An Efficient Synthesis of 2-Substituted Benzimidazoles via Photocatalytic Condensation of o-Phenylenediamines and Aldehydes

Article abstract of DOI:10.1021/acscombsci.6b00107

A photocatalytic method has been developed for the efficient synthesis of functionalized benzimidazoles. This protocol involves photocatalytic condensation of o-phenylenediamines with various aldehydes using the Rose Bengal as photocatalyst. The method was found to be general and was successfully employed for accessing pharmaceutically important benzimidazoles by the condensation of aromatic, heteroaromatic and aliphatic aldehydes with o-phenylenediamines, in good-to-excellent yields. Notably, the method was found to be effective for the condensation of less reactive heterocyclic aldehydes with o-phenylenediamines.

Full text of DOI:10.1021/acscombsci.6b00107

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Article
An Efficient Synthesis of 2-Substituted Benzimidazoles via
Photocatalytic Condensation of o-Phenylenediamine and Aldehydes
Jeshma Kovvuri, Burri Nagaraju, Ahmed Kamal, and Ajay Kumar Srivastava
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00107 • Publication Date (Web): 15 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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An Efficient Synthesis of 2-Substituted
Benzimidazoles via Photocatalytic Condensation of
o-phenylenediamine and Aldehydes
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Jeshma Kovvuri†,‡, Burri Nagaraju†,‡, Ahmed Kamal*†,‡§ and Ajay K. Srivastava*†,‡
†Academy of Scientific and Innovative Research (AcSIR), New Delhi-110025, India
‡Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India
§Catalytic Chemistry Chair, Chemistry Department College of Science, King Saud University,
Riyadh, Saudi Arabia
KEYWORDS: Benzimidazole, Photocatalytic condensation, Rose Bengal, o-phenylenediamine
ABSTRACT
A photocatalytic method has been developed for the efficient synthesis of functionalized
benzimidazoles. This protocol involves photocatalytic condensation of o-phenylenediamines
with various aldehydes using the Rose Bengal as photocatalyst. The method was found to be
general and was successfully employed for accessing pharmaceutically important
benzimidazoles by the condensation of aromatic, heteroaromatic and aliphatic aldehydes with o-
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phenylenediamines, in good-to-excellent yields. Notably, the method was found to be effective
for the condensation of less reactive heterocyclic aldehydes with o-phenylenediamines.
INTRODUCTION
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The benzofused nitrogen containing heterocyclic compounds have a great importance in drug
discovery, among them benzimidazole scaffold is of particular interest and has been categorized
as a privileged scaffold.1 The benzimidazole moiety is structurally correlated to the purine bases
and is profusely found in a variety of natural products including vitamin B12.2 Several
benzimidazole derivatives exhibit diversified pharmaceutical properties such as antimicrobial,3
anticancer,4 antiviral,5 antihelmintic,6 antioxidant,7 antiulcer,8 antihypertensive9 and
antitubercular.10 For example, benzimidazoloquinolinone conjugate ‘Dovitinib(I)’, a potent
EGFR-3 inhibitor, is currently in phase-III clinical trials for the treatment of metastatic renal cell
cancer,11 the thiazolobenzimidazole derivative ‘Tiabendazole (II)’ acts as an anthelmintic drug12
and Pimobendan (III) has been used as a vasodilator for the management of heart failure in
dogs13(Figure 1). Additionally, the bisbenzimidazole containing Hoechst stain (IV) is widely
used to stain DNA in fluorescence microscopy, immunohistochemistry and flow cytometry
(Figure 1).14
H
3C
N
N
N
O
N
N
NH
N
H
S
N
II
Thiabendazole;
Anthelmintic drug
H
H2N
I
Dovitinib;
F
EGFR-3 inhibitor
H
N
N
N
OMe
HO
NH
H
N
N
N
H
N
N
H
O
N
III
Pimobendan:
Calcium sensitizer drug
IV
Hoechst 33258;
DNA stain
Figure1. Representative examples of benzimidazole containing important molecules
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Owing to the vast importance of benzimidazoles in drug discovery, enormous efforts have
been made to develop operationally simple synthetic methods for the construction of
benzimidazole derivatives.15 Usually, the condensation of o-phenylenediamines with aldehydes
in the presence of acid,16 base17 or metal catalyst18 produces benzimidazoles. The other methods
include condensation of o-phenylenediamines with carboxylic acids, nitriles and ortho-esters
under dehydrating conditions.19 The dehydration of N-acylated o-phenylenediamines by using
acetic acid,19c-e p-TSA19f or Amberlyst-1519g also produces benzimidazoles. Recently, a flow
chemistry protocol has been developed to synthesize benzimidazoles by the condensation of o-
phenylenediamines with aldehydes.20 Though the reported methods are efficient and widely used,
they possess several limitations such as the condensation of o-phenylenediamine and aldehyde in
the presence of acid or base requires longer reaction times and produces N1-benzylated
benzimidazole as an undesirable side product that is often very difficult to separate (Scheme 1,
eq 1).21 The metal catalyzed condensations require high temperature and the residual
contamination of metal with the product might cause toxicity at the later stage of pharmaceutical
applications (Scheme 1, eq 2).22 Therefore, a mild, efficient and environment friendly method for
the synthesis of benzimidazoles is of high importance. Considering the benefits of recently
developed photocatalytic condensations under visible light,23 we envisioned to explore the
photocatalytic condensation of o-phenylenediamines with heteroaromatic aldehydes to
synthesize pharmaceutically important benzimidazoles.24 Herein, we report a photocatalytic
method for the synthesis of benzimidazoles by the condensation of o-phenylenediamines with
aldehydes (Scheme 1, eq 3).
