Synthesis of benzimidazole and quinoxaline derivatives using reusable sulfonated rice husk ash (RHA-SO3H) as a green and efficient solid acid catalyst

Article abstract of DOI:10.1007/s11164-015-2075-5

In this work, a simple, rapid and efficient method for the preparation of benzimidazoles and quinoxalines from the condensation of o-phenylene diamines with aldehydes and/or 1,2-dicarbonyl compounds in the presence of sulfonated rice husk ash (RHA-SO₃H) as an efficient green catalyst is reported. RHA-SO₃H can be easily prepared using a readily available organic compound by simple modification of rice husk ash. All reactions are performed under mild reaction conditions with high to excellent yields. The method is applicable to aromatic, unsaturated and hetero aromatic aldehydes. The advantages of this method are short reaction times, milder conditions, easy work-up, solvent-free conditions and catalyst reusability.

Full text of DOI:10.1007/s11164-015-2075-5

Res Chem Intermed
DOI 10.1007/s11164-015-2075-5
Synthesis of benzimidazole and quinoxaline derivatives
using reusable sulfonated rice husk ash (RHA-SO3H)
as a green and efficient solid acid catalyst
Mahnaz Shamsi-Sani1 Farhad Shirini1
•
•
Masoumeh Abedini1 Mohadeseh Seddighi1
•
Received: 18 December 2014 / Accepted: 20 April 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract In this work, a simple, rapid and efficient method for the preparation of
benzimidazoles and quinoxalines from the condensation of o-phenylene diamines
with aldehydes and/or 1,2-dicarbonyl compounds in the presence of sulfonated rice
husk ash (RHA-SO3H) as an efficient green catalyst is reported. RHA-SO3H can be
easily prepared using a readily available organic compound by simple modification
of rice husk ash. All reactions are performed under mild reaction conditions with
high to excellent yields. The method is applicable to aromatic, unsaturated and
hetero aromatic aldehydes. The advantages of this method are short reaction times,
milder conditions, easy work-up, solvent-free conditions and catalyst reusability.
Keywords Sulfonated rice husk ash Á Benzimidazoles Á Quinoxalinesis Á
Reusable catalyst Á Solvent-free conditions
Introduction
Benzimidazole derivatives are one of the most important classes of heterocyclic
compounds that occur widely in natural products. Benzimidazoles are also a class of
interesting pharmacophores with various useful pharmacological properties, such as
anti-inflammatory, antiviral, antimicrobial and anticancer activities [1–4]. Recent
results indicate that the benzimidazole structure can bind in the DNA minor groove
[5] and can act as ligands to transition metals [6]. Numerous synthetic strategies for
the synthesis of benzimidazoles have been reported by employing aromatic and
&
&
1
Farhad Shirini
shirini@guilan.ac.ir
Masoumeh Abedini
mabedini@guilan.ac.ir
Department of Chemistry, College of Science, University of Guilan, Post Box 1914,
41335 Rasht, Islamic Republic of Iran
123

M. Shamsi-Sani et al.
heteroaromatic 2-nitroamines [7], aldehydes [8], carboxylic acids [9], carbonitriles,
[10], arylamino oximes [11], cyclization of o-bromoaryl derivatives [12] and
orthoesters [13]. In spite of the applicability of these methods, one-pot condensation
of o-phenylenediamines with aryl aldehydes is more efficient and simple [14].
Organic compounds containing the quinoxaline moiety have also received
considerable synthetic attention. These compounds are widely distributed in nature
and exhibit a broad spectrum of biological activity, including antibacterial [15],
antitubercular, antimicrobial, antifungal, antimalarial, anti-inflammatory, antileish-
manial, and antitumor activities, as well as functioning as herbicides and insecticides
[16]. So, they have been synthesized by many research groups using numerous
methods involving the condensation of 1,2-diamines with a-diketones [17],
diazenylbutenes [18] and epoxides [19]. Recent research groups have presented
reports concerning the synthesis of different quinoxaline derivatives involving several
environmentally friendly (‘‘green’’) methodologies, including recyclable catalysts,
microwave-assisted synthesis and reactions in aqueous media [20].
Recently, some of the other methods for the synthesis of quinoxaline derivatives
have been reported [21–25].
Although these procedures provide improvements, many of the applied catalysts
or activators suffer from disadvantages, such as the use of organic solvents or toxic
reagents, harsh reaction conditions, long reaction times, the need for excess amounts
of reagent, and non-recoverability of the catalyst. Therefore, simple, efficient and
mild procedures with easily separable and reusable solid catalysts to overcome these
problems are still in demand.
In recent years, the use of green reagents in organic reactions has attracted the
attention of many organic chemists. This attention can be attributed to the reduction
of environmental pollution and the low cost of the applied methods. Rice husk ash is
one of these types of reagents recently used as a solid acid catalyst in some of the
important organic reactions [26–29].
Herein, and in continuation of these studies, we wish to report the applicability of
sulfonated rice husk ash (RHA-SO3H) as a newly reported derivative of rice husk
ash [30, 31] in promoting synthesis of benzimidazole and quinoxaline derivatives.
All reactions are performed under mild conditions with relatively short reaction
times in good to high yields.
Experimental
Chemicals were purchased from Fluka, Merck and Aldrich chemical companies. All
yields refer to the isolated products. Products were characterized by their physical
constants and via comparison with authentic samples. Determining the purity of the
substrate and monitoring the reaction were accompanied by thin layer chromatog-
raphy (TLC) on silica-gel polygram SILG-UV 254 plates.
123

Synthesis of benzimidazole and quinoxaline derivatives…
General procedure for the synthesis of benzimidazoles derivatives
1,2-Phenylenediamine (1 mmol) was added to a mixture of RHA-SO3H (30 mg)
and aldehyde (1 mmol) and the resulting mixture was stirred at 80 °C for the
appropriate time in an oil bath. After completion of the reaction, as monitored by
TLC (EtOAc: n-hexane 3:7), ethyl acetate (20 mL) was added and the catalyst was
separated by filtration. The solvent was then removed under reduced pressure and
the resulting solid product was recrystallized from ethanol, producing the pure
product in good to high yields.
General procedure for the synthesis of quinoxaline derivatives
To a mixture of 1,2-diaminobenzene (1 mmol) and 1,2-dicarbonyl compound
(1 mmol), RHA-SO3H (15 mg) was added and the mixture was stirred at room
temperature for the appropriate time. The progress of the reaction was monitored by
TLC (EtOAc: n-hexane 2:8). After completion of the reaction, ethyl acetate (20 mL)
was added to the mixture and the solid catalyst was separated. Then the solvent was
evaporated and the resulting solid product was recrystallized from ethanol,
producing the pure product in high yields.
Selected spectral data
2-(3-Bromophenyl)-1H-benzo[d]imidazole: 1H NMR (400 MHz-DMSO-d6): d
(ppm): 7/35–7/39 (m, 2H), 7/61 (t, J = 8 Hz, 1H), 7–7/74 (m, 2H, 7/80 (dt,
J = 8 Hz, 1H), 7/20 (dt, J = 8 Hz, J = 16 Hz, 1H), 8/41 (t, J = 16 Hz, 1H).
NH2
NH2
N
N
RHA-SO3H (30 mg)
Solvent-free, 80 oC
Ar
R
R
+ ArCHO
Scheme 1 RHA-SO3H catalyzed the synthesis of benzimidazole derivatives
Table 1 Optimization of the reaction conditions catalyzed by RHA-SO3H
Entry
Catalyst (mg)
Condition
Temperature (°C)
Time (min)
Conversion (%)a
1
2
0
10
15
20
25
30
30
30
30
30
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
EtOH
80
30
30
30
30
30
10
60
60
60
60
0
10
80
3
80
10
4
80
50
5
80
70
6
80
100
30
7
25
8
Reflux
Reflux
Reflux
100
30
9
H2O
10
CH3CN
50
a
GC
123

M. Shamsi-Sani et al.
Table 2 Synthesis of benzimidazole derivatives catalyzed by RHA-SO3H
Entry Diamine
Aldehyde
C6H5CHO
Time (min) Yield (%)a Mp (°C) (references)
NH2
NH2
1
10
98
288–290 [32]
2
4-ClC6H4CHO
2-ClC6H4CHO
3-ClC6H4CHO
3-BrC6H4CHO
4-FC6H4CHO
10
20
15
25
15
20
30
15
25
15
25
25
15
15
15
20
98
98
93
90
98
85
90
85
90
98
85
90
98
88
98
98
294–296 [33]
225–226 [34]
234–235 [35]
249–252 [22]
249–251 [36]
306–308 [34]
184–186 [34]
223–225 [37]
207–209 [36]
285–287 [34]
180–182 [34]
285–287 [22]
198–199 [32]
283–285 [33]
218–220 [38]
202–204 [34]
3
4
5
6
7
4-NO2C6H4CHO
3-NO2C6H4CHO
4-MeOC6H4CHO
3-MeOC6H4CHO
4-Me2NC6H4CHO
2-HOC6H4CHO
4-HOC6H4CHO
PhCH=CHCHO
Furfural
8
9
10
11
12
13
14
15
16
17
2-Naphthaldehyde
C6H5CHO
O2N
NH2
NH2
18
10
20
21
22
23
24
4-ClC6H4CHO
4-NO2C6H4CHO
3-NO2C6H4CHO
4-MeOC6H4CHO
3-MeOC6H4CHO
2-HOC6H4CHO
C6H5CHO
20
35
45
40
30
30
10
98
90
80
85
85
95
98
302–304 [39]
332–334 [34]
280–282 [40]
236–238 [34]
137–139 [40]
276–278 [40]
233–236 [39]
Me
NH2
NH2
25
26
27
4-MeOC6H4CHO
4-FC6H4CHO
C6H5CHO
15
15
10
97
90
98
171–173 [39]
178–180 [39]
95–97 [37]
H2N
NH2
28
29
30
31
32
a
4-MeOC6H4CHO
4-BrC6H4CHO
10
15
20
10
92
94
98
92
96
147–148 [37]
244–246 [37]
230–232 [37]
289–290 [37]
103–105 [37]
4-NO2C6H4CHO
4-Me2NC6H4CHO
3-Pyridinecarboxaldehyde 25
Isolated yield
123

Synthesis of benzimidazole and quinoxaline derivatives…
6-Nitro-2,3-diphenylquinoxaline: IR (KBr): 1H NMR (400 MHz, CdCl3) d
(ppm): 7.38–7.48 (m, 6H), 7.55–7.61 (m, 4H), 8.33 (d, J = 9.2 Hz, 1H), 8.55–8.58
(dd, 1 H), 9.11 (d, J = 2.4 Hz, 1H).
Results and discussion
On the basis of the research information obtained on the applicability of RHA-SO3H
in the promotion of different types of organic reactions, we expected that this
reagent could also be efficiently used in promoting the synthesis of benzimidazoles
and quinoxaline; these compounds function as acidic catalysts and speed up the
reaction. Initially, optimizal reaction conditions were studied by investigating the
effect of various reactant molar ratios and solvents. and also solvent-free conditions,
on the reaction of 4-chlorobenzaldehyde (1 mmol) and 1,2-phenylene diamine
(1 mmol) in terms of time and the product yield.
The obtained results showed that the reaction using 30 mg of the catalyst at
80 °C under a solvent-free condition produced the highest yield during a very short
time (Scheme 1; Table 1, entry 6). Any further increase of the temperature or the
catalyst amount did not improve the reaction time and yield.
After optimizing the reaction conditions and in order to show the general
applicability of this method, the preparation of benzimidazoles derivatives with a
variety of simple, readily available substrates under the optimal conditions was
investigated. Several aldehydes having electron donating and electron withdrawing
groups underwent the conversion to form a series of aryl benzimidazoles in good to
excellent yields. (Table 2, entries 1–16). As can be seen, o-phenylene diamines with
electron-withdrawing groups gave the desired products in lower yields within longer
times (Table 2, entries 17–26).
In addition, 1,2-ethylenediamine was reacted with aromatic aldehydes under the
same reaction conditions, and the desired products were obtained in very short times
in excellent yields (Table 2, entries 27–32).
Furthermore, this method was found to be useful for the synthesis of
benzimidazole derivatives from the reaction of diamines with heteroaromatic
aldehydes or a,b-unsaturated aldehydes in very short reaction times and with very
excellent yields (Table 2, entries 14, 15, 32).
It seems that the electronic or strict effect of different substituents on the
aromatic ring of the aldehydes had no obvious effect on the yield or reaction time
under the optimal conditions.
After the successful synthesis of benzimidazoles, the preparation of quinoxaline
derivatives, as the other useful heterocyclis compounds, in the presence of RHA-
SO3H, was nominated for further study.
N
N
Ar
Ar
NH2
NH2
O
O
RHA-SO3H (15 mg)
Solvent-free, r.t.
R
R
+
Ar
Ar
Scheme 2 RHA-SO3H catalyzed the synthesis of quinoxaline derivatives
123

M. Shamsi-Sani et al.
Table 3 Synthesis of quinoxaline derivatives catalyzed by RHA-SO3H
Entry
Diamine
1,2-Dicarbonyl compound
Time
(min)
Yield
(%)a
Mp (°C)
(references)
NH2
NH2
O
O
1
5
98
123–124 [27]
OMe
2
3
15
90
98
146–147 [27]
O
O
MeO
O
O
10
217–219 [27]
4
5
5
98
90
237–240 [27]
190–192 [41]
O
O
O
O
15
Br
Br
O2N
NH2
NH2
O
O
6
7
15
30
95
90
188–191 [27]
190–192 [27]
OMe
O
O
MeO
8
15
10
5
98
98
98
322–324 [27]
232–234 [25]
116–119 [24]
O
O
Me
NH2
NH2
9
O
O
O
O
10
OMe
11
10
98
124–126 [24]
O
O
MeO
a
Isolated yields
123

Synthesis of benzimidazole and quinoxaline derivatives…
98 98
96
96
94
90
16
12
12
10
10
10
Time (min)
Fig. 1 Reusability of RHA-SO3H (Table 2, entry 1; Table 3, entry 3)
Yield (%)
Table 4 Comparison of the result obtained from the reaction of o-phenylenediamine and benzaldehyde
in the presence of RHA-SO3H with those obtained using some of the other catalysts
Entry
Catalyst (mol%)
Reaction
conditions
Time
(h)
Yield (%)
(references)
1
2
Co(OH)2 (10)
EtOH, r.t.
4
5
96 [42]
85 [43]
(Bromodimethyl)sulfonium
bromide (100)
CH3CN, r.t.
3
4
Cu(OH)2 (10)
TBAF (5)
MeOH, r.t.
4
98 [44]
94 [45]
H2O, ultrasonic
irradiations, r.t.
0.5
5
6
7
8
9
LaCl3 (10)
CH3CN, r.t.
3
88 [38]
88 [22]
95 [34]
28
Nano-ZnO (10)
Fe(HSO4)3 (1)
RHA (0.72)
EtOH, reflux
100 min
25 min
1
EtOH, r.t.
Solvent-free, 80 °C
Solvent-free, 80 °C
RHA-SO3H (0.72)
10 min
98
Our investigations clarified that by using this method, the best results can be
obtained when the reaction proceeded using lower amounts of the catalyst (15 mg)
under solvent-free conditions at ambient temperatures. It is important to note that
this reaction was not completed in different types of solvents even after a long times
under reflux conditions. The selected conditions are shown in Scheme 2.
To assess the efficiency of RHA-SO3H in the preparation of quinoxaline
derivatives, various aromatic aldehydes were subjected to the optimal conditions.
It was observed that under the selected conditions, all the substrates containing
electron-withdrawing groups, as well as electron-donating groups, were easily
reacted in short reaction times with good to excellent isolated yields (Table 3,
entries 1–11).
To check the reusability of the catalyst, the reaction of o-phenylenediamine with
benzaldehyde or phenanthrene-9,10-dione under the optimized reaction conditions
123

M. Shamsi-Sani et al.
was studied again. When the reaction was completed, ethyl acetate was added and
the catalyst was separated by filtration. The recovered catalyst was washed with
dichloromethane, dried and reused for the same reaction. The recovered catalyst was
reused six times with a slight decrease in reusability in comparison to fresh catalyst
(Fig. 1).
In order to show the efficiency of the present method, our result obtained from
the reaction between o-phenylenediamine and benzaldehyde in the presence of
RHA-SO3H was compared with some of the other results reported in the literature
for the same reaction. As can be seen in Table 4, this method avoids the
disadvantages of other procedures such as long reaction times, excess reagents and
organic solvents.
Conclusion
In conclusion, we used RHA-SO3H as a highly solid acid catalyst for the simple and
efficient synthesis of benzimidazole and quinoxaline and their derivatives. The
procedure has several advantages, such as ease of preparation and handling of the
catalyst, being a simple experimental procedure, having high reaction rates,
producing excellent yields and the use of inexpensive and reusable catalyst.
Furthermore, this process avoids problems associated with the use of organic
solvents and liquid acids, which makes it a useful and attractive strategy in view of
these economic and environmental advantages.
Acknowledgments We are thankful to the University of Guilan Research Council for partial support of
this work.
References
1. B. Narasimhan, D. Sharma, P. Kumar, Med. Chem. Res. 21, 269 (2012)
2. M. Gaba, S. Singh, C. Mohan, Eur. J. Med. Chem. 76, 494 (2014)
3. K.P. Barot, S. Nikolova, I. Ivanov, M.D. Ghate, Mini-Rev. Med. Chem. 13, 1421 (2013)
4. F. Fei, Z.M. Zhou, Expert Opin. Ther. Pat. 23, 1157 (2013)
5. A.A. Ivanov, O.Y. Susova, V.I. Salyanov, K.I. Kirsanov, A.L. Zhuze, J. Biomol. Struct. Dyn. 31, 52
(2013)
6. J. Jayabharathi, V. Thanikachalam, K. Jayamoorthy, R. Sathishkumar, Spectrochim. Acta A 97, 384
(2012)
7. E.J. Hanan, B.K. Chan, A.A. Estrada, D.G. Shore, J.P. Lyssikatos, Synlett 18, 2759 (2010)
8. D. Yang, D. Fokas, J. Li, L. Yu, C.M. Baldino, Synthesis 1, 47 (2005)
9. W. Cui, R.B. Kargbo, Z. Sajjadi-Hashemi, F. Ahmed, J.F. Gauuan, Synlett 23, 247 (2012)
10. J. Sluiter, J. Christoffers, Synlett 1, 63 (2009)
11. B.C. Wray, J.P. Stambuli, Org. Lett. 12, 4576 (2010)
12. P. Saha, T. Ramana, N. Purkait, M.A. Ali, R. Paul, T. Punniyamurthy, J. Org. Chem. 74, 8719 (2009)
´
13. G. Bastug, C. Eviolitte, I.E. Marko, Org. Lett. 14, 3502 (2012)
14. K. Bahrami, M.M. Khodaei, I. Kavianinia, Synthesis 417, 417 (2007)
15. A. Go, G. Lee, J. Kim, S. Bae, B.M. Lee, B.H. Kim, Tetrahedron 71, 1215 (2015)
16. F.A.R. Rodrigues, I.D.S. Bomfima, B.C. Cavalcanti, C.D. Pessoa, J.L. Wardell, S.M.S.V. Wardell,
A.C. Pinheiro, C.R. Kaiser, Bioorg. Med. Chem. Lett. 24, 934 (2014)
17. J. Brown Desmond, C.T. E., A. Ellman Jonathan, The Chemistry of Heterocyclic Compounds (Wiley,
New York) (2004)
123

Synthesis of benzimidazole and quinoxaline derivatives…
18. D. Aparicio, O.A. Attanasi, P. Filippone, R. Ignacio, S. Lillini, F. Mantellini, F. Palacios, J.M. de los
Santos, J. Org. Chem. 71, 5897 (2006)
19. S. Antoniotti, E. Dunach, Tetrahedron Lett. 43, 3971 (2002)
20. Y.V.D. Nageswar, K.H.V. Reddy, K. Ramesh, S.N. Murthy, ChemInform 44 (2013)
21. M. Lande, M. Navgire, S. Rathod, J. Ind. Eng. Chem. 18, 277 (2012)
22. A. Teimouri, A. Najafi Chermahini, H. Salavati, L. Ghorbanian, J. Mol. Catal. A Chem. 373, 38
(2013)
23. A. Hasaninejad, A. Zare, M. Shekouhy, A.R. Moosavi-Zare, Eur.-J. Chem. 6(S1), S247 (2009)
24. M.M. Heravi, Kh. Bakhtiari, M.H. Tehrani, N.M. Javadi, H.A. Oskooie, ARKIVOC 16, 247 (2006)
25. A. Zare, A. Hasaninejad, A. Parhami, A.R. Moosavi-Zare, J. Serb. Chem. Soc. 75, 1315 (2010)
26. F. Shirini, S. Akbari-Dadamahaleh, A. Mohammad-Khah, J. Mol. Catal. A Chem. 363, 10 (2012)
27. F. Shirini, S. Akbari-Dadamahaleh, A. Mohammad-Khah, A.R. Aliakbar, C. R. Chim. 16, 207 (2013)
28. F. Shirini, S. Akbari-Dadamahaleh, A. Mohammad-Khah, C. R. Chim. 16, 945 (2013)
29. F. Shirini, S. Akbari-Dadamahaleh, A. Mohammad-Khah, Chin. J. Catal. 34, 2200 (2013)
30. F. Shirini, M. Mamaghani, M. Seddighi, Catal. Commun. 36, 31 (2013)
31. M. Seddighi, F. Shirini, M. Mamaghani, RSC Adv. 3, 24046 (2013)
32. R.R. Nagawade, D.B. Shinde, Indian J. Chem. 46B, 349 (2007)
33. S.B. Rathod, M.K. Lande, B.R. Arbad, Bull Korean Chem. Soc. 31, 2835 (2010)
34. H. Eshghi, M. Rahimizadeh, A. Shiri, P. Sedaghat, Bull Korean Chem. Soc. 33, 515 (2012)
35. L.S. Gadekar, B.R. Arbad, M.K. Lande, Chin. Chem. Lett. 21, 1053 (2010)
´
´
36. S.E. Lopez, J. Restrepo, B. Perez, S. Ortiz, J. Salazar, Bull Korean Chem. Soc. 30, 1628 (2009)
37. P. Gogoi, D. Konwar, Tetrahedron Lett. 47, 79 (2006)
38. Y. Venkateswarlu, S. Ramesh Kumar, P. Leelavathi, Org. Med. Chem. Lett. 1, 11 (2013)
39. K. Bahrami, M.M. Khodaei, A. Nejati, Green Chem. 12, 1237 (2010)
40. J. Yuan, Z. Zhao, W. Zhu, H. Li, X. Qiao, Y. Xu, Tetrahedron 69, 7026 (2013)
41. P. Karastatiris, J.A. Mikroyannidis, I.K. Spiliopoulos, Macromolecules 37, 7867 (2004)
42. M.A. Chari, D. Shobha, T. Sasaki, Tetrahedron Lett. 52, 5575 (2011)
43. B. Das, H. Holla, Y. Srinivas, Tetrahedron Lett. 48, 61 (2007)
44. M.A. Chari, Z.A. Mosaa, D. Shobha, S. Malayalam, Int. J. Org. Chem. 3, 243 (2013)
45. R.S. Joshi, P.G. Mandhane, S.K. Dabhade, C.H. Gill, J. Chin. Chem. Soc. 57, 1227 (2010)
123