Design and synthesis of new biprivileged molecular scaffolds: Indolo-fused benzodiazepinyl/quinoxalinyl benzimidazoles

Article abstract of DOI:10.1002/asia.201200121

The present article describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4-fluoro-3-nitrobenzoic acid, 2-chloro-3-nitrobenzoic acid

Full text of DOI:10.1002/asia.201200121

DOI: 10.1002/asia.201200121
Design and Synthesis of New Biprivileged Molecular Scaffolds: Indolo-Fused
Benzodiazepinyl/quinoxalinyl benzimidazoles
Indrajeet J. Barve, Chan-Yu Chen, Deepak B. Salunke, Wen-Sheng Chung,* and
Chung-Ming Sun*[a]
Abstract: The present article describes
the design and synthesis of new biprivi-
leged molecular scaffolds with diverse
structural features. Commercially avail-
able, simple heterocyclic building
blocks such as 4-fluoro-3-nitrobenzoic
acid, 2-chloro-3-nitrobenzoic acid, and
indoline were utilized for the synthesis
of the novel heterocycles. Pictet–Spen-
gler-type condensation was used as
key step to construct tetracyclic
indolo-benzodiazepines and indolo-qui-
noxalines linked with substituted benzi-
midazoles. Analysis of single crystals of
representative compounds showed that
these molecular skeletons have the po-
tential to present various substituents
with distinct three-dimensional orienta-
tions.
a
Keywords: drug discovery · hetero-
cycles · Pictet–Spengler-type reac-
tions
·
privileged structures
·
synthesis design
Introduction
highlighting the limitations of the synthesis of flat chemical
libraries over diversity-oriented non-flat libraries. Several
reports on the combinatorial synthesis of chiral complex li-
braries have been published.[6] To understand the impor-
tance of these molecular scaffolds and to use the concept of
privileged structures, the present article describes the design
and synthesis of new biprivileged molecular scaffolds 1 and
2 that can provide multiple ligands in distinct three-dimen-
sional orientations (Figure 1).
“Privileged Structures” are highly fascinating molecular
scaffolds in pharmaceutical research.[1] Through the modifi-
cation of various functional groups, a privileged scaffold can
provide potent and selective ligands for a range of different
biological targets.[2] Over the past twenty years this concept
has emerged as a fruitful approach to the discovery of novel
lead compounds. A significant amount of drugs currently on
the market comprise privileged structures.[3] The main func-
tion of the privileged structure in a drug molecule is to posi-
tion the functional groups in the right direction to achieve
an optimal interaction with the desired biomolecules (pro-
teins, enzymes, receptors, or nucleic acids), which are capa-
ble of diverse functions ranging from molecular recognition
to catalysis because of their precise three-dimensional terti-
ary or quaternary structures. Hence, small molecules with
three-dimensional complex structures that fit best into the
active-site crevices of these biopolymers can selectively
modulate their functions. By analyzing a database of more
than two million compounds, Lovering et al. provided evi-
dence that the complexity of a molecule is a key determi-
nant of its success in the transition from discovery to clinical
testing and finally to an approved drug.[4] Increases in the
level of molecular complexity of molecules have been corre-
lated with an improved potency of drug candidates,[5] thus
Figure 1. Molecular scaffolds with multiple privileged structures. For
structures 1 and 2, sites for incorporation of additional steric bulk leading
to rigid basic skeletons are marked by two asterisks.
[a] I. J. Barve, C.-Y. Chen, D. B. Salunke, Prof. W.-S. Chung,
Prof. C.-M. Sun
To increase the rigidity of the basic skeletons of 1 and 2,
we envisioned to incorporate fused indoline and indole moi-
eties leading to molecules 3 and 4 (Figure 1). Overall, the
newly designed skeletons consist of four important privi-
leged structures, namely benzimidazole, benzodiazepine/
benzopyrazine, and indole.[7–12] The new molecular scaffolds
can be utilized to explore novel dimensions in the drug dis-
Department of Applied Chemistry
National Chiao Tung University
Hsinchu 300 (Taiwan)
wschung@ nctu.edu.tw
E-mail: cmsun@mail.nctu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200121.
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FULL PAPERS
covery process. Increased hit rates at a comparably small li-
brary size are expected from such complex skeletons. To the
best of our knowledge, the synthesis of such benzimidazole-
linked heterocycles with four annulated rings has not been
reported. Herein, the synthesis of benzimidazoles[13] and
indolo-quinoxalines/benzodiazepines[14] was combined for
the synthesis of a library having multiple privileged struc-
tures. The real challenge was to devise a synthetic protocol
for the scaffold-based synthesis of these highly constrained
chimeric skeletons.
in 10 by indoline to deliver 11 using triethylamine, diisopro-
pylethylamine as well as potassium carbonate as a base
under various conditions (heating at reflux, heating in
a sealed tube, or microwave irradiation) failed. The reaction
was possibly impeded because of steric effects. The desired
compound 13 was obtained in an alternative approach in
which formation of the benzimidazole ring was carried out
first before the actual chloro displacement by indoline, in an
anticipation to improve the electrophilicity of the ring for
the desired ipso-substitution. Intramolecular ring closure
through nucleophilic attack of the secondary amine on the
amide carbonyl in 10 was brought about in refluxing 1,2-di-
chloroethane with TFA (10%) and anhydrous MgSO4 to
furnish benzimidazole-linked nitrochlorobenzene 12. As ex-
pected, an electron-withdrawing resonance effect was ob-
served in methyl 2-(2-chloro-3-nitrophenyl)-1-isobutyl-1H-
benzo[d]imidazole-5-carboxylate 12, as evidenced by the de-
shielding of the aromatic proton at position 6 of the 2-
chloro-3-nitrophenyl moiety of 12 in comparison to that in
methyl 3-(2-chloro-3-nitrobenzamido)-4-(isobutylamino)ben-
zoate 10. Our initial effort to displace the chloro functionali-
ty in 12 by indoline applying NaH and Cs2CO3 as a base
using heat and microwave irradiation conditions were unsuc-
cessful to deliver 13. The same
Results and Discussion
Commercially
available
4-fluoro-3-nitrobenzoic
acid
(FNBA) 5 was esterified to its methyl ester, which was used
as the starting material for the further synthesis. The first
point of structural diversity was achieved in the next step by
ipso-fluoro displacement of the activated aromatic fluoride
in 6, which was conducted at ambient temperature for
2 hours using various primary amines (Scheme 1). The nitro
functionality in aniline derivatives 7 was reduced by zinc
and ammonium formate leading to diamines 8.
nucleophilic substitution reac-
tion using organic bases like
TEA and DIPEA at reflux tem-
perature, microwave irradia-
tion, and sealed-tube heating
conditions resulted in the for-
mation of the desired product
13 in very low yields (5–10%).
