Divergent synthesis of unsymmetrical annulated biheterocyclic compound libraries: Benzimidazole linked indolo-benzodiazepines/quinoxaline

Article abstract of DOI:10.1021/co200022u

Diversity-oriented synthesis of novel benzimidazole linked indolo-benzodiazepine/quinoxaline ring systems using poly(ethylene glycol) as soluble polymer support is described. Commercially available 4-fluoro-3-nitrobenzoic acid and indoline were utilized f

Full text of DOI:10.1021/co200022u

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Divergent Synthesis of Unsymmetrical Annulated
Biheterocyclic Compound Libraries: Benzimidazole Linked
Indolo-benzodiazepines/quinoxaline
Li-Hsun Chen, Chia-Mao Chang, Deepak B. Salunke, and Chung-Ming Sun*
Laboratory of Combinatorial Drug Discovery, Department of Applied Chemistry National Chiao Tung University,
Hsinchu 300-10, Taiwan
S Supporting Information
b
ABSTRACT: Diversity-oriented synthesis of novel benzimidazole
linked indolo-benzodiazepine/quinoxaline ring systems using poly-
(ethylene glycol) as soluble polymer support is described. Commer-
cially available 4-fluoro-3-nitrobenzoic acid and indoline were utilized
for the construction of these annulated biheterocyclic compound
libraries having multiple privileged structures with three-point structural
diversity. A reagent based diversification approach coupled with the
PictetꢀSpengler-type condensation was used to construct the tetra-
cyclic indolo-benzodiazepines/quinoxalines on substituted benzimida-
zoles.
KEYWORDS: indolo-benzodiazepines/quinoxalines, PictetꢀSpengler,
diversity-oriented synthesis, PEG
’ INTRODUCTION
On the basis of the diverse biological properties of these
classes of compounds, the present article describes the design
and combinatorial synthesis of new biheterocyclic scaffold having
multiple privileged structures. A few reports on linked hetero-
cyclic compounds bearing benzimidazole-like groups have ap-
peared. For example, benzimidazole linked quinoxaline 1 was
identified as DNA topoisomerase I inhibitor,10 and several head-
to-head symmetric bisbenzimidazole-based DNA minor groove
binding agents 2 demonstrated potential antitumor activity.11 A
new series of benzimidazolyl-thiadiazepines 3 was synthesized
and evaluated as antibacterial agents.12 We earlier reported the
synthesis of pharmaceutically interesting angular-bisbenzimida-
zoles 4 having potential vascular endothelial growth factor
receptor 3 inhibition activity.13 To the best of our knowledge,
no report on the synthesis of benzimidazole linked heterocycles
with four annulated rings exists in the literature.
Chimeric skeletons of this type, shown in Figure 1, may
provide advantages in drug discovery if they can be accessed
efficiently. To accelerate the discovery process, we implemen-
ted a liquid phase combinatorial synthetic protocol14 using
poly(ethylene glycol) (PEG) as soluble polymer support. Un-
like the use of an insoluble matrix, PEG conjugated intermedi-
ates remain in homogeneous solution during reactions, and are
precipitated when desired by the addition of diethyl ether. After
precipitation, unwanted reagents and byproducts are simply
filtered away.
