Facile Synthesis of Some 3-(Benzimidazol-2-yl)-And 3,6-Di(Benzimidazol-2-yl)-9-ethyl-9H-carbazoles

Article abstract of DOI:10.1080/00397911.2015.1094819

A simple and efficient synthesis of novel 3-(benzimidazol-2-yl)-And 3,6-di(benzimidazol-2-yl)-9-ethyl-9H-carbazoles is described. The synthetic approach for the preparation of 2-substituted benzimidazoles 4-8 and bis-benzimidazoles 9-12 was achieved by the condensation of carbazole-3-carbaldehyde 2 and carbazole-3,6-dicarbaldehyde 3 with o-phenyldiamines in dimethylformamide or dimethylsulfoxide in moderate to excellent yield. The identities of synthesized compounds were confirmed using ¹H NMR, ¹³C NMR, infrared (IR), and high-resolution mass spectrometry (HRMS).

Full text of DOI:10.1080/00397911.2015.1094819

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Facile Synthesis of Some 3-(Benzimidazol-2-
yl)- and 3,6-di(Benzimidazol-2-yl)-9-ethyl-9H-
carbazoles
Hakan Kandemir & Ibrahim F. Sengul
To cite this article: Hakan Kandemir & Ibrahim F. Sengul (2015): A Facile Synthesis of
Some 3-(Benzimidazol-2-yl)- and 3,6-di(Benzimidazol-2-yl)-9-ethyl-9H-carbazoles, Synthetic
Communications, DOI: 10.1080/00397911.2015.1094819
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Date: 08 October 2015, At: 07:28

A facile synthesis of some 3-(benzimidazol-2-yl)- and 3,6-di(benzimidazol-2-yl)-9-
ethyl-9H-carbazoles
Hakan Kandemir1, Ibrahim F. Sengul2
1Department of Chemistry, Faculty of Art and Science, Namık Kemal University,
Tekirdag, Turkey, 2Department of Chemistry, Faculty of Science, Gebze Technical
University, Gebze, Kocaeli, Turkey
Corresponding Author to Ibrahim F. Sengul: E-mail: fazilsengul@gtu.edu.tr
Abstract
A simple and efficient synthesis of novel 3-(benzimidazol-2-yl)- and 3,6-
di(benzimidazol-2-yl)-9-ethyl-9H-carbazoles is described. The synthetic approach for the
preparation of 2-substituted benzimidazoles 4-8 and bis-benzimidazoles 9-12 was
achieved by the condensation of carbazole-3-carbaldehyde 2 and carbazole-3,6-
dicarbaldehyde 3 with o-phenyldiamines in dimethylformamide or dimethylsulfoxide in
moderate to excellent yield. The identities of synthesized compounds were confirmed
using 1H NMR, 13C NMR, IR and high resolution mass spectrometry.
KEYWORDS: Benzimidazole, bis-benzimidazole, carbazole, Vilsmeier-Haack method
1

INTRODUCTION
Nitrogen containing heterocycles have been the subject of intense study and considerable
effort has been devoted to the synthesis of these heterocyclic systems as they are found in
a wide range of biologically active molecules and alkaloids.[1,2] Among these,
benzimidazole and carbazole derivatives are of significant synthetic interest due to their
diverse range of biological activity.
Benzimidazole and its derivatives are an important class of nitrogen containing aromatic
heterocyclic compounds, having long attracted attention from researchers due to their
valuable properties.[3] They have a multitude of interesting biological activities, including
antimicrobial, anti-inflammatory, antitumor, antiviral and antihypertensive activity.[4-8] In
recent years, they have also attracted particular interest due to their anticancer
activities.[9-10] In particular, benzimidazole compounds have been explored as
topoisomerase I, PARP-1, kinase Chk2, metallo and serine protease inhibitors.[11]
Furthermore, compounds possessing benzimidazole express significant activity against
several viruses such as HIV, herpes (HSV-1) and RNA influenza.[12-14]
More complex benzimdazoles, such as bis-benzimidazoles, are also very important
biologically active scaffold that are found in many pharmacologically active alkaloids.
For example, Hoechst 33258 (also known as Pibenzimol) is an A/T base pair selective
compound that binds in the minor groove of DNA.[15]
2