We therefore focused our atten-
tion subsequently towards the
metal-catalyzed coupling reac-
tion of indoline with compound
12. Accordingly, indoline and
12 were subjected to Ullman
coupling conditions. Attempts
using CuI in combination with
Cs2CO3 as well as Cs2CO3 and
1,10-phenanthroline resulted in
the recovery of starting materi-
al. The screening of metal-cata-
lyzed coupling reactions under
various Buchwald conditions
Scheme 1. General strategy for the synthesis of intermediate 13.
like palladium acetate in the
The selective condensation of 2-chloro-3-nitrobenzoic acid
9 with 8 via the in situ generated DCC-activated ester in di-
chloromethane at room temperature resulted in the forma-
tion of anilides 10. Because of the presence of the ester
functionality on the ring, which deactivates the secondary
amine and facilitates the amide coupling with the primary
amine site, exclusive selectivity was achieved. The selectivity
was assessed by 1H NMR spectroscopy, which showed no
change in the chemical shift of the R1 methylene group
(R1 =isobutyl). Efforts to displace the chloro functionality
presence of triACHTGUNTERNNU(G o-tolyl)phosphine and palladium acetate in
combination with (2-biphenyl)di-tert-butylphosphine and
sodium tert-butoxide did not lead to 13 as well. Hence, we
speculated that the coupling reaction requires harsh condi-
tions which can be promoted in solvent-free conditions.
Consequently, the hindered chloro displacement by indoline
in compound 12 was achieved at heating for 4 hours in
a sealed tube, resulting in 13 in a moderate yield. The de-
crease in the steric effect and an additional electron-with-
drawing resonance effect of the benzimidazole ring in 12 as
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Indolo-Fused Benzodiazepinyl/quinoxalinyl benzimidazoles
compared to that in substrate 10 might have promoted the
indoline substitution.
Compound 13 was utilized as the common intermediate
for the synthesis of indolo-fused benzodiazepinyl and qui-
noxalinyl benzimidazoles 15, 18, and 19 (Scheme 2). The
aldehydes and cyclic as well as noncyclic ketones were ap-
plied during this unusual Pictet–Spengler-type cyclization.
To visualize the importance of these molecular skeletons
that have the potential to present various substituents in
particular three-dimensional orientations, single crystals of
the representative compounds
15i and 18a were grown from
a hot, saturated, and filtered so-
lution of these compounds in
CH2Cl2/CH3OH mixtures. Suit-
able crystals were obtained by
slow evaporation of the solvent
at room temperature. Com-
pounds 15i and 18a crystallized
as yellow and pale yellow crys-
tals, respectively. The best crys-
tals were selected and the X-
ray diffraction data were col-
lected.[16] As it can be clearly
observed in the ORTEP17 dia-
grams (Figure 2), the molecules
possess a distinct three-dimen-
sional orientation due to the
hindered rotation about the
À
single bond (C1 C14) between
the benzimidazole ring and the
tetracyclic indolo-benzodiaze-
pine ring (15i) or indolo-qui-
noxaline ring (18a).
Scheme 2. Synthesis of indolo-fused benzodiazepinyl and quinoxalinyl benzimidazole derivatives.
Non-planarity in the basic
nitro functionality in 13 was reduced to amine using Zn and
ammonium formate in methanol to yield amino-indolinyl in-
termediate 14. On the other hand, the indoline ring of com-
pound 13 was first oxidized to indole-bearing compound 16
using DDQ, and the nitro group in 16 was further reduced
by similar reducing conditions to furnish amino-indolyl pre-
cursor 17 at room temperature. The key step in this process
was to accomplish the Pictet–Spengler-type heterocycliza-
tion to furnish the desired highly constrained chimeric skele-
tons. The indoline-substituted intermediate 14 furnished the
desired tetrahydroindolo-benzodiazepinyl benzimidazoles 15
when reacted with various aldehydes and ketones (Table 1)
in the presence of TFA and MgSO4 in refluxing chloroform
for 12 hours. By contrast, under these acid-catalyzed dehy-
drating conditions, the amino-indolyl intermediate 17 result-
ed in dihydroindolo-quinoxalinyl benzimidazoles 18 when
reacted with ketones (Table 1, entries 18a and 18b).
tetracyclic indolo-benzodiazepine ring system 15i was also
observed as a result of a twist between the two planes com-
prising the indoline ring and the phenyl ring connected by
N3 and C19. This was enforced by the linkage with a tetrahe-
dral carbon (C28) and a nitrogen (N4) atom, resulting in
a seven-membered diazepino ring junction that has a partial
envelope conformation. A similar non-planarity was also ob-
served in indolo-quinoxaline skeleton 18a. Suitable solubili-
ty and salt-forming properties (important for oral absorption
and bioavailability) can be expected from these non-planar
heterocycles that contain several basic nitrogen atoms as
well as a carboxylate functionality. The carboxylate func-
tionality as well as the aromatic halo/nitro functionalities on
several library members can be further utilized according to
structure–activity relationship (SAR) requirements.
Similarly, using aldehydes in place of ketones, indolo-qui-
noxalinyl benzimidazoles 19 were obtained in good yields.
The dihydropyrazine ring was found to be easily air-oxidized
during this transformation to deliver fully aromatic tetracy-
clic flat skeletons 19 linked to benzimidazole. During this
Pictet–Spengler-type condensation,[15] 14 underwent an elec-
trophilic cyclization with ketones at the phenyl ring,[14b]
while compound 17 cyclized onto its electron-rich pyrrole
ring[14a] to furnish the required heterocycles in good to excel-
lent yields (Table 1). Various aromatic and heteroaromatic
Conclusions
Novel privileged structures comprising indolo-fused benzo-
diazepinyl/quinoxalinyl benzimidazoles were synthesized in
good to excellent yield. The concept of atropisomerism was
used to construct these non-flat skeletal compound libraries.
Commercially available 4-fluoro-3-nitrobenzoic acid, 2-
chloro-3-nitrobenzoic acid, and indoline were utilized for
the synthesis of these complex molecular scaffolds. The vari-
ous electron densities on the indoline and indole rings of
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Table 1. Indolo-fused benzodiazepinyl/quinoxalinyl benzimidazoles 15,
18, and 19.
tative compounds demonstrated that these molecular skele-
tons have the potential to present various substituents with
distinct three-dimensional orientations. The compound libra-
ries will be screened against various biological targets.
Experimental Section
Entry
R1
Aldehydes or
Ketones
Isolated
Yield [%]
General
All reactions 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 Kieselgel 60 F254 plates.
Compound purification was carried out by flash chromatography on
silica gel 60 (230–400 mesh). IR spectra were recorded using a HORIBA
FT-720 FREEXACT-II IR spectrophotometer. 1H and 13C NMR spectra
were recorded on a Bruker DX-300 spectrometer. Chemical shifts are re-
ported in parts per million (ppm) on the scale from an internal standard
(TMS). Mass spectra were recorded on a JEOL TMS-HX 110 mass spec-
trometer; samples were introduced by the infusion method using the
electrospray ionization technique. Starting compounds were purchased
from Matrix Scientific, Accela ChemBio Inc., and Alfa Aesar, and used
without purification.