Heterocyclic structures have myriad biomedical applications
and play important roles in drug discovery. Many of the best
selling drugs currently in use contain one or more heterocyclic
rings. Among the various heterocyclic structures, several fused
heterocyclic systems1 as well as biheterocyclic frameworks2 are
known to provide ligand landing zones for more than one type of
bioreceptors and are often included in the category of privileged
structures. Particularly common in drugs and lead-compounds
are the indole, benzimidazole, benzopyrazine, or benzodiazepine
groups, and the biheterocyclic phenylimidazole unit is also found
in many natural products.1,3 Several reports on the design and
synthesis of new chemical libraries based on these privileged
structures have appeared in the recent literature.4
A large number of indole fused ring systems with a range of
biological activities are known.5 For example, benzimidazoles are
structurally related to indoles as well as to purine bases and are
ligands for serotonin receptors (5-HT), histamine (H4) recep-
tors, bradykinin (B2) receptors, and dopamine (D4) receptors.6
Molecules containing the benzimidazole scaffold exhibit antiar-
rhythmic, antihistamine, antiulcer, anticancer, inotropic, fungicidal,
anthelmintical, and antiviral activities.7 The related benzopyr-
azines (quinoxalines) and their derivatives have also received
much attention owing to their antimicrobial, antifungal, antic-
ancer, and antihelmentic properties.4c Benzodiazepines are the
class of compounds to which the term “privileged structure” was
first applied by Evans in 1988.8 The therapeutic applications of
benzodiazepines include anxiolytics, antiarrhythmics, vasopres-
sin antagonists, HIV reverse transcriptase inhibitors, and chole-
cystokinin antagonists.9
Received: February 3, 2011
Revised:
May 8, 2011
Published: June 07, 2011
r
2011 American Chemical Society
391
dx.doi.org/10.1021/co200022u ACS Comb. Sci. 2011, 13, 391–398
|

ACS Combinatorial Science
RESEARCH ARTICLE
’ RESULTS AND DISCUSSION
dichloromethane resulted in the formation of anilide conjugates
10. The observed selectivity was achieved because of the
presence of the ester functionality on the ring, which deactivated
the secondary amine and facilitated the amide coupling exclu-
sively with primary amine. Further intramolecular ring closure
through the nucleophilic attack of the secondary amine on the
amide carbonyl was brought about in refluxing 1,2-dichloro-
ethane in the presence of TFA (10%) and anhydrous MgSO4.
The subsequent aromatic substitution on immobilized benzimi-
dazole linked o-fluoro nitrobenzene 11 by indoline 12 was
achieved in refluxing acetonitrile. The reaction took 12 h for
the complete disappearance of the starting materials. To monitor
the progression of reaction, a small portion of the reaction
mixture was pulled out, the compound was precipitated and
washed with cold ether and dried to record the proton NMR
spectrum (Figure 2). Upon completion of the reaction, the
polymer bound compound mixtures were purified by the same
precipitation and washing protocol.
In the next step, the nitro functionality in conjugate 13 was
reduced to amine using zinc and ammonium formate in metha-
nol at room temperature (Scheme 2). No loss of yield was
observed during this reductive transformation, suggesting that
the polymer support remained intact. The amino-indolinyl inter-
mediate 14 was used in Pictet-Spengler type heterocyclization
reactions with various aldehydes or ketones (Table 1) in the
presence of TFA and MgSO4 in refluxing chloroform, to give
the desired benzimidazole linked tetrahydro-indolobenzodia-
zepines 16.
Commercially available 4-fluoro-3-nitrobenzoic acid (FNBA)
6 and indoline 12 were utilized for the construction of these
annulated biheterocyclic compound libraries. The stepwise
synthesis was initiated by loading FNBA on PEG-6000 using
1,3-dicyclohexylcarbodiimide (DCC) and catalytic 4-dimethyla-
minopyridine (DMAP). The first point of structural diversity was
installed in the next step by the ipso-fluoro displacement of the
activated aromatic fluoride in PEG ester conjugate 7 using
various primary amines (Scheme 1).
Reduction of the aryl nitro group in the resulting derivative 8
was accomplished with a suspension of Zn/NH4Cl in methanol
to afford immobilized diamine 9 at room temperature. These
ortho-diamino ester conjugates 9 were earlier used for the parallel
synthesis of substituted benzimidazoles, amino/thio-benzimida-
zoles, benzimidazolones, quinoxalinones and benzimidazolyl
quinoxalinones.15 The benzimidazole ring in the present synth-
esis was constructed using another molecule of FNBA. The
selective condensation of FNBA 6 with the aniline conjugates 9
via the in situ generated DCC activated ester in refluxing
Different aromatic aldehydes having variable electron densi-
ties on the aromatic ring were utilized for this cyclization;
aliphatic aldehyde (Table 1, entry 16g) as well as cyclic (Table 1,
entry 16l) and noncyclic (Table 1, entry 16j, 16k) ketones were
also incorporated successfully. The use of a cyclic ketone to give
spiro compound 16l was particularly interesting.
One limitation emerged under these acid catalyzed dehy-
drating conditions for para-nitrobenzaldehyde (Table 1, entry
16e, 16n, and 16o), in which cyclization was followed by
Figure 1. Benzimidazole-linked biologically active compounds.
