Facile and efficient synthesis of pyrimido[1,2-a]benzimidazole and tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one derivatives using Br?nsted acidic ionic liquid supported on rice husk ash (RHA-[pmim]HSO4)

Article abstract of DOI:10.1007/s13738-016-0918-7

In this work, a green and efficient procedure has been reported for the synthesis of pyrimido[1,2-a]benzimidazole and tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one derivatives using Br?nsted acidic ionic liquid supported on rice husk ash (RHA-[pmim]HSO

Full text of DOI:10.1007/s13738-016-0918-7

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0918-7
ORIGINAL PAPER
Facile and efficient synthesis of pyrimido[1,2‑a]benzimidazole
and tetrahydrobenzimidazo[2,1‑b]quinazolin‑1(2H)‑one
derivatives using Brönsted acidic ionic liquid supported on rice
husk ash (RHA‑[pmim]HSO4)
Farhad Shirini1 · Mohadeseh Seddighi1 · Omid Goli‑Jolodar1
Received: 19 December 2015 / Accepted: 17 June 2016
© Iranian Chemical Society 2016
Abstract In this work, a green and efficient procedure has
been reported for the synthesis of pyrimido[1,2-a]benzimi-
dazole and tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-
one derivatives using Brönsted acidic ionic liquid supported
on rice husk ash (RHA-[pmim]HSO4) as the catalyst. These
reactions were performed at 100 °C under solvent-free con-
ditions with high yields in very short reaction times.
quinazolinones which can be prepared via the condensation
of substituted aldehydes with 2-aminobenzimidazole as
amine sources and dimedone. For this purpose, a variety of
conditions have been reported [4–11].
Pyrimido[1,2-a]benzimidazoles are another group of
N-containing heterocycles which have two biologically
active heterocyclic cores. These compounds show anti-
diabetic [12], antioxidant, antimicrobial [13], antibiotic
and antiarrhythmic [14] properties. Additionally, they
act as calcium antagonistic [15], and as lipid peroxida-
tion inhibitor [16]. In the literature, a few methods for
the synthesis of these compounds have been reported
[17–19].
Keywords Benzimidazo-quinazolinones · Pyrimido[1,2-a]
benzimidazoles · Immobilized acidic ionic liquid ·
RHA-[pmim]HSO4 · Rice husk ash
Introduction
Although the reported procedures used for the syn-
thesis of the above-mentioned heterocyclic compounds
provide an improvement, they suffer from disadvantages
such as long reaction times, harsh reaction conditions,
need to excess amounts of the reagent, use of organic
solvents, use of toxic reagents and non-recoverability of
the catalyst. Therefore, there is still a demand for intro-
ducing simple, efficient and mild procedures with easily
separable and reusable solid catalysts to overcome these
problems.
Very recently, we have reported the preparation and
characterization of a new Brönsted acidic ionic liquid sup-
ported on rice husk ash (RHA-[pmim]HSO4) (Fig. 1),
and its applicability in the promotion of the formylation
of amines and alcohols [21], and the synthesis of 1-(ben-
Heterocyclic compounds as widely distributed compounds
in nature are essential to life. Quinazolinone derivatives are
an important class of these types of compounds showing a
broad scope of pharmacological and biological activities
[1, 2]. For example, they can be found as important motif
in a variety of potent commercial drugs such as Quazinone
(a cardiotonic and vasodilator drug which was developed
and marketed in the 1980s), Anagrelide (a drug used for
the treatment of essential thrombocytosis (ET), or over-
production of blood platelets), Alfuzosin (an α1 receptor
antagonist used to treat benign prostatic hyperplasia) and
Prazosin (a sympatholytic drug used to treat high blood
pressure) [3]. Tetrahydrobenzimidazo[2,1-b]quinazolin-
1(2H)-ones are an important class of N-fused heterocyclic
zothiazolylamino)phenylmethyl-2-naphthols
[22].
In
continuation of these studies and in order to overcome
the above-mentioned restrictions, we were interested to
investigate the applicability of this reagent in the promo-
tion of the synthesis of pyrimido[1,2-a]benzimidazole and
tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one deriva-
tives, which need the acidic catalyst to speed-up.
* Farhad Shirini
shirini@guilan.ac.ir
1
Department of Chemistry, College of Science,
University of Guilan, Rasht 41335, I.R. Iran
1 3