15a
15b
15c
94
90
86
15d
15e
15 f
92
88
85
Synthesis of Key Intermediate 13
H2SO4 (5 mL, 0.3m) was added to a solution of 4-fluoro-3-nitrobenzoic
acid 5 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), and the reaction mixture
was heated to reflux for 5 h. After removal of the solvent under reduced
pressure, the mixture was dissolved in EtOAc (150 mL), washed with sa-
turated NaHCO3 (20 mLꢁ2), water (10 mLꢁ2), and brine (10 mL). The
organic layer was dried over anhydrous Na2SO4 and evaporated to afford
methyl 4-fluoro-3-nitrobenzoate 6 (95%) as a white solid. Compound 6
(2.0 g, 10.2 mmol) and a primary amine (3 equiv) in dry CH2Cl2 (50 mL)
were stirred for 2 h at room temperature or under MW irradiation
(100 W, 1008C) in dry CH2Cl2 (5 mL) in a sealed vial for 10 min. Subse-
quently, the solvents were removed under reduced pressure, and the
crude product was purified by flash chromatography to afford amino/
nitro benzoates 7 (85 to 90%). For the next step, zinc dust (15 equiv,
71.4 mmol) and ammonium formate (7.5 equiv, 35.7 mmol) were added
to a solution of 7 (2.0 g, 4.8 mmol) in dry MeOH (100 mL), and the re-
sulting reaction mixture was stirred for 10 min at room temperature. Sub-
sequently, Zn dust was filtered off through a bed of celite, the solvent
was evaporated, and the product was dissolved in CH2Cl2 (100 mL). The
precipitated ammonium formate was filtered off and the solvent was
evaporated to furnish 8 (92–96%). The crude products obtained were
15g
15h
15i
90
88
87
15j
88
95
18a
18b
19a
92
95
19b
95
used directly for the next step of the synthesis, in which
8 (1.0 g,
4.8 mmol), 2-chloro-3-nitrobenzoic acid (1.3 g, 6.7 mmol), DCC (1.4 g,
6.6 mmol), and catalytic DMAP (0.006 g, 0.05 mmol) in dry CH2Cl2
(25 mL) were stirred in a round-bottomed flask for 16 h at 258C. After
cooling to 08C the solid dicyclohexylurea (DCU) formed was filtered off
and the solvent was evaporated. The crude product was further purified
by precipitation and washing with n-hexane (20 mLꢁ3) to afford amide
10 in 60–70% yield. Next, amide 10 (1.0 g, 2.8 mmol) in 1,2-dichloro-
ethane (50 mL) was heated to reflux for 16 h in the presence 10% tri-
fluoroacetic acid (TFA) (0.43 mL, 5.61 mmol) and MgSO4 (0.5 g,
4.14 mmol) or heated under MW irradiation (100 W, 1208C) for 10 min
in a sealed vial in 1,2-dichloroethane (5 mL) containing five drops of
TFA. Subsequently, the volatilities were removed and the crude product
purified by flash chromatography to give 12 (84–95%). Nucleophilic aro-
matic substitution of indoline (10 equiv, 30.0 mmol) with compound 12
(1.0 g, 3.0 mmol) was brought about in a sealed tube by heating for 4 h at
1508C. The obtained crude product was purified by flash chromatography
to afford key intermediate 13 (48–52%).
19c
19d
19e
19 f
19g
88
87
90
90
92
19h
88
Synthesis of Tetrahydroindolo-benzodiazepinyl-benzimidazoles (15)
compounds 14 and 17 were utilized for Pictet–Spengler-type
cyclization reactions to furnish benzodiazepinyl or quinoxa-
linyl structural units. Analysis of single crystals of represen-
The nitro functionality in compound 13 was reduced to amine using Zn/
ammonium formate as described above to afford compound 14 (93–
95%). Next, an aldehyde or ketone (3.0 equiv), anhydrous magnesium
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Indolo-Fused Benzodiazepinyl/quinoxalinyl benzimidazoles
Methyl 2-[6-(2-bromophenyl)-1,2,6,7-
tetrahydroindolo[1,7-ab]-
AHCTUNGTRENNG[UN 1,5]benzodiazepin-11-yl]-1-(furan-2-
AHCTUNGTRENNUNG
ylmethyl)-1H-benzimidazole-5-carbox-
ylate (15b). IR (neat): n˜ =2927, 2852,
2381, 2348, 2312 cmÀ1
;
1H NMR
(300 MHz, d6-Acetone): d=8.39 (d,
J=1.2 Hz, 1H), 7.94 (dd, J=8.5,
1.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H),
7.62 (dd, J=7.9, 0.9 Hz, 1H), 7.26 (s,
1H), 7.03 (d, J=7.2 Hz, 3H), 6.96 (dd,
J=7.7, 1.7 Hz, 2H), 6.80 (t, J=7.6 Hz,
2H), 6.66 (t, J=7.3 Hz, 2H), 6.28 (dd,
J=3.2, 1.9 Hz, 1H), 6.16 (d, J=2.5 Hz,
1H), 5.76 (s, 2H), 5.38 (m, 2H), 3.92
(s, 3H), 3.48 (m, 1H), 3.27 (m, 1H),
2.73 ppm (t, J=8.5 Hz, 2H); 13C NMR
(75 MHz,
d6-Acetone):
d=167.2,
156.5, 149.3, 146.9, 143.7, 143.4, 142.0,
138.7, 136., 133.3, 131.6, 130.8, 129.5,
127.7, 127.5, 127.4, 124.9, 124.6, 124.3,
124.2, 124.0, 123.7, 121.8, 121.5, 118.8,
111.2, 110.8, 109.6, 64.9, 54.2, 51.8,
41.8, 28.4 ppm; MS (ESI+) m/z: 632.0
Figure 2. ORTEP view of compounds 15i and 18a (No atropselective synthesis was carried out. The relative
stereo-chemistries in structures are shown for clarity).
(M+H)+;
HRMS:
calcd
for
C35H27BrN4O3 m/z: 630.1267; found:
630.1262.
sulfate (20%), and 2 drops of trifluoroacetic acid (TFA) were added to
a
solution of compound 14 (0.1 g, 0.26 mmol, 1.0 equiv) in CHCl3
Methyl
2-[6-(2-bromophenyl)-1,2,6,7-tetrahydroindoloACHTUNGTRENNUNG[1,7-ab]-
(10 mL). The resulting reaction mixture was refluxed for 14 h. Subse-
quently, the mixture was passed through a thin layer of Celite to remove
MgSO4. The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography to afford tetrahydroindo-
lo-benzodiazepinyl-benzimidazoles 15 in good to excellent yields (85–
94%, Table 1).