Carbazole and its derivatives are rigid heterocyclic systems that have been a source of
great interest for chemists due to their reactivity to electrophilic substitutions and wide
spectrum of biological properties.[16] The preferred site of electrophilic substitution for
carbazole is the C3 position. The blocking of this position directs the electrophilic
substitution to the C6 position. This gives the opportunity for the realization of further
substitutions on the C6 position.
Also, diaryl or heteroaryl carbazoles have been associated with cytotoxic and
antiplatelet activitiy, and are attractive molecules for the potential development of anti-
tumor agents.[17-18] Furthermore, carbazole derivatives are widely used as building blocks
for new organic materials and play a very important role in electroactive and photoactive
materials.[19] Currently, there is a strong interest in the synthesis of novel
heteroarylcarbazole derivatives having their important structural features and promising
biological activities.[20] Although most heteroarylcarbazoles reported in the literature
contain a common heterocyclic ring moiety fused with a carbazole such as
pyridocarbazoles, thienocarbazole, quino and chromecarbazoles, pyranocarbazoles,
pyrrolo carbazoles, indolocarbazoles and their synthetic analogues, to the best of our
knowledge, there are very few reports where the heteroaryl moiety is substituted with a
carbazole unit.[21-26] Consequently, the synthesis of such compounds is desirable. In this
regard, we previously reported the synthesis of some di-(2-indolyl)heteroarenes in which
the linker between two indoles is a carbazole.[27-28]
3

Recently, carbazole based benzimidazoles have been reported to show significant
biological activities including telomerase inhibition and anti-cancer activities.[29-31]
Considering the importance of benzimidazole and carbazole derivatives, we are interested
in the synthesis of mono- and bis-benzimidazoles linked by the structurally rigid
carbazole ring system. The synthesis of mono-benzimidazoles is also important due to
having a reactive C6 position for further substitutions.
RESULTS AND DISCUSSION
Many synthetic approaches have been reported for the synthesis of benzimidazole ring
systems.[32] Traditionally, benzimidazoles have most commonly been prepared from the
condensation of o-phenylenediamines with carbonyl compounds such as aldehydes or
carboxylic acids and their derivatives, which often require strongly acid conditions,
sometimes combined with very high temperatures or microwave irradiation.[32] In this
current study, the construction of benzimidazole-carbazole hybrid molecules was
successfully achieved via the condensation of o-phenylenediamines with
carbazolecarbaldehydes in dimethysulfoxide or dimethlyformamide.
The synthesis of carbazole-linked mono- and bis-benzimidazoles began with the
formylation of N-ethylcarbazole 1 using POCl3/DMF via the Vilsmeier-Haack method,
which gave mono- and diformylcarbazoles 2 and 3 in 70% and 90% yields, respectively
(Scheme 1).[33] With the carbazole-3-carbaldehyde 2 and carbazole-3,6-dicarbaldehyde 3
in hand, it was of interest to use a monomeric model for the preparation of mono-
benzimidazoles 4-8 before extending the chemistry to bis-benzimidazoles. Initially,
4