Scheme 1. Synthesis of Key Intermediate Ready for Further Diversification
392
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
Figure 2. Proton NMR monitoring reaction progress.
Scheme 2. Synthesis of benzimidazole linked
indolobenzodiazepines
tetrahydro-indolobenzodiazepine 16. Comparatively lower
yields were observed for these reactions [Table 1, entry 16e
(62%), 16n (60%)]. In another p-nitrobenzaldehyde case, a
small amount of unoxidized product was isolated (Table 1,
entry 16o), and further adjustment of the reaction conditions
completely abolished this additional oxidation (Table 1, entry
16r). Overall, it became apparent that p-nitrobenzaldehyde
gave structures 160 when the reaction was carried out for more
than 14 h, whereas the unoxidized compound 16 was isolated
after 10 h with the reaction being incomplete. The use of ortho/
meta-nitrobenzaldehydes did not produce any oxidized products
(Table 1, entry 16f, 16h, 16i) during this reaction.
The highly efficient nature of the benzodiazepine formation
during this Pictet-Spengler type condensation reaction deserves
some comment. In this step, the iminium ion generated in situ
undergoes CꢀC bond formation with the C-7 of the indoline
ring in compound 14 to furnish the indolobenzodiazepine. The
success of this step presumably requires the presence of a
sufficiently reactive aromatic nucleus (provided by the indoline
nitrogen) as well as conformational restrictions induced by the
anilinic nature of the substrate (compared to aliphatic amines in
the classical PictetꢀSpengler isoquinoline synthesis). The final
cleavage of the soluble polymer support was achieved using
potassium cyanide (1%) in methanol at room temperature to
oxidation of the benzodiazepine ring to give the benzimidazole-
linked dihydro-indolobenzodiazepine skeleton 160 instead of the
393
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
Table 1. Benzimidazole-Linked Indolo-benzodiazepine Conjugate Library
a [M þ H]þ. b Isolated yields determined on weight of purified samples. c HPLC recorded after the cleavage f1ollowed by precipitation and washing.
d Only the oxidized product (160) was isolated. e Mixture of both 16 and 160 compounds formed. f Aggregrate purity; 160/16: 57/23. g Reaction was
carried out for 10 h; no 16r0 formed.
obtain polymer-free benzimidazole linked indolobenzodiaze-
pines 16 and 160 in good to excellent yields (60ꢀ87%, Table 1).
Using a similar synthetic sequence via indole instead of
indoline, benzimidazole linked indoloquinoxalinones were also
synthesized (Scheme 3).16 Treatment of conjugate 13 with
palladium catalyst and cyclohexene in refluxing ethanol yielded
indole-substituted aniline conjugate 17 by transfer hydrogena-
tion, both reducing the nitro group and dehydrogenating the
indoline to indole17 in one step. The amino-indolyl intermediate
17 could also be obtained by the oxidation of the indoline ring in
polymer conjugate 14 through the application of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ). Treatment of 17 with
various aldehydes (Table 2) in the presence of TFA and MgSO4
in refluxing chloroform gave the desired benzimidazole-linked
indoloquinoxalines 20 in moderate to good yields (62ꢀ89%,
Table 2). The intermediate dihydropyrazine ring was found to be
easily air oxidized during this transformation to deliver the more
stable fully aromatic skeleton. During these condensation reactions,
the iminium ion generated in situ undergoes CꢀC bond forma-
tion with the electron rich C-2 of the indole ring in 17. When
ketones were employed in place of aldehydes, the corresponding
dihydroindoloquinoxaline scaffold 21 was produced on the
polymer support. The polymer free final products (75ꢀ90%,
Table 3) were obtained as before using potassium cyanide (1%)
in methanol at room temperature. Complete cleavage during this
1
reaction was verified by H NMR of the recovered polymer
support.
The use of relatively hindered ketones (3-methylbutan-2-one
and 1-(thiophen-2-yl)ethanone, Table 3, entries 21e and 21f)
illustrated a limitation to the reaction, giving none of the desired
products under standard conditions even after prolonged reac-
tion time (48 h reflux). These substrates were incorporated by
heating the reaction mixtures in a sealed tube for 20 h. Lower
yields (56ꢀ61%), as well as poor HPLC purity (50%), are the
result of the harsh reaction conditions, which could not be further
improved. Nonplanarity in the annulated indoloquinoxaline
394
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 3. Synthesis of Benzimidazole-Linked Indoloquinoxalines
skeleton was clearly indicated by X-ray crystallographic analysis
spectrum was recorded. The reaction progress and the stepwise
transformations on a polymer support after each stage of the
synthetic sequence from 4-fluoro-3-nitrobenzoic acid to the
desired products were cleanly observed in proton NMR spectra
(Figure 2).
of spiro compound 21h (ORTEP18 diagram shown in Figure 3).
