Highly efficient solvent-free synthesis of quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones using tetrabutylammonium bromide as novel ionic liquid catalyst

Article abstract of DOI:10.1016/j.cclet.2010.01.032

A simple and efficient procedure for the synthesis of 2-arylquinazolin-4(3H)-ones has been developed through cyclocondensation of 2-aminobenzamide with aromatic aldehydes using tetrabutylammonium bromide (TBAB) as novel neutral ionic liquid catalyst in the presence of copper (II) chloride (CuCl₂) as oxidizing agent under solvent-free conditions at 100 °C. In the absence of CuCl₂ and under a nitrogen atmosphere, the unoxidized intermediates, 2-aryl-2,3-dihydroquinazolin-4(1H)-ones, were isolated. Treatment of these intermediates with CuCl₂ in TBAB media gave the oxidized products 2-arylquinazolin-4(3H)-ones. On the other hand, cyclocondensation of 2-aminobenzamide with aromatic aldehydes in TBAB under microwave irradiation directly gave 2-arylquinazolin-4(3H)-ones.

Full text of DOI:10.1016/j.cclet.2010.01.032

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Chinese Chemical Letters 21 (2010) 550–553
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Highly efficient solvent-free synthesis of quinazolin-4(3H)-ones and
2,3-dihydroquinazolin-4(1H)-ones using tetrabutylammonium
bromide as novel ionic liquid catalyst
*
A. Davoodnia , S. Allameh, A.R. Fakhari, N. Tavakoli-Hoseini
Department of Chemistry, Faculty of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran
Received 10 September 2009
Abstract
A simple and efficient procedure for the synthesis of 2-arylquinazolin-4(3H)-ones has been developed through cyclocondensa-
tion of 2-aminobenzamide with aromatic aldehydes using tetrabutylammonium bromide (TBAB) as novel neutral ionic liquid
catalyst in the presence of copper (II) chloride (CuCl2) as oxidizing agent under solvent-free conditions at 100 8C. In the absence of
CuCl2 and under a nitrogen atmosphere, the unoxidized intermediates, 2-aryl-2,3-dihydroquinazolin-4(1H)-ones, were isolated.
Treatment of these intermediates with CuCl2 in TBAB media gave the oxidized products 2-arylquinazolin-4(3H)-ones. On the other
hand, cyclocondensation of 2-aminobenzamide with aromatic aldehydes in TBAB under microwave irradiation directly gave 2-
arylquinazolin-4(3H)-ones.
# 2010 A. Davoodnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Quinazolinones; Aromatic aldehydes; Tetrabutylammonium bromide (TBAB); Copper (II) chloride (CuCl2); Microwave irradiation
Quinazolin-4-ones are an important class of heterocycles with a wide range of pharmacological and biological
activities [1–4]. Various methods have already been proposed for the synthesis of these compounds (see a recent
review on quinazolinones and quinazolines and references cited therein) [5] and the most general ones involves
cyclocondensation of anthranilamides with aldehydes in the presence of various promoting agents, such as Sc(OTf)3
[6], p-toluenesulfonic acid/DDQ [7], I2/KI in water [8], CuCl2 in ethanol [9] and KMnO4 under microwave irradiation
[10]. Other methods such as cyclocondensation of 2-aminobenzamides with substituted benzoyl chlorides [11], one-
pot reaction of isatoic anhydride, ammonium acetate and aldehydes using Ga(OTf)3 [12] or I2 under solvent-free
conditions [13] are also reported for the synthesis of these compounds. However, some of these methodologies have
limitations of harsh reaction conditions, use of expensive acid catalysts in organic solvents, long reaction time and
tedious work-up. Hence, the development of simple, efficient, clean, high-yielding, and environmentally benign
protocols using new catalysts for the synthesis of these important compounds is still desirable and is in demand.
Ionic liquids (ILs), being recognized as environmentally benign media, have been widely applied as catalysts or
dual catalyst—solvents in green chemistry processes [14,15]. Recently tetrabutylammonium bromide (TBAB) has
* Corresponding author.
E-mail addresses: adavoodnia@yahoo.com, adavoodnia@mshdiau.ac.ir (A. Davoodnia).
1001-8417/$ – see front matter # 2010 A. Davoodnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.01.032

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A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 550–553
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Table 1
Synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones 2a–g.
Productsa
Ar
Time (min)
Yield (%)b
Mp (8C)
Found
Reported
2a
2b
2c
2d
2e
2f
C6H5
90
90
45
90
60
60
90
82
72
84
75
83
75
80
221–223
168–170
178–181
231–232
197–199
203–205
308–311
225–226 [13]
173–175 [13]
183–184 [13]
229–231 [13]
195–197 [13]
207–208 [13]
310–312 [13]
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-O2NC6H4
2g
a
All products were characterized by 1H NMR and IR spectral data and comparision of their melting points with those of authentic samples.
Isolated yields.
b
been used as an extremely useful homogeneous catalyst in various organic transformations [16–18]. TBAB is a readily
available IL with inherent properties like environmental compatibility, nonflammability, operational simplicity, non-
corrosive nature, