Microwave assisted straightforward synthetic method for benzimidazole linked quinoxalinones on soluble polymer support

Article abstract of DOI:10.1016/j.tet.2011.01.040

The simple and efficient method was developed for the synthesis of benzimidazole linked quinoxalinones on soluble polymer support using microwave conditions. The acid catalyzed condensation of 4-fluoro-3-nitrobenzoic acid with polymer immobilized o-phenyl

Full text of DOI:10.1016/j.tet.2011.01.040

Tetrahedron 67 (2011) 2110e2117
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave assisted straightforward synthetic method for benzimidazole linked
quinoxalinones on soluble polymer support
,
a,
Cheng-Ting Chou a, Gorakh S. Yellol a, Wong-Jin Chang a, Mei-Lian Sun b , Chung-Ming Sun
*
*
a Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
b General Education Center, National University of Kaohsiung, Kaohsiung 811-48, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
The simple and efficient method was developed for the synthesis of benzimidazole linked quinox-
alinones on soluble polymer support using microwave conditions. The acid catalyzed condensation of
4-fluoro-3-nitrobenzoic acid with polymer immobilized o-phenylenediamine, ipso-fluoro nucleophilic
substitution with various primary amines and cyclization with acetyl chloride are the key steps involved
in implemented linear synthesis. In key cyclization step, the regioselective N-acylation at secondary
amine with chloroacetyl chloride followed by spontaneous intramolecular ring closure through ortho-
amine functionality generate the quinoxaline skeleton under microwave irradiation. The removal of
polymer support and exposure of quinoxalines for auto-oxidation finally produce the benzimidazole
linked quinoxalinone derivatives with high purity and yields.
Received 19 November 2010
Received in revised form 31 December 2010
Accepted 14 January 2011
Available online 26 January 2011
Keywords:
Benzimidazole
Quinoxalinones
Microwave synthesis
Polymer supported synthesis
Polyethylene glycol
Combinatorial parallel synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
molecular architectures. Typically, the substrate can be anchored
on the support at the beginning of multistep synthetic sequence. All
Combinatorial synthetic methodologies provide the main driv-
ing force for the preparation of large number of structurally diverse
libraries for discovery of lead compounds and high-throughput
screening in medicinal chemistry.1 The rapid development of high-
throughput strategies and multidisciplinary synergetic approaches
for the generation of arrays of small heterocyclic molecules are high
priority programs in modern drug discovery.2 Various solution
phase and solid phase synthetic methods have been developed in
combinatorial chemistry. Solid phase synthesis has its advantages
and disadvantages over conventional synthetic methods.3 The use
of soluble polymer support is emerging as a leading strategy that
combines the advantages of product isolation and purification of
solid-phase chemistry with the benefits of traditional solution-
phase reactions.4 The concept of immobilizing the substrate on
a soluble support material is now not new; numerous synthesis
including multicomponent coupling reactions were developed on
soluble polymer support as examples of supported substrate syn-
thetic systems. With an expanding assortment of these soluble
polymer supported system, it becomes increasingly viable to con-
struct advanced synthetic routes based on multi-step conversions
to generate both combinatorial libraries and more complex
synthetic steps carried out with no detachment of support by using
the advantages of solution phase method for reaction process and
reaction monitoring along with the advantages of polymer support
for separation and purification of products at every stage. The
polymer support could remove at the end of synthetic strategy to
liberate the final compounds with molecular complexity and sub-
stitutional diversity. The impact of this method has been tremen-
dous in effectively utilizing the chemical space, which is necessary
for the diversity oriented organic synthesis.5
This combinatorial parallel synthesis has expanded the struc-
tural diversity, permitting generation of new molecules required
for the lead identification and optimization in the drug discovery
process.1c,e In general practice of drug optimization that usually
develop one active scaffold and expand the extraneous group
around it to increase the complexity. Based on privileged structural
motifs, new scaffolds synthesized by diversity oriented technique
have the ability to address different targets by varying the sub-
stitution pattern. The combining two pharmacophore as bi-het-
erocyclic system and expanding the diversity around it for better
bioactivity is the familiar method in drug design and optimization.
Bi-heterocyclic compounds offer better binding opportunities with
enzyme active site owing to its three dimensional special
arrangement.6 Moreover the activity can be enhanced by changing
the substituent around the bi-heterocyclic skeleton. We also used
this concept to devise our research. With our interest in
* Corresponding authors. E-mail addresses: lian@nuk.edu.tw (M.-L. Sun),
cmsun@mail.nctu.edu.tw (C.-M. Sun).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.040

C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
2111
quinoxalinone and benzimidazole moieties,7 we decided to link
quinoxalinone skeleton with benzimidazole moiety and expand the
diversity around it with various substitutions for its intended ex-
tension of biologically activity.
DCC activation. Accordingly, anilide conjugates 2 were obtained by
the condensation of 4-fluoro-3-nitrobenzoic acid with polymer
conjugates 1 through activated ester generated by DCC and DMAP
in dichloromethane in 10 min under microwave irradiation
(Scheme 1). For the construction of benzimidazole ring, anilide
conjugates 2 were subjected to acid catalyzed cyclization in pres-
ence of 10% trifluoroacetic acid in 1,2-dichloroethane. The forma-
tion of the bi-heterocyclic o-fluoronitrobenzene 3 was achieved in
30 min under microwave irradiations. After completion of the re-
action, the polymer conjugate was purified by precipitating out the
reaction mixtures with excess of cold ether. The PEG supported
nitrobenzene 3 was treated with various primary amines to sub-
stitute the fluorine atom through ipso-fluoro nucleophilic sub-
stitution reaction under microwave irradiation. The reaction was
carried out in dichloromethane by open vessel microwave condi-
tions in 12 min to obtain the PEG supported nitroamine 4 with good
yield. Various aliphatic and aromatic amines were used to create
the second diversity in the targeted framework. All PEG supported
nitroamines 4 were separated and purified by precipitation in ether
solution. The ipso-fluoro displacements were confirmed by con-
ventional proton NMR spectrum directly on polymer conjugate 4.
For the reduction of nitro group, compound 4 was treated with zinc
and ammonium chloride in methanol. Formation of the amine
conjugates 5 was achieved in 3 h at room temperature. However, by
the application of microwave irradiation, the desired conjugates 5
were obtained within 10 min. It is noteworthy to say that the metal
reduction was proceeded smoothly under microwave condition.