AHCTUNGTERG[NNUN 1,5]benzodiazepin-11-yl]-1-(furan-2-ylmethyl)-1H-benzimidazole-5-car-
boxylate (15c). IR (neat): n˜ =2950, 2925, 2854, 2360, 1714 cmÀ1; H NMR
(300 MHz, d6-Acetone): d=8.36 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.61 (d,
J=8.7 Hz, 1H), 7.32 (s, 1H), 7.13 (d, J=8.3 Hz, 2H), 7.01 (m, 4H), 6.84
(t, J=7.6 Hz, 2H), 6.64 (m, 3H), 6.22 (s, 1H), 5.52 (s, 1H), 5.08 (m, 2H),
3.91 (s, 3H), 3.56 (s, 3H), 3.43 (m, 1H), 3.20 (m, 1H), 2.66 ppm (m, 2H);
13C NMR (75 MHz, d6-Acetone): d=167.2, 158.9, 156.9, 149.4, 146.5,
143.8, 143.1, 138.7, 135.9, 135.4, 131.4, 129.7, 127.7, 126.7, 124.7, 124.0,
123.6, 121.8, 121.7, 118.6, 113.8, 111.2, 110.6, 109.5, 64.0, 60.1, 555.0, 54.7,
54.6, 51.7, 41.5, 28.3 ppm; MS (ESI+) m/z: 583.1 (M+H)+; HRMS: calcd
for C36H30N4O4 m/z: 582.2267; found: 582.2260.
1
Synthesis of Indoloquinoxalinyl-benzimidazoles (18 and 19)
A solution of compound 13 (0.5 g, 1.2 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature in the presence of DDQ (0.80 g, 3.6 mmol)
for 6 h. Subsequently, CH2Cl2 (50 mL) was added, and the organic layer
was washed with NaOH solution (1n, 10 mLꢁ3), water (10 mLꢁ3), and
brine (10 mL), dried over anhydrous Na2SO4, and evaporated to furnish
16 (90–98%). The nitro functionality in compound 16 was reduced to
amine using Zn/ammonium formate as described earlier to afford com-
pound 17 (80–94%). To a solution of compound 17 (0.1 g, 0.26 mmol,
1.0 equiv) in CHCl3 (10 mL), ketone (3.0 equiv), anhydrous magnesium
sulfate (20%), and 2 drops of trifluoroacetic acid (TFA) were added. The
resulting reaction mixture was refluxed for 14 h. After completion of the
reaction, the compound mixtures were passed through a thin layer of
Celite to remove MgSO4. The solvent was removed under reduced pres-
sure and the crude product was purified by flash chromatography to
afford dihydroindolo-quinoxalinyl-benzimidazoles 18 in excellent yields
(92–95%, Table 1). Compounds 19 were obtained using aldehydes and
following a similar protocol as described above.
Methyl
[1,7-ab]
IR (neat): n˜ =2950, 2852, 2360, 1716, 1616 cmÀ1
1-(furan-2-ylmethyl)-2-[6-(furan-3-yl)-1,2,6,7-tetrahydroindolo-
[1,5] benzodiazepin-11-yl]-1H-benzimidazole-5-carboxylate (15d).
1H NMR (300 MHz, d6-
G
ACHTUNGTRENNUNG
;
Acetone): d=8.39 (d, J=1.2 Hz, 1H), 7.95 (dd, J=8.5, 1.5 Hz, 1H), 7.30
(s, 1H), 7.20 (s, 1H), 7.14 (d, J=6.0 Hz, 1H), 7.00 (t, J=7.6 Hz, 2H),
6.90 (t, J=7.6 Hz, 2H), 6.66 (d, J=7.4 Hz, 1H), 6.45 (s, 1H), 6.19 (s,
1H), 5.98 (br, 1H), 5.75 (br, 1H), 5.41 (s, 1H), 5.30–4.85 (m, 2H), 3.91 (s,
3H), 3.42 (m, 1H), 3.20 (m, 1H), 2.63 ppm (m, 2H); 13C NMR (75 MHz,
d6-Acetone): d=167.2, 156.8, 149.5, 146.0, 143.9, 143.7, 143.0, 141.1,
138.8, 135.7, 131.6, 129.4, 127.0, 126.8, 124.7, 124.6, 124.1, 123.7, 121.9,
121.8, 121.7, 118.5, 111.2, 110.6, 110.5, 109.2, 57.2, 54.6, 51.8, 41.2,
28.3 ppm; MS (ESI+) m/z: 543.1 (M+H)+; HRMS: calcd for C33H26N4O4
m/z: 542.1985; found: 542.1959.
Methyl
1-(furan-2-ylmethyl)-2-[6-(thiophen-2-yl)-1,2,6,7-
tetrahydroindoloACUTHGNTRNENU[NG 1,7-ab]ACHTUNGTRNE[NUNG 1,5] benzodiazepin-11-yl]-1H-benzimidazole-5-
carboxylate (15e). IR (neat): n˜ =2950, 2925, 2854, 2360, 1714 cmÀ1
;
Characterization Data for 15a–j, 18a,b, and 19a–h
1H NMR (300 MHz, d6-Acetone): d=8.37 (d, J=1.2 Hz, 1H), 7.03 (dd,
J=8.6, 1,5 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.21 (s, 1H), 7.11(dd, J=7.6
1.6 Hz, 2H), 7.04 (m, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.69 (t, J=7.4 Hz,
1H), 6.64 (s, 1H), 6.20 (m, 1H), 5.85 (m, 1H), 5.76 (m, 1H), 5.08 (m,
2H), 3.91 (s, 3H), 3.48 (m, 1H), 3.20 (m, 1H), 2.65 ppm (m, 2H);
13C NMR (75 MHz, d6-Acetone): d=167.2, 156.8, 149.5, 149.4, 148.5,
146.1, 143.8, 143.4, 143.0, 142.2, 138.8, 135.6, 131.8, 127.7, 127.1, 126.5,
125.2, 124.7, 124.1, 124.0, 122.1, 121.9, 121.7, 118.6, 111.3, 110.6, 109.3,
60.6, 60.1, 54.6, 51.8, 41.5, 28.3 ppm; MS (ESI+) m/z: 559.1 (M+H)+;
HRMS: calcd for C33H26N4O3S m/z: 558.1726; found: 558.1736.
Methyl 2-[6-(2-fluorophenyl)-1,2,6,7-tetrahydroindoloACTHNUTRGENN[GU 1,7-ab]HCATUNGTREN[NNGU 1,5]-benzo-
diazepin-11-yl]-1-(furan-2-ylmethyl)-1H-benzimidazole-5-carboxylate
1
(15a). IR (neat): n˜ =2925, 2852, 2358, 1714 cmÀ1; H NMR (300 MHz, d6-
Acetone): d=8.39 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz,
1H), 7.08 (m, 3H), 6.99 (m, 2H), 6.81 (t, J=7.2 Hz, 2H), 6.68 (t, J=
7.2 Hz, 2H), 6.26 (s, 1H), 6.06 (s, 1H), 5.81 (s, 1H), 5.70 (s, 1H), 5.40–
5.00 (m, 2H), 3.91 (s, 3H), 3.46 (m, 1H), 3.23 (m, 1H), 2.70 ppm (m,
2H); 13C NMR (75 MHz, d6-Acetone): d=167.2, 162.8, 159.5, 156.6,
149.3, 147.0, 143.8, 143.3, 142.4, 138.7, 136.3, 131.6, 130.6, 130.4, 130.3,
130.3, 129.6, 129.5, 127.8, 127.5, 127.4, 124.8, 124.5, 124.2, 124.1, 124.0,
123.4, 121.9, 121.8, 121.7, 118.8, 115.7, 115.4, 111.2, 110.7, 109.6, 60.1,
59.9, 54.3, 51.8, 41.7, 28.4 ppm; MS (ESI+) m/z: 571.1 (M+H)+; HRMS:
calcd for C35H27FN4O3 m/z: 570.2067; found: 570.2075.
Methyl
2-[6-(1,3-benzodioxol-5-yl)-1,2,6,7-tetrahydroindoloACHTUNGTRENNUNG[1,7-ab]-
AHCTUNGTERG[NNUN 1,5]benzodiazepin-11-yl]-1-(3-methoxypropyl)-1H-benzimidazole-5-car-
1
boxylate (15 f). IR (neat): n˜ =2952, 2927, 2360, 2316, 1714 cmÀ1; H NMR
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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Chung-Ming Sun et al.
FULL PAPERS
(300 MHz, d6-Acetone): d=8.40 (d, J=1.1 Hz, 1H), 7.99 (dd, J=8.6,
1.6 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.06 (d, J=7.4 Hz, 2H), 6.99 (d, J=
7.1 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.83 (s, 1H), 6.75 (t, J=9.1 Hz,
3H), 6.66 (d, J=7.2 Hz, 1H), 5.96 (s, 2H), 5.49 (s, 1H), 4.25 (m, 1H),
3.93 (s, 4H), 3.40 (m, 1H), 3.15 (br, 1H), 2.64 (m, 3H), 1.73 (m, 1H),
1.48 ppm (br, 1H); 13C NMR (75 MHz, d6-Acetone): d=167.3, 156.9,
148.3, 147.0, 146.2, 143.6, 139.0, 137.8, 135.7, 131.4, 127.8, 127.0, 124.5,
124.0, 123.7, 122.4, 122.2, 121.8, 121.7, 118.6, 110.9, 109.0, 108.1, 101.5,
69.0, 64.4, 57.9, 54.4, 51.7, 41.7, 28.4 ppm; MS (ESI+) m/z: 589.2 (M+H)+
; HRMS: calcd for C32H34N4O2 m/z: 588.2373; found: 588.2365.
1.81 (s, 3H), 15.3 (s, 3H), 0.59 (s, 3H), 0.33 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=168.2, 155.9, 144.7, 143.7, 139.2, 138.6, 134.4, 129.3,
125.9, 125.2, 124.7, 124.4, 122.4, 122.4, 121.2, 120.6, 120.3, 118.6, 111.3,
110.4, 98.2, 53.8, 52.6, 52.5, 50.9, 28.5, 20.3, 20.0 ppm; MS (EI+) m/z:
478.2 (M+); HRMS: calcd for C30H30N4O2 m/z: 478.2369; found:
478.2374.
Methyl
a]quinoxalin]-1’-yl)-1H-benzimidazole-5-carboxylate (18b). IR (neat):
n˜ =2931, 2856, 2360, 1716, 1612 cmÀ1 1H NMR (300 MHz, CDCl3): d=
1-(2-methylpropyl)-2-(5’H-spiro[cyclohexane-1,6’-indoloACHTUNGTRENNUNG[1,2-
;
8.63 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.33–7.23
(2H), 7.42 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.87–6.66 (2H),
6.48 (s, 1H), 6.34 (d, J=7.6 Hz, 1H), 3.99 (s, 1H), 3.15–2.88 (2H), 2.38–
2.21 (m, 1H), 2.13–1.41 (10H), 0.85 (s, 1H), 0.33 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=168.2, 155.9, 145.3, 143.6, 138.6, 138.6, 134.3, 129.3,
125.9, 125.8, 125.6, 124.7, 124.4, 122.4, 122.4, 121.2, 120.6, 120.3, 118.7,
111.2, 110.4, 98.6, 53.9, 52.5, 50.9, 28.4, 25.6, 22.2, 21.9, 20.3, 19.9 ppm;
MS (EI+) m/z: 518.3 (M+); HRMS: calcd for C33H34N4O2 m/z: 518.2682;
found: 518.2685.
Methyl 2-[6-(furan-3-yl)-1,2,6,7-tetrahydroindolo
pin-11-yl]-1-(3-methoxypropyl)-1H-benzimidazole-5-carboxylate
IR (neat): n˜ =2925, 2852, 2360, 1714, 1612 cmÀ1 1H NMR (300 MHz, d6-
ACHUTGTNRNEUG[N 1,7-ab]ACHTGNUTRENNUNG
;
Acetone): d=8.40 (s, 1H), 7.98 (dd, J=8.5, 1.5 Hz, 1H), 7.62 (d, J=
8.5 Hz, 1H), 7.46 (s, 1H), 7.13 (dd, J=7.7, 1.7 Hz, 1H), 7.08 (dd, J=7.6,
1.6 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.92 (t, J=7.6 Hz, 2H), 6.66 (t, J=
7.4 Hz, 1H), 6.50 (s, 1H), 5.42 (s, 1H), 4.19 (m, 1H), 3.93 (s, 4H), 3.41
(m, 1H), 3.12 (br, 1H), 2.98 (s, 3H), 2.77 (br, 2H), 2.57 (m, 2H),
1.63 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=168.1, 156.4, 145.6,
144.2, 143.3, 141.2, 138.8, 135.5, 127.7 124.9, 124.7, 124.2, 122.6, 122.4,
122.2, 118.9, 110.2, 110.2, 77.6, 68.8, 58.8, 57.7, 54.5, 52.5, 41.6, 32.3, 30.1,
29.8, 29.6, 28.8, 23.1 ppm; MS (ESI+) m/z: 535.1 (M+H)+; HRMS: calcd
for C32H30N4O4 m/z: 534.2267; found: 534.2263.
Methyl 2-[6-(4-methoxyphenyl)indolo
propyl)-1H-benzimidazole-5-carboxylate (19a). IR (neat): n˜ =2954, 2360,
1718, 1606, 1504 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.71 (d, J=
ACHTUNGTRENUN[NG 1,2-a]quinoxalin-1-yl]-1-(2-methyl-
;
1.1 Hz, 1H), 8.21 (dd, J=7.8, 1.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 2H), 8.06
(dd, J=7.8, 1.5 Hz, 1H), 7.95 (dd, J=8.5, 1.5 Hz, 1H), 7.73 (d, J=8.0 Hz,
1H), 7.64 (t, J=7.8 Hz, 1H), 7.34 (s, 1H), 7.14 (d, J=8.9 Hz, 1H), 7.08
(d, J=9.7 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.56 (t, J=7.9 Hz, 1H), 4.01
(s, 3H), 3.95 (s, 3H), 2.96 (m, 1H), 2.41 (m, 1H), 1.41 (m, 1H), 0.43 (d,
J=6.1 Hz, 3H), 0.15 ppm (d, J=6.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=168., 162.0, 156.2, 155., 143.6, 138.8, 138.5, 135.0, 133.3,
131.9, 130.4, 130.1, 129.2, 127.3, 125.7, 125.0, 124.7, 124.3, 123.4, 122.7,
122.2, 119.1, 114.6, 113.6, 110.4, 104.7, 52.6, 51.3, 30.1, 28.5, 20.2,
19.9 ppm; MS (ESI+) m/z: 555.2 (M+H)+; HRMS: calcd for C35H30N4O3
m/z: 554.2318; found: 554.2315..