J IRAN CHEM SOC
(10 mg, 0.8 mol %) was heated in an oil bath at 100 °C
under solvent-free conditions for the appropriate time.
After completion of the reaction (monitored by TLC),
EtOH was added and the catalyst was separated by filtra-
tion. Then water was added, and the precipitated product
was separated by filtration in high purity. The spectral data
of the new compound are as follows:
Fig. 1 Brönsted acidic ionic liquid supported on rice husk ash
(RHA-[pmim]HSO4)
Compound 1i 1H NMR (DMSO-d6, 400 MHz): δ = 2.43
(3H, s, SCH3), 5.18 (1H, s, CH), 6.83 (2H, s, NH2), 7.0
(1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.2 Hz), 7.20–7.25
Experimental
General
(5H, m), 7.62 (1H, d, J = 8 Hz), 8.56 (1H, s, NH) ppm; 13
C
NMR (DMSO-d6, 100 Mz): δ = 15.1, 53.3, 62.3, 112.8,
116.5, 119.6, 120.3, 123.8, 126.6, 127.0, 129.7, 138.2,
139.8, 144.0, 149.6, 152.1.; IR (KBr, cm−1): 3462, 3323,
3218, 3060, 2912, 2188, 1677, 1598, 1521, 1461, 1402,
1347.
All chemicals were purchased from Merck, Aldrich and
Fluka Chemical Companies and used without further puri-
fication. Products were characterized by their physical con-
stant and comparison with authentic samples. The purity
determination of the substrates and reaction monitoring were
accompanied by TLC using silica gel SIL G/UV 254 plates.
Compound 1j 1H NMR (DMSO-d6, 400 MHz): δ = 5.43
(1H, s, CH), 6.89 (2H, s, NH2), 7.01 (1H, td, J1 = 8 Hz,
J2 = 1.2 Hz), 7.11 (1H, td, J1 = 8 Hz, J2 = 1.2 Hz), 7.24
(1H, d, J = 7.6 Hz), 7.46-7.53 (3H, m), 7.68 (1H, d,
J = 8.0 Hz), 7.79 (1H, s), 7.87-7.89 (2H, m), 7.93 (1H, d,
J = 8.8 Hz), 8.72 (1H, s, NH) ppm; 13C NMR (DMSO-d6,
100 Mz): δ = 54.0, 62.3, 112.9, 116.5, 119.6, 120.3, 123.8,
124.8, 125.0, 126.7, 126.9, 128.0, 128.3, 129.1, 129.7,
133.0, 140.5, 144.1, 149.7, 152.2; IR (KBr, cm−1): 3436,
3301, 3229, 3056, 2913, 2187, 1679, 1600, 1464, 1398.
Preparation of 1‑methyl‑3‑(trimethoxysilylpropyl)‑
imidazolium hydrogen sulfate supported on RHA
(RHA‑[pmim]HSO4)
A mixture of 10 mmol 1-methylimidazole and 10 mmol
(3-chloropropyl)trimethoxysilane was refluxed at 90 °C
for 30 h. Then, the reaction mixture was cooled down.
The crude product was washed with Et2O (2 × 5 mL) and
dried under vacuum to obtain [pmim]Cl as a slightly yel-
low viscous oil. Then, 0.6 g (2 mmol) of [pmim]Cl was dis-
solved in 25 mL of CH2Cl2 and treated with 2 g of RHA.
The reaction mixture was refluxed with stirring for 3 days.
Then, the reaction mixture was cooled to room temperature
and the solid was isolated by filtration and washed with
20 mL of boiling dichloromethane to remove the unreacted
ionic liquid. In the next step, the material was dried to give
2.5 g RHA-[pmim]Cl as a gray powder. In continue, 3 g of
RHA-[pmim]Cl was suspended in 20 mL of dry CH2Cl2.
Under vigorous stirring and in an ice bath (0 °C), 2.9 mmol
of concentrated H2SO4 (97 %) was added dropwise to this
mixture. The mixture was then warmed to room tempera-
ture and heated under reflux for 30 h. When the formed
HCl was completely distilled off, the solution was cooled
and CH2Cl2 was removed under vacuum to afford RHA-
[pmim]HSO4 as the product (Fig. 1).
General procedure for the synthesis
of tetrahydrobenzimidazo[2,1‑b]quinazolin‑1(2H)‑one
derivatives
A mixture of aldehyde (1 mmol), 2-aminobenzimida-
zole (1 mmol), dimedone (1 mmol), RHA-[pmim]HSO4
(50 mg,4 mol%) was heated in an oil bath at 100 °C under
solvent-free conditions for the appropriate time. After com-
pletion of the reaction (monitored by TLC), EtOH was
added and the catalyst was separated by filtration. Then
water was added, and the precipitated product was sepa-
rated by filtration in high purity. The spectral data of the
new compound are as follows:
Compound 2j 1H NMR (DMSO-d6, 400 MHz): δ = 0.92
(3H, s, CH3), 1.07 (3H, s,CH3), 2.07 (2H, d, J = 16.0 Hz),
2.16 (2H, d, J = 16.0 Hz), 6.56 (1H, s), 6.98 (1H, td,
J1 = 7.6 Hz, J2 = 0.8 Hz), 7.08 (1H, td, J1 = 7.6 Hz,
J2 = 0.8 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.54 (2H, dd,
J1 = 5.0 Hz, J2 = 1.6 Hz), 7.75 (2H, dd, J1 = 5.0 Hz,
J2 = 1.6 Hz), 11.26 (1H, s, NH) ppm.
General procedure for the synthesis of pyrimido[1,2‑a]
benzimidazole derivatives
A mixture of aldehyde (1 mmol), 2-aminobenzimidazole
(1 mmol), malononitrile (1.1 mmol), RHA-[pmim]HSO4
1 3

J IRAN CHEM SOC
In order to establish the effectiveness and the acceptabil-
ity of the method, we explored the protocol with a variety
of simple readily available substrates under the optimal
conditions (Table 2). It was observed that under the applied
conditions, a wide range of aromatic aldehydes containing
electron-withdrawing as well as electron-donating substitu-
ents including Cl, Br, F, i-Pr, SCH3 and NO2 in the ortho,
meta, and para positions of the benzene ring were easily
converted to the corresponding pyrimido[1,2-a]benzimi-
dazoles (1) in good to excellent yields during short reac-
tion times (Table 2, entries 1–9). As can be seen, the effect
of the nature of the substituents on the aromatic ring did
not show obvious effects in terms of yields and reaction
times under the selected reaction conditions. Furthermore,
2-naphthaldehyde as a polycyclic aromatic aldehyde also
provided the desired product in very good yield (Table 2,
entry 10). However, under this catalytic system, application
of the aliphatic aldehyde was not successful.
After the successful application of RHA-[pmim]HSO4
in the synthesis of pyrimido[1,2-a]benzimidazoles, this
catalyst was also used in the three-component condensa-
tion of aromatic aldehydes and dimedone (5,5-dimethyl-
1,3-cyclohexanedione) with 2-aminobenzimidazole leading
to tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-ones (2).
But under the same conditions used for the preparation of
pyrimido[1,2-a]benzimidazoles, this reaction was not com-
pleted. Optimization of the reaction conditions clarified that
50 mg RHA-[pmim]HSO4 was adequate to accomplish the
reaction effectively at 100 °C (Scheme 1). Subsequently,
to reveal the generality of this method, the condensation
was carried out with various aromatic aldehydes contain-
ing electron-withdrawing (Cl, Br, NO2) or electron-donat-
ing (CH3, OCH3, OH) groups, and the corresponding
pyrano[2,3-d]pyrimidinones were obtained in high yields
and short reaction times (Table 2, entries 11-19).
Results and discussion
At first, we focused our attention to study the synthe-
sis of pyrimido[1,2-a]benzimidazoles. For optimization
of the reaction conditions, the condensation of 4-chlo-
robenzaldehyde, 2-aminobenzimidazole and malononi-
trile leading to 2-amino-3-cyano-4-(4-chlorophenyl)-1,4-
dihydropyrimido[1,2-a] benzimidazole was selected as
a model reaction under various conditions (Table 1). As
reaction media, different solvents such as EtOH, H2O,
EtOH:H2O and MeCN and also solvent-free conditions
were used and the best results were obtained in the absence
of solvent. Having accomplished the optimization of the
reaction media, more experiments were performed to
delineate the best reaction. It was observed that 10 mg of
RHA-[pmim]HSO4 was the optimal catalyst loading for
this reaction, and higher catalyst loading did not improve
the yield of the product to a greater extent. In addition,
the results indicated that the reaction at 100 °C proceeded
with highest yield and shortest time. Finally, the best result
was obtained using 10 mg of RHA-[pmim]HSO4 at 100 °C
under solvent-free conditions (Scheme 1).
Table 1 Optimization of the reaction conditions for the reaction of
4-chloro benzaldehyde, 2-aminobenzimidazole and malononitrile in
the presence of RHA-[pmim]HSO4
Entry Catalyst Solvent
(mg)
Temperature Time
Yield (%)
(°C)
(min)
1
2
3
4
5
6
7
8
9
0
15
15
15
15
15
10
7
H2O
90
9 h
20
30
30
120
3
70 [17]
90
H2O
90
MeCN
Reflux
91
EtOH: H2O 80
40
EtOH
Reflux
Trace
93
Solvent-free 100
Solvent-free 100
Solvent-free 100
Solvent-free 80
The proposed mechanism for the synthesis of
pyrimido[4,5-d]pyrimidinones and pyrano[2,3-d]pyrimidi-
nones in the presence of RHA-[pmim]HSO4 as a promoter
is shown in Scheme 2. On the basis of this mechanism,
3
94
10
5
91
10
93
Scheme 1 Synthesis of pyrimido[1,2-a]benzimidazole and tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one derivatives catalyzed by RHA-
[pmim]HSO4
1 3

J IRAN CHEM SOC
Table 2 Preparation
of pyrimido[1,2-a]
Entry
Aldehyde
Product
Time (min)
Yield (%)
Melting point (°C)
benzimidazole and
Found
Reported [Ref]
tetrahydrobenzimidazo[2,1-b]
quinazolin-1(2H)-one
derivatives catalyzed by RHA-
[pmim]HSO4
1
C6H5–
1a
1b
1c
1d
1e
1f
3
5
3
3
3
3
5
3
4
3
3
3
2
3
4
3
3
3
4
4
91
89
93
90
92
91
88
92
91
92
91
87
89
91
90
90
91
92
93
92
225–227
232-234
230-232
231–233
242–244
260–262
226–228
230–232
228–230
228–229
343–345
336–338
348–350
331–333
320–323
341–343
316–318
335–337
341–343
340–342
235–236 [17]
236–238 [18]
234–236 [18]
238–240 [18]
240–242 [20]
266–268 [18]
230–232 [18]
236 [17]
2
2-ClC6H4–
4-ClC6H4–
3-BrC6H4–
4-BrC6H4–
4-FC6H4–
3
4
5
6
7
4-i-PrC6H4–
3-NO2C6H4–
4-CH3SC6H4–
2-Naphthyl-
C6H5–
1 g
1 h
1i
8
9
–
10
11
12
13
14
15
16
17
18
19
20
1j
–
2a
2b
2c
2d
2e
2f
>300 [6]
340 [5]
4-ClC6H4–
4-BrC6H4–
4-CH3C6H4–
2-CH3OC6H4–
4-CH3OC6H4–
4-OHC6H4–
3-NO2C6H4–
4-NO2C6H4–
4-CNC6H4–
>300 [6]
330–332 [5]
325–327 [5]
>300 [6]
>300 [6]
>300 [4]
>300 [6]
–
2g
2h
2i
2j
Reaction conditions for 1 (a–j): Aldehyde (1 mmol), 2-aminobenzimidazole (1 mmol), malononitrile
(1.1 mmol), RHA-[pmim]HSO4 (10 mg) at 100 °C under solvent-free conditions; and for 2 (a–j): Aldehyde
(1 mmol), 2-aminobenzimidazole (1 mmol), dimedone (1 mmol), RHA-[pmim]HSO4 (50 mg) at 100 °C
under solvent-free conditions
Scheme 2 The proposed mechanism for the synthesis of pyrimido[4,5-d]pyrimidinones and pyrano[2,3-d]pyrimidinones in the presence of
RHA-[pmim]HSO4
1 3

J IRAN CHEM SOC
Fig. 2 The changes of
pyrimido[1,2-a]benzimidazole
and tetrahydrobenzimidazo[2,1-
b]quinazolin-1(2H)-one deriva-
tives from visible to fluores-
cence wavelength
Fig. 3 Reusability of the
catalyst
1 3

J IRAN CHEM SOC
RHA-[pmim]HSO4 catalyzes the reaction by the activation
of the carbonyl groups against the nucleophilic attack.
An important and interesting point about the obtained
products is that these compounds showed strong fluores-
cence emission. The changes of some of these derivatives
from visible to fluorescence wavelength (at 365 nm) are
displayed in Fig. 2.
References
1. K. Ozaki, Y. Yamada, T. Oine, T. Ishizuka, Y. Iwasawa, J. Med.
Chem. 28, 568 (1985)
2. W. Wang, L.M. Lagniton, R.N. Constantine, M.C. Desai, Patent
US 7, 939, 539 B2 (2011)
3. T.P. Selvam, P.V. Kumar, Res. Pharm. 1, 1 (2011)
4. A. Shaabani, E. Farhangi, A. Rahmati, Comb. Chem. High. T.
Scr. 9, 771 (2006)
To check the reusability of the catalyst, the syn-
5. A.E. Mourad, A.A. Aly, H.H. Farag, E.A. Beshr, Beilstein J. Org.
thesis
of
2-amino-3-cyano-4-
(4-chlorophenyl)-
Chem. 3, 11 (2007)
1,4-dihydropyrimido[1,2-a]benzimidazole (1c) under the
optimized reaction conditions was studied again. When the
reaction completed, EtOH was added and the catalyst was
separated by filtration. The recovered catalyst was washed
with EtOH, dried and reused for the same reaction. These
processes were carried out over five runs, and all reactions
led to the desired products without significant changes in
terms of the reaction time and yield which clearly demon-
strates practical recyclability of this catalyst (Fig. 3).
6. M.M. Heravi, L. Ranjbar, F. Derikvand, B. Alimadadi, H.A.
Oskooie, F.F. Bamoharram, Mol. Divers. 12, 181 (2008)
7. M.M. Heravi, F. Derikvand, L. Ranjbar, Synth. Commun. 40,
677 (2010)
8. G.M. Ziarani, A. Badiei, Z. Aslani, N. Lashgari, Arab. J. Chem.
8, 54 (2015)
9. R.G. Puligoundla, S. Karnakanti, R. Bantu, N. Kommu, S.B.
Kondra, L. Nagarapu, Tetrahedron Lett. 54, 2480 (2013)
10. G. Krishnamurthy, K.V. Jagannath, J. Chem. Sci. 125, 807
(2013)
11. M.R. Mousavi, M.T. Maghsoodlou, Monatsh. Chem. 145, 1967
(2014)
12. A.C.White, R.M. Black, US 3 989 709 (1997)
13. S.P. Vartale, P.N. Ubale, S.G. Sontakke, N.K. Halikar, M.M.
Pund, World J. Pharm. Sci. 2, 665 (2014)
Conclusion
14. P.F. Asobo, H. Wahe, J.T. Mbafor, A.E. Nkengfack, Z.T. Fomum,
E.F. Sopbue, D. Döpp, J. Chem. Soc. Perkin Trans. 1, 457 (2001)
15. R. Alajarin, J.J. Vaquero, J. Alvarez-Builla, M.F. de Casa-Juana,
C. Sunkel, J.G. Priego, P. Gomez-Sal, R. Torres, Bioorg. Med.
Chem. 2, 323 (1994)
16. C.G. Neochoritis, T. Zarganes-Tzitzikas, C.A. Tsoleridis, J.
Stephanidou-Stephanatou, C.A. Kontogiorgis, D.J. Hadjipav-
lou-Litina, T. Choli-Papadopoulou, Eur. J. Med. Chem. 46, 297
(2011)
17. A. Shaabani, A. Rahmati, A.H. Rezayan, M. Darvishi, Z. Badri,
A. Sarvari, QSAR Comb. Sci. 26, 973 (2007)
18. M.V. Reddy, J. Oh, Y.T. Jeong, C. R. Chim. 17, 484 (2014)
19. Y. Cui, J. Wang, J. Yin, C. Ji, C. Guo, Chin. J. Appl. Chem. 1, 53
(2010)
In conclusion, in this study we have introduced RHA-
[pmim]HSO4 as a highly powerful supported acidic ionic
liquid for the simple and efficient synthesis of pyrimido[1,2-
a]benzimidazole and tetrahydrobenzimidazo[2,1-b]quina-
zolin-1(2H)-one derivatives. The obtained results show
that this method is convincingly superior to other reported
procedures in the terms of reaction times and yields. Sim-
ple experimental procedure and use of inexpensive and
reusable catalyst with lower loading are other advantages
of this procedure. Furthermore, this process avoids prob-
lems associated with organic solvents and liquid acids use,
which makes it a useful and attractive strategy in view of
economic and environmental advantages.
20. G. Liu, Q. Shao, S. Tu, L. Cao, C. Li, D. Zhou, B. Han, J. Het-
erocyclic Chem. 45, 1127 (2008)
21. F. Shirini, M. Seddighi, M. Mamaghani, RSC Adv. 4, 50631
(2014)
22. M. Seddighi, F. Shirini, M. Mamaghani, C. R. Chim. 18, 573
(2015)
Acknowledgments We are thankful to the University of Guilan
Research Council for the partial support of this work.
1 3