The last two decades have been growing research in drugs con-
taining quinoxalinone andbenzimidazolecoresandhenceincreasing
interest in the chemistry of these compounds. Quinoxalinone moiety
shows broad spectrum of biological activity, such as anticancer, an-
timicrobial, antithrombotic, antiallergic, anxiolytic, antispastic, and
analgesic activity.8 Quinoxalinones also shows moderate to good
inhibition against HIV-1 and HIV-2 in MT-4 cells I (Fig. 1).9 Some of
the quinoxalinone derivatives are strong sodium ion channel in-
hibitor II.10 Quinoxalinone III acts as a PDE5 inhibitor and also
inhibited P-glycoprotein activity.11 The bi-heterocyclic skeleton with
quinoxaline (IV) is established as PI3 kinase inhibitors.12 Similarly,
benzimidazole is other privileged heterocycles known for a wide
range of biological activities.13 The applications of benzimidazole
derivatives are found in diverse therapeutic areasincluding antiulcer,
antihypertensive, antiviral, antifungal, anticancer, antihistaminic,
antitubercular, antiallergic, antioxidant, antimicrobial, and in vitro
anti Q3HIV-1activities.14 Benzimidazoleringisveryuseful subunitof
the development of biologically promising molecules.15 More par-
ticularly, the installation of benzimidazole moiety on bioactive qui-
noxalinone skeleton could more promisingly expands its bioactive
profile or enhance the activity of present biological portrait. Hence
further development of a benzimidazole skeleton linked with qui-
noxalinones to expand its bioactive profile is warranted.
HO
H2N
Ar
O
N
OH
F3C
O
N
N
O
N
N
N
OH
O
O
O
N
N
N
N
O
N
N
N
N
N
I
II
III
IV
Fig. 1. Related bioactive molecules.
The discovery of more novel biological targets from chemical
genetics research creates an immediate need to develop efficient
synthetic method for the preparation of small molecular entities.16
Hence in our continuous effort to develop the expedite and efficient
synthetic methods to medicinally important small heterocyclic
molecules,17 here we report the rapid and straightforward syn-
thesis of benzimidazole linked quinoxalinones on soluble polymer
support under microwave irradiation.
The excess zinc and ammonium formate were removed by filtra-
tion. Amine conjugates 5 were obtained in pure form by further
precipitation in cold ether.
The next critical step was the construction of terminal qui-
noxaline ring across the amine functionalities on this skeleton. The
functionalized PEG diamine conjugates 5 were reacted with
chloroacetyl chloride in methanol in the presence of triethyl amine.
The cyclization to form new ring across terminal amine function-
alities with chloroacetyl chloride resulting into quinoxaline skele-
ton was achieved in microwave cavity within 25 min. The
cyclization occurs through the N-acylation followed by N-alkyl-
ation steps. Initially, more reactive secondary amine nitrogen was
acylated to form N-chloroacetyl conjugate. The primary amine ni-
trogen in the transient N-chloroacetyl conjugate is located in a fa-
vorable position to form six member ring through intramolecular
cyclization by N-alkylation, which subsequently affords the qui-
noxaline ring skeleton. It is worthy to note that a facile and high
yielding ring closure reaction is quite distinct compared to the
regular synthetic approach toward the amino acid functionalized,
benzimidazole linked quinoxalines. Finally, removal of PEG support
from compound 6 was achieved by 3.5 N ammonia solution in
methanol. This is very mild and high yielding method as well as this
method replaces the highly toxic KCN reagent required for PEG
cleavage and also the reaction is fast than use of NaOMe. The PEG
support was smoothly removed by this method at room
2. Results and discussion
On our research plan to develop the straightforward method for
the synthesis of benzimidazole linked quinoxalinones, we planned
the construction of benzimidazole ring with attached fragment,
which later can modify into quinoxalinone ring system. The family
of long chain polymers link through covalent attachment with
a substrate, polyethylene glycol (PEG), is commonly used to syn-
thesize and modify a variety of drug molecules. Here we decided to
use PEG 4000 with reactive hydroxyl functionality at both end as
a soluble polymer support in our synthetic strategy. Accordingly,
the present strategy commenced with the synthesis of polymer
immobilized ortho-phenylenediamine 1 from 4-fluoro-3-nitro-
benzoic acid with built-in structural diversity (R1) through three
step protocol.18 PEG immobilized diamine 1 was N-acylated at the
primary amine functionality with 4-fluoro-3-nitrobenzoic acid via

2112
C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
NO2
O
F
NO2
O
HO
PEG
NH2
O
10% TFA, MgSO4
O
O
F
PEG
NH
NH
NH
R1
O
ethylene dichloride
MW, 30 min
DCC, DMAP
CH2Cl2,
2
2
MW, 20 min
R1
1
2
O
O
NO2
NO2
NH
PEG
PEG
H2N R2
N
N
O
O
F
CH2Cl2
MW, 12 min
N
R1
N
R1
4
R2
2
2
3
O
O
NH2
Cl
PEG
Cl
Zn, NH4Cl
N
N
O
NH
R2
Et3N
MeOH
ethylene dichloride
2
MW, 10 min
R1
MW, 25 min
5
O
HN
O
O
HN
H3C
3.5 N NH3
MeOH, rt, 48 h
PEG
N
N
R1
7
O
O
N
N
N
R2
O
N
R2
2
R1
6
O
N
H3C
O
N
N
auto-oxidation
O
O
N
R2
R1
8
Scheme 1. Synthesis of benzimidazolyl-quinoxalinones on polymer support.
temperature within 48 h. The reaction mixtures were precipitated
with ice cold ether and the polymer was removed by filtration. The
filtrates were concentrated to furnish benzimidazole linked qui-
noxaline 7 with good yields, which was subjected to HPLC analysis.
Analyzing the spectroscopic data, we observed that the final
product is a mixture of two compounds. After careful analysis of
spectroscopic data, it was observed that the final product is the
mixture of quinoxaline 7 and quinoxalinone 8. Based on the anal-
ysis and spectroscopic data, it was contemplated that quinox-
alinone was produced from quinoxaline 7 by auto-oxidation.
Initial study of this particular reaction was carried out with five
different substrates and the progress of the reaction was carefully
monitored. The results obtained after the cleavage of polymer
support step were summarized in Table 1. We observed the similar
results with all the substrate, which depict the two peaks in the
HPLC analysis of products corresponds to quinoxaline 7 and qui-
noxalinone 8 (Table 1). The quinoxaline 7 is unstable and is found to
be easily air oxidized to furnish the more stable quinoxalinone 8
skeleton resulting into mixture of quinoxaline 7 and quinoxalinone
8. The beginning of auto-oxidation and the rate of auto-oxidation is
depends on the substituents on quinoxaline ring. For detailed
study, we recorded the 1H NMR spectrum for compound 7i im-
mediate after isolation (spectrum A, Fig. 2), which does not show
respective auto-oxidized product. However, by keeping the
Table 1
Obtained mixture of quinoxalines 7 and quinoxalinones 8
Entry
R1NH2
R2NH2
Yeilda(%)
78
HPLCb
7
8
a
32
52
b
c
77
79
37
29
59
53
d
92
85
24
46
63
37
e
a
Total yield of samples (%).
