Council for
financial support for this research (NSC 98-2119-M-009-
002-MY3). This work is particularly supported by "Aim for
the Top University Plan" of the National Chiao-Tung
University and Ministry of Education, Taiwan.
1H NMR (300 MHz, CDCl3): ꢀ 8.44 (s, 1H), 7.97 (dd, J =
8.5, 1.2 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 4.29-4.13 (m, 3H),
3.94 (s, 3H), 3.87-3.70 (m, 2H), 3.01-2.93 (m, 2H), 2.08-
1.58 (m, 4H), 1.49 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): ꢀ 168.2, 159.0, 142.6, 139.3, 124.3, 124.1, 121.8,
109.7, 78.1, 68.6, 52.4, 48.1, 29.6, 26.1, 21.3, 12.0; IR (cm-1,
neat): 2948, 2871, 1712, 1436; MS (ESI-MS) m/z: 289
(M+H+); HRMS calcd for C16H21N2O3: m/z 289.1552; Found
CONFLICT OF INTEREST
Declared none.
289.1549.
REFERENCES
[1]
Kedar, M. S.; Dighe, N. S.; Pattan, S. R.; Musmade, D. S.; Thakur,
D.; Bhosale, M.; Gaware, V. M. Benzimidazole in medicinal
chemistry: an overview. Der. Pharma. Chemica, 2010, 2(2), 249-
256.
Srikanth, L.; Raj, V. V.; Raghunandan, N.; Venkateshwerlu, L.
Recent advances and potential pharmacological activities of
benzimidazole derivatives. Der. Pharma. Chemica, 2011, 3(2),
172-193.
Boiani, M.; Gonzaelz, M. Imidazole and benzimidazole derivatives
as chemotherapeutic agents. Mini Rev. Med. Chem., 2005, 5(4),
409-424.
Sun, Q.; Wu, R.; Cai, S.; Lin, Y.; Sellers, L.; Sakamoto, K.; He, B.;
Peterson, B. R. Synthesis and biological evaluation of analogues of
AKT (protein kinase B) inhibitor-IV. J. Med. Chem., 2011, 54(5),
1126-1139.
Methyl 2-phenethyl-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo
[d]imidazole-5-carboxylate (4p)
1H NMR (300 MHz, CDCl3): ꢀ 8.47 (s, 1H), 7.99 (dd, J =
8.5, 1.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.32-7.16 (m, 5H),
4.23-4.00 (m, 3H), 3.96 (s, 3H), 3.86-3.68 (m, 2H), 3.35-
3.16 (m, 4H), 2.06-1.47 (m, 4H); 13C NMR (75 MHz,
CDCl3): ꢀ 168.2, 157.2, 142.6, 141.4, 139.1, 129.0, 128.8,
126.8, 124.5, 124.2, 121.9, 109.8, 78.0, 68.6, 52.5, 48.0,
34.3, 30.1, 29.5, 26.1; IR (cm-1, neat): 2952, 1714, 1438; MS
(ESI-MS) m/z: 365 (M+H+); HRMS calcd for C22H25N2O3:
m/z 365.1865; Found 365.1866.
[2]
[3]
[4]
[5]
[6]
[7]
Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-Kinase-
AKT pathway in human cancer. Nat. Rev. Cancer, 2002, 2(7), 489-
501.
Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B.
Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat.
Rev. Drug Discov., 2005, 4(12), 988-1004.
Miller, J. F.; Turner, E. M.; Gudmundsson, K. S.; Jenkinson, S.;
Spaltenstein, A.; Thomson, M.; Wheelan, P. Novel N-substituted
benzimidazole CXCR4 antagonists as potential anti-HIV agents.
Bioorg. Med. Chem. Lett., 2010, 20(7), 2125-2128.
Song, A.; Zhang, J.; Lebrilla, C. B.; Lam, K. S. Solid-phase
synthesis and spectral properties of 2-alkylthio-6H-pyrano[2,3-
Methyl 2-methyl-1-(thiophen-2-ylmethyl)-1H-benzo[d]imida-
zole-5-carboxylate (4q)
1H NMR (300 MHz, CDCl3): ꢀ 8.41 (s, 1H), 7.99 (dd, J =
8.5, 1.4 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 5.1,
1.2 Hz, 1H), 6.96-6.91 (m, 2H), 5.47 (s, 2H), 3.94 (s, 3H),
2.68 (s, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 168.0, 153.6,
142.7, 138.3, 127.6, 126.4, 126.3, 124.8, 124.5, 124.2, 121.9,
109.3, 52.5, 43.1, 14.5; IR (cm-1, neat): 2948, 1716, 1517,
1432; MS (ESI-MS) m/z: 287 (M+H+); HRMS calcd for
C15H15N2O2S: m/z 287.0854; Found 287.0853.
[8]
[9]
f]benzimidazole-6-ones:
a
combinatorial approach for 2-
alkylthioimidazocoumarins. J. Comb. Chem., 2004, 6(4), 604-610.
Zhang, W. Fluorous technologies for solution-phase high
throughput organic synthesis. Tetrahedron, 2003, 59(25), 4475-
4489.
Methyl 1-(2-methylphenethyl)-2-(tetrahydrofuran-2-yl)-1H-
benzo[d]imidazole-5-carboxylate (4r)

One-Pot Synthesis of Benzimidazoles
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5 417
[10]
[11]
Zhang, W. Fluorous synthesis of heterocyclic systems. Chem. Rev.,
2004, 104(5), 2531-2556.
Lin, M.-J.; Zhang, W.; Sun, C.-M. Fluorous and traceless synthesis
of substituted indole alkaloids. J. Comb. Chem., 2007, 9(6), 951-
958.
[13]
[14]
Still, W. C.; Kahn, M.; Mitra, A. Rapid chromatographic technique
for preparative separations with moderate resolution. Org. Chem.,
1978, 43(14), 2923-2925.
Curran, D. P., Luo, Z. Fluorous synthesis with fewer fluorines
(light fluorous synthesis): separation of tagged from untagged
products by solid-phase extraction with fluorous reverse phase
silica gel. J. Am. Chem. Soc., 1999, 121(39), 9069-9072.
[12]
Zhang, W.; Lu, Y. Automation of F-SPE for parallel synthesis. J.
Comb. Chem., 2006, 8(6), 890-896.
Received: July 3, 2011
Revised: November 7, 2011
Accepted: November 14, 2011