POCl3-mediated synthesis of 2-substituted benzimidazolyl-coumarin, benzimidazolyl-indole, and styrylbenzimidazole derivatives

Article abstract of DOI:10.1080/00397911.2016.1160412

2-Substituted benzimidazolyl heterocycles and styrylbenzimidazoles have been synthesized by the reaction of substituted o-phenylenediamine with different heterocyclic carboxylic acids and cinnamic acid respectively in the presence of POCl₃as a

Full text of DOI:10.1080/00397911.2016.1160412

Synthetic Communications
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POCl3 Mediated Synthesis of 2-Substituted
Benzimidazolyl-Coumarin, Benzimidazolyl-Indole
and Styrylbenzimidazole Derivatives
Veerendra Kumar A. Kalalbandi & J. Seetharamappa
To cite this article: Veerendra Kumar A. Kalalbandi & J. Seetharamappa (2016): POCl3
Mediated Synthesis of 2-Substituted Benzimidazolyl-Coumarin, Benzimidazolyl-
Indole and Styrylbenzimidazole Derivatives, Synthetic Communications, DOI:
10.1080/00397911.2016.1160412
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Date: 14 March 2016, At: 01:05

POCl3 mediated synthesis of 2-substituted benzimidazolyl-coumarin,
benzimidazolyl-indole and styrylbenzimidazole derivatives
Veerendra Kumar A. Kalalbandi1, J. Seetharamappa1
1Department of Chemistry, Karnatak University, Dharwad, India
Corresponding author to J. Seetharamappa: E-mail: jseetharam@yahoo.com
Abstract
2-substituted benzimidazolyl heterocycles and styrylbenzimidazoles have been
synthesized by the reaction of substituted o-phenylenediamine with different heterocyclic
carboxylic acids and cinnamic acid respectively in the presence of POCl3 as a solvent and
catalyst. The proposed reaction has prominent features of affording high yields, short
reaction time as well as operational simplicity. In addition, the scope and limitations were
explored and a plausible reaction mechanism was proposed. The synthesized molecules
were characterized by IR, 1H NMR, 13C NMR and mass spectral data. Further, single
crystals of 2-(1H-indol-2-yl)-1H-benzo[d]imidazole have been developed and its
structural parameters were collected from X-ray diffraction data.
KEYWORDS: 1H-benzimidazoles; Benzimidazolyl heterocycles; crystal structure;
POCl3
1

INTRODUCTION
Benzimidazole nucleus may be termed as ‘Master Key’, since it is an important core in
several compounds acting at different targets to elicit varied pharmacological properties.
Fig. 1 reveals that a suitable substitution around the benzimidazole core nucleus has
resulted in many lead compounds of diverse range of therapeutic properties.
Benzimidazole derivatives are structural isosters of naturally occurring nucleotides,
which allow them to interact easily with biopolymers of the living system. In addition to
the biological significance of benzimidazoles, these moieties serve as important
intermediates in numerous organic reactions[1,2] and also employed as fluorescent
pigments and found their applications in optical/electro devices.[3] The broad usefulness
of these moieties has provoked significant efforts towards their synthesis.
Several methods have been reported for the synthesis of benzimidazoles. Conventionally,
benzimidazoles are commonly prepared from the reaction of o-phenylenediamines with
carboxylic acids, aldehydes, nitriles and orthoesters under strong dehydrating reaction
conditions and in the presence of strong acids[4] or under microwave irradiation.[5] Fig. 2
exemplifies various catalytic systems that were employed for the synthesis of 2-aryl
benzimidazoles.[6-20]
Particularly, Tsay et al.[21] have synthesized a library of coumarin-benzimidazole hybrid
compounds by the condensation of substituted
o-phenylendiamine and
3-(ethoxycarbonyl)coumarins in 85% o-phosphoric acid for 8 h at 165 ºC with 40-67%
2