’ CONCLUSION
A reagent-based diversification approach coupled with the
PictetꢀSpengler type condensation was used to construct tetra-
cyclic indolo-benzodiazepines/quinoxalines on substituted ben-
zimidazoles in a divergent fashion. A small library of these
unsymmetrical annulated biheterocyclic compounds were pre-
pared in good to excellent yield, with methods that provide three
points of structural diversity. The use of a soluble polymer
supported was found to be effective and convenient, and the
scaffolds and methods provide ample opportunities for further
functionalization.
Synthesis of Key Intermediate (13). PEG 6000 (1.2 g,
0.2 mmol), FNBA 6 (0.222 g, 1.2 mmol), DCC (0.247 g, 1.2 mmol),
and DMAP (0.015 g, 0.12 mmol) in dry CH2Cl2 (15 mL) were
stirred in a round-bottom flask at 25 °C for 24 h. Upon
completion of the reaction, CH2Cl2 (10 mL) was added, and
the reaction mixture was cooled to 0 °C. The solid dicyclohex-
ylurea (DCU) formed was filtered off and CH2Cl2 layer was
evaporated. To this crude material, cold diethyl ether (10 mL)
was added to precipitate the PEG-bound fluoro-nitro aryl inter-
mediate 7. The precipitate was then collected on a sintered glass
funnel and thoroughly washed with diethyl ether (10 mL ꢁ 2) to
remove the excess reagents and dried. This PEG supported aryl
fluoride 7 (1.14 g, 0.18 mmol) and isobutylamine (0.066 g,
0.90 mmol) were stirred in 10 mL of CH2Cl2 for 3 h. After
completion of reaction, the solution was concentrated by rotary
evaporation and reaction mixture was precipitated by slow
addition of cold diethyl ether with stirring. Polymer bound
product was then filtered under aspirator pressure using a flitted
funnel and washed several times with cold ether and dried in
vacuo. Zinc dust (0.11 g, 1.7 mmoL, 10.0 equiv) and NH4Cl
(0.045 g, 0.85 mmoL, 5.0 equiv) were added to the solution of
polymer bound fluoro-nitro aryl intermediate 8 (1.1 g, 0.17 mmol)
in MeOH (20 mL), and the resulting suspension was stirred at
25 °C for 3 h. The heterogeneous catalyst was removed by
filtration during the workup and the polymer-bound diamine 9
was purified by precipitation and dried in vacuum. To the solution
of PEG bound aniline conjugate 9 (1.02 g, 0.16 mmol) and FNBA
6 (0.30 g, 1.6 mmol) in CH2Cl2 15 mL, were added DCC (0.66 g,
3.2 mmol) and DMAP (0.04 g, 0.32 mmol) and the resulting
reaction mixture was refluxed for 10 h. The crude anilide conjugate
’ EXPERIMENTAL PROCEDURES
General Remarks. 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 Kiselgel 60 F254 plates. Com-
pound purification was carried out using flash chromatography
grade silica gel 60 (230ꢀ400 mesh). IR spectra were recorded on
1
an FT-IR spectrophotometer. H and 13C NMR spectra were
recorded on a 300 and 75 MHz spectrometer, respectively.
Chemical shifts are reported in parts per million (ppm) on the
scale from an internal standard. Mass spectra were recorded on a
time-of-flight mass spectrometer, samples being introduced by
infusion method using the electrospray ionization technique. All
starting compounds were purchased from commercial sources
and used without purification. To monitor the progression of
reaction on a polymer support, a small portion of the reac-
tion mixture was pulled out, compound was precipitated and
washed with cold ether, subsequently dried and proton NMR
395
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
Table 2. Benzimidazole-Linked Indoloquinoxaline Conju-
gate Library Using aldehydes
Table 3. Benzimidazole-Linked Indoloquinoxaline Conju-
gate Library Using Ketones
a [M þ H]þ. b Isolated yields determined on weight of purified samples.
c HPLC recorded after the cleavage followed by precipitation and
washing. d Reaction mixtures were heated in sealed tube for 20 h
a [M þ H]þ. b Isolated yields determined on weight of purified samples.
c HPLC recorded after the cleavage followed by precipitation and
washing.