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work
Previous
NH2
5
6
7
8
N
N
N
O
or
Strong acid Base
R2
R1
R1
R1
+
+
+
R2
1)
2)
(eq
(eq
H
R2
Polar solvents
N
H
NH2
R2
9
NH2
NH2
N
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catalyst
Metal
O
R2
R1
R1
temperature
High
H
R2
N
H
work
This
R2
R2
NH
-
-
-
N
Photocatalytic
conversion rate
O
3)
(eq
R1
R1
R3
+
High
Chemoselective
mol%)
Bengal (2
H
R3
Rose
N
NH2
Acetonitrile,rt, 2h
R2
=
Me
R2
Me
=
H,
H,
Scheme 1. Condensation of o-phenylenediamines and aldehydes for the synthesis of
benzimidazoles
RESULTS AND DISCUSSION
Initially, we intended to utilize the reported method by Cho et al25 for the photocatalytic
condensation of o-phenylenediamine and pyrazolocarboxaldehyde to obtain the
pyrazolobenzimidazole analogues as they exhibit excellent anticancer properties.24 Our initial
results showed that the method was not suitable for the heterocyclic aldehydes such as
pyrazolocarboxaldehyde 2{1} as the desired 2-pyrazolobenzimidazole 3{1,1} was obtained in
very poor yield in absence of photocatalyst (entry 1, Table 1). Change of solvent from methanol
to water or acetonitrile did not improve the yield (entries 2-3, Table 1). Therefore, in order to
facilitate the condensation, we decided to screen the organic photocatalysts such as Methylene
Blue, Eosin Y, Rhodamine B and Rose Bengal (RB) under various reaction conditions (entries 4-
7, Table 1) along with the ruthenium-based photocatalyst Ru(bpy)3(PF6)2 (Entry 8, Table 1).
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To our delight, addition of the photocatalyst significantly improved the yield of desired
pyrazolobenzimidazole 3{1,1}. Among the four organic photocatalysts screened, Rose Bengal
(RB) gave the best yield when the reaction was performed in acetonitrile with 2 mol% of catalyst
loading (entries 6 and 9-12, 14-16, Table 1). Efforts were also made to perform the condensation
in environment friendly solvents such as water and ethanol (Entries 9, 12-13, Table 1). However,
moderate yields were obtained in these solvents. Poor yields were observed in the absence of
light and under the anaerobic conditions (entries 17-20, Table 1).
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Table 1.Optimization of the Reaction Conditions:
H
3C
NH
OHC
H
NH2
NH2
3C
N
N
N
N
1
Conditions, Table
N
F
1 1
{ }
2 1
{ }
3
1,1
F
{
}
Entry
1.
Solvent
Methanol
Water
T (°C)/ t(h)
rt/12
rt/12
rt/12
rt/2
Visible light
Photocatalyst
Yielda(%)
+
+
+
+
+
+
+
+
+
+
--
--
--
12
10
15
63
55
90
81
80
50
46
2.
3.
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Water
4.