yield. Bakhtiari et al.[22] have reported the synthesis of 3-(1H-Benzo[d]imidazol-2-yl)-2H-
chromen-2-one by the reaction of o-phenylenediamine with coumarin-3-
carboxylic acid in sulphuric acid for 8 h at reflux temperature with 55% yield. Similarly,
Arora et al.[23] also synthesized the
one by the reaction of
3-(1H-Benzo[d]imidazol-2-yl)-2H-chromen-2-
o-phenylenediamine and coumarin-3-carboxylic
1 h at 175 ºC with 75% yield. Further, Shingalapur
acid in polyphosphoric acid for
et al.[24] have reported the synthesis of series of 5-(nitro/bromo)-styryl-2-benzimidazoles
and studied their antitubercular and antimicrobial activities. The reported synthetic
method involved the condensation of 5-(nitro/bromo)-o-phenylenediamine with trans-
cinnamic acids in ethylene glycol for 6 h at around 200 ºC with 75-82% yield. However,
most of these methods suffer from one or more disadvantages such as low yields, long
reaction times, drastic reaction conditions, use of excessive oxidant, use of expensive
catalysts, tedious work-up procedures, and co-occurrence of several side reactions which
makes them undesirable under the sustainable and industrial applications. In view of
ample applications of benzimidazole as a significant bioactive molecule as well as
precursor for various organic transformations and for designing fluorescent materials,
there is still necessary for mild, simple, less expensive and feasible reaction protocol for
its synthesis.
RESULTS AND DISCUSSION
In the course of our efforts to develop a new route for the synthesis of
2-
substituted benzimidazoles, we here in report phosphoryl chloride mediated simple and
viable method for the synthesis of 2-substituted benzimidazolyl heterocycles and
styrylbenzimidazoles by utilizing the dehydrating ability of phosphoryl chloride.
3

Initially, the reaction of o-phenylenediamine with coumarin-3-carboxylic acid was
selected as a model reaction to find out a suitable reaction condition for the synthesis of
2-substituted benzimidazoles. The desired product, 3-(1H-benzo[d]imidazol-2-yl)-2H-
chromen-2-one was obtained by the excess use of POCl3 as a cyclizing agent and solvent
as well at 80 ºC.
To optimize the reaction conditions, the investigator has carried out the same reaction
using different solvents with different reaction time intervals. The optimized reaction
conditions are given in Table 1. Initially, the reaction was carried out in the presence of
catalytic amounts of POCl3 with different solvents. Solvent screening experiments
demonstrated that the role of solvent was crucial; poor yields of products were obtained
when organic solvents were used in the reaction. The yield of the desired product, 3-(1H-
benzo[d]imidazol-2-yl)-2H-chromen-2-one was improved significantly (up to 93% yield),
when the reaction was conducted in the presence of POCl3 only. Subsequent reaction
temperature screening revealed the decreased yield of the product when the temperature
was reduced and the reaction time was extended. After several trials, we found that a
temperature of 80 ºC was ideal. Highest yield of the compound was obtained in
h. However, prolonged reaction time resulted in decreased yields.
1
Under the optimized conditions, a variety of substituted
o-
phenylenediamine and coumarin-3-carboxylic acid, indole-2-carboxylic acid and
cinnamic acids were prepared (Scheme 1) to explore the scope and generality of the
process. In most of the cases, good yields of products were obtained. The yields were
4

better when cinnamic acid was used for the synthesis of styrylbenzimidazoles (7a-e).
This might be due to the decreased steric hindrance.
A mechanistic rationale for the formation of 3a is suggested in Scheme 2. Coumarin-3-
carboxylic acid 2 forms acid chloride II by an intramolecular substitution via the
intermediate of the dichlorophosphate ester I. Reaction of the acid chloride II with o-
phenylenediamine 1a leads to an intermediate o-amino amide III by a nucleophillic
attack at the trigonal carbon of the acid chloride. An intramolecular nucleophillic addition
followed by a proton transfer leads to a cyclic aminal IV. Under the reaction conditions
aminal IV undergoes dehydration to give benzimidazole V. Under the acidic reaction
conditions compound V undergoes protonation to yield protonated benzimidazole VI
which upon neutralization with 25% ammonia gives free 3-(1H-benzo[d]imidazol-2-yl)-
2H-chromen-2-one (3a).
1H NMR spectra of all compounds showed a broad peak at 9.8-12.91 ppm due to amine
proton of benzimdiazole. In compounds 3a-e, a sharp singlet was observed at 9.13 ppm
due to C4-H of coumarin moiety. Further, the absence of OH proton of coumarin-3-
carboxylic acid and the presence of only one amine proton at 12.55 ppm confirmed the
formation of benzimidazolyl coumarins. In compounds 5a-e, in addition to amine proton
of benzimidazole, a broad peak observed at 11.94 ppm was attributed to amine proton of
indole moiety. In compounds 7a-e, two doublets in the region at 7.3 ppm and 8.08 ppm
were noticed due to vinylic protons. The coupling constant of these vinylic protons was
found to be ~ 16 Hz which suggested that these two protons were trans to each other.
5