carbazolecarbaldehyde 2 was treated with o-phenylenediamine in a variety of solvents,
such as ethanol, isopropanol, nitrobenzene and dimethylformamide, to optimize the
reaction and to obtain the maximum yields and highest purity of the products. It was
found that when the reaction was conducted in dimethylformamide at 100 °C, 94% yield
of benzimidazole 4 was obtained. In contrast, the use of other solvents resulted in a
mixture of products, which could not be separated by column chromatography. Similarly,
treatment of carbazolecarbaldehyde 2 with other o-phenylenediamine derivatives in DMF
afforded the corresponding benzimidazole derivatives 5-8 in good yields (Table-1). It is
worth noting here that compound 4 was reported as a neuropeptide Y5 receptor.[34] Also,
the antimicrobial activity of compound 4 against Bacillus subtilis and Escherichia coli
was previously investigated.[35]
Compounds 5-8 are novel and their structures were established with the help of
spectroscopic data. The 1H NMR and 13C NMR spectra of compound 5 were
characteristic for compounds 5-8. The 1H NMR spectrum (DMSO) of 5 showed the
appearance of a new singlet at 12.6 ppm correlating to the NH proton of the
benzimidazole ring. The disappearance of the CHO proton for the spectrum indicated that
benzimidazole cyclisation had taken place. Further structural verification was obtained
via mass spectroscopy, with MALDI mass spectra revealing (M+1) peaks at m/z 312,
326, 346, 342 and 357, consistent for compounds 4-8 respectively.
Having successfully used this method to prepare monomeric carbazole linked
benzimidazoles, preparation of related bis-benzimidazole systems was next examined. It
5

is worth noting here that bis-benzimidazole 9 was previously synthesized via a three steps
process from the reaction between N-ethylcarbazole-3,6-dicarboxylic acid and o-
phenylenediamine in the presence of polyphosphoric acid.[36] Herein, we report the
successful preparation of carbazole linked bis-benzimidazoles 9-12 with a convenient
three-step process, as shown in Scheme 1.
The reaction between 3 and o-phenylenediamine derivatives was first performed in
DMF, however, a clean product was not obtained after column chromatography.
Therefore, dicarbaldehyde 3 was condensed with o-phenylenediamine in
dimethylsulfoxide and the carbazole linked bis-benzimidazole 9 was successfully
produced in 63% yield. Similarly, treatment of carbazole-3,6-dicarbaldehyde 3 with other
o-phenylenediamine derivatives gave the corresponding bis-benzimidazoles 10-12 in
moderate yields (Table 1). Unfortunately, the reaction of compound 3 with 4-nitro-o-
phenylenediamine produced a mixture of products which could not be separated by flash
column chromatography.
The structures of compounds 9-12 were supported by 1H NMR and 13C NMR
spectroscopic data. The 1H NMR spectrum of the compound 10 in DMSO, as a typical
example of the carbazole linked bis-benzimidazoles 9-12, displayed a broad singlet at
12.9 ppm corresponding to the benzimidazole ring NH proton, and the carbazole CH2 and
CH3 protons appeared as a quartet and triplet at 1.44 ppm and 4.55 ppm respectively. The
13C NMR spectrum displayed the carbazole CH2 and CH3 peaks at 14.3 and 37.9 ppm
respectively.
6

CONCLUSION
In the present study, a series of mono- (4-9) and bis-benzimidazoles (10-12) connecting
benzimidazoles to N-ethylcarbazole units were synthesized and characterized. While
mono-benzimidazoles were produced in DMF, DMSO was needed for a clean synthesis
of bis-benzimidazoles.
EXPERIMENTAL
All reagents and solvents were obtained from commercial sources and appropriately
purified, if necessary. The deuterated solvent (DMSO) for NMR spectroscopy was
obtained from Merck. Following chemicals were obtained from Sigma Aldrich Melting
points were measured using a Mel-Temp melting point apparatus and are uncorrected.
Measurements IR spectra were recorded between 4000 and 650 cm-1 using a Perkin
Elmer Spectrum 100 FT-IR spectrometer 1H and 13C NMR spectra were recorded in
DMSO solution on a Varian 500 MHz spectrophotometer. Matrix-assisted laser
desorption/ionization time-of- flight mass spectrometry (MALDI-TOF-MS)
measurements were performed on a Bruker Daltonics microTOF. High resolution mass
spectra (HRMS) reported to 4 decimal places were recorded on a Agilent G6530B
Accurate-Mass Q-TOF LC/MS.
General Procedure for the preparation of mono-benzimidazoles (4-8). A mixture of
3-carbaldehyde 2 and o-phenyldiamine derivatives (1:1 eq) was heated at 100 °C in DMF
(4 mL) for 8 h. The reaction mixture was poured into ice-water and the resulting
precipitate was filtered, washed with water and dried. The crude product was purified by
7

