Cholinesulfuric acid ionic liquid catalyzed an eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-one in aqueous media

Article abstract of DOI:10.1007/s11164-016-2849-4

An efficient and straightforward approach to the synthesis of 2,3-dihydroquinazolin-4(1H)-one from 2-aminobenzamide and carbonyl compounds (aldehydes and ketones) using biocompatible choline sulfate-based acidic ionic liquid as a cheap and readily available catalyst in water has been developed. Various 2,3-dihydroquinazolin-4(1H)-one have been prepared using low-cost and environmental friendly solvent and catalyst in good to excellent yields in a shorter reaction time. The choline sulfate catalyst was prepared using a simple method from readily available starting material and was confirmed by ¹H NMR, FTIR, and TGA. The ease of the product separation without organic solvent and column chromatography and the reusability of the acidic ionic liquid catalyst makes this method economically affordable for large-scale synthesis.

Full text of DOI:10.1007/s11164-016-2849-4

Res Chem Intermed
DOI 10.1007/s11164-016-2849-4
Cholinesulfuric acid ionic liquid catalyzed an eco-
friendly synthesis of 2,3-dihydroquinazolin-4(1H)-one
in aqueous media
Najmedin Azizi1 Fatemeh Shirdel1
•
Received: 25 June 2016 / Accepted: 26 December 2016
Ó Springer Science+Business Media Dordrecht 2017
Abstract An efficient and straightforward approach to the synthesis of 2,3-dihy-
droquinazolin-4(1H)-one from 2-aminobenzamide and carbonyl compounds (alde-
hydes and ketones) using biocompatible choline sulfate-based acidic ionic liquid as
a cheap and readily available catalyst in water has been developed. Various 2,3-
dihydroquinazolin-4(1H)-one have been prepared using low-cost and environmental
friendly solvent and catalyst in good to excellent yields in a shorter reaction time.
The choline sulfate catalyst was prepared using a simple method from readily
1
available starting material and was confirmed by H NMR, FTIR, and TGA. The
ease of the product separation without organic solvent and column chromatography
and the reusability of the acidic ionic liquid catalyst makes this method economi-
cally affordable for large-scale synthesis.
Keywords Quinazolinone Á Recyclable catalyst Á Acidic ionic liquid Á
Green chemistry
Introduction
Sustainable and eco-friendly development of chemical processes is an
important goal from an ecological point of view for chemists in both academia
and industry [1, 2]. One approach to address this challenge involves the
development of green solvents and biodegradable novel catalysts [3, 4]. In this
context, organic reactions in water have proven to be highly popular and very
attractive in recent years due to water’s specific properties such as nontoxic,
&
Najmedin Azizi
azizi@ccerci.ac.ir
1
Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
123

N. Azizi, F. Shirdel
nonflammable, inexpensive and friendliness to the environment [5, 6]. On
the other hands, green catalysts have a big impact in today’s society on the
environmental acceptability of industrial processes in a facile and environ-
mentally friendly manner [7, 8].
Choline sulfate (2-(trimethylammonio)ethyl sulfate) the sulfate ester of choline
is a naturally-occurring osmolyte that is synthesized by plants, lichens, algae,
fungi, and several bacterial species [9]. This neutral nonabsorbed zwitterion
betaine appears to be a useful reservoir for sulfur in plants [10]. Choline sulfate
also plays an important role in the microbial transformation of sulfur to the soil.
Choline sulfate is particularly interesting in metabolic adaptations to stress in
physiology and biochemistry [11]. However, the application of naturally-
occurring choline sulfate hydrochloride in the field of dihydroquinazoline has
not been reported [12, 13].
The quinazolineones scaffold is a central part of biologically active compounds
with multiple pharmacophores, and is responsible for a wide range of bioactivities
such as thymidylate synthase inhibition, antibiotic and antidefibrillatory effects and
sedative effects [14]. Furthermore, 2,3-dihydroquinazolinones as well as the
oxidized form, have been identified as synthetic building blocks as well as structural
scaffolds in various natural products [15]. Based on this wide range of applications,
numerous protocols for the preparation of 2,3-dihydroquinazolin-4(1H)-ones have
been developed and reported in the literature [16–20]. The most popular and simple
methods in the preparation of quinazolinones involve the condensation reaction of
2-aminobenzoicacid or its derivatives with aldehydes or ketones in the presence of
catalysts or promoters [21–28]. A wide range of useful biological properties, as well
as some marketed drugs based a 4-quiazolinone core (Fig. 1), have attracted
researchers searching for new routes and strategies for the synthesis of quinazoli-
nones that are operationally simpler and more compatible with the environment
[29–43].
O
O
O
O
O
O
O
N
S
S
H
N
H2N
NH
NH
H2N
N
N
H
N
H
O
HO
Quinethazone
Fenquizone
Febrifugine
O
O
N
N
O
NH
NH
CN
N
H
N
NCI Substance TID19143(Anticancer)
Cyanoquinazolinone
Methaqualone
Fig. 1 Examples of the quinazolinones skeleton with pharmacological activities
123

Cholinesulfuric acid ionic liquid catalyzed an…
Experimental
Materials and methods
All chemicals such as choline chloride, 2-aminobenzamide, carbonyl compounds
(aldehydes and ketones) and chlorosoulfonic acid are commercially available.
1
Solvents were distilled before use. All products were confirmed by H NMR and
1
FT-IR spectroscopy. H NMR spectra were recorded on a 500 MHz spectrometer
using DMSO-d6 as a solvent, and chemical shifts have been expressed in (ppm)
downfield from TMS. Melting points were recorded in a Buchi 535 melting point
apparatus and are uncorrected. FT-IR spectra were determined on a Bruker Vector-
1
22 infrared spectrometer using KBr disks. H NMR spectra were recorded at room
temperature on a FT-NMR Bruker Ultra Shield TM 500.
Preparation of the catalyst
To a magnetically stirred mixture of choline chloride (20 mmol, 2.79 g) in 30 mL
of dichloromethane in a three-necked round-bottom flask equipped with a dropping
funnel containing chlorosulfonic acid and a gas inlet tube for conducting HCl,
chlorosulfonic acid (22 mmol, 1.43 mL) was added dropwise over a period of
60 min in an ice-bath. The resulting mixture was stirred for another 3 h at room
temperature and then filtered to obtain a white solid which was washed with
(2 9 25 mL) of ethyl acetate and dried at room temperature (Fig. 2).
General procedure
To a solution of the catalyst (10 mg) in H2O (2 mL), 2-aminobenzamide (0.5 mmol)
and carbonyl compounds (0.5 mmol) were added. The resulting mixture was stirred
under room temperature for 20–120 min. After completion of the reaction, water
(5 mL) was added and the precipitated products were filtered and then recrystallized
from ethanol or ethyl actete to get the pure final product. The catalyst remaining in
the water filter liquor could be used directly as a catalyst media for subsequent runs.
Results and discussion
Previously, we successfully used choline chloride-based deep eutectic solvents as a
green reaction medium in the synthesis of biologically active nitrogen-based
heterocycles [44–46]. As part of our ongoing efforts to explore novel catalyst sin
CH2Cl2
+
OSO3H
+
N
ClSO3H
N
0oC-rt
HO
Cl
Cl-
Fig. 2 Preparation of choline sulfate-based catalyst
123

N. Azizi, F. Shirdel
water for heterocyclic synthesis, we report here a straightforward and eco-
compatible procedure for the synthesis of 2,3-dihydroquinazolin-4 (1H)-one from
2-aminobenzamide and carbonyl compounds using a choline sulfate-based acidic
ionic liquid catalyst in water (Fig. 2). The catalyst was prepared by treating
commercially available choline chloride with chlorosulfonic acid in CH2Cl2 at room
temperature under argon. The structure of the catalyst was characterized by various
1
techniques such as Fourier transform infrared spectroscopy (FTIR), H NMR, and
TG–DTA, and the spectral data confirmed were the structures of the title catalyst.
The FT-IR spectra of ChSO3HCl are presented in Fig. 3. The spectra of the catalyst
exhibits major absorption bands at 1069 and 1229 cm-1 to confirm the presence of –
SO3H groups due to the S=O stretching vibrations in the catalyst. The stability and
the weight loss patterns of the catalyst were investigated by thermal gravimetric
(TG) analysis and are shown in Fig. 4, from wihch it can be seen that there is a
negligible weight loss about 1.37% below 300 °C due to the removal of the
physically adsorbed water, and a complete loss of weight occurs at above 300 °C.
Furthermore, the DTG curve shows that the decomposition temperature of the
1
catalyst was about 320–340 °C. The H NMR spectra of the catalyst are given in
Fig. 5. The 1H NMR (D2O) spectrum showed three signals and the proton of SO3H
was exchanged with D2O.
Initially, we began our study with the reaction of 2-aminobenzamide 1
(0.5 mmol), benzaldehyde 2a (0.5 mmol) in water (2 mL) in the presence of
ChSO3HCl (10 mg) as a model reaction to explore the feasibility of the system
using different solvents (Table 1). When the reaction mixture was stirred under
solvent-free conditions at room temperature, the desired product 3a was obtained in
45% isolated yield after 20 min (Table 1, entry 9). Although the reaction proceeds
very rapidly, a longer reaction time did not improve the yield because of the massive
solidification of the reaction mixture. The yield of the desired product was found to
increase with the additionof the solvent. When polar solvents such as ethanol
(Table 1, entry 1) or water (Table 1, entry 2) were used as solvents, complete
Fig. 3 FT-IR spectra of the catalyst
123