Aromatic protons were observed in the expected region. 13C NMR spectra of compounds
3a-e showed a peak at 160 ppm due to carbonyl carbon atom of coumarin moiety. In
compounds 3a-e, the peak noticed at 142 ppm was attributed to C2 of benzimidazole
whereas the same carbon atom was resonated around 146 ppm and around 149 ppm in
compounds 5a-e and 7a-e, respectively. Rest of the carbon atoms were resonated in the
expected region. The mass spectra of all the compounds have shown m/z values which
corresponded to their respective molecular masses.
Further, single crystals of 2-(1H-indol-2-yl)-1H-benzo[d]imidazole (5a) were grown
from its alcoholic solution. Crystal refinement data and unit cell parameters of compound
5a are presented in Table 2. Fig. 3 and Fig. 4 illustrate the ORTEP and packing diagrams
of this compound. The bond lengths and bond angles of the compound were observed to
be in the expected region. The molecules in the solid state were stabilized by hydrogen
bonding of N3-H3···N2 atoms. The hydrogen bonding network in compound 5a is
depicted in Fig. 5 and the corresponding hydrogen bonding parameters are given in
Table 3. From the data, it is evident that the indole plane was slightly deviated from the
mean plane of benzimidazole by an angle of 22.37º in compound 5a.
SUMMARY
In conclusion, a simple and practicable route for the synthesis of
2-
substituted benzimidazoles has been proposed that includes condensation of
o-
aryldiamines with aromatic acid in the presence of POCl3. This method has advantages
6

such as the use of an inexpensive and commercially available dehydrating agent (POCl3),
high yields of products, short reaction times, and a simple workup procedure.
EXPERIMENTAL
General Method For The Synthesis Of Benzimidazolyl Coumarin (3a-E),
Benzimidazolyl Indole (5a-E) And Styryl Benzimidazoles (7a-E)
A mixture of o-phenylenediamine (1mmol) and heterocyclic (coumarin and indole) or
cinnamic acids (1mmol) was heated to 80 ºC in POCl3 (5 mmol) for about one hour. The
completion of the reaction was monitored by TLC. After the completion of reaction, the
reaction mixture was poured on to crushed ice and the pH of the solution was adjusted to
neutral pH using 20% NH3 solution. The separated solid was thoroughly washed with
water. Then, the solid was filtered and dried to obtain a pure product.
3-(1H-benzo[d]imidazol-2-yl)-2H-chromen-2-one (3a): Yield: 93%; m.p: 230-232 ºC; IR
(KBr, cm-1): 3340 (NH), 1707 (C=O); 1H NMR (DMSO-d6, 400 MHz, δ): 7.08 (t, 2H, J =
6.4 and 8.0 Hz, C5,C6-H of benzimidazole), 7.21 (d, 1H, J = 8.4 Hz, , C8-H of
coumarin), 7.42 (t, 1H, J = 7.6 Hz, C6-H of coumarin), 7.49-7.70 (m, 3H, Ar-H) 7.98 (d,
1H, J = 7.6 Hz, C5-H of coumarin), 9.13 (s, 1H, C4-H of coumarin moiety), 12.55 (s,
1H, NH); 13C NMR (DMSO-d6, 100 MHz, δ): 112.80, 116.12, 116.63, 118.49, 119.02,
122.16, 122.42, 125.05, 129.57, 132.92, 134.81, 141.75, 142.86, 145.74, 153.23, 159.25;
MS (m/z): 262 (M+); Elemental analysis: calcd. for C16H10N2O2 (262.26): C, 73.27%; H,
3.84%; N, 10.68%; Found: C, 73.31%; H, 3.85%; N, 10.62%.
7

2-(1H-indol-2-yl)-1H-benzo[d]imidazole (5a): Yield: 93%; m.p: 160-162 ºC; IR (KBr,
cm-1): 3428 (NH); 1H NMR (DMSO-d6, 400 MHz, δ): 7.05 (t, 1H, J = 8 and 7.2 Hz, C5-
H of benzimidazole), 7.13-7.40 (m, 3H, Ar-H), 7.45 (d, 1H, J = 8Hz, C4-H of
benzimidazole), 7.63 (d, 1H, J = 8Hz, C8-H of benzimidazole), 11.93 (s, 1H, NH of
indole), 12.91 (s, 1H, NH of benzimidazole); 13C NMR (DMSO-d6, 100 MHz, δ): 102.10,
111.68, 112.48, 118.99, 120.23, 121.33, 122.21, 123.11, 123.32, 128.37, 129.17, 135.26,
137.74, 144.17, 146.67; MS (m/z): 233 (M+); Elemental analysis: calcd. for C15H11N3
(233.27): C, 77.23%; H, 4.75%; N, 18.01%; Found: C, 77.19%; H, 4.73%; N, 17.96%.
(E)-2-styryl-1H-benzo[d]imidazole (7a): Yield: 91%; m.p: 114-116 ºC; IR (KBr, cm-1):
1
3423 (NH); H NMR (DMSO-d6, 400 MHz, δ): 7.32 (d, 1H,J = 16.8 Hz, H2 of vinylic
proton), 7.37-7.70 (m, 9H, Ar-H), 8.08 (d, 1H, J = 16.8 Hz, H1 of vinylic proton), 9.81
(s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz, δ): 112.54, 114.13, 120.19, 124.63,
127.75, 129.23, 130.30, 134.06, 134.65, 139.99, 149.08; MS (m/z): 219 (M-H)+;
Elemental analysis: calcd. for C15H12N2 (220.27): C, 81.79%; H, 5.49%; N, 12.72%;
Found: C, 81.83%;
H, 5.53%; N, 12.69%.
Characterizations of the all the remaining synthesized compounds are given in the
supplementary file.
ACKNOWLEDGEMENTS
The authors acknowledge the University Scientific Instrumentation Centre (USIC),
Karnatak University, Dharwad for SC-XRD and analytical data. We wish to thank the
8

University Grants Commission (UGC), New Delhi, [F. No. 14-3/2012 (NS/PE) dated 14-
03-2012] for providing financial support under “Antitumor activity: an integrated
approach” a focused area of UPE program.
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10

Table 1. Optimized reaction conditions for the synthesis of 2-substituted benzimidazoles.
Compound POCl3 in
equivalents
Solvent
Time
Yield (%)
0.2
0.5
1
Ethanol
Ethanol
Ethanol
Ethanol
1,4-Dioxane
DMSO
---
6 h (Reflux)
6 h (Reflux)
6 h (Reflux)
6 h (Reflux)
6 h (Reflux)
6 h (Reflux)
6 h (Reflux)
2 h (80 ºC)
1 h (80 ºC)
10
15
18
24
21
18
78
82
93
3a
3a
3a
3a
3a
3a
3a
3a
3a
5
5
5
5
5
---
5
---
11

Table 2. The crystallographic data and refinement parameters of compound 5a.
Parameter
5a
Empirical formula
Crystal system
Space group
C15H11N3
Monoclinc
P 1 21/c 1
a = 14.1835(10) (Å)
b = 9.1141(6) (Å)
c = 9.5262(6) (Å)
α = 90°
Unit cell dimensions
β = 108.015(5)°
γ = 90°
Limiting indices
-19<=h<=18, -9<=k<=12,
-12<=l<=13
Volume
1171.08(13) (Å3)
Z, Calculated density
Reflections collected
No. of independent reflections
4, 1.329 mg/m3
11287
3112 [R(int) = 0.0239]
Data/Restraints/Paramaeters
Final R indices [I > 2σ(I)]
R indices (all data)
3112 / 0 / 164
R1 = 0.0518, wR2 = 0.1307
R1 = 0.1072, wR2 = 0.1630
1425672
CCDC number
12

Table 3. Hydrogen bonding parameters in compound 5a.
D–H···A
d(D–H)
d(H···A)
D(D···A)
2.897
DHA
N3–H3···N2
0.860
2.076
159.60
13

Scheme 1. Synthesis of 2-substituted benzimidazoles
14

Scheme 2. Plausible mechanism for the formation of 3a
15

Figure 1. A multifunctional nucleus, benzimidazole
16

Figure 2. Various catalytic systems used for the synthesis of 2-aryl benzimidazoles
17

Figure 3. ORTEP diagram of compound 5a.
18

Figure 4. Packing diagram of compound 5a.
19

Figure 5. Hydrogen bonding network in compound 5a.
20