HPLC analysis of crude mixture (%).
b

C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
2113
Fig. 2. Comparative proton NMR spectrums of compound 7 and 8.
samples at room temperature, we monitored the status of com-
pound by proton NMR analysis. Interestingly it is observed that
quinoxaline 7i was auto-oxidized completely into quinoxalinone 8i
in 5 h as seen from 1H NMR spectrums (spectrum B, Fig. 2). The
comparative proton NMR analysis was depicted in Fig. 2. The peak
for Ha and Hb protons was observed at 4.10 ppm along with NeH
proton peak at 4.68 ppm in the spectrum A of compound 7i. These
peaks corresponds to Hb proton and NeH proton disappeared in
the spectrum B of compound 8i while Ha proton peak shifted
downfield substantially and appeared at 8.37 ppm. Moreover the
peaks corresponds to aromatic protons (Hd, He & Hf) of quinoxaline
ring shifted downfield indicates the change of electronic environ-
ment of relative rings. These all observations clearly show the auto-
oxidation of quinoxaline to quinoxalinone system.
To avoid the critical separation of these products and limited
sources to control auto-oxidations, we decided to synthesize pure
benzimidazole linked quinoxalinone derivatives. Accordingly, all
the above mixture of compounds (7aþ8a to 7eþ8e) were exposed
to auto-oxidation and obtained as a single quinoxalinone com-
pounds (8a to 8e). Additionally, using different mixture of various
amines we synthesized PEG supported diamines 5. These com-
pounds 5 were cyclized with chloroacetyl chloride and sub-
sequently polymer support was cleaved to obtain benzimidazolyl
quinoxalines in good yields. The obtained compounds were further
exposed for auto-oxidation to afford pure benzmidazolyl-quinox-
alinones in good overall yields. Various primary amines were used
in combination with each other in the synthetic pathway to gen-
erate substitution diversity on benzmidazolyl-quinoxalinones.
Gratifyingly, all the reaction work smoothly along with auto-oxi-
dation to furnish various benzmidazolyl-quinoxalinones de-
rivatives. Table 2 depicts the generality of this methodology.
The observed outcome of regioselectivity in cyclization is sup-
ported by the results obtained in the reaction and are explained
mechanistically. The possible steps involved in regioselective cycli-
zation were depicted in Fig. 3.
The bifunctional diamine compound 5 treated with chloroacetyl
chloride, the nucleophilic attack can occur either from the primary
amine functionality or from secondary amine functionality of
compound 5 on the reactive carbonyl carbon of chloroacetyl chlo-
ride. The selectivity depends on the difference in nucleophilicities
and steric environments of the two possible sites of nucleophilic
attack. The nucleophilic attack by more reactive secondary amine
functionality of 5 to chloroacetyl chloride can lead to the in-
termediate A through route 1 with expel of HCl molecule in the
form of triethyl amine hydrochloride. Similarly, nucleophilic attack
by less hindered primary amine functionality could form in-
termediate B via route 2. Eventually, the possibility of route 2 is
discarded on the basis of observed auto-oxidized product. After the
cyclization of compound B into C further auto-oxidation into
compound D is not possible owing to formation of unstable qua-
ternary ammonium compound. However we observed the com-
plete oxidized product at the end of reaction sequence as seen from
HPLC and NMR. This confirms that the nucleophilic attack occurs
regioselectivity to produce compound 7 through route 1, which
subsequently auto-oxidized into compound 8.
3. Conclusion
The combination of two well established techniques, the use of
PEG linkers for facilitating purification and microwave energy for
speeding up organic reactions, was effectively used to develop
multidisciplinary synergetic approach to speed up the combinato-
rial parallel synthetic methods. The simple and efficient linear
method was developed for the synthesis of biologically interesting
bi-heterocyclic benzimidazole linked quinoxalinones on soluble
polymer support under microwave conditions. The key cyclization

2114
C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
Table 2
Route 2
NH2
Synthesized Benzimidazole linked quinoxalinone derivatives
O
O
N
Cl
H3C
Cl
O
N
O
NH
R2
N
Route 1
N
R2
5
R1
-HCl
8
Route 1
Route 2
O
Entry
R1NH2
R2NH2
LRMSa Yeildb(%) HPLCc
Cl
8a
466
78
84
NH2
HN
H2N
O
O
Cl
H2N
H2N
N
NH
R2
R2
8b
8c
468
496
77
79
96
82
O
H2N
A
B
-HCl
-HCl
H2N
H2N
O
HN
HN
8d
8e
8f
456
468
423
92
85
86
87
83
68
N
O
O
H2N
N
R2
H2N
R2
6
C
auto-oxidation
not possible
H2N
auto-oxidation
H2N
H2N
O
N
HN
H2N
H2N
O
N
N
8g
8h
418
444
82
81
78
79
H2N
H2N
R2
O
R2
8
D
not formed
H2N
H2N
Fig. 3. Possible steps involved in regioselective cyclization.
8i
484
484
466
76
84
85
84
89
79
H2N
of PEG supported o-phenylenediamine with chloroacetyl chloride
in regioselective manner generate the quinoxaline skeleton under
microwave irradiation. The exposure of quinoxalines for auto-oxi-
dation finally produces the bi-heterocyclic benzimidazole linked
quinoxalinone derivatives. The linear sequence using combination
of simple reactions to achieve the synthesis of biologically in-
teresting family of small molecules with two points of diversity is
the main feature of this combinatorial parallel synthesis. Short
reaction time, easy work up procedure, high yields, pure products,
and diversity scope are advantages of this parallel synthetic
method. This method dramatically shortens the time required for
overall reaction sequence and increases efficiency of the total
process. This approach provides a vision to develop combinatorial
parallel synthesis by combination of simple reactions with ad-
vanced techniques for the rapid synthesis of molecular libraries
with high degree of structural diversity.
8j
H2N
H2N
8k
H2N
H2N
H2N
8l
484
430
74
89
83
90
H2N
8m
H2N
H2N
H2N
H2N
8n
8o
466
478
92
86
92
86
H2N
O
4. Experimental
H2N
H2N
4.1. General experimental methods
8p
490
520
93
85
79
68
O
O
Dichloroethane and methanol were distilled before use. All re-
actions were performed under an inert atmosphere 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 in-
dicated solvent and silica gel 60 (Merck, 230e400 mesh). 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded on
a Bruker DX-300 spectrometer. Chemical shifts are reported in
parts per million (ppm) on the scale from an internal standard.