Cholinesulfuric acid ionic liquid catalyzed an…
Fig. 4 TG–DTG curves of the catalyst
Fig. 5 1H NMR spectra of the catalyst
123

N. Azizi, F. Shirdel
Table 1 Screening of various solvents
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
EtOH
92
95
25
45
56
38
28
42
45
H2O
Toluene
CH3CN
CH2Cl2
CH3CO2Et
THF
n-hexane
Without solvent
conversions of the starting materials were observed at 20 min. However, using
toluene, n-hexane, dichloromethane, ethyl acetate and tetrahydrofuran as solvents,
the corresponding products were isolated in moderate yields (Table 1, entries 3–8).
Furthermore, the effect of the catalyst amount on the reaction yields was
investigated. When 5, 15 and 20 mg cholinesulfuric acid were used for the model
reaction, this gave 3a in 72, 95, and 95% yields, respectively. Therefore, it was
concluded that cholinesulfuric acid (10 mg) was sufficient to catalyze the reaction at
room temperature.
Using the optimized reaction conditions, (water, room temperature, 10 mg,
catalyst), the diversity of our protocol was investigated by a wide range of aromatic
aldehydes and 2-aminobenzamide and the results are shown in Table 2. A series of
2,3-dihydroquinazolin-4(1H)-ones were synthesized at room temperature within a
few minutes in good to excellent yields under the optimized reaction conditions, and
representative results are listed in Table 2. The reaction proceeded smoothly using
differently-substituted electron-withdrawing or electron-donating substituents to the
aldehyde core to give the corresponding products. Aromatic aldehydes bearing
electron-donating groups (OMe) participated more rapidly in this protocol and gave
better yields than those of aldehydes with alkyl groups (Me) or halogen-substituted
(Br, Cl). For aldehydes carrying an electron-withdrawing group (NO2, CO2Me), the
rate of the reaction was relatively slow and the yield of the product was also lower
123

Cholinesulfuric acid ionic liquid catalyzed an…
Table 2 Synthesis of the diversified 2,3-dihydroquinazolinones derivatives
Entry
R (2)
Product (3)
Time (min.)
Yield (%)
M.p./°C
Found
Reported [Lit.]
1
Ph
3a
3b
3c
3d
3e
3f
20
60
120
70
45
80
65
40
55
62
50
95
95
74
72
75
72
72
82
88
80
76
218–220
207–211
188–191
217–219
211–213
224–227
162–164
225–227
197–199
203–205
144–146
219–220 [19]
207–208 [33]
198–201 [18]
218–220 [35]
210–212 [17]
187–188 [35]
165–167 [17]
229–231 [33]
198–200 [33]
205–208 [39]
142–144 [39]
2
4-Cl-C6H4
4-OMe-C6H4
4-CO2Me-C6H4
3-NO2-C6H4
2,4-di OMe-C6H4
2,4-di Cl-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
O
3
4
5
6
7
3g
3h
3i
8
9
10
11
3j
3k
12
13
3l
120
120
80
78
166–168
166–168
164–165 [19]
169–171 [36]
O
S
3m
14
15
16
17
3n
3o
3p
3q
120
120
80
74
70
00
00
224–226
224–226 [34]
O
196–198
200–202 [35]
O
O
–
–
–
–
80
due to the electron deficiency. Heterocyclic aldehydes gave the corresponding
products in good yields. To further expand the scope of the green method ,we were
keen to explore a variety of cyclic ketones like cyclohexanone and tetrahydro-4H-
pyran-4-one in this reaction under the optimized reaction conditions and found the
formation of desired products in good yield.
However, aliphatic aldehyde such as isobutyraldehyde and acetophenone as a
linear ketone failed to give the corresponding products 3p and 3q, respectively,
123

N. Azizi, F. Shirdel
Runs
1
2
3
4
Yield (%)
95
93
90
90
Fig. 6 Recyclability of the ionic catalyst in the model reaction
Table 3 Comparison of ionic catalyst with previous procedure
Entry Solvent
Catalyst (9mol%)
Temp.
(°C)
Time
Yield
(%)
References
[41]
1
Chloroform BINOL-phosphoric acid
(10 mol %)
-15
24 h
96
2
3
Water
Water
Cholin hydroxide (3.5 mL)
80
25
50 min
25 min
96
95
[47]
[37]
b-Cyclodextrine-SO3H
(10 mol %)
4
5
Water
KOH
100
25
8 h
75
95
[16]
[19]
Ethanol
Poly(VPyPS)-PW (0.2 g)-
ultrasound
6 min
6
Water
Water
Toluene
Water
Water
Wang-OSO3H (10 mol%)
100
120
110
80
24 min
16 h
84
100
100
97
[18]
7
–
[21]
8
–
18 h
[22]
9
Phosphatidylcholine (0.5 g)
Cholinesulfuric acid (10 mg)
15 min
20
[48]
10
25
95
This work
under these conditions but led to a mixture of products that that it was impossible to
separate.
Notably, from the viewpoint of green chemistry, not only did compound
purification not require chromatography but there is also no need for the use of
harmful organic solvents in the reaction or separation processes. After completion of
the reaction, the crude product was filtered off and washed with water, then
recrystallized from ethanol to yield the desired compounds 3a–3o in 70–95%
overall yields.
Finally, recycling experiments were carried out for the evaluation of the
reusability of the catalyst which is highly important for economic considerations
and environmental concerns. An attractive advantage of this procedure is its simple
separation using filtration. To demonstrate this issue, the recycling efficiency of the
catalyst was investigated for compound 3a (Table 2, entry 1). The spent catalyst
was completely water soluble and was recovered by simple filtration of the products
from aqueous solutions containing the catalyst. The results shown in Fig. 6 reveal
that the ionic catalyst can be recycled for at least 4 cycles without significant loss of
its reactivity. Furthermore, no significant change in catalyst reactivity in either the
yield or the time was observed, indicating that the recovered ionic catalyst was
recoverable, which was confirmed by the FT-IR analysis of the reused ionic catalyst.
123

Cholinesulfuric acid ionic liquid catalyzed an…
Finally, comparison of the cholinesulfuric acid ionic liquid-catalyzed synthesis of
2,3-dihydroquinazolin-4(1H)-one in water with a range of other methodologies
demonstrated the high yields, short reaction times, low loading of the catalyst and
eco-friendly nature of the protocol (Table 3).
Conclusion
In summary, we developed a simple and a straightforward procedure for the novel
acidic ionic liquid-catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones in
water. The most important features of this procedure are an environmentally benign
catalyst and solvent, effective recovery and reusability of the catalyst, operational
simplicity and short reaction times.
Acknowledgements Financial support of this work by Chemistry and Chemical Engineering Research
Center of Iran is gratefully appreciated.
References
1. R.A. Sheldon, J.P.M. Sanders, Catal. Today 239, 3 (2015)
2. G.L. Khatik, A. Kumar, A.K. Chakraborti, Org. Lett. 8, 2433 (2006)
3. A.S. Amarasekara, Chem. Rev. 116, 6133 (2016)
4. R.A. Sheldon, Chem. Soc. Rev. 41, 1437 (2012)
5. P. Wang, F.-P. Ma, Z.-H. Zhang, J. Mol. Liq. 198, 259 (2014)
6. N. Azizi, B. Mirmashhori, M.R. Saidi, Catal. Commun. 8, 2198 (2007)
7. P.M. Pawar, K.J. Jarag, G.S. Shankarling, Green Chem. 13, 2130 (2011)
8. P. Liu, J.W. Hao, L.P. Mo, Z.H. Zhang, RSC Adv. 5, 48675 (2015)
9. J. Rivoal, A.D. Hanson, Plant Physiol. 106, 1187 (1994)
10. P. Nissen, A.A. Benson, Science 134, 1759 (1961)
11. M.A. Chaudhari, J.B. Gujar, D.S. Kawade, P.V. Shinde, M.S. Shingare, Res. Chem. Intermed. 44,
10027 (2015)
12. S.L. Schreiber, Nat. Chem. Biol. 1, 64 (2005)
13. P.N. Kalaria, S.P. Satasia, J.R. Avalani, D.K. Raval, Eur. J. Med. Chem. 83, 655 (2014)
14. S.P. Satasia, P.N. Kalaria, J.R. Avalani, D.K. Raval, Tetrahedron 70, 5763 (2014)
15. J.F. Wolfe, T.L. Rathman, M.C. Sleevi, J.A. Campbell, T.D. Greenwood, J. Med. Chem. 33, 161
(1990)
16. X.-F. Wu, S. Oschatz, A. Block, A. Spannenberg, P. Langer, Org. Biomol. Chem. 12, 1865 (2014)
17. N. Azizi, M.R. Saidi, Phosphorus Sulf. Silicon Relat. Elem. 178, 1255 (2003)
18. A.V.D. Rao, B.P. Vykunteswararao, T. Bhaskarkumar, N.R. Jogdand, D. Kalita, J.K.D. Lilakar, V.
Siddaiah, P.D. Sanasi, A. Raghunadh, Tetrahedron Lett. 56, 4714 (2015)
19. J. Wang, Y. Zong, R. Fu, Y. Niu, G. Yue, Z. Quan, X. Wang, Y. Pan, Ultrason. Sonochem. 21, 29
(2014)
20. R. Sharma, A. K. Pandey, P. M. S. Chauhan, Synlett 23, 2209 (2012)
21. H. Hikawa, Y. Ino, H. Suzuki, Y. Yokoyama, J. Org. Chem. 77, 7046 (2012)
22. S. Hakim, K. Kon, A.S. Touchy, K.I. Shimizu, Catal Sci. Technol. 4, 1716 (2014)
23. R.A. Bunce, B. Nammalwar, J. Heterocycl. Chem. 48, 991 (2011)
24. G. Cai, X. Xu, Z. Li, W.P. Weber, P. Lu, J. Heterocycl. Chem. 39, 1271 (2002)
25. W. Su, B. Yang, Aust. J. Chem. 55, 695 (2002)
26. S. Tarannum, N. Ahmed, Z.N. Siddiqui, Catal. Commun. 66, 60 (2015)
27. D. Kumar, P.S. Jadhavar, M. Nautiyal, H. Sharma, P.K. Meena, L. Adane, S. Pancholia, A.K.
Chakraborti, RSC Adv. 5, 30819 (2015)
28. S. Guo, Y. Li, L. Tao, W. Zhang, X. Fan, RSC Adv. 4, 59289 (2014)
29. M. Boomhoff, R. Ukis, C. Schneider, J. Org. Chem. 80, 8236 (2015)
123

N. Azizi, F. Shirdel
30. J.K. Laha, K.S.S. Tummalapalli, A. Nair, N. Patel, J. Org. Chem. 80, 11351 (2015)
31. H.R. Lobo, B.S. Singh, G.S. Shankarling, Catal. Commun. 27, 179 (2012)
32. T.B. Nguyen, L. Ermolenko, A. Al-Mourabit, Green Chem. 15, 2713 (2013)
33. M. Prakash, S. Jayakumar, V. Kesavan, Synthesis 45, 2265 (2013)
34. Y. Liu, L. Lu, Y.-J. Zhou, X.-S. Wang, Res. Chem. Intermed. 40, 2823 (2014)
35. Z.H. Zhang, X.N. Zhang, L.P. Mo, Y.X. Li, F.P. Ma, Green Chem. 14, 1502 (2012)
36. L.Y. Zeng, C. Cai, J. Heterocycl. Chem. 47, 1035 (2010)
37. J. Wu, X. Du, J. Ma, Y. Zhang, Q. Shi, L. Luo, B. Song, S. Yang, D. Hu, Green Chem. 16, 3210
(2014)
38. A.K. Sanap, G.S. Shankarling, New J. Chem. 39, 206 (2015)
39. X.N. Zhao, G.F. Hu, M. Tang, T.T. Shi, X.L. Guo, T.T. Li, Z.H. Zhang, RSC Adv. 4, 51089 (2014)
40. S. Santra, M. Rahman, A. Roy, A. Majee, A. Hajra, Catal. Commun. 49, 52 (2014)
41. B. Zhang, L. Shi, R. Guo, Catal. Lett. 145, 1718 (2015)
42. A. Taheri, B. Lai, C. Cheng, Y. Gu, Green Chem. 17, 812 (2015)
43. J. Wang, M.M. Zhang, X.S. Wang, Res. Chem. Intermed. (2016). doi:10.1007/s11164-016-2807-1
44. N. Azizi, E. Batebi, Catal. Sci. Technol. 2, 2445 (2012)
45. N. Azizi, E. Gholibeglo, RSC Adv. 2, 7413 (2012)
46. N. Azizi, S. Dezfooli, M.M. Hashemi, J. Mol. Liq. 194, 62 (2014)
47. P.N. Borase, P.B. Thale, G.S. Shankarling, RSC Adv. 6, 63078–63083 (2016)
48. F. Tamaddon, M.T. KazemiVarnamkhasti, Synlett 27, 2510 (2016)
123