10 was obtained using the same procedure as described earlier.
The anilide conjugate 10 (1.00 g, 0.15 mmol), in the presence of
TFA (0.1 mL) and MgSO4 (0.5 g) was further refluxed in 1,2-
dichloroethane (10 mL) for 15 h. After completion of the reaction,
MgSO4 was removed by the 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 compound
11 in high purity. To this crude material 11 (1.00 g, 0.15 mmol) in
dry CH3CN (10 mL) was added indoline 12 (0.09 g, 0.75 mmol),
and the reaction mixture was refluxed for overnight. The crude
Figure 3. ORTEP view of compound 21h.
product 13 (1.05 g) was purified by precipitating and washing with
excess cold ether (20 mL ꢁ 3) and dried in vacuo. This was used as
it is for the further transformations.
396
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
Synthesis of Benzimidazole, Indoline/Indole Substituted
Aniline Conjugates (14) and (17) from Intermediate (13):
Reagent-Based Diversification. Zinc dust (10.0 equiv, 0.1 g,
1.5 mmol) and ammonium formate (10.0 equiv, 0.09 g, 1.5 mmol)
were added to a solution of polymer bound benzimidazole
linked fluoro-nitro aryl intermediate 13 (1.0 g, 0.15 mmol) in
MeOH (20 mL), and the reaction mixture was stirred at room
temperature for 1 h. Upon completion of reaction, the mixtures
were filtered through Celite to remove insoluble zinc dust, and
the filtrate was collected and concentrated under reduced
pressure. Dichloromethane (15 mL) was added to precipitate
ammonium formate, and the mixture was again passed through
a thin layer of Celite to remove ammonium formate. The
organic layer was concentrated and the crude product (14)
obtained was used as it is for the further transformations. In
another experiment, to the solution of intermediate 13 (1.0 g,
0.15 mmol) in EtOH (20 mL) was added 10% Pd/C (0.1 g,
10 Wt % of 13) followed by cyclohexene (2 mL) was added, and
the reaction mixture was refluxed for 4 h. The solid palladium
on charcoal was filtered off and the solvent was evaporated.
PEG-bound aniline conjugate 17 was isolated by the same
precipitation and washing technique using diethyl ether. Com-
pound 17 was also obtained from intermediate 14. The solution
of compound 14 (1.0 g, 0.15 mmol) in CH2Cl2 (10 mL) was stirred
at room temperature in the presence of DDQ (0.17 g, 0.75 mmol)
for overnight. The reaction mixture was filtered and the precipitate
was washed with CH2Cl2 (50 mL). The combined organic layers
were concentrated; compound obtained was dried and used as it is
for the further transformations.
General Procedure for the PictetꢀSpengler Cyclization
and Cleavage from Support. To a solution of indoline/indole-
substituted aniline conjugates 14 or 17 (1.0 equiv) in CHCl3
(10 mL), aldehyde or 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 pressure and diluted with slow addition
of excess of cold ether (50 mL). The precipitated PEG linked
biheterocyclic conjugates (15, 18, or 19) were filtered through a
fritted funnel and washed with excess cold ether (20 mL ꢁ 3) and
dried in vacuo. Potassium cyanide (0.01 equiv.) was added to a
solution of these conjugates (15, 18, or 19) in methanol (10 mL).
The mixtures were stirred at ambient temperature for 12 h. The
solvent was removed under reduced pressure, and the mixtures
were precipitated and washed with ether (50 mL ꢁ 3). The
filtrates were collected, and products 16, 160, 20, or 21 were
obtained in good yields and purity (Tables 1ꢀ3).19
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data for all
b
the synthesized compounds, copies of HPLC, 1H and 13C NMR,
MS, HRMS and IR spectra. X-ray crystallographic data for 21h.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Funding Sources
National Science Council of Taiwan for the financial assistance.
’ REFERENCES
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The combinatorial
synthesis of bicyclic privileged structures or privileged substructures.