Methylene Blueb
Eosin Yb
5.
rt/2
Rose Bengalb
Rhodamine Bb
6.
rt/2
7.
rt/2
b
8.
rt/2
Ru(bpy)3(PF6)2
9.
rt/2
Rose Bengalb
Rose Bengalb
10.
DCM
rt/2
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Rose Bengalb
Rose Bengalb
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Methanol
rt/2
rt/2
rt/2
rt/2
rt/2
rt/2
+
+
+
+
+
+
55
60
65
72
81
89
18
5
Ethanol
Ethanol
Rhodamine Bb
Rose Bengalc
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Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Methanol
Rose Bengald
Rose Bengale
Rose Bengalb
Rose Bengalb
Rose Bengal f
Rose Bengal f
45°C /6
rt/12
Dark
Dark
+
rt/12
10
5
rt/12
+
aIsolated yields,bReactions were tried with 2 mol% of the catalyst, c0.5%of RB, d1 mol %of RB,
e3 mol % of RB, fInert atmosphere (under argon)
One of the most significant advantages with Rose Bengal is it’s reusability without losing its
catalytic potential.26 Therefore, in order to check the recovery and reusability of the Rose Bengal
in this condensation process, we recovered the catalyst during column purification of the product
3{1,1} and reused it for the same condensation (Table 2). The recovered catalyst could be reused
up to three cycles with almost similar catalytic activity as shown in table 2. The slight decrease
in the yields might be associated with the uncharacterized impurities in the recovered catalyst.
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Table 2.Yields of the product with 3 cycles of the catalyst
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Entry Reaction cycle Yield (%)
9
1
2
3
Fresh run
1st cycle
2nd cycle
90
88
84
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3rd cycle
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With the optimized conditions in hand, we evaluated the reactions of substituted o-
phenylenediamines with
pyrazolocarboxaldehyde
a
variety of heterocyclic aldehydes such as substituted
(2{1}-2{3}), β-carbolinecarboxaldehyde (2{4}), indole-3-
carboxaldehydes (2{5}, 2{6}), imidazothiazole-4-carboxaldehydes (2{7}, 2{8}), propanal
(2{9}), 3-phenylpropanaldehyde (2{10}), quinolinecarboxaldehydes (2{11}, 2{12}),
chromonecarboxaldehyde (2{13}), furfural (2{14}), imidazole carboxaldehyde (2{15}) and
substituted benzaldehydes (2{16}-2{21}). Among these aldehydes aromatic and heteroaromatic
aldehydes gave better yields than aliphatic aldehydes (Figure 2 and 3). Interestingly, the
procedure was highly functional group tolerant and worked well with electron rich and electron
deficient substrates (Figure 3). Further, to check the compatibility of this protocol with N-alkyl
o-phenylenediamines, the condensation between N-Methyl-o-phenylenediamine and propanal
was studied with the optimized reaction conditions that yielded the desired product 3{8, 9} in 69
% yield (Figure 2 and 3). All the synthesized benzimidazoles were characterized by H &13C
1
NMR, and HRMS spectral analysis.
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Me
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Cl
1
3
{ }
1
1
1
4
{ }
1
{ }
2
{ }
8
9
H
N
NH2
F
NH2
NH2
MeO
Me
Me
NH2
NH2
10
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Me
NH2 Cl
NH2
1
1
1
8
5
6
1 7
{ }
{ }
{ }
{ }
1
Chemset
F
MeO
MeO
OMe MeO
O
N
O
H
H
O
O
H
O
H
H
N
N
H
N
N
N
H
N
N
N
Ph
1
Ph
Ph
2
5
{ }
2
2
4
{ }
2
2
3
{ }
2
{ }
{ }
OMe
O
O
O
O
H
H
H
O
MeO
N
H
N
S
Ph
H
H
N
N
N
S
H
2
10
}
2
{
9
{ }
2 7
{ }
2
2
8
{ }
6
{ }
H
O
H
O
O
O
O
O
O
HN
I
MeO
H
N
H
O
N
}
N
Cl
2
15
{
}
2
14
2
11
2
12
2
13
{
}
{
{
}
{
}
O
O
O
O
O
H
O
H
H
H
H
H
HO
HO
NC
MeO
F
OH
OH
3C
}
2
21
}
2
2
2
2
17
18
19
20
{
{
}
{
}
{
}
{
2
16
{
}
2
Chemset
Figure 2: Chemsets; o-phenylenediamines Chemset 1; Aldehydes Chemset 2.