flash column chromatography using dichloromethane/ethyl acetate (9:1) as eluent to
afford the mono-benzimidazoles.
3-(1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (4). This compound was obtained
as a white solid; yield: 94%; m.p: 255-257 oC; IR (KBr): ʋmax 3648, 3049, 2977, 1628,
1599, 1488, 1470, 1439, 1403, 1374, 1346, 1328, 1150, 744 cm-1 ; 1H NMR (500 MHz,
DMSO): δ 1.54 (s, 3H, CH3), 4.68 (s, 2H, CH2), 7.38 (s, 2H, aryl H), 7.47 (s, H, aryl H),
7.71 and 7.97 (m, 5H, aryl H), 8.43 (s, H, aryl H), 8.50 (s, H, aryl H), 9.18 (s, H aryl H),
13.05 (s, H, benzimidazole NH); 13C NMR (DMSO): δ 13.8 (CH3), 37.3 (CH2), 119.0,
119.1, 120.0, 121.1, 121.9, 121.9, 122, 124.7, 126.4, 140.3, 140.6, 152.8 (aryl C and CH);
Maldi (TOF); m/z 312 [M]+; HRMS (ESI): Found m/z 312.1501 [M]+; calculated for
C21H17N3 312.1510.
General Procedure For The Preparation Of Bis-Benzimidazoles (9-12)
A mixture of 3,6-dicarbaldehyde 3 (1 eq) and o-phenylenediamine derivative (2 eq) was
heated at 120 °C in DMSO (5 mL) for 24 h. The reaction mixture was poured into ice-
water and the resulting precipitate was filtered, washed with water and dried. The crude
product was purified by flash column chromatography using dichloromethane/ethyl
acetate (5:5) as eluent to afford the bis-benzimidazoles.
3,6-di(1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (9). This compound was
obtained as a brown solid; yield: 63%; m.p: >320 oC (lit.[33] m.p: >300 oC); IR (KBr):
ʋmax 3638, 3052, 2971, 2925, 1602, 1485, 1437, 1400, 1364, 1276, 1230, 1147, 804, 734
8

cm-1 ; 1H NMR (500 MHz, DMSO): δ 1.41 (t, 3H, J=7.10 Hz, CH3), 4.55 (q, 2H, J=7.03
Hz, CH2), 7.21 (s, 4H, aryl H), 7.62(s, 4H, aryl H), 7.83 (d, 2H, J=8.54 Hz, aryl H), 8.37
(d, 2H, J=8.36 Hz, aryl H), 9.14 (s, 2H, aryl H), 12.9 (s, 2H, 2x benzimidazole H); 13C
NMR (DMSO): δ 14.3 (CH3), 37.9 (CH2), 110.4, 119.3, 122.1, 122.2, 122.9, 125.2,
141.4, 152.8 (aryl C and CH); Maldi (TOF); m/z 428 [M]+; HRMS (ESI): Found m/z
428.1878 [M]+; calculated for C28H21N5 428.1875.
ACKNOWLEDMENTS
We thank the Research Fund of The Scientific and Technological Research Council of
Turkey (TUBITAK Project Number: 113Z159) and Namik Kemal University (Project
Number: NKUBAP.00.10.AR.15.17) for the financial support given to the research
projects.
SUPPLEMENTAL MATERIAL
Detailed experimental procedures and spectral characterizasion data for this article can be
accessed on the publisher’s website.
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Table 1. Synthesis of mono-benzimidazoles (4-8) and bis-benzimidazoles (9-12).
Comp.
Substrates
Products
Yields
94
4
5
6
90
73
7
89
78
8
13

63
51
46
9
10
11
42
12
14

Scheme 1. Reagents and conditions: a) DMF, POCl3, reflux; b) o-Phenylenediamine
derivatives DMF, 100 °C, 8h; c) o-Phenylenediamine derivatives, DMSO, 120 °C, 24h.
15