Chem. Rev. 2003, 103, 893–930.
(2) Steel, P. J. Aromatic biheterocycles: syntheses, structures, and
properties. Adv. Heterocycl. Chem. 1996, 67, 1–117.
(3) (a) Sharma, V.; Kumar, P.; Pathak, D. Biological importance of
the indole nucleus in recent years: a comprehensive review. J. Heterocycl.
Chem. 2010, 47, 491–502. (b) Boiani, M.; Gonzalez, M. Imidazole and
benzimidazole derivatives as chemotherapeutic agents. Mini-Rev. Med.
Chem. 2005, 5, 409–424. (c) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G.
Chemistry, biological properties, and SAR analysis of quinoxalinones.
Mini Rev. Med. Chem. 2006, 6, 1179–1200. (d) Costantino, L.; Barlocco,
D. Privileged structures as leads in medicinal chemistry. Curr. Med.
Chem. 2006, 13, 65–85. (e) Ahmed, B.; Rashid, M. Chemistry and
biological activity of benzodiazepines. Org. Chem. Indian J. 2008, 4,
486–507.
(4) (a) Frazen, R. G. Recent advances in the preparation of hetero-
cycles on solid support: A review of the literature. J. Comb. Chem. 2000,
2, 195–214. (b) Nicolaou, K. C.; Roecker, A. J.; Hughes, R.; van
Summeren, R.; Pfefferkorn, J. A.; Winssinger, N. Novel strategies for
the solid phase synthesis of substituted indolines and indoles. Bioorg.
Med. Chem. 2003, 11, 465–476. (c) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N.; Rao, M. V. Recent advances in the solid-phase
combinatorial synthetic strategies for the quinoxaline, quinazoline and
benzimidazole based privileged structures. Mini-Rev. Med. Chem. 2006,
6, 71–89. (d) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.;
Reddy, D. R. Recent advances in the solid-phase combinatorial synthetic
strategies for the benzodiazepine based privileged structures. Mini-Rev.
Med. Chem. 2006, 6, 53–69.
(5) (a) de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. From nature
to drug discovery: The indole scaffold as a “privileged structure”. Mini-
Rev. Med. Chem. 2009, 9, 782–793. (b) Kochanowska-Karamyan, A. J.;
Hamann, M. T. Marine indole alkaloids: Potential new drug leads for the
control of depression and anxiety. Chem. Rev. 2010, 110, 4489–4497.
(6) Todorovic, A.; Joseph, C. G.; Sorensen, N. B.; Wood, M. S.;
Haskell-Luevano, C. Structureꢀactivity relationships of melanocortin
agonists containing the benzimidazole scaffold. Chem. Biol. Drug. Des.
2007, 69, 338–349.
(7) Kamal, A.; Kumar, P. P.; Sreekanth, K.; Seshadri, B. N.; Ramulu,
P. Synthesis of new benzimidazole linked pyrrolo[2,1-c][1,4]ben-
zodiazepine conjugates with efficient DNA-binding affinity and potent
cytotoxicity. Bioorg. Med. Chem. Lett. 2008, 18, 2594–2598.
1-(3-Methoxy-propyl)-2-(6-phenyl-1,2,6,7-tetrahydro-benzo-
[2,3][1,4]diazepino[6,7,1-hi]indol-9-yl)-1H-benzoimidazole-
5-carboxylic Acid Methyl Ester (16a). IR (neat): 2924, 1713,
1471, 1302 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 8.51 (d, J =
1.1 Hz, 1H), 7.97 (dd, J = 8.5, 1.1 Hz, 1H), 7.37 (d, J = 8.5 Hz,
1H), 7.35ꢀ7.10 (m, 6H), 7.05 (s, 2H), 6.89 (d, J = 8.5 Hz, 2H),
6.53ꢀ6.48 (m, 2H), 5.34 (s, 1H), 4.25 (m, 2H), 4.12 (t, J =
7.1 Hz, 2H), 3.93 (s, 3H), 3.20 (m, 4H), 3.16 (s, 3H), 1.86 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 168.1, 155.4, 144.5, 143.0,
142.4, 139.6, 139.2, 137.8, 131.7, 129.0 (2C), 128.6 (2C), 128.0,
127.9, 125.1, 124.3, 124.2, 124.0, 122.9, 121.9, 121.7, 120.5,
119.2, 115.7, 110.0, 69.1, 65.4, 59.0, 52.4, 42.2, 31.3, 30.2, 27.8.