Methyl 1-(2-methylpropyl)-2-(6-phenyl-1,2,6,7-tetrahydroindolo
ACHTUNGTRENN[UNG 1,7-ab]-
ACHTUNGTRENNUNG
(neat): n˜ =2956, 2927, 2383, 2360, 1716 cmÀ1; 1H NMR (300 MHz, d6-Ace-
tone): d=8.42 (s, 1H), 7.99 (dd, J=8.5, 1.5 Hz, 1H), 7.69 (d, J=8.6 Hz,
2H), 7.32 (s, 4H), 7.25 (br, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.01 (m, 2H),
6.88 (t, J=7.6 Hz, 1H), 5.55 (s, 1H), 4.112 (dd, J=14.2, 5.5 Hz, 1H), 3.92
(s, 3H), 3.76 (br, 1H), 3.37 (d, J=9.3 Hz, 1H), 3.08 (br, 1H), 2.60 (t, J=
7.8 Hz, 2H), 1.91 (m, 1H), 0.63 (d, J=6.8 Hz, 3H), 0.38 ppm (s, 3H);
13C NMR (75 MHz, d6-Acetone): d=167.3, 157.0, 146.1, 143.8, 139.2,
135.9, 131.5, 129.1, 128.8, 128.0, 127.4, 124.8, 124.5, 124.0, 123.6, 123.1,
122.2, 121.8, 118.5, 111.2, 54.0, 51.8, 51.7, 28.5, 19.7, 19.4, 13.9, 13.8 ppm;
MS (ESI+) m/z: 529.2 (M+H)+; HRMS: calcd for C34H32N4O2 m/z:
528.2525; found: 528.2529.
Methyl 1-(2-methylpropyl)-2-[6-(4-nitrophenyl)indolo
yl]-1H-benzimidazole-5-carboxylate (19b). IR (neat): n˜ =2954, 2925,
2856, 2381, 2346 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.54 (d, J=
ACHTUNGERTN[NUNG 1,2-a]quinoxalin-1-
;
8.8 Hz, 1H), 8.34 (d, J=8.8 Hz, 2H), 8.26 (dd, J=7.8, 1.6 Hz, 1H), 8.15
(dd, J=7.7, 1.6 Hz, 1H), 7.97 (dd, J=8.6, 1.5 Hz, 1H), 7.77 (d, J=8.0 Hz,
1H), 7.71 (t, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.11 (t, J=8.6 Hz, 2H), 6.59 (t,
J=5.3 Hz, 1H), 4.02 (s, 3H), 3.05–2.90 (1H), 2.50–2.30 (1H), 1.45 (quint,
1H), 0.46 (d, J=5.8 Hz, 3H), 0.17 ppm (d, J=5.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=168.0, 155.0, 154.4, 149.4, 143.8, 143.6, 138.8, 138.0,
135.2, 134.6, 132.4, 130.0, 129.5, 129.1, 127.6, 126.0, 124.9, 124.5, 123.8,
122.8, 122.4, 119.4, 113.7, 110.5, 104.5, 51.3, 28.6, 20.2 ppm; MS (EI+) m/
z: 569.3(M+); HRMS: calcd for C34H27N5O4 m/z: 569.2063; found:
569.2057.
Methyl
diazepin-11-yl]-1-(3-methoxypropyl)-1H-benzimidazole-5-carboxylate (15i).
IR (neat): n˜ =2956, 2927, 2381, 2354, 2310 cmÀ1 1H NMR (300 MHz, d6-
2-[6-(furan-3-yl)-1,2,6,7-tetrahydroindoloACHTGNUTERNNU[G 1,7-ab]ACTHUNGTREN[NUNG 1,5]benzo-
;
Acetone): d=8.57 (d, J=1.1 Hz, 1H), 8.04 (dd, J=8.5, 1.5 Hz, 1H), 7.37
(d, J=8.4 Hz, 2H), 7.24 (dd, J=5.6, 3.6 Hz, 1H), 7.02 (d, J=7.1 Hz, 1H),
6.94 (m, 3H), 6.71 (t, J=7.3 Hz, 1H), 6.14 (br, 1H), 5.77 (br, 1H), 5.50
(s, 1H), 3.98 (s, 4H), 3.85 (dd, J=14.0, 4.6 Hz, 1H), 3.60 (br, 2H), 2.97
(br, 2H), 2.58 (m, 2H), 1.91 (m, 1H), 0.69 (d, J=7.5 Hz, 3H), 0.27 ppm
(s, 3H); 13C NMR (75 MHz, d6-Acetone): d=168.1, 156.7, 156.5, 145.7,
143.5, 143.0, 138.7, 135.8, 131.9, 128.5, 124.9, 124.7, 124.3, 123.0, 122.9,
122.8, 118.8, 110.5, 110.2, 109.2, 59.6, 54.0, 52.6, 52.1, 34.8, 30.1, 29.0, 28.9,
21.8, 20.3, 19.8 ppm; MS (ESI+) m/z: 519.1 (M+H)+; HRMS: calcd for
C32H30N4O3 m/z: 518.2318; found: 518.2328.
Methyl
2-[6-(4-bromophenyl)indoloACTHNGUTERNNU[G 1,2-a]quinoxalin-1-yl]-1-(2-methyl-
propyl)-1H-benzimidazole-5-carboxylate (19c). IR (neat): n˜ =2954, 1716,
1
1616, 1590, 1527 cmÀ1; H NMR (300 MHz, CDCl3): d=8.71 (s, 1H), 8.22
(d, J=7.8 Hz, 1H), 8.10 (d, J=7.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.96
(d, J=8.5 Hz, 1H), 7.85–7.70 (m, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.66 (t,
J=7.8 Hz, 1H), 7.29 (s, 1H), 7.08 (t, J=7.8 Hz, 2H), 7.02 (d, J=8.6 Hz,
Methyl
[1,7-ab]
IR (neat): n˜ =2954, 2859, 2306, 1714, 1656 cmÀ1
1-(furan-2-ylmethyl)-2-[6-(furan-3-yl)-1,2,6,7-tetrahydroindolo-
[1,5] benzodiazepin-11-yl]-1H-benzimidazole-5-carboxylate (15j).
1H NMR (300 MHz, d6-
G
ACHTUNGTRENNUNG
;
1H), 6.56 (t, J=7.8 Hz, 1H), 4.01ACTHNGUTER(NNUG s, 1H), 3.05–2.85 (m, 1H), 2.50–2.26
Acetone): d=8.43 (s, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 7.68 (d, J=
8.5 Hz, 1H), 7.24 (dd, J=7.5 Hz, 1H), 7.16 (dd, J=7.7, 1,5 Hz, 1H), 7.09
(d, J=7.9 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.66 (t, J=7.5 Hz, 1H), 3.94
(s, 3H), 3.91 (m, 2H), 3.30 (s, 1H), 2.55 (m, 2H), 1.89 (m, 7H), 0.53 ppm
(d, J=4.6 Hz, 6H); 13C NMR (75 MHz, d6-Acetone): d=167.3, 157.0,
145.5, 143.7, 142.8, 139.4, 136.1, 131.2, 129.6, 127.3, 124.5, 124.4, 124.0,
123.8, 123.0, 122.7, 122.1, 121.8, 118.8, 111.0, 68.8, 54.0, 51.7, 51.7, 28.4,
23.5, 19.5 ppm; MS (ESI+) m/z: 507.2 (M+H)+; HRMS: calcd for
C32H34N4O2 m/z: 506.2682; found: 506.2692.