H2N
8q
O
H2N
H2N
a
LRMS were detected with ESI ionization source.
HPLC purity of unpurified samples.
Yields were determined on the weight of purified samples (%).
b
c

C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
2115
High-resolution mass spectra (HRMS) were recorded on a JEOL
TMS-HX 110 mass spectrometer. Normal phase HPLC was per-
formed on a Shimadzu LC-10AT series machine with a Hypersil
(250ꢀ4.6 mm) analytical column. PEG was purchased from
SHOWA. A monomode CEM DiscoverÔ microwave reactor with
standard configuration operating at a maximum power of 300 W
and equipped with an infrared pyrometer for the control of tem-
perature and compressed air system for cooling was used. All the
microwave experiments were performed under optimized reaction
conditions of power and temperature in open vessel. To monitor
the progression of reaction on a polymer support, a small portion of
the reaction mixture was pulled out, compound was precipitated
and washed with cold ether, subsequently dried and proton NMR
spectrum was recorded.
Dichloromethane (10 mL) was then added to salt out ammonium
formate. The reaction mixture was filtered through filter paper to
remove ammonium formate to obtain the PEG conjugate 5.
4.6. General procedure for the preparation of polymer bound
substituted benzimidazolyl-quinoxalinone derivatives 6
To a solution of 5 in dichloroethane (25 mL), chloroacetyl
chloride (0.0629 g, 3 equiv) and triethyl amine (0.77 mL, 3 equiv)
was added under nitrogen atmosphere. The reaction mixture was
irradiated under microwave condition for 25 min to complete
coupling and cyclization reaction. After completion of the reaction,
insoluble materials were removed by filtration through Celite. The
reaction mixtures were precipitated by slow addition of excess of
cold ether (100 mL) and filtered through a fritted funnel to obtain
the compound 6 in high purity.
4.2. General procedure for the preparation of polymer
bound3-(4-fluoro-3-nitrobenzamido)-4-(substituted amino)
carboxylates 2
4.7. General procedure for the cleavage of polymer to get
benzimidazolyl-quinoxalinone derivatives 8
Polymer bound o-phenylenediamine 1 (PEG 4000) (1.0 g,
0.25 mmol, 1.0 equiv) dissolved in dichloromethane (5 mL) was
To a solution of conjugates 6 in methanol (10 mL), 3.5 N ammonia
solution in methanol (10 mL) was added and stirred for 48 h at room
temperature. Aftercompletion of the reaction, monitoredbyTLC, the
crude mixture was precipitated with excess of cold ether (100 mL)
and the polymer was filtered off and subjected to rotavapor. The
residue was dried under vacuum and subjected to crude HPLC
analysis and further purified by neutral silica gel column chroma-
tography. The obtained solid was further subjected to air for auto-
oxidation and monitored by thin-layer chromatography and proton
NMR spectrum. After complete auto-oxidation, the title compounds
8 in good yield and subsequently subjected to spectral analysis.
added to
a solution of 4-fluoro-3-nitrobenzoic acid (0.11 g,
0.60 mmol, 2.4 equiv) in dichloromethane (5 mL) in the presence
of N,N0-dicyclohexylcarbodiimide (DCC) (0.144 g, 0.70 mmol,
2.4 equiv) and N,N0-dimethylamino pyridine (DMAP) (3 mg). The
reaction mixture was stirred at room temperature and sub-
sequently irradiated under microwave for 20 min to obtain the
polymer bound amide conjugates 2. After completion of the re-
action, the suspensible dicyclohexyl urea (DCU) was filtered
through filter paper. The reaction mixture was precipitated by slow
addition of cold ether and precipitated amide conjugate 2 was fil-
tered through fritted funnel. The crude product was washed suc-
cessively with ether to remove the undesired impurity and dried
for further steps.
4.7.1. 2-(1-Benzyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-butyl-1H-
benzoimidazole-5-carboxylic acid methyl ester (8a). 1H NMR
(300 MHz, CDCl3)
d
8.52 (d, J¼1.0 Hz, 1H), 8.47 (s, 1H), 8.21
4.3. General procedure for the preparation of polymer bound
benzimidazole derivatives 3
(d, J¼1.5 Hz, 1H), 8.07 (dd, J¼8.5, 1.0 Hz, 1H), 7.94 (dd, J¼8.7, 1.5 Hz,
1H), 7.47e7.44 (m, 2H), 7.37e7.29 (m, 5H), 5.54 (s, 2H), 4.31
(t, J¼7.5 Hz, 2H), 3.96 (s, 3H), 1.87e1.79 (m, 2H), 1.34e1.25 (m, 2H),
To a solution of 2 in 1,2-dichloroethane, trifluoroacetic acid
(0.5 mL) and MgSO4 (0.5 g) were added and irradiated under mi-
crowave conditions for 30 min. After completion of the reaction,
MgSO4 was removed by filtration through Celite. The reaction
mixtures were precipitated by slow addition of excess of cold ether
(100 mL) and filtered through a fritted funnel to obtain the com-
pound 3 in high purity.
0.88 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 167.41, 154.97,
151.49, 142.32, 134.54, 133.92, 133.34, 132.23, 130.82, 129.14, 128.20,
128.07, 126.92, 125.17, 124.83, 123.54, 123.38, 122.07,121.89, 115.69,
110.08, 52.21, 45.79, 45.03, 31.89, 19.98, 13.54; MS (EI) m/z 466;
HRMS (EI) m/z calcd for C28H26N4O3 466.2005, found 466.2012; IR
(KBr): 2927, 2854, 1713, 1667, 1440, 1302, 1086, 735 cmꢁ1
.
4.7.2. 1-Cyclopentyl-2-(1-furan-2-ylmethyl-2-oxo-1,2-dihydro-quinox-
4.4. General procedure for the preparation of polymer bound
substituted benzimidazole derivatives 4
alin-6-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester (8b). 1H
NMR (300 MHz, CDCl3)
d
8.56 (d, J¼1.0 Hz, 1H), 8.40 (s, 1H), 8.13 (d,
J¼1.2 Hz, 1H), 8.04 (d, J¼8.5, 1.0 Hz, 1H), 8.01 (d, J¼8.7, 1.2 Hz, 1H),
7.83 (d, J¼8.5 Hz, 1H), 7.57 (d, J¼8.7 Hz, 1H), 7.36 (d, J¼3.6 Hz, 1H),
6.46 (d, J¼4.5 Hz, 1H), 6.35e6.34 (m, 1H), 5.49 (s, 2H), 5.00e4.94
(m, 1H), 3.96 (s, 3H), 2.39e2.30 (m, 2H), 2.20e2.03(m, 4H),
The polymer bound benzimidazole derivative 3 was treated
with various primary amines (5 equiv) in 1,2-dichloroethane
(5 mL). The reaction mixtures were irradiated under microwave
condition for 12 min to complete SNAr reaction and the reaction
mixtures were washed with cold ether (100 mL), dried to obtain the
conjugate 4 in quantitative yields.
1.80e1.77 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 167.45, 154.36,
154.10, 151.27, 148.11, 143.11, 142.72, 136.39, 133.62, 133.08, 132.27,
131.07, 125.92, 124.62, 124.05, 122.55, 115.33, 111.65, 110.75, 109.87,
57.94, 52.13, 38.67, 29.66, 25.24; MS (EI) m/z 468; HRMS (EI) m/z
calcd for C27H24N4O4 468.1798, found 468.1787; IR (KBr): 2851,
4.5. General procedure for the preparation of polymer bound
diamine derivatives 5
1713, 1673, 1436, 1305, 1224, 1087, 735 cmꢁ1
.
To a solution of 4 in methanol, Zn (0.5 g, 7.5 mmol, 30 equiv) and
ammonium chloride (0.24 g, 3.75 mmol, 15.0 equiv) were added.
The reaction mixtures were stirred for 30 min for complete re-
duction of nitro group, which was evident from color change from
yellow to colorless. The reaction mixtures were then subjected to
centrifugation for removal of Zn and the supernatant liquid was
concentrated by rotary evaporation to remove methanol.
4.7.3. 2-[1-(2-Cyclohex-1-enyl-ethyl)-2-oxo-1,2-dihydro-quinoxalin-
6-yl]-1-cyclopentyl-1H-benzoimidazole-5-carboxylic acid methyl ester
(8c). 1H NMR (300 MHz, CDCl3)
d
8.53 (d, J¼0.9 Hz, 1H), 8.34 (s, 1H),
8.13 (d, J¼1.5 Hz, 1H), 8.02e7.97 (m, 2H), 7.56 (d, J¼8.5 Hz, 1H), 7.50
(d, J¼8.7 Hz, 1H), 5.44 (s, 1H), 5.06e4.94 (m, 1H), 4.35 (t, J¼7.8 Hz,
2H), 3.95(s, 3H), 2.38e2.28(m, 4H), 2.18e2.14(m, 2H), 2.12e2.05 (m,
4H), 2.01e1.87 (m, 2H),1.77 (m, 2H),1.69e1.61 (m, 2H),1.58e1.51(m,

2116
C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
2H); 13C NMR (75 MHz, CDCl3)
d
167.48, 154.50, 154.21, 151.28,
3H); 13C NMR (75 MHz, CDCl3)
d 168.83, 167.64, 155.01, 142.46,
143.35, 136.49, 133.64, 133.57, 133.17, 132.12, 131.25, 125.71, 124.53,
124.29,123.97,122.65,114.66,111.58, 70.51, 57.94, 52.18, 41.05, 35.21,
30.55, 29.66, 28.49, 25.24, 25.22, 22.76, 22.09; MS (EI) m/z 496;
HRMS (EI) m/z calcd for C30H32N4O3 496.2474, found 496.2468; IR
138.89, 137.96, 130.77, 124.85, 124.56, 124.23, 121.93, 119.90, 119.52,
116.18, 115.88, 109.81, 56.65, 52.09, 48.79, 44.82, 42.05, 31.84, 28.45,
25.52, 19.96, 13.57; MS (EI) m/z 444; HRMS (EI) m/z calcd for
C26H28N4O3 444.2161, found 444.2163; IR (KBr): 2923, 1721, 1666,
(KBr): 2851, 1713, 1667, 1436, 1304, 1087, 754 cmꢁ1
.
1617, 1437, 1224, 771 cmꢁ1
.
4.7.4. 2-(1-Butyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-furan-2-yl-
4.7.9. 1-Butyl-2-[1-(2-cyclohex-1-enyl-ethyl)-2-oxo-1,2-dihydro-
quinoxalin-6-yl]-1H-benzoimidazole-5-carboxylic acid methyl ester
methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (8d). 1H
NMR (300 MHz, CDCl3)
d
8.61 (s, 1H), 8.42 (d, J¼1.8 Hz, 1H), 8.37
(8i). 1H NMR (300 MHz, CDCl3)
d
8.54 (d, J¼1.5 Hz, 1H), 8.36 (s, 1H),
(s, 1H), 8.24 (d, J¼8.7 Hz, 1H), 8.11 (dd, J¼8.7, 1.8 Hz, 1H), 7.61e7.55
(m, 2H), 7.45e7.44 (d, J¼4.3 Hz,1H), 6.44e6.40 (m, 2H), 5.48 (s, 2H),
4.29 (t, J¼7.2 Hz, 2H), 3.96 (s, 3H), 1.83e1.72 (quint, J¼7.4 Hz, 2H),
1.57e1.45 (m, 2H), 1.02 (d, J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
8.21 (dd, J¼8.4,1.5 Hz,1H), 8.08e8.04 (m, 2H), 7.53 (d, J¼8.5 Hz,1H),
7.47 (d, J¼8.4 Hz, 1H), 5.45 (s, 1H), 4.40e4.31 (t, J¼7.4 Hz, 2H), 3.97
(s, 3H), 3.39 (t, J¼6.8 Hz, 2H), 2.39 (m, 2H), 2.09e1.96 (m, 2H),
1.90e1.80 (m, 4H), 1.70e1.54 (m, 4H), 1.30 (sext, J¼7.2 Hz, 2H), 0.88
d
168.85, 167.43, 154.64, 153.73, 151.33, 148.39, 143.33, 142.48,
(t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 167.51, 164.99, 154.97,
139.07, 133.81, 133.31, 132.19, 131.44, 125.19, 124.89, 122.18, 114.71,
110.68,110.29,109.19, 52.15, 42.42, 41.97, 29.34, 20.19,13.73; MS (EI)
m/z 456; HRMS (EI) m/z calcd for C26H24N4O4 456.1798, found
142.25, 138.73, 136.53, 134.21, 129.31, 124.40, 124.10, 123.51, 123.39,
122.8, 121.72, 119.53, 115.21, 114.67, 109.70, 51.98, 47.27, 44.68,
34.92, 31.69, 28.37, 25.17, 22.74, 22.12, 19.82, 13.44; MS (EI) m/z 484;
HRMS (EI) m/z calcd for C29H32N4O3 484.2474, found 484.2460; IR
456.1805; IR (KBr): 2853, 1720, 1670, 1617, 1436, 773, 735 cmꢁ1
.
(KBr): 2928, 1723, 1674, 1303, 1086 cmꢁ1
.
4.7.5. 2-(1-Cyclopentyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-furan-
2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester (8e). 1H
4.7.10. 2-[1-(2-Cyclohex-1-enyl-ethyl)-2-oxo-1,2-dihydro-quinoxalin-
6-yl]-1-isobutyl-1H-benzoimidazole-5-carboxylic acid methyl ester
NMR (300 MHz, CDCl3)
d
8.51 (d, J¼1.0 Hz,1H), 8.35 (d, J¼1.8 Hz,1H),
8.28 (s, 1H), 8.08e8.01 (m, 2H), 7.64 (d, J¼8.7 Hz, 1H), 7.52
(d, J¼8.4 Hz, 1H), 7.42e7.41 (d, J¼4.3 Hz, 1H), 6.38e6.35 (m, 2H),
5.55e5.43 (m, 1H), 5.41 (s, 2H), 3.93 (s, 3H), 2.33e2.23 (m, 2H),
2.14e2.00 (m, 4H), 1.81e1.76 (m, 2H); 13C NMR (75 MHz, CDCl3)
(8j). 1H NMR (300 MHz, CDCl3)
d
8.55 (d, J¼1.4 Hz, 1H), 8.36 (s, 1H),
8.20 (d, J¼1.1 Hz, 1H), 8.08e8.02 (m, 2H), 7.53e7.45 (m, 2H), 5.45 (s,
1H), 4.37 (t, J¼7.6 Hz, 2H), 4.20 (t, J¼7.5 Hz, 2H), 3.97 (s, 3H), 2.39 (t,
J¼7.5 Hz, 2H), 2.13e2.09 (m, 1H), 1.70e1.62 (m, 4H), 1.59e1.54 (m,
d
168.81, 167.42, 155.32, 153.68, 151.76, 148.39, 143.33, 142.39,
4H), 0.78 (d, J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 167.49,
139.05, 133.98, 131.73, 131.48, 125.22, 124.92, 124.44, 122.14, 115.51,
110.68, 110.30, 109.19, 55.35, 52.15, 42.42, 41.96, 29.66, 28.03, 25.74;
MS (EI) m/z 468; HRMS (EI) m/z calcd for C27H24N4O4 468.1798,
154.57, 153.84, 151.41, 139.06, 133.68, 133.27, 132.19, 131.07, 124.99,
124.63, 124.35, 123.70, 123.43, 122.57, 122.31, 114.79, 110.39, 52.34,
52.18, 41.15, 29.71, 29.07, 28.56, 25.27, 22.81, 22.70, 20.04; MS (EI)
m/z 484; HRMS (EI) m/z calcd for C29H32N4O3 484.2474, found
found 468.1791; IR (KBr): 2850, 1651, 1402, 764, 642 cmꢁ1
.
484.2461; IR (KBr): 3053, 2926, 1713, 1666, 1265, 740, 705 cmꢁ1
.
4.7.6. 1-Butyl-2-(1-isobutyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1H-
indole-5-carboxylic acid methyl ester (8f). 1H NMR (300 MHz,
4.7.11. 2-(1-Benzyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-isobutyl-
CDCl3)
d
8.54 (s, 1H), 8.38 (s, 1H), 8.20 (d, J¼1.8 Hz, 1H), 8.09e8.03
1H-indole-5-carboxylic acid methyl ester (8k). 1H NMR (300 MHz,
(m, 2H), 7.51 (d, J¼8.7 Hz, 1H), 7.47 (d, J¼8.7 Hz, 1H), 4.34
(t, J¼7.2 Hz, 2H), 4.17 (d, J¼7.5 Hz, 2H), 3.96 (s, 3H), 2.34e2.25
(m, 1H), 1.92e1.81 (quint, J¼7.2 Hz, 2H), 1.39e1.26 (sext, J¼7.2 Hz,
2H), 1.04 (d, J¼6.8 Hz, 6H), 0.90 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3)
d
8.51 (d, J¼1.2 Hz, 1H), 8.47 (s, 1H), 8.21 (d, J¼1.8 Hz, 1H),
8.04 (dd, J¼8.5, 1.2 Hz, 1H), 7.90 (dd, J¼8.7, 1.8 Hz, 1H), 7.46e7.43
(m, 2H), 7.37e7.16 (m, 5H), 5.53 (s, 2H), 4.15 (d, J¼7.4 Hz, 2H), 3.95
(s, 3H), 2.18e2.09 (m, 1H), 0.77 (d, J¼7.3 Hz, 6H); 13C NMR (75 MHz,
CDCl3)
d
168.77, 167.53, 155.09, 153.49, 151.43, 142.52, 138.90,
CDCl3) d 168.59, 158.71,157.89,149.61, 144.78, 142.56, 141.98,141.85,
133.94, 133.25, 131.93, 130.84, 125.38, 124.84, 122.27, 115.12, 109.93,
52.13, 48.88, 44.93, 41.97, 31.89, 27.27, 20.10, 13.84; MS (EI) m/z 432;
HRMS (EI) m/z calcd for C25H28N4O3 432.2161, found 432.2146; IR
137.54, 129.68, 128.04, 127.78, 127.45, 127.02, 126.57, 123.54, 123.14,
122.53, 119.85, 112.57, 53.35, 52.19, 48.96, 27.58, 19.04; MS (EI) m/z
466; HRMS (EI) m/z calcd for C28H26N4O3 466.2005, found
(KBr): 2958, 1715, 1667, 1618, 1301, 771, 753 cmꢁ1
.
466.2013; IR (KBr): 2825, 1713, 1667, 1620, 1435, 772, 734 cmꢁ1
.
4.7.7. 1-Butyl-2-[1-(2-methoxy-ethyl)-2-oxo-1,2-dihydro-quinox-
4.7.12. 1-Isobutyl-2-[1-(3-methyl-benzyl)-2-oxo-1,2-dihydro-qui-
noxalin-6-yl]-1H-benzoimidazole-5-carboxylic acid methyl ester
alin-6-yl]-1H-benzoimidazole-5-carboxylic acid methyl ester (8g). 1H
NMR (300 MHz, CDCl3)
d
8.56 (s, 1H), 8.38 (s, 1H), 8.19 (d, J¼2.1 Hz,
(8l). 1H NMR (300 MHz, CDCl3)
d
8.55 (d, J¼1.2 Hz, 1H), 8.49 (s, 1H),
1H), 8.10e8.05 (m, 2H), 7.74 (d, J¼8.7 Hz, 1H), 7.47 (d, J¼8.7 Hz, 1H),
4.51 (t, J¼6.4 Hz, 2H), 4.34 (t, J¼7.4 Hz, 2H), 3.96 (s, 3H), 3.79
(t, J¼6.4 Hz, 2H), 3.33 (s, 3H), 1.92e1.81 (quint, J¼7.4 Hz, 2H),
1.36e1.29 (sext, J¼7.4 Hz, 2H), 0.90 (t, J¼7.4 Hz, 3H); 13C NMR
8.22 (d, J¼1.8 Hz, 1H), 8.07 (dd, J¼8.5, 1.2 Hz, 1H), 7.95 (d, J¼8.5 Hz,
1H), 7.47 (dd, J¼8.5, 1.8 Hz, 1H), 7.40 (d, J¼8.5 Hz, 1H), 7.23
(t, J¼7.8 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J¼7.8 Hz, 2H), 5.51 (s, 2H), 4.19
(d, J¼7.5 Hz, 2H), 3.96 (s, 3H), 2.32 (s, 3H), 2.18e2.09 (m, 1H), 0.77
(75 MHz, CDCl3)
d
167.20, 154.90, 152.91, 151.37, 144.25, 142.15,
(d, J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 167.48, 154.84, 151.40,
140.75, 134.98, 133.19, 132.20, 130.66, 125.72, 125.25, 121.63, 116.23,
110.28, 69.72, 59.22, 52.31, 45.24, 42.66, 31.87, 20.00, 13.57; MS (EI)
m/z 434; HRMS (EI) m/z calcd for C24H26N4O4 434.1954, found
142.54, 139.10, 138.93, 134.21, 133.69, 133.28, 132.19, 130.83, 128.92,
128.84, 128.77, 127.20, 126.04, 124.77, 124.47, 123.91, 122.36, 115.57,
110.29, 52.23, 52.15, 45.75, 29.01, 19.98, 19.90; MS (EI) m/z 480;
HRMS (EI) m/z calcd for C29H28N4O3 480.2161, found 480.2148; IR
434.1942; IR (KBr): 2923, 1725, 1666, 1303, 1084, 771 cmꢁ1
.
(KBr): 2925, 2359, 1716, 1667, 1302, 1085, 772 cmꢁ1
.
4.7.8. 1-Butyl-2-(1-cyclopentyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-
1H-indole-5-carboxylic acid methyl ester (8h). 1H NMR (300 MHz,
4.7.13. 1-Cyclopentyl-2-(1-isopropyl-2-oxo-1,2-dihydro-quinoxalin-
CDCl3)
d
8.53 (d, J¼1.8 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J¼2.1 Hz, 1H),
6-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester (8m). 1H
8.06 (dd, J¼8.5, 1.8 Hz, 1H), 8.02 (dd, J¼8.7, 2.1 Hz, 1H), 7.66
(d, J¼8.7 Hz, 1H), 7.46 (d, J¼8.5 Hz, 1H), 5.55e5.46 (m, 1H), 4.33
(t, J¼7.4 Hz, 2H), 3.96 (s, 3H), 2.32e2.26 (m, 2H), 2.16e2.03 (quint,
J¼7.3 Hz, 2H),1.90e1.80 (m, 4H),1.38e1.17 (m, 4H), 0.90 (t, J¼7.3 Hz,
NMR (300 MHz, CDCl3)
d
8.54 (s, 1H), 8.29 (s, 1H), 8.13 (d, J¼1.8 Hz,
1H), 8.03e7.95 (m, 2H), 7.74 (d, J¼8.7 Hz, 1H), 7.56 (d, J¼8.7 Hz, 1H),
5.38e5.34 (m, 1H), 5.06e4.94 (m, 1H), 3.96 (s, 3H), 2.39e2.29
(m, 2H), 2.19e2.03 (m, 4H),1.80e1.74 (m, 2H),1.69 (d, J¼7.2 Hz, 6H);

C.-T. Chou et al. / Tetrahedron 67 (2011) 2110e2117
2117
13C NMR (75 MHz, CDCl3)
d
168.71, 167.51, 155.19, 154.15, 152.05,
Supplementary data
143.28, 136.47, 133.76, 131.60, 131.43, 125.50, 124.53, 124.23, 123.98,
122.61, 111.61, 57.93, 52.13, 41.97, 30.54, 29.66, 25.25; MS (EI) m/z
430; HRMS (EI) m/z calcd for C25H26N4O3 430.2005, found
The 1H NMR spectrums and HPLC spectrums of compounds
9ae9q are available free of charge through Internet. Supplementary
data related to this article can be found online at doi:10.1016/
j.tet.2011.01.040.
430.1988; IR (KBr): 2852, 1667, 1620, 1436, 1304, 771, 755 cmꢁ1
.
4.7.14. 1-Cyclopentyl-2-[1-(2-methoxy-ethyl)-2-oxo-1,2-dihydro-
quinoxalin-6-yl]-1H-benzoimidazole-5-carboxylic acid methyl ester
References and notes
(8n). 1H NMR (300 MHz, CDCl3)
d 8.52 (s, 1H), 8.36 (s, 1H), 8.11
(d, J¼0.9 Hz, 1H), 8.02e7.94 (m, 2H), 7.73 (d, J¼8.5 Hz, 1H), 7.55
(d, J¼8.7 Hz, 1H), 5.05e4.93 (m, 1H), 4.49 (t, J¼7.2 Hz, 2H), 3.94
(s, 3H), 3.78 (t, J¼7.2 Hz, 2H), 3.32 (s, 3H), 2.39e2.30 (m, 2H),
2.20e2.03 (m, 4H), 1.80e1.77 (m, 2H); 13C NMR (75 MHz, CDCl3)
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132.05, 130.89, 125.72, 124.55, 123.98, 122.56, 115.78, 111.61, 69.67,
59.14, 57.93, 52.10, 42.53, 30.53, 25.23; MS (EI) m/z 446; HRMS (EI)
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1716, 1667, 1439, 1304, 1225, 974 cmꢁ1
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4.7.15. 2-(1-Benzyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-cyclo-
pentyl-1H-benzoimidazole-5-carboxylic acid methyl ester (8o). 1H
NMR (300 MHz, CDCl3)
d
8.51 (d, J¼1.5 Hz, 1H), 8.47 (s, 1H), 8.15
(d, J¼1.9 Hz, 1H), 8.00 (dd, J¼8.5, 1.5 Hz, 1H), 7.85 (dd, J¼8.7, 1.9 Hz,
1H), 7.54 (d, J¼8.5 Hz, 1H), 7.45 (d, J¼8.7 Hz, 1H), 7.38e7.26 (m, 5H),
5.54 (s, 2H), 5.01e4.90 (m, 1H), 3.95 (s, 3H), 2.39e2.30 (m, 2H),
2.20e2.03(m, 4H), 1.80e1.77 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
167.5, 1.55.0, 154.1, 151.4, 143.1, 136.4, 134.6, 133.8, 133.3, 132.3,
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Patent 20,100,113,461 A1, 2010.
131.2, 129.3, 128.1, 126.9, 125.9, 124.7, 124.1, 122.6, 115.6, 111.7, 58.0,
52.2, 45.8, 30.6, 29.7, 25.3, 23.9; MS (EI) m/z 478; HRMS (EI) m/z
calcd for C29H26N4O3 478.2005, found 478.2002; IR (KBr): 2873,
1715, 1667, 1439, 1221, 1087, 734 cmꢁ1
.
4.7.16. 2-(1-Benzyl-2-oxo-1,2-dihydro-quinoxalin-6-yl)-1-furan-2-
ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester (8p). 1H
NMR (300 MHz, CDCl3)
d
8.56 (s, 1H), 8.48 (s, 1H), 8.41 (d, J¼0.9 Hz,
1H), 8.09e8.04 (m, 2H), 7.55 (d, J¼8.2 Hz,1H), 7.48 (d, J¼8.5 Hz,1H),
7.43 (d, J¼3.4 Hz, 1H), 7.38e7.28 (m, 5H), 6.44e6.34 (m, 2H), 5.55 (s,
2H), 5.42 (s, 2H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 167.17,
154.91, 151.53, 143.50, 138.57, 134.47, 133.36, 132.38, 132.01, 131.51,
129.12, 128.11, 128.06, 127.82, 126.86, 125.32, 124.01, 121.76, 117.76,
115.72, 110.75, 110.51, 109.47, 106.45, 53.39, 45.76, 42.56; MS (EI) m/
z 490; HRMS (EI) m/z calcd for C29H22N4O4 490.1641, found
11. Cartaa, A.; Pirasa, S.; Pagliettia, G.; Priclb, S.; La Collac, P.; Busonerac, B.; Loddo,
R. Med. Chem. 2008, 4, 194e205.
12. Ren, P.; Liu, Y.; Li, L.; Chan, K.; Wilson, T. E. WO Patent, WO 2010036380A1,
2010.
490.1653; IR (KBr): 2851, 1667, 1619, 1436, 1303, 735 cmꢁ1
.
13. (a) Hasegawa, M.; Nishigaki, N.; Washio, Y.; Kano, K.; Harris, P. A.; Sato, H.;
Mori, I.; West, R. I.; Shibahara, M.; Toyoda, H.; Wang, L.; Nolte, R. T.; Veal, J. M.;
Cheung, M. J. Med. Chem. 2007, 50, 4453e4470; (b) Hirashima, S.; Suzuki, T.;
Ishida, T.; Noji, S.; Ando, I.; Komatsu, M.; Ikede, S.; Hashimoto, H. J. Med. Chem.
2006, 49, 4721e4736; (c) Li, Y. F.; Wang, G. F.; He, P. L.; Huang, W. G.; Gao, H. Y.;
Tang, W.; Luo, Y.; Feng, C. L.; Shi, L. P.; Ren, Y. D.; Lu, W.; Zuo, J. P. J. Med. Chem.
2006, 49, 4790e4794; (d) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R. J. Med.
Chem. 1994, 37, 4338e4345.
14. (a) Islam, I.; Skibo, E. B.; Dorr, R. T. J. Med. Chem. 1991, 34, 2954e2961; (b)
Nakano, H.; Inoue, T.; Kawasaki, N. Chem. Pharm. Bull. 1999, 47, 1573e1578; (c)
Kus, C.; Ayhan-Kicigil, G.; Iscan, M. Arch. Pharmacal Res. 2004, 27, 156e163; (d)
Samia, R.; Soda, A.; El-Hesham, M.; Fahmy, T. Y. Arch. Pharmacal Res. 2006, 29,
826e833.
15. Boyer, P. L.; Hughes, S. H.; Buckheit, R. W. J. Med. Chem. 1997, 40, 4199.
16. Tolliday, N.; Clemons, P. A.; Ferraiolo, P. ,; Koehler, A. N.; Lewis, T. A.; Li, X.;
Schreiber, S. L.; Gerhard, D. S.; Eliasof, S. Cancer Res. 2006, 66, 8935e8942.
17. (a) Chou, L. C.; Chen, C. T.; Lee, J. C.; Way, T. D.; Huang, C. H.; Huang, S. M.; Teng,
C. M.; Yamori, T.; Wu, T. S.; Sun, C. M.; Chien, D. S.; Qian, K.; Morris-Natschke, S.
L.; Lee, K. H.; Huang, L. J.; Kuo, S. C. J. Med. Chem. 2010, 53, 1616e1626; (b) Maiti,
B.; Chanda, K.; Sun, C. M. Org. Lett. 2009, 11, 4826e4829; (c) Chen, C. H.; Chien,
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Comb. Chem. 2009, 11, 1038e1046.
4.7.17. 1-Furan-2-ylmethyl-2-[1-(4-methoxy-benzyl)-2-oxo-1,2-di-
hydro-quinoxalin-6-yl]-1H-benzoimidazole-5-carboxylic acid methyl
ester (8q). 1H NMR (300 MHz, CDCl3)
d
8.52 (d, J¼0.9 Hz, 1H), 8.46
(s,1H), 8.37 (d, J¼1.0 Hz,1H), 8.06e8.00 (m, 2H), 7.52 (d, J¼8.4,1.0 Hz,
1H), 7.49 (d, J¼8.6 Hz, 1H), 7.42e7.41 (d, J¼4.3 Hz, 1H), 7.23
(d, J¼7.3 Hz, 2H), 6.86 (d, J¼7.3 Hz, 2H), 6.39e6.34 (m, 2H), 5.47
(s, 2H), 5.39(s, 2H), 3.95 (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
167.40,159.31, 154.94,153.63,151.43,148.33, 143.35,142.40,139.01,
138.31, 133.91, 133.37, 132.19, 131.38, 128.39, 126.55, 125.24, 124.93,
122.17, 115.53, 114.45, 110.69, 110.30, 109.22, 55.29, 53.40, 45.22,
42.42; MS (EI) m/z 520; HRMS (EI) m/z calcd for C30H24N4O5 520.1747,
found 520.1739;IR(KBr):2851,1712,1666,1620,1251,1086, 737 cmꢁ1
.
Acknowledgements
We thank the NSC (National Science Council) and the NCTU
(National Chiao Tung University) at Taiwan for financial support of
this work.
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