Microwave promoted simple, efficient and regioselective synthesis of trisubstituted imidazo[1,2-a]benzimidazoles on soluble support

Article abstract of DOI:10.1021/co1000037

An efficient microwave-assisted and soluble polymer-supported synthesis of medicinally important imidazole-fused benzimidazoles has been developed. The protocol involves the rapid condensation of polymer-bound amino benzimidazoles with various α-bromoketo

Full text of DOI:10.1021/co1000037

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Microwave Promoted Simple, Efficient and Regioselective Synthesis
of Trisubstituted Imidazo[1,2-a]benzimidazoles on Soluble Support
Li-Hsun Chen, Ya-Shan Hsiao, Gorakh S. Yellol, and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
S Supporting Information
b
ABSTRACT: An efficient microwave-assisted and soluble
polymer-supported synthesis of medicinally important
imidazole-fused benzimidazoles has been developed. The
protocol involves the rapid condensation of polymer-
bound amino benzimidazoles with various R-bromoke-
tones and subsequent in situ intramolecular cyclization
under microwave irradiation resulting in a one pot synth-
esis of imidazole interlacing benzimidazole polymer con-
jugates. The condensed product was obtained with
excellent regioselectivity. The biologically interesting
imidazo[1,2-a]benzimidazoles was released from polymer support at ambient temperature. Diversity in the triheterocyclic nucleus
was achieved by the different substitutions at its 2, 3, and 9 positions. The new protocol has the advantages of short reaction time,
easy workup process, excellent yields, reduced environmental impact, wide substrate scope and convenient procedure.
KEYWORDS: microwave-assisted, polymer-supported, amino benzimidazoles, biologically interesting
’ INTRODUCTION
imidazo-benzimidazoles were prepared and evaluated for anti-
anxiety activity7 1, anticancer activity8 2, and neuropsychotropic
activity9 3 (Figure 1).
As a distinct feature of nature’s fundamental amino acid
scaffold and emanating from a variety of biogenic processes,
the guanidine nucleus has been intimately woven into the diverse
and evolving fabric of the natural world. The guanidine-containing
derivatives constitute a very important class of therapeutic
agents for the treatment of a wide spectrum of diseases.1 The
elaborate interlacing frameworks in which nature has embedded
the guanidine core with the two or three heterocyclic fused ring
skeleton of the molecule also continues to inspire the develop-
ment of creative strategies for its construction.2 One of the
guanidine embedded fused ring system, imidazo-benzimidazole,
is an important structural subunit and recognition element found
in a number of bioactive compounds including small-molecule
natural products and related unnatural compounds.3 The phar-
macological properties of imidazole fused benzimidazole deriva-
tives depend both on the type of cycle containing the guanidine
pharmacophore group and on the substituent introduced into
the nucleus of this tricycle.4 The combination of diverse biolo-
gical activity and structural complexity make imidazo[1,2-a]-
benzimidazoles and its derivatives an attractive scaffold in the
heterocyclic community.
Recent advances in high-throughput screening have resulted
in fast library collection being a top priority for initial drug
discovery. Combinatorial chemistry provided the eminent solu-
tion by rapid synthesis of compound libraries to balance this
demand. Development of novel synthetic methods for rapid
organic synthesis remains central to new compounds with
pharmaceutical potential. Thus the technologies that could
accelerate and facilitate synthesis of compounds have become
highly significant. The advent of microwave technology has
enabled organic chemists to dramatically reduce the reaction
time of single, as well as multistep, synthesis.10 In addition,
improved yields and cleaner reactions are frequently observed
under microwave conditions.11
Parallel to the advances in microwave synthesis, the utilization
of polymer support to accomplish novel chemistry has allowed
for a vast array of compounds to be synthesized and subsequently
screened for SAR study.12 Soluble polymer supported techniques
circumvent the tedious chromatographic separation by simple
precipitation methods along with advantages of monitoring
reaction progress by regular proton NMR techniques. Recent
developments in soluble polymer supported synthesis have
provided even more expansive ways to create diversified chemical
libraries with improved quality and purity. Chemists are increasingly
There has been an increasing interest in the chemistry of
imidazole fused benzimidazoles because of their broad spectrum
of biological activity. Many of them show antihistamine, anti-
oxidant, analgetic, hypotensive, anti-inflammatory and potent
anesthetic activity.5 The aminoketone derivatives of imidazo[1,2-a]-
benzimidazoles are effective adrenoblockers, spasmolytics,
antiarrhythmogens, and antimicrobial agents.6 Some analogs of
Received: September 18, 2010
Revised:
December 23, 2010
Published: January 31, 2011
r
2011 American Chemical Society
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looking for the application of advanced techniques in conjunc-
tion with soluble polymer support to develop novel strategies
that make compound synthesis easier, faster and more practical
with an emphasis on quality and high-throughput purification
techniques. Consequently, the development of novel methodol-
ogies that combine the advantages of microwave heating with
soluble polymer supported liquid phase synthesis have become
more popular in recent days.13
To the best of our knowledge, the synthesis of imidazo[1,2-a]-
benzimidazole derivatives was mainly reported by the Ugi
multicomponent reaction as well as conventional linear pro-
tocol.14 All the reported methods suffered from the drawbacks
such as prolonged reaction time, low yields, narrow scope of
substrates or tedious workup procedures. Because of the con-
strains in the available synthetic methods and the broad spectrum
of pharmacological applications of the imidazole-fused benzimi-
dazole scaffold, there is an urgent need to develop an alternative,
advanced protocol for the simple and rapid synthesis of imidazo-
[1,2-a]benzimidazole derivatives.
support for the synthetic protocol. The requisite PEG
supported 2-amino-benzimidazole 5 with diversity through
N-substitution was prepared from immobilized ortho-fluor-
onitrobenzene by microwave assisted protocol. Accordingly,
4-fluoro-3-nitrobenzoic acid 4 was attached to polyethylene
glycol by esterification followed by coupling with various
amines through ipso-fluoro-nucleophilic substitution. The
nitro-group of the polymer bound nitroaniline was reduced
using ammonium formate and zinc. Subsequently, cyclization
with cyanogen bromide furnished the requisite PEG bound
benzimidazole derivatives 5.
For the preliminary evaluation of polymer supported one pot
condensation, we have carried out the investigation under
microwave irradiations at 150 °C with PEG bound 2-amino-
1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate 5a (5:
R1 = 2-methoxy ethyl) and 2-bromo-1-p-tolylethanone as a
representative example. It was observed that the desired con-
densed product was not obtained when the model reaction was
carried out in acetone. Attempts to use methanol as a solvent for
the reaction (as its microwave coefficient was much higher)
resulted in very low yield (18%) of the desired PEG bound
9-(2-methoxyethyl)-2-(4-methylphenyl)-9H-imidazo[1,2-a]-
benzoimidazole-6-carboxylate 6a (6 R1 = 2-methoxy ethyl, R2 =
H, R3 = 4-methyl phenyl). After a few trials as well as analysis of
earlier studies,17 we decided to carry out the reaction in a binary
solvent mixture. Surprisingly in our first attempt of the reaction
in 1:1 (v/v) mixture of methanol and acetone under microwave
irradiation at 150 °C (15 bar), the desired condensed product
was obtained in 60% yield within 20 min. Consequently the
proportion of solvents was optimized and set to 1:3 (v/v) mixture
of methanol and acetone, in order to improve the yields (72%)
and also to reduce the time (15 min) required for complete
conversion. The temperature of the reaction was also investi-
gated for better results; the most suitable temperature remains at
150 °C. The reaction involves the rapid condensation of PEG
attached 2-amino-benzimidazole 5a with R-bromoketones and
subsequent in situ intramolecular cyclization under microwave
irradiation leading to one pot synthesis of imidazole fused
benzimidazole polymer conjugates 6a. Excellent regioselectivity
was observed during the condensation reaction. Finally, the
polymer support was removed by treating the PEG bound
imidazo[1,2-a]benzimidazoles 6a with one molar solution of
potassium cyanide in methanol at room temperature for 12 h.
This furnished the desired imidazo[1,2-a]benzimidazoles 7a in
quantitative yields.
In continuing with our ongoing work on the development of
multidisciplinary synergetic approaches15 for the rapid access to
biologically active small heterocyclic molecules, we herein demon-
strate that using soluble support in conjunction with microwave
irradiation could facilitate the synthesis of imidazo[1,2-a]-
benzimidazoles. In addition, as shown in our previous reports,16
such a procedure also results in an easy workup process.
’ RESULTS AND DISCUSSIONS
By considering the solubility profile and loading capacity
of the polymer derivatives, polyethylene glycol (PEG) of
average molecular weight 4000 was chosen as the polymer
Figure 1. Representative bioactive imidazo[1,2-a]benzimidazole deri-
vatives.
Scheme 1. General Synthetic Strategy Towards Imidazo[1,2-a]benzimidazoles
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Table 1. Representative Imidazo[1,2-a]benzimidazole Derivatives
a Mass recorded ESI as M þ H. b Isolated yield after purification. c Crude HPLC purity after PEG cleavage.
The reaction progress was monitored by regular proton NMR
spectroscopy (stepwise comparison of spectra of 5a, 6a, and 7a are
given in Supporting Information). The aromatic protons of PEG
bound 2-amino-bezimidazole 5a wereshiftedtoitsdownfield region
after condensation and appeared at 8.27, 8.14, and 7.45 ppm in the
spectrum of PEG bound imidazo[1,2-a]benzimidazoles 6a. These
protons were subsequently shifted upfield in the 1H NMR spectrum
of compound 7a after removal of the polymer support. The
characteristic peak for the newly formed imidazole ring proton
(present at position 3 of imidazo-benzimidazole ring) appeared as a
singlet at 7.63 ppm. Additional doublets integrating for two protons
each in the aromatic region and one singlet for three protons at 2.38
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Figure 2. Possible mechanism for regioselective condensation reaction.
ppm from the 4-methyl phenyl group (substitution at 2-position)
were evidence for the condensation of ketone with benzimidazole.
The complete removal of PEG support was evidenced by the
absences of a distinctive peak at 3.67 ppm which represented the
polyethylene glycol absorbance in the proton NMR spectrum of
compound 7a.
On the basis of these optimized reaction conditions, a re-
presentative library of imidazo[1,2-a]benzimidazoles derivatives
7 was synthesized by the reaction of equimolar amounts of PEG
bound 2-aminobenzimidazoles 5 and various R-bromoketones in
a 1:3 mixture of methanol and acetone under microwave
irradiation followed by the removal of the polymer support.
The results are summarized in Table 1. The protocol was applied
not only to aromatic ketones with electron-withdrawing groups
or electron-donating groups, but also to aliphatic ketones which
highlighted the versatility of the methodology. Reactions with
aliphatic ketones provided the desired product in good yields
(Table 1, entry e, h and p) while heteroaromatic ketones resulted
in moderate yields (Table 1, entry j, k and s). In the case of
aromatic ketones with electron-donating and electron-withdraw-
ing groups, no reasonable differences were observed on the
yields. Hence, the new protocol could be applied to a wide range
of substrate including different types of primary and secondary
R-bromoketones (Table 1, entries d, q, and t). Furthermore, the
reaction procedure is fast and easy to operate and the soluble
PEG support facilitates the workup procedure as it requires only
simple precipitation and purification by ether wash. To demon-
strate the advantages of microwave heating, a similar reaction of
PEG bound 2-amino-1-(2-methoxyethyl)-1H-benzo[d]imidazole-
5-carboxylate 5a and 2-bromo-1-p-tolylethanone in a mixture of
acetone-methanol was investigated using conventional heating
condition. It was observed that the condensation reaction via
conventional heating required 20 h and afforded PEG bound
imidazo[1,2-a]benzimidazoles 6a in moderate yield (59%).
However, the same reaction under microwave irradiation took
only 15 min and afforded 6a in 97% yield. This demonstrates that
microwave-promoted reaction not only reduces the reaction time
but also improves the yields significantly.
Figure 3. Important NOE interactions in compound 7i.
benzimidazoles are depicted in Figure 2. Based on the observed
outcome of the reaction, we proposed that the reaction proceeded
via a sequence of nucleophilic bromo-substitution, intramolecular
cyclization, followed by aromatization. Initially the bromo-group
was selectively substituted by secondary amine through the electro-
nic resonance of the 2-amino group of 5 leading to the N-alkylated
adduct 8 which further liberation of protons afford intermediate 9.
The regioselectivity is due to the character of internal secondary
amines as a soft nucleophile which preferentially reacts with soft
halide electrophile. Subsequently, the intramolecular cyclization
through condensation of amine with carbonyl functionality of
ketone affords intermediate 10, which on proton exchange leads
to cyclic adduct 11. Aromatization with elimination of a water
molecule from adduct 11 affords imidazole fused benzimidazole 6.
To confirm the results obtained along with the regioselectivity
of the condensation reaction, we carried the 1D NOE analysis of
compound 7i. The characteristic NOE interaction is shown in
Figure 3. The irradiation of the Ha proton leading to enhance-
ment of the Hb and Hd proton signals by 0.63% and 1.25%,
respectively, which also enhanced the Hi proton signal by 1.92%.
Additionally, irradiating the Hd proton enhances the Ha proton
peak by 0.63% and He/Hf proton signals by 2.65%. Moreover, in
the NOESY spectrum of compound 7i, Hd proton shows
interaction with Ha, He and Hf protons. Since there is no
correlation of Ha with He and Hf protons, this clearly confirms
the structure of compound 7i and demonstrates the regioselec-
tive outcome of the condensation reaction (Figure 3).
The plausible steps involved in the regioselective condensation of
benzimidazole with R-haloketones to provide the imidazole fused
To further confirm the structure for the regioselectivity
and to support the NOE study, we further undertook the
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Figure 4. ORTEP diagram of compound 7i.
X-ray crystallographic study of compound 7i. The Figure 4
depicts the ORTEP diagram of compound 7i (X-ray crystal-
lographic data were specified in Supporting Information).
The X-ray crystal structure of compound 7i indicates that the
3-methoxy benzyl group was present at C8 carbon and the C7
carbon bears hydrogen atom which unambiguously confirms
its structure.
series machine with a Hypersil (250 ꢀ 4.6 mm) analytical
column. PEG was purchased from SHOWA.
(The general procedure applied to the synthesis of 7a was
applied to the synthesis of all the other final compounds of
general formula 7)
Methyl 9-(2-Methoxyethyl)-2-(4-methylphenyl)-9H-imidazo-
[1,2-a]benzoimidazole-6-carboxylate (7a). PEG-bound 2-ami-
no-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate
5a was prepared as described in Supporting Information.
2-Bromo-1-p-tolylethanone (0.426 g, 2.0 mmol) was added
to a solution of PEG bound 2-amino-1-(2-methoxyethyl)-1H-
benzo[d]imidazole-5-carboxylate 5a (2.234 g, 1.0 mmol) in
methanol-acetone (1:3, 20 mL). The reaction mixture was
irradiated under microwave at 150 °C (15 bar) for 15 min. The
’ CONCLUSION
In conclusion, we have developed a liquid phase method for the
construction of guanidine embedded heterocyclic library. The simple
and rapid synthesis of various imidazole-fused benzimidazole deriva-
tives was achieved on soluble polymer support using focused micro-
wave irradiations. The key steps in this synthesis includes the
alkylation of PEG linked amino-benzimidazole with R-bromoketones,
followed by intramolecular cyclization to furnish imidazo[1,2-a]benzi-
midazole derivatives in one pot. The excellent regioselectivity was
observed during the one pot condensation reaction which was further
supported by its NOE and X-ray crystallographic studies. The micro-
wave heating dramatically shortens the time required for the reaction,
while PEG support facilitates the workup procedures by simple
precipitation. This novel protocol provides the rapid pathway to
access the biologically interesting small heterocyclic molecules using
microwave conditions in conjunction with soluble polymer support.
1
reaction is monitored by thin layer chromatography and H
NMR spectroscopy. When the reaction had completed, the
reaction mixture was concentrated under reduced pressure
and precipitated with cold ether (35 mL). The precipitate was
filtered, washed by cold ether and dried well to furnish the
PEG-bound 9-(2-methoxyethyl)-2-(4-methylphenyl)-9H-imidazo-
[1,2-a]benzoimidazole-6-carboxylate 6a. The solution of this PEG-
bound imidazo[1,2-a]benzoimidazole 6a in methanol (20 mL) was
added to a solution of potassium cyanide (0.130 g, 2.0 mmol.) in
5 mL of methanol. The mixture was stirred at ambient temperature
for 12 h. The solvent was removed under reduced pressure and the
mixture was precipitated by cold ether solution. The PEG was
removed by filtration and was washed by cold ether (25 mL ꢀ 3).
The combined filtrate was collected and dried well to afford title
compounds 7a, which was directly submitted to crude HPLC purity.
After column chromatography purification over silica gel using ethyl-
acetate/n-hexane (1:3) as eluent, methyl 9-(2-methoxyethyl)-2-(4-
methylphenyl)-9H-imidazo[1,2-a]benzoimidazole-6-carboxylate 7a
was obtained in overall 72% yield.
’ EXPERIMENTAL PROCEDURES
General Methods. Methanol and acetone were distilled
before use. All reactions were performed under an inert atmo-
sphere with unpurified reagents and dry solvents. Analytical thin-
layer chromatography (TLC) was performed using 0.25 mm
silica gel coated Kiselgel 60 F254 plates. Flash chromatography
was performed using the indicated solvent and silica gel 60
(Merck, 230-400 mesh). All the microwave experiments were
performed in a Biotage initiator under optimized reaction condi-
tions of power and pressure. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Bruker DX-300 spectrom-
eter. Chemical shifts are reported in parts per million (ppm) on the
scale from an internal standard. High-resolution mass spectra
(HRMS) were recorded on a JEOL TMS-HX 110 mass spectrometer.
Normal phase HPLC was performed on a Shimadzu LC-10AT
1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 1.4 Hz, 1H), 8.01
(dd, J = 8.5, 1.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H),
7.41 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 4.42 (t, J = 5.2
Hz, 2H), 3.96 (s, 3H), 3.89 (t, J = 5.2 Hz, 2H), 3.34 (s, 3H), 2.38
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 167.3, 150.3, 145.4,
139.8, 137.1, 132.1, 129.6, 125.5, 125.4, 124.5, 122.2, 122.5,
110.1, 102.2, 71.0, 59.3, 52.5, 44.0, 21.6. MS (ESIþ) m/z: 364 (M þ
H)þ. HRMS Calcd for C21H22N3O3: m/z 364.1661; Found
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364.1664 (M þ 1)þ. IR (cm-1, neat): 2929, 1712, 1600, 889.
HPLC Purity: 97%.
MHz, CDCl3): δ 8.23 (d, J = 1.2 Hz, 1H), 8.00 (dd, J = 8.6, 1.2
Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.68
(s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.36 (t,
J = 7.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H),
7.22 (d, J = 3.5 Hz, 1H), 6.97 (dd, J = 5.0, 3.5 Hz, 1H), 5.62 (s,
2H), 3.97 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 167.1, 150.2,
145.1, 141.2, 140.2, 138.6, 137.7, 134.0, 129.1, 127.7, 127.6,
127.5, 127.5, 127.3, 126.2, 126.0, 125.7, 124.9, 122.8, 112.9,
109.8, 102.9, 52.6, 42.3. MS (ESIþ) m/z: 464 (M þ H)þ. HRMS
Calcd for C28H22N3O2S: m/z 464.1433; Found 464.1435. IR
(cm-1, neat): 2942, 1698, 1592, 842, 701. HPLC Purity: 81%
Methyl 2-(tert-Butyl)-9-(tetrahydro-2-furanylmethyl)-9H-
Methyl 2-(4-Chlorophenyl)-9-(2-methoxyethyl)-9H-imidazo[1,2-a]-
benzoimidazole-6-carboxylate (7b). 1H NMR (300 MHz,
CDCl3): δ 8.23 (d, J = 1.3 Hz, 1H), 8.06 (dd, J = 8.5, 1.3 Hz, 1H),
7.79 (d, J = 8.6 Hz, 2H), 7.67 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H),
7.37 (d, J = 8.6 Hz, 2H), 4.43 (t, J = 5.2 Hz, 2H), 3.97 (s, 3H),
3.90 (t, J = 5.2 Hz, 2H), 3.35 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 167.2, 150.4, 144.2, 139.9, 133.5, 133.0, 129.1, 126.8,
125.7, 124.4, 122.5, 112.7, 110.3, 102.8, 70.9, 59.4, 52.6, 44.1.
MS (ESIþ) m/z: 384 (M þ H)þ. HRMS Calcd for C20H19-
ClN3O3: m/z 384.1115; Found 384.1117 (M þ 1)þ. IR
(cm-1, neat): 3060, 1706, 1625, 831. HPLC Purity: 93%
Methyl 9-Butyl-2-(4-nitrophenyl)-9H-imidazo[1,2-a]benzo-
1
imidazo[1,2-a]benzoimidazole-6-carboxylate (7h). H NMR
(300 MHz, CDCl3): δ 8.14 (d, J = 1.5 Hz, 1H), 7.97 (dd, J = 8.6,
1.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.10 (s, 1H), 4.43 (m, 1H),
4.36 (dd, J = 14.5, 3.6 Hz, 1H), 4.22 (dd, J = 14.5, 6.3 Hz, 1H),
3.94 (s, 3H), 3.86-3.65 (m, 2H), 2.16-1.73 (m, 4H), 1.37 (s,
9H). 13C NMR (75 MHz, CDCl3) δ 167.5, 156.4, 150.2, 139.7,
125.0, 124.7, 122.0, 112.1, 110.3, 100.6, 78.0, 68.7, 52.5, 48.0,
33.1, 30.4(3C), 29.2, 26.2. MS (ESIþ) m/z: 356 (M þ H)þ.
HRMS Calcd for C20H26N3O3: m/z 356.1974; Found 356.1976
(M þ 1)þ. IR (cm-1, neat): 2956, 1716, 1596. HPLC Purity: 99%
Methyl 9-Cyclohexyl-2-(2-methoxyphenyl)-9H-imidazo[1,2-
1
imidazole-6-carboxylate (7c). H NMR (300 MHz, CDCl3):
δ 8.24 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 8.05 (dd, J =
8.5, 1.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H), 7.29 (d,
J = 8.5 Hz, 1H), 4.24 (t, J = 7.4 Hz, 2H), 3.97 (s, 3H), 1.97 (quint,
J = 7.4 Hz, 2H), 1.45 (sextet, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 167.0, 150.9, 146.7, 143.1,
141.1, 139.4, 126.2, 125.6, 124.5, 124.1, 122.5, 113.2, 109.5,
104.9, 52.7, 43.8, 30.8, 20.5, 14.0. MS (ESIþ) m/z: 393 (M þ
H)þ. HRMS Calcd for C21H21N4O4: m/z 393.1563; Found
393.1565. IR (cm-1, neat): 2950, 1714, 1606, 1500, 759. HPLC
Purity: 60%
1
a]benzoimidazole-6-carboxylate (7i). H NMR (300 MHz,
CDCl3): δ 8.23 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 8.6, 1.5 Hz,
1H), 7.67 (s, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.0 Hz,
1H), 7.37 (d, J = 8.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.82 (dd,
J = 8.0, 2.3 Hz, 1H), 4.38 (m, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 2.43
(q, J = 12.2 Hz, 2H), 2.07-1.79 (m, 4H), 1.51 (quint, J = 12.2
Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 167.3, 160.3, 149.9,
145.1, 138.5, 136.5, 129.9, 125.3, 124.9, 121.7, 118.2, 113.1,
112.8, 111.1, 110.0, 102.3, 56.0, 55.7, 52.5, 30.9, 26.2, 25.5. MS
(ESIþ) m/z: 404 (M þ H)þ. HRMS Calcd for C24H26N3O3: m/
z 404.1974; Found 404.1976 (M þ 1)þ. IR (cm-1, neat): 2931,
1708, 1610, 742. HPLC Purity: 95%
Methyl 9-Butyl-3-methyl-2-phenyl-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7d). H NMR (300 MHz, CDCl3):
δ 8.26 (d, J = 1.3 Hz, 1H), 8.04 (dd, J = 8.5, 1.3 Hz, 1H), 7.74 (d,
J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H),
7.27 (d, J = 8.5 Hz, 1H), 4.25 (t, J = 7.4 Hz, 2H), 3.98 (s, 3H),
2.85 (s, 3H), 1.96 (quint, J = 7.4 Hz, 2H), 1.43 (sextet, J = 7.4 Hz,
2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
167.4, 148.7, 140.3, 139.5, 135.7, 128.8, 128.1, 126.9, 125.4,
125.1, 121.8, 114.8, 112.4, 108.9, 52.6, 43.6, 30.9, 20.5, 14.1, 11.5.
MS (ESIþ) m/z: 362 (M þ H)þ. HRMS Calcd for C22H24N3O4:
m/z 362.1868; Found 362.1870. IR (cm-1, neat): 2950, 1716,
1602, 761. HPLC Purity: 89%
Methyl 9-Isopentyl-2-(2-thienyl)-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7j). H NMR (300 MHz, CDCl3):
Methyl 2-(tert-Butyl)-9-(2-thienylmethyl)-9H-imidazo[1,2-a]-
benzoimidazole-6-carboxylate (7e). H NMR (300 MHz,
δ 8.23 (d, J = 1.4 Hz, 1H), 8.04 (dd, J = 8.5, 1.4 Hz, 1H), 7.60 (s,
1H), 7.40 (dd, J = 3.5, 1.1 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.24
(dd, J = 5.0, 1.1 Hz, 1H), 7.07 (dd, J = 5.0, 3.5 Hz, 1H), 4.25 (t, J =
7.6 Hz, 2H), 3.97 (s, 3H), 1.86 (q, J = 7.0 Hz, 2H), 1.71 (sextet,
J = 6.7 Hz, 1H), 1.03 (d, J = 6.5 Hz, 6H). 13C NMR (75 MHz,
CDCl3): δ 167.2, 150.3, 140.2, 139.1, 138., 128.0, 125.6, 124.4,
124.1, 123.1, 122.3, 112.9, 109.3, 102.1, 52.6, 42.4, 37.4, 26.2,
22.8. MS (ESIþ) m/z: 368 (M þ H)þ. HRMS Calcd for
1
CDCl3): δ 8.14 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.5, 1.3 Hz,
1H), 7.23 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 5.0, 1.0 Hz, 1H), 7.13
(dd, J = 3.5, 1.0 Hz, 1H), 7.12 (s, 1H), 6.92 (dd, J = 5.0, 3.5 Hz,
1H), 5.55 (s, 2H), 3.93 (s, 3H), 1.40 (s, 9H). 13C NMR (75
MHz, CDCl3): δ 171.5, 156.6, 149.6, 138.4, 138.0, 127.5, 127.4,
126.0, 125.1, 125.0, 122.3, 112.3, 109.6, 100.9, 52.5, 42.2, 33.2,
30.4. MS (ESIþ) m/z: 368 (M þ H)þ. HRMS Calcd for
C20H22N3O2S: m/z 368.1433; Found 368.1435. IR (cm-1
,
C20H22N3O2S: m/z 368.1433; Found 368.1436. IR (cm-1
,
neat): 2954, 1716, 1623, 701. HPLC Purity: 95%
Methyl 9-Isopropyl-2-(2-thienyl)-9H-imidazo[1,2-a]benzo-
neat): 2925, 1716, 1623, 707. HPLC Purity: 97%
Methyl 9-Benzyl-2-(3-methoxyphenyl)-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7k). H NMR (300 MHz, CDCl3):
1
imidazole-6-carboxylate (7f). H NMR (300 MHz, CDCl3): δ
δ 8.23 (d, J = 1.5 Hz, 1H), 8.02 (dd, J = 8.6, 1.5 Hz, 1H), 7.61 (s,
1H), 7.41 (dd, J = 3.6, 1.1 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.23
(dd, J = 5.1, 1.1 Hz, 1H), 7.07 (dd, J = 5.1, 3.6 Hz, 1H), 4.87
(septet, J = 6.9 Hz, 1H), 3.97 (s, 3H), 1.74 (d, J = 6.9 Hz, 6H).
13C NMR (75 MHz, CDCl3): δ 167.2, 149.6, 140.2, 138.7, 138.2,
127.9, 125.4, 124.5, 124.1, 123.0, 122.0, 112.8, 110.1, 101.7, 52.6,
48.4, 21.0. MS (ESIþ) m/z: 340 (M þ H)þ. HRMS Calcd for
8.25 (d, J = 1.3 Hz, 1H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 7.71 (s,
1H), 7.49 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H),
7.37-7.27 (m, 6H), 7.15 (d, J = 8.5 Hz, 1H), 6.85 (dd, J = 8.0, 1.6
Hz, 1H), 5.47 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 167.2, 160.3, 150.7, 145.3, 139.0, 136.3, 135.7,
130.0, 129.3, 128.5, 127.8, 125.7, 124.8, 122.6, 118.1, 113.5,
112.9, 110.9, 110.0, 103.0, 55.7, 52.6, 47.6. MS (ESIþ) m/z: 412
(M þ H)þ. HRMS Calcd for C25H22N3O3: m/z 412.1661;
Found 412.1664. IR (cm-1, neat): 2954, 1714, 1604, 761. HPLC
Purity: 84%
C18H18N3O2S: m/z 340.1120; Found 340.1122. IR (cm-1
,
neat): 2979, 1714, 1592, 705. HPLC Purity: 66%
Methyl 2-(tert-Butyl)-9-cyclohexyl-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7l). H NMR (300 MHz, CDCl3): δ
Methyl 2-(4-Phenylphenyl)-9-(2-thienylmethyl)-9H-imida-
zo[1,2-a]benzoimidazole-6-carboxylate (7g). H NMR (300
8.15 (d, J = 1.5 Hz, 1H), 7.94 (dd, J = 8.6, 1.5 Hz, 1H), 7.33 (d, J =
8.6 Hz, 1H), 7.11 (s, 1H), 4.37 (m, 1H), 3.93 (s, 3H), 2.33 (q,
1
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RESEARCH ARTICLE
J = 12.4 Hz, 2H), 2.01-1.65 (m, 4H), 1.51-1.41 (quint, J =
12.4, 4H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
167.4, 156.6, 149.5, 138.2, 124.8, 124.5, 121.2, 112.2, 109.9,
99.9, 55.6, 52.4, 33.1, 30.8, 30.5(3C), 26.1, 25.5. MS (ESIþ)
m/z: 354 (M þ H)þ. HRMS Calcd for C21H28N3O2: m/z
354.2181; Found 354.2179 (M þ 1)þ. IR (cm-1, neat): 2948,
1714, 1623, 1577; HPLC Purity: 70%
(M þ H)þ. HRMS Calcd for C23H20N3O2S: m/z 402.1276;
Found 402.1278. IR (cm-1, neat): 2937, 1706, 1629, 763. HPLC
Purity: 69%
Methyl 2-(tert-Butyl)-9-isopropyl-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7r). H NMR (300 MHz, CDCl3): δ
8.15 (d, J = 1.5 Hz, 1H), 7.95 (dd, J = 8.6, 1.5 Hz, 1H), 7.31 (d, J =
8.6 Hz, 1H), 7.11 (s, 1H), 4.84 (septet, J=6.9Hz, 1H), 3.94(s, 3H),
1.68(d, J= 6.9 Hz, 6H), 1.37 (s, 9H). 13C NMR(75MHz, CDCl3):
δ 167.4, 156.6, 149.4, 138.0, 124.8, 124.7, 121.3, 112.3, 109.8, 100.0,
52.4, 48.0, 33.1, 30.4(3C), 20.9. MS (ESIþ) m/z: 314 (M þ H)þ.
IR (cm-1, neat): 2956, 1716, 1581. HPLC Purity: 69%
Methyl 2-Ethyl-9-(2-thienylmethyl)-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7m). H NMR (300 MHz, CDCl3):
δ 8.16 (d, J = 1.4 Hz, 1H), 7.97 (dd, J = 8.5, 1.4 Hz, 1H), 7.28 (d,
J = 8.5 Hz, 1H), 7.20 (dd, J = 3.5, 1.3 Hz, 1H), 7.14 (dd, J = 5.0,
1.3 Hz, 1H), 7.14 (s, 1H), 6.94 (dd, J = 5.0, 3.5 Hz, 1H), 5.56 (s,
2H), 3.96 (s, 3H), 2.78 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 167.3, 149.6, 148.7, 138.4,
138.0, 127.4, 127.4, 126.1, 125.2, 125.0, 116.6, 112.5, 109.7, 102.7,
50.6, 42.2, 23.3, 13.8. MS (ESIþ) m/z: 340 (M þ H)þ. HRMS
Calcd for C18H18N3O2S: m/z 340.1120; Found 340.1122. IR
(cm-1, neat): 1712, 1621, 1594, 703. HPLC Purity: 61%
Methyl 2-(4-Chlorophenyl)-9-[2-(1-cyclohexenyl)ethyl]-9H-
Methyl 9-Cyclohexyl-2-(2-thienyl)-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7s). H NMR (300 MHz, CDCl3): δ
8.23 (d, J = 1.5 Hz, 1H), 8.02 (dd, J = 8.6, 1.5 Hz, 1H), 7.60 (s,
1H), 7.41 (dd, J = 3.5, 1.1 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.23
(dd, J = 5.1, 1.1 Hz, 1H), 7.07 (dd, J = 5.1, 3.5 Hz, 1H), 4.40 (m,
1H), 3.97 (s, 3H), 2.43 (q, J = 12.4 Hz, 2H), 2.08-1.98 (m, 4H),
1.53 (quint, J = 12.4 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ
167.3, 149.8, 140.1, 138.7, 138.4, 127.9, 125.3, 124.4, 124.1,
123.1, 121.9, 112.8, 110.2, 101.7, 56.0, 52.6, 30.9, 26.2, 25.5. MS
(ESIþ) m/z: 380 (M þ H)þ. HRMS Calcd for C21H22N3O2S:
m/z 380.1433; Found 380.1430 (M þ 1)þ. IR (cm-1, neat):
3060, 1697, 1592, 701. HPLC Purity: 86%
1
imidazo[1,2-a] benzoimidazole-6-carboxylate (7n). H NMR
(300 MHz, CDCl3): δ 8.20 (d, J = 1.3 Hz, 1H), 8.02 (dd, J = 8.5,
1.3 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.62 (s, 1H), 7.35 (d, J = 8.5
Hz, 2H), 7.24 (d, J = 8.5 Hz, 1H), 5.27 (br.s, 1H), 4.29 (t, J = 7.1
Hz, 2H), 3.96 (s, 3H), 2.53 (t, J = 7.1 Hz, 2H), 2.06-2.02 (m,
2H), 1.82-1.76 (m, 2H), 1.57 (m, 2H), 1.42 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 167.2, 150.5, 144.2, 139.2, 133.9, 133.6,
132.9, 129.1, 126.8, 125.5, 125.3, 124.8, 122.2, 112.2, 109.4,
102.5, 52.6, 42.6, 36.7, 28.6, 25.5, 23.1, 22.4; MS (ESIþ) m/z:
434 (M þ H)þ. HRMS Calcd for C25H25ClN3O2: m/z
434.1635; Found 434.1633(M þ 1)þ. IR (cm-1, neat): 2927,
1716, 1594, 835. HPLC Purity: 68%
Methyl 3-Methyl-2-phenyl-9-(tetrahydro-2-furanylmethyl)-9H-
1
imidazo[1,2-a]benzoimidazole-6-carboxylate (7t). H NMR
(300 MHz, CDCl3): δ 8.27 (d, J = 1.4 Hz, 1H), 8.02 (dd, J =
8.6, 1.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 2H), 7.47 (d, J = 8.6 Hz, 1H),
7.44 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 4.50 (m, 1H), 4.36
(dd, J = 14.7, 3.6 Hz, 1H), 4.23 (dd, J = 14.7, 6.5 Hz, 1H), 3.96 (s,
3H), 3.85-3.70 (m, 2H), 2.83 (s, 3H), 2.13 (m, 1H), 1.93-1.77
(m, 3H). 13CNMR(75MHz, CDCl3):δ167.4, 148.9, 140.1, 135.6,
128.8, 128.0, 126.9, 125.4, 125.0, 122.1, 114.9, 112.2, 110.3, 77.9,
68.7, 52.5, 48.0, 31.3, 29.3, 26.2, 11.4. MS (ESIþ) m/z: 390 (M þ
H)þ. HRMS Calcd for C23H24N3O3: m/z 390.1818; Found
390.1814; IR (cm-1, neat): 2948, 1712, 1604, 1241, 700. HPLC
Purity: 95%
Methyl 2-(4-Chlorophenyl)-9-isobutyl-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7o). H NMR (300 MHz, CDCl3): δ
8.24 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.80 (d, J =
8.5 Hz, 2H), 7.66 (s, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5
Hz, 1H), 4.04 (d, J = 7.5 Hz, 2H), 3.97 (s, 3H), 2.51 (sextet, J =
6.8 Hz, 1H), 1.03 (d, J = 6.8 Hz, 6H). 13C NMR (75 MHz,
CDCl3): δ 167.2, 150.9, 144.3, 139.7, 133.6, 133.0, 129.1, 126.9,
125.6, 124.3, 122.2, 112.9, 109.5, 102.6, 52.6, 51.3, 28.6, 20.6. MS
(ESIþ) m/z: 382 (M þ H)þ. HRMS Calcd for C21H21ClN3O2:
m/z 382.1322; Found 382.1320. IR (cm-1, neat): 2956, 1708,
1594, 831. HPLC Purity: 60%
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures, 1H NMR, 13C NMR, LRMS, HRMS, and FT-IR spectral
data of compounds 7a-t, and the NOESY spectrum and X-ray
crystallographic data of compound 7i. This material is available
free of charge via the Internet at http://pubs.acs.org.
Methyl 2-(tert-Butyl)-9-isobutyl-9H-imidazo[1,2-a]benzo-
1
imidazole-6-carboxylate (7p). H NMR (300 MHz, CDCl3): δ
8.15 (d, J = 1.4 Hz, 1H), 7.96 (dd, J = 8.4, 1.4 Hz, 1H), 7.22 (d, J =
8.4 Hz, 1H), 7.10 (s, 1H), 4.00 (d, J = 7.5 Hz, 2H), 3.94 (s, 3H),
2.41 (sextet, J = 6.8 Hz, 1H), 1.37 (s, 9H), 0.98 (d, J = 6.8 Hz,
6H). 13C NMR (75 MHz, CDCl3): δ 167.4, 156.6, 150.3, 139.4,
124.9, 124.6, 121.6, 112.3, 109.1, 100.3, 52.5, 51.0, 33.1, 30.4,
28.6, 20.5. MS (ESIþ) m/z: 328 (M þ H)þ. HRMS Calcd for
C19H26N3O2: m/z 328.2025; Found 328.2028. IR (cm-1, neat):
2958, 1716, 1623. HPLC Purity: 90%
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Funding Sources
The authors thank the National Science Council of Taiwan for
the financial assistance.
Methyl 3-Methyl-2-phenyl-9-(2-thienylmethyl)-9H-imidazo-
1
[1,2-a]benzoimidazole-6-carboxylate (7q). H NMR (300
MHz, CDCl3): δ 8.27 (d, J = 1.4 Hz, 1H), 7.99 (dd, J = 8.5,
1.4 Hz, 1H), 7.76 (dd, J = 7.8, 1.2 Hz, 2H), 7.46 (t, J = 7.8 Hz,
2H), 7.32 (dt, J = 7.8, 1.2 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.21
(dd, J = 5.0, 1.1 Hz, 1H), 7.18 (dd, J = 3.5, 1.1 Hz, 1H), 6.95 (dd,
J = 5.0, 3.5 Hz, 1H), 5.58 (s, 2H), 3.96 (s, 3H), 2.83 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 167.3, 148.3, 140.3, 138.8, 137.8,
135.6, 128.8, 128.0, 127.5, 127.4, 127.0, 126.2, 125.4, 125.3,
122.5, 115.2, 112.4, 109.5, 52.6, 42.1, 11.5. MS (ESIþ) m/z: 402
’ ACKNOWLEDGMENT
The authors thank the authorities of the National Chiao Tung
University for providing the laboratory facilities.
’ REFERENCES
(1) (a) Suhs, T.; Konig, B. Synthesis of Guanidines in Solution. Mini-
Rev. Org. Chem. 2006, 3, 315–331. (b) Ganesan, A. Solid-Phase
118
dx.doi.org/10.1021/co1000037 |ACS Comb. Sci. 2011, 13, 112–119

ACS Combinatorial Science
RESEARCH ARTICLE
Synthesis in the Twenty-First Century. Mini-Rev. Med. Chem. 2006
6, 310.
(c) Hayes, B. Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002.
(2) (a) Bucknall, R. A.; Swallow, D. L.; Moores, H.; Harrad, J. A
Novel Substituted Guanidine with High Activity in vitro against
Rhinoviruses. Nature 1973, 246, 144–145. (b) Medina-Molner, A.;
Blacque, O.; Spingler, B. The Synthesis of 1,2-Bis(1,5,9-triazacyclodo-
decyl)ethane: A Showcase for the Importance of the Linker
Length within Bis(alkylating) Reagents. Org. Lett. 2007, 9, 4829–4831.
(c) Cantillo, D.; Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Light,
M. E.; Palacios, J. C. Stepwise Cycloadditions of Mesoionic Systems:
Thionation of Thioisom€unchnones by Isothiocyanates. Org. Lett. 2008,
10, 1079–1082. (d) Martos, V.; Castreno, P.; Royo, M.; Albericio, F.; de
Mendoza, J. Solid-Phase Synthesis of Chiral Bicyclic Guanidinium
Oligomers. J. Comb. Chem. 2009, 11, 410–421.
(12) (a) Gravert, D. J.; Janda, K. D. Organic Synthesis on Soluble
Polymer Supports: Liquid-Phase Methodologies. Chem. Rev. 1997, 97,
489–509. (b) Sun, C. M. In Combinatorial Chemistry Methods and
Protocols; Bellavance, L., Ed.; The Humana Press: New Jersey, 2002;
pp 345-371.(c) Lu, J.; Toy, P. H. Organic Polymer Supports for
Synthesis and for Reagent and Catalyst Immobilization. Chem. Rev.
2009, 109, 815–838.
(13) (a) Lietard, J.; Meyer, A.; Vasseur, J. J.; Morvan, F. New
Strategies for Cyclization and Bicyclization of Oligonucleotides by Click
Chemistry Assisted by Microwaves. J. Org. Chem. 2008, 73, 191–200.
(b) Crauste, C.; Perigaud, C.; Peyrottes, S. Insights into the Soluble
PEG-Supported Synthesis of Cytosine-Containing Nucleoside 50-Mono-,
Di-, and Triphosphates. J. Org. Chem. 2009, 74, 9165–9172.
(3) (a) Eggers, H. J.; Waidner, E. Effect of 2-(R-Hydroxybenzyl)-
benzimidazole and Guanidine on the Uncoating of Echovirus 12. Nature
1970, 227, 952–953. (b) Langer, P.; Wuckelt, J.; Doring, M.; Schreiner,
P. R.; Gorls, H. Regioselective Anionic [3 þ 2] Cyclizations of Imidazole
Dinucleophiles with Oxaldiimidoyl Dichlorides—A Combined Experi-
mental and Theoretical Study. Eur. J. Org. Chem. 2001, 12, 2245–2255.
(c) Letourneau, J. J.; Liu, J.; Ohlmeyer, M. H. J.; Riviello, C.; Rong, Y.; Li,
H.; Appell, K. C.; Bansal, S.; Jacob, B.; Wong, A.; Webb, M. L. Synthesis
and Initial Evaluation of Novel, Non-peptidic Antagonists of the
Rv-Integrins Rvβ3 and Rvβ5. Bioorg. Med. Chem. Lett. 2009, 19, 352–355.
(4) Preston, P. N.; Smith, D. M.; Benzimidazoles and Its Congeneric Tricyclic
Compounds, Part 2; Tennant, G., Ed.; Wiley Interscience: New York, 1981.
(5) (a) Ogura, H.; Takayanagi, H.; Yamazaki, Y.; Yonezawa, S.;
Takagi, H.; Kobayashi, S.; Kamioka, T.; Kamoshita, K. Heterocyclic
compounds. 10. Synthesis of some imidazo[1,2-a]benzimidazoles with
potent analgetic activities. J. Med. Chem. 1972, 15, 923–926. (b) Spasov,
A. A.; Chernikov, M. V.; Anisimova, V. A.; Kuzmenko, T. A.; Osipova,
M. M. Search for antihistamine drugs among imidazobenzimidazoles
and triazolobenzimidazoles. Pharm. Chem. J. 2000, 34, 48–52. (c)
Anisimova, V. A.; Spasov, A. A.; Kosolapov, V. A.; Chernikov, M. V.;
Stukovina, A. Y.; Eltsova, L. V.; Larionov, N. P.; Libinzon, R. E.;
Vatolkina, O. E. Synthesis and Biological Activity of 9-Dialkylani-
moethyl-2-oxy(dioxy)-phenylimidazole[1,2-a]benzimidazole. Pharm.
Chem. J. 2006, 40, 521–529. (d) Shapiro, H. K. Pharmaceutical Com-
positions and Method for Treatment of Chronic Inflammatory Diseases.
U.S. Patent 2008234380, 2008.
(14) (a) Guchhait, S. K.; Madaan, C.; Thakkar, B. S. A Highly
Flexible and Efficient Ugi-Type Multicomponent Synthesis of Versatile
N-Fused Aminoimidazoles. Synthesis 2009, 19, 3293–3300. (b) Anisimova,
V. A.; Spasov, A. A.; Kosolapov, V. A.; Tolpygin, I. E.; Porotikov, V. I.;
Kucheryavenko, A. F.; Sysoeva, V. A.; Tibirkova, E. V.; Eltsova, L. V.
Synthesis and Pharmacological Activity of 3-(2,2,2-Trichloro-1-hydroxy-
ethyl)imidazo[1,2-a]benzimidazole Dihydrochlorides. Pharm. Chem. J.
2009, 43, 491–494.
(15) Hsiao, Y. S.; Yellol, G. S.; Chen, L. H.; Sun, C. M. Multi-
disciplinary Synthetic Approach for Rapid Combinatorial Library Synth-
esis of Triaza-Fluorenes. J. Comb. Chem. 2010, 12, 723–732.
(16) (a) Maiti, B.; Chanda, K.; Sun, C. M. Traceless Synthesis of
Hydantoin Fused Tetrahydro-β-carboline on Ionic Liquid Support in
Green Media. Org. Lett. 2009, 11, 4826–4829. (b) Lai, J. J.; Salunke,
D. B.; Sun, C. M. Multistep Microwave-Assisted Divergent Synthesis of
Indolo-Fused Pyrazino-/Diazepinoquinoxalinones on PEG Support.
Org. Lett. 2010, 12, 2174–2177.
(17) (a) Elders, N.; Schmitz, R. F.; De Kanter, F. J. J.; Ruijter, E.;
Groen, M. B.; Orru, R. V. A. A Resource-Efficient and Highly Flexible
Procedure for a Three-Component Synthesis of 2-Imidazolines. J. Org.
Chem. 2007, 72, 6135–6142. (b) Karrothu, S. B.; Kolla, N.; Lekkala,
A. R.; Golla, C. M.; Anand, R. V.; Gandu, V.; Bhattacharya, A.; Padi,
P. R.; Bandichhor, R. Effect of Solvent on Stereoselectivity in Pd/C
(Type 39K)-Catalyzed Hydrogenation of Methyl 3-Oxo-4-aza-5-an-
drostene-17-carboxylate, A Key Intermediate for Finasteride and Du-
tasteride. Org. Process Res. Dev. 2007, 11, 889–891.
(6) Anisimova, V. A.; Avdyunina, N. I.; Spasov, A. A.; Barchan, I. A.
Synthesis and Pharmacological Activity of Aminoketones and Aminoal-
coholes of the Imidazo[1,2-a]benzimidazole series. Pharm. Chem. J.
2002, 36, 377–381.
(7) (a) George, P.; Peretti, D. D.; Roy, J.; Schmitt, J. P.; Sevrin, M.
9H-Imidazo[1,2a]benzimidazole-3-acetamide Derivatives, Their Prep-
arations and Their Therapeutic Applications. U.S. Patent 5466706,
1995. (b) Han, X.; Pin, S. S.; Burris, K.; Fung, L. K.; Huang, S.; Taber,
M. T.; Zhang, J.; Dubowchik, G. M. Synthesis and Structure-Activity
Relationship of Imidazo[1,2-a]benzimidazoles as Corticotropin-Releas-
ing Factor 1 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2005, 15,
4029–4032.
(8) Haber, M.; Norris, M. Small Molecule Inhibitor for MRP1 and
Other Multidrug Transporter. WO Patent 2005113004, 2005.
(9) Morozov, I. S.; Anisimova, V. A.; Avdyunina, N. I.; Lukova, O. A.;
Pyatin, B. M.; Militareva, N. A.; Bykov, N. P.; Dvalishvili, E. G.; Khranilov,
A. A. Synthesis and Neuro-psychotropic Activity of Adamantylimidazo[1,2-a]-
benzimidazoles. Pharm. Chem. J. 2004, 38, 539–543.
(10) (a) Swamy, K. M. K.; Yeh, W. B.; Lin, M. J.; Sun, C. M.
Microwave-Assisted Polymer-Supported Combinatorial Synthesis of
Heterocyclic Libraries. Curr. Med. Chem. 2003, 10, 2403–2424. (b)
Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry;
Wiley-VCH: Weinheim, Germany, 2005. (c) Yanez, C. O.; Andrade,
C. D.; Belfield, K. D. Characterization of novel sulfonium photoacid
generators and their microwave-assisted synthesis. Chem. Commun.
2009, 7, 827–829.
(11) (a) Kappe, C. O.; Dallinger, D. The Impact of Microwave
Synthesis on Drug Discovery. Nat. Rev. Drug Discovery 2006, 5, 51–63.
119
dx.doi.org/10.1021/co1000037 |ACS Comb. Sci. 2011, 13, 112–119