(m, 1H), 1.41 (quint., 1H), 0.43 (d, J=5.2 Hz, 3H), 0.15 ppm (d, J=
5.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=168.0, 155.6, 155.2, 143.5,
138.8, 138.2, 1, 135.1, 133.9, 132.4, 132.1, 130.5, 129.7, 129.2, 127.4, 125.8,
125.3, 125.1, 124.8, 124.6, 123.6, 122.7, 122.3, 119.2, 113.6, 110.4, 104.6,
52.6, 51.3, 28.5, 20.2, 20.0 ppm; MS (EI+) m/z: 602.1 (M+); HRMS:
calcd for C34H27BrN4O2 m/z: 602.1317; found: 602.1326.
Methyl 2-[6-(furan-2-yl)indolo
1H-benzimidazole-5-carboxylate (19d). IR (neat): n˜ =2954, 2925, 2312,
1716, 1614 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.71 (d, J=1.2 Hz,
ACHTUNGTREN[NUNG 1,2-a]quinoxalin-1-yl]-1-(2-methylpropyl)-
;
Methyl
methylpropyl)-1H-benzimidazole-5-carboxylate (18a). IR (neat): n˜ =
3342, 2958, 2927, 2362, 1716 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.89
(d, J=8.5 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H),
7.25(t, J=8.7 Hz, 1H),7.04 (d, J=7.7 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H),
6.79 (t, J=7.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H). 6.44 (s, 1H), 6.34 (t, J=
7.8 Hz, 1H), 3.99 (s, 3H), 3.02 (d, J=9.4 Hz, 2H), 1.90–1.70 (m, 1H),
2-(6,6-dimethyl-5,6-dihydroindolo
[1,2-a]quinoxalin-1-yl)-1-(2-
1H), 8.22 (dd, J=7.9, 1.6 Hz, 1H), 8.06 (dd, J=7.7, 1.5 Hz, 1H), 7.95
(dd, J=8.5, 1.5 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.82 (d,
J=7.9 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.10 (t,
J=8.0 Hz, 1H), 6.76 (dd, J=3.5, 1.8 Hz, 1H), 6.55 (t, J=7.1 Hz, 1H),
4.02 (s, 3H), 2.86 (m, 1H), 2.31 (m, 1H), 1.42 (m, 1H), 0.40 (d, J=
6.4 Hz, 1H), 0.10 ppm (d, J=6.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=168.1, 155.3, 152.2, 145.5, 143.6, 138.7, 138.0 134.6, 133.6, 131.8, 129.4,
;
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Indolo-Fused Benzodiazepinyl/quinoxalinyl benzimidazoles
127.9, 127.5, 125.7, 125.1, 124.7, 124.3, 123.5, 122.7, 122.3, 119.0, 114.3
113.6, 112.8, 110.4, 104.4, 52.6, 51.1, 28.5, 20.1, 19.9 ppm; MS (EI+) m/z:
514.0 (M+); HRMS: calcd for C32H26N4O3 m/z: 514.2005; found:
514.2011.
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Methyl
1H-benzimidazole-5-carboxylate (19e). IR (neat): n˜ =2925, 2856, 2360,
1714, 1614 cmÀ1 1H NMR (300 MHz, CDCl3): d=8.69 (d, J=1.0 Hz,
1-(3-methoxypropyl)-2-(6-phenylindoloACTHNGUTER[NNUG 1,2-a]quinoxalin-1-yl)-
Acknowledgements
;
The authors thank the National Science Council of Taiwan for financial
support and the authorities of the National Chiao Tung University for
providing the laboratory facilities. This study was particularly supported
by the “Aim for the Top University Plan” of the National Chiao Tung
University and Ministry of Education, Taiwan.
1H), 8.25 (dd, J=7.9, 1.4 Hz, 1H), 8.18–8.10 (m, 2H), 8.06 (dd, J=7.6,
1.5 Hz, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 7.70–7.60 (m, 4H), 7.31 (s,
1H), 7.13 (t, J=7.7 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 6.59 (t, J=7.9 Hz,
1H), 4.01 (s, 3H), 3.35–3.00 (m, 2H), 2.84–2.60 (m, 2H), 1.20–1.00 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=168.1, 156.9, 155.3, 143.6, 138.7,
138.5, 137.9, 135.1, 133.4, 132.2, 130.9, 130.4, 129.2, 128.9, 127.7, 125.6,
125.1, 124.9, 124.4, 123.4, 122.7, 122.3, 118.7, 113.6, 110.3, 104.8, 68.5,
58.8. 52.6, 40.9, 29.0 ppm; MS (EI+) m/z: 540.3(M+); HRMS: calcd for
C34H28N4O3 m/z: 540.2161; found: 540.2170.
[1] Y. Hu, J. Bajorath, J. Chem. Inf. Model. 2010, 50, 500–510.
[2] R. W. DeSimone, K. S. Currie, S. A. Mitchell, J. W. Darrow, D. A.
Pippin, Comb. Chem. High Throughput Screen. 2004, 7, 473–494.
[3] M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol.
2010, 14, 347–361.
Methyl 1-(3-methoxypropyl)-2-[6-(thiophen-2-yl)indoloACTHNUTRGNEU[GN 1,2-a]quinoxalin-
1-yl]-1H-benzimidazole-5-carboxylate (19 f). IR (neat): n˜ =2923, 2852,
1
2377, 2312, 1712 cmÀ1; H NMR (300 MHz, CDCl3): d=8.69 (s, 1H), 8.21
[4] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752–
6756.
(d, J=8.0 Hz, 1H), 8.14 (d, J=3.7 Hz, 1H), 8.04 (d, J=6.8 Hz, 1H), 7.97
(d, J=8.6 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.67 (d, J=2.3 Hz, 1H), 7.65
(s, 2H), 7.32 (d, J=4.4 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 7.11 (t, J=
3.5 Hz, 1H), 7.89 (d, J=3.5 Hz, 1H), 6.60 (t, J=7.9 Hz, 1H), 4.01 (s,
3H), 3.20 (m, 1H), 3.01 (m, 1H), 2.87 (s, 3H), 2.68 (m, 2H), 1.08 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=168.1, 155.3, 149.8, 143.6, 141.9,
138.7, 138.2, 1345.0, 133.3, 131.8, 130.1, 129.4 129.3, 129.1, 128.4, 127.4,
125.6, 125.1, 124.8, 124.4, 123.5, 122.7, 122.3, 118.8, 113.6, 110.3, 103.8,
68.4, 58.7, 52.6, 40.8, 29.0 ppm; MS (EI+) m/z: 546.3 (M+); HRMS:
calcd for C32H26N4O3S m/z: 546.1726; found: 546.1729.
[5] K. Kingwell, Nat. Rev. Drug Discovery 2009, 8, 931.
[6] a) Chiral synthesis on polymer support: a combinatorial approach.
D. B. Salunke, C. M. Sun in Polymeric chiral catalyst design and
chiral polymer synthesis (Ed.: S. Itsuno), Wiley-Blackwell, USA,
2010, Chap. 6 and the references cited therein; b) G. S. Yellol, C. T.
Chou, W. J. Chang, B. Maiti, C. M. Sun, Adv. Synth. Catal. 2012, 354,
187–196; c) C. H. Chen, J. Kuo, G. S. Yellol, C. M. Sun, Chem.
Asian J. 2011, 6, 1557–1565; d) K. Chanda, C. T. Chou, J. J. Lai, S. F.
Lin, G. S. Yellol, C. M. Sun, Mol. Diversity 2011, 15, 569–581.
[7] V. Sharma, P. Kumar, D. Pathak, J. Heterocycl. Chem. 2010, 47, 491–
502.
[8] M. Boiani, M. Gonzalez, Mini Rev. Med. Chem. 2005, 5, 409–424.
[9] A. Carta, S. Piras, G. Loriga, G. Paglietti, Mini Rev. Med. Chem.
2006, 6, 1179–1200.
[10] L. Costantino, D. Barlocco, Curr. Med. Chem. 2006, 13, 65–85.
[11] B. Ahmed, M. Rashid, Org. Chem. Indian J. 2008, 4, 486–507.
[12] F. R. de Sa Alves, E. J. Barreiro, C. A. M. Fraga, Mini Rev. Med.
Chem. 2009, 9, 782–793.
Methyl 2-[6-(1,3-benzodioxol-5-yl)indolo
heptyl-1H-benzimidazole-5-carboxylate (19g). IR (neat): n˜ =3747, 3677,
2925, 2856 cmÀ1 1H NMR (300 MHz, CD3OD): d=8.24 (d, J=7.9 Hz,
ACHTUNGTRENN[UNG 1,2-a]quinoxalin-1-yl]-1-cyclo-
;
1H), 7.96 (d, J=8.7 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.82 (d, J=8.0 Hz,
1H), 7.76 (t, J=7.8 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.57 (m, 2H), 7.45
(s, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.11 (d, J=
8.0 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 6.15ACHTNUTGRNEUNG(s, 1H), 3.99 (s, 3H), 3.49 (m,
1H), 1.89 (m, 2H), 1.60–0.80 (m, 8H), 0.68–0.46 (m, 1H), 0.36–0.20 ppm
(m, 1H); 13C NMR (75 MHz, CDCl3): d=167.9, 155.9, 154.6, 150.1, 148.6,
143.1, 138.2, 136.5, 135.6, 132.2, 131.8, 130.4, 129.2, 127.6, 125.8, 125.2,
124.7, 124.5, 123.5, 123.4, 122.4, 118.0, 113.6, 112.6, 109.2, 109.0, 104.8,
102.0, 59.8, 52.6, 35, 31.7, 27.8, 26.7, 26.0, 25.8 ppm; MS (EI+) m/z:
608.3(M+); HRMS: calcd for C38H32N4O4 m/z: 608.2424; found: 608.2418.
[13] K. Chanda, J. Kuo, C. H. Chen, C. M. Sun, J. Comb. Chem. 2009, 11,
252–260.
[14] a) L. Zheng, J. Xiang, Q. Dang, S. Guo, X. Bai, J. Comb. Chem.
2005, 7, 813–815; b) L. Zheng, J. Xiang, Q. Dang, S. Guo, X. Bai, J.
Comb. Chem. 2006, 8, 381–387.
Methyl
1-cycloheptyl-2-[6-(5-nitrofuran-2-yl)indoloACTHNGUTERN[UNG 1,2-a]quinoxalin-1-
[15] B. Kundu, D. Sawant, P. Partani, A. P. Kesarwani, J. Org. Chem.
2005, 70, 4889.
yl]-1H-benzimidazole-5-carboxylate (19h). IR (neat): n˜ =2929, 2857,
1
1716, 1616, 1585 cmÀ1; H NMR (300 MHz, CDCl3): d=8.66 (s, 1H), 8.21
[16] A single crystal was selected by using an Olympus stereo zoom mi-
croscope and the X-ray diffraction data were collected on a Bruker
X8 APEX CCD diffractometer with omega and phi scan mode,
kMoKa =0.71073 ꢂ at T=100(2) K. All data were corrected for Lor-
entzian, polarization, and absorption effects using Brukerꢃs SAINT
and SADABS programs. The crystal structure was solved by direct
methods using SHELXS-97 and the refinement was performed by
full matrix least-squares on F2 using SHELXTL software package,
see: G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112–122.
Hydrogen atoms were included in the refinement as per the riding
model.
(d, J=7.7 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J=7.4 Hz, 1H), 7.93 (d, J=
8.8 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.80–7.64 (m, 1H),
7.61 (s, 1H), 7.38–7.21 (m, 3H), 7.15 (t, J=7.3 Hz, 1H), 6.64 (t, J=
7.7 Hz, 1H), 4.01 (s, 3H), 3.23 (m, 1H), 1.68 (m, 2H), 1.38 (m, 1H), 1.23
(m, 6H), 0.95 (m, 1H), 0.33 (m, 1H), 0.07 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=168.0,154.5, 153.8, 152.9, 144.2, 143.3, 137.5, 136.8,
135.3, 135.0, 132.5, 129.6, 128.3, 127.2, 125.8, 124.9, 124.5, 124.0, 122.9,
122.7, 119.2, 115.2, 114.0, 113.5, 104.8, 59.9, 52.6, 34.9, 31.7, 27.9, 26.7,
26.0, 25.6 ppm; MS (ESI+) m/z: 599.2 (M+H)+; HRMS: calcd for
C35H29N5O5 m/z: 599.2169; found: 599.2178.
[17] M. N. Burnett, C. K. Johnson, ORTEP III, report ORNL-6895, Oak
Ridge National Laboratory, TN, USA, 1996.
Crystallographic Data
CCDC 861548 (15i) and CCDC 861536 (18a) contain the supplementary
Received: February 8, 2012
crystallographic data for this paper. These data can be obtained free of
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ

FULL PAPERS
Privileged Structures
Indrajeet J. Barve, Chan-Yu Chen,
Deepak B. Salunke,
Wen-Sheng Chung,*
Chung-Ming Sun*
&&&& — &&&&
Design and Synthesis of New Biprivi-
leged Molecular Scaffolds: Indolo-
Fused Benzodiazepinyl/quinoxalinyl
benzimidazoles
Feeling privileged: Benzimidazole-
linked tetracyclic indolo-benzodiaze-
pines and indolo-quinoxalines were
designed and synthesized as new bipri-
viliged molecular scaffolds. The key
step in the synthesis is a Pictet–Spen-
gler-type condensation. Analysis of
single crystals of representative com-
pounds showed that these molecular
scaffolds have the potential to present
various substituents with distinct three-
dimensional orientations.
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!