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CH3
F
CH3
CH3
H
3CO
OCH3
H
3CO
OCH3
H
3CO
F
H
3CO
N
N
N
H
3CO
NH
N
N
N
NH
H
3CO
NH
NH
NH
NH
N
N
N
N
N
N
N
N
N
N
Ph
N
N
Ph
Ph
Ph
};
Ph
90%
Ph
3
3
3
3
{
3
3
81%
2,3
};
85%
82%
78%
86%
1,3
2,1
2,2
{1,1}
{1,2}
{
};
{
};
{
10
11
12
13
14
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16
17
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OCH3
Cl
Cl
Cl
Cl
OCH3
H
3CO
H
3CO
F
H
N
N
3CO
N
N
N
N
H
3CO
NH
NH
NH
NH
NH
NH
N
N
N
N
N
N
H
N
N
N
H
N
Ph
Ph
Ph
H
3
91%
3,6
};
3
{
3
{
77%
3
3
5,4
{
89%
83%
86%
};
3,1
};
3,2
};
3,3
};
3
{
79%
};
{
2,5
{
OCH3
CH3
Cl
H
3C
H
3CO
N
N
NH
N
N
N
N
NH
H
3CO
NH
NH
NH
NH
N
N
N
N
N
N
H
S
N
S
S
S
N
N
N
H
3
3
{
3
3
{
3
{
3
4,8
{ };
88%
NH
84%
83%
F
82%
77%
80%
1,6
4,6
1,7
};
2,7
3,7
{
};
};
{
};
};
H
3C
Cl
CH3
N
N
NH
N
O
N
N
N
NH
N
NH
N
H
3CO
NH
H
S
N
N
O
S
N
Cl
N
N
N
3
80%
2,13
};
3
90%
3
{
{
84%
2,12
3
{
2,8
87%
{
};
};
3
{
93%
1,11
};
1,8
};
3
{
90%
6,11
};
F
Cl
N
Cl
N
I
HN
HN
N
N
N
H
Cl
N
N
N
N
H
N
N
N
O
H
H
N
H
N
H
3
3
3
3
3
3
6,15
{
75%
N
78%
89%
CH3
82%
91%
};
88%
2,9
3,9
2,10
3,14
2,15
{
};
{
};
{
};
{
};
{
};
Cl
CH3
CH3
N
N
N
N
N
NH
N
NH
N
H
NH
NH
NH
HO
HO
N
H
3CO
OH
84%
NC
F
3C
OH
78%
3
3
3
3
3
3
3
8,9
{
2,16 92%
85%
93%
89%
2,21
};
69%
};
{
3,17
7,18
2,19
1,20
};
{
};
{
};
{
};
{
};
{
Figure 3.Synthesized benzimidazoles
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A plausible mechanism for the condensation of o-phenylenediamine with aldehyde to afford 2-
5
6
substituted benzimidazole, using Rose Bengal as a photocatalyst in the presence of visible light,
7
8
9
has been outlined in the Figure 4.
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NH2
H
2O
H
N
NH2
NH2
N
1
R
N
H
5
R
_
O
RB*
4
RB
R
H
_
2
O2
RB
O2
HO2
H
H
N
N
H
R
R
N
N
H
O2
H
2O2
3
6
Figure4. Plausible mechanism
Imine, (4) is formed from the condensation between 1 and 2. RB,* the excited state of RB,
generated under visible light irradiation, is able to abstract an electron from imine via a single
electron transfer (SET) process.27 The photo-redox cycle is completed by the oxidation of the RB
radical anion back to the ground state RB by dioxygen. The imine radical cation (5) donates one
hydrogen atom to the dioxygen radical anion and results in the formation of 6 and hydrogen
abstraction by hydroperoxyl radical (HOO.) results in the formation of desired product.
CONCLUSION
In summary, we have developed a robust, operationally simple and extremely general method for
the synthesis of functionalized benzimidazoles by the photocatalytic condensation of o-
phenylenediamines and aldehydes in metal-free conditions. The method does not require any
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harsh reaction condition and can be used with the sensitive substrates. The procedure was found
to be suitable for the condensations of relatively unreactive electron rich aldehydes such as
substituted pyrazolo-, β-carboline-, imidazothiazolo-, quinoline-, chromone and indole-
carboxaldehydes with o-phenylenediamines to obtain pharmaceutically important
benzimidazoles.