MS (ESI): m/z 545 (MHþ). HRMS Calcd for C34H33N4O3:
m/z 545.2553; Found 545.2551.
(8) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson,
P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods for drug discovery:
Development of potent, selective, orally effective cholecystokinin an-
tagonists. J. Med. Chem. 1988, 31, 2235–2246.
(9) Zhao, H. Y.; Liu, G. Solution-phase parallel synthesis of diverse
1,5-benzodiazepin-2-ones. J. Comb. Chem. 2007, 9, 1164–1176.
397
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398

ACS Combinatorial Science
RESEARCH ARTICLE
(10) Alper, S.; Ozlem, T. A.; Esin, A. S.; Yalcin, I. Some new bi- and
ter-benzimidazole derivatives as topoisomerase I inhibitors. Farmaco
2003, 58, 497–507.
(11) Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.; Parkin-
son, G.; Kelland, L. R.; Neidle, S. A new class of symmetric bisbenzi-
midazole-based DNA minor groove-binding agents showing antitumor
activity. J. Med. Chem. 2001, 44, 138–144.
(12) Reddy, V. M.; Reddy, K. R. Synthesis and antibacterial acti-
vity of some novel 6-(1H-benz[d]imidazol-2-yl)-8-(5-nitro-2-furyl)-3-
(4-pyridyl)-7,8-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines.
Chem. Pharm. Bull. 2010, 58, 1081–1084.
(13) Chen, C. H.; Chien, M. H.; Kuo, M. L.; Chou, C. T.; Lai, J. J.;
Lin, S. F.; Thummanagoti, S.; Sun, C. M. Diversity-oriented synthesis of
angular bis-benzimidazole derivatives under microwave irradiation.
J. Comb. Chem. 2009, 11, 1038–1046.
(14) Sun, C. M. Recent advances in liquid-phase combinatorial
chemistry. Comb. Chem. High Throughput Screen. 1999, 2, 299–318.
(15) (a) Chang, L. J.; Kulkarni, M. V.; Sun, C. M. Parallel synthesis of
novel benzimidazoles on a soluble polymer support. Central Eur. J. Chem.
2005, 3, 288–294. (b) Bendale, P. M.; Sun, C. M. Rapid microwave-
assisted liquid-phase combinatorial synthesis of 2-(arylamino)benzimi-
dazoles. J. Comb. Chem. 2002, 4, 359–361. (c) Yeh, C. M.; Tung, C. L.;
Sun, C. M. Combinatorial liquid-phase synthesis of structurally diverse
benzimidazole libraries. J. Comb. Chem. 2000, 2, 341–348. (d) Pan, P. C.;
Sun, C. M. High-throughput combinatorial synthesis of substituted
benzimidazolones. Tetrahedron Lett. 1999, 40, 6443–6446. (e) Tung,
C. L.; Sun, C. M. Liquid phase synthesis of chiral quinoxalinones by
microwave irradiation. Tetrahedron Lett. 2004, 45, 1159–1162. (f)
Chanda, K.; Kuo, J.; Chen, C. H.; Sun, C. M. Enantioselective synthesis
of benzimidazolyl quinoxalinones on soluble polymer support using
focused microwave irradiation. J. Comb. Chem. 2009, 11, 252–260.
(16) Lai, J. J.; Salunke, D. B.; Sun., C. M. Multistep microwave-
assisted divergent synthesis of indolo-fused pyrazino-/diazepinoquinox-
alinones on PEG support. Org. Lett. 2010, 12, 2174–2177.
(17) Hara, T.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Highly
efficient dehydrogenation of indolines to indoles using hydroxyapatite-
bound Pd catalyst. Tetrahedron Lett. 2003, 44, 6207–6210.
(18) Burnett, M. N.; Johnson, C. K. ORTEP III; Report ORNL-
6895; Oak Ridge National Laboratory: Oak Ridge, TN, U.S.A., 1996.
(19) Characterization data for 16bꢀ16r, 20aꢀ20l, and 21aꢀ21h is
included in Supporting Information.
398
dx.doi.org/10.1021/co200022u |ACS Comb. Sci. 2011, 13, 391–398