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EXPERIMENTAL SECTION
General Information
All chemicals, reagents and photocatalysts were purchased from the commercial sources and
were used without further purification. Reactions were monitored by TLC on silica gel glass
1
plate containing 60 GF-254, and visualization was done by UV light and iodine vapor. H and
13C NMR spectra were recorded on Bruker UXNMR/XWIN-NMR (300 MHz) or InovaVarian-
VXR-unity (400, 500 MHz) instruments. Chemical shifts were expressed in parts per million (δ
in ppm) downfield from TMS expressed as internal standard and coupling constants are
1
expressed in Hz. H NMR spectral data were reported in the following order: multiplicity (s,
singlet; brs, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet), coupling
constants in Hz, and number of protons. ESI mass spectra were recorded on a Micromass Quattro
LC using ESI+ software with capillary voltage 3.98 kV and an ESI mode positive ion trap
detector. High resolution mass spectra were recorded on a QSTAR XL Hybrid MS-MS mass
spectrometer. Melting points were determined with an electro thermal digitalmelting point
apparatus IA9100 and are uncorrected. All the reactions were performed one by one in
borosilicate glass vials using following general procedure and setup.
General Procedure for the synthesis of 2-substituted benzimidazoles: In a 30 ml clear glass
vial charged with magnetic bead, aldehyde (1.0 mmol), o-phenylenediamine (1.0 mmol),
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acetonitrile (10mL) and 2 mol % of Rose Bengal were taken. The reaction mixture was placed
beside the 11 Watt LED bulb (the reaction also worked well with 5 or 7 Watt LED bulbs) in
photochemical reactor box, open air and stirred until the complete consumption of starting
materials observed on TLC analysis. After completion of the reaction, solvent was evaporated
under vacuum and the residue was purified by the column chromatography by using
hexane/ethylacetate as eluent to afford the final product. After isolation of the product, Rose
Bengal was eluted by using chloroform/methanol that can be reused after evaporation of solvent
under vacuum.
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5-methyl-2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole[3{1,1}]
Light brown solid; yield 90% (124.5 mg); mp 187-189 ˚C; 1H NMR (300 MHz, CDCl3+DMSO-
d6) δ 8.65 (s, 1H), 7.86 (dd, J = 8.3, 5.6 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 7.53 – 7.41 (m, 3H),
7.34 (t, J = 7.1 Hz, 2H), 7.05 (dd, J = 11.6, 5.4 Hz, 3H), 2.47 (s, 3H); 13C NMR (75 MHz,
CDCl3+DMSO-d6) δ 161.50 (d, J = 246.9 Hz), 148.66, 144.13, 138.08, 137.18, 136.05, 130.70,
129.18, 129.08, 128.36, 127.53, 125.77, 122.58, 117.56, 114.01, 113.72, 113.07, 111.33, 20.44;
HRMS (ESI) : calcd for C23H18N4F [M+H]+ 369.1505, found 369.1510.
ASSOCIATED CONTENT
Supporting Information
1
Characterization data, Copies of H &13C NMR, and HRMS Spectra of all the synthesized
compounds.“This material is available free of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
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*Email: aksrivastava@iict.res.in; Contact No: +91-40-2719-1646
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Author Contributions
8
9
The manuscript was written through contributions of all the authors. All authors have given
approval to the final version of the manuscript.
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Funding Sources
This work was supported by DST-INSPIRE, New Delhi and Council of Scientific & Industrial
Research (CSIR), New Delhi under the XIIth Five Year Plan Project ‘Affordable Cancer
Therapeutics (ACT)’ [Grant No. CSC0301]
Notes
Any additional relevant notes should be placed here.
ACKNOWLEDGMENTS
The authors JK and BN thankful to Department of Science & Technology, New Delhi for
providing fellowships under DST-INSPIRE programme.
ABBREVIATIONS
RTK, receptor tyrosine kinase; LED, light emitting diode; RB, rose Bengal; SET, single electron
transfer; DCM, dichloromethane; TLC, thin layer chromatography.
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Table of Contents Graphic:
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R2
N
R2
M
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11
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-
-
-
Photocatalytic
NH
O
Visible
Light
R1
R3
to 94%
Up
37
yields
R1
+
Rose Bengal
Acetonitrile
examples
H
R3
N
NH2
O
rt
2-3
h,
=
A
Without catalyst
H
N
R3
S
R1
=
B
With catalyst
N
N
N
N
N
R1
=
C
After
completion
reaction
of the
N
N
N
H
O
N
H
R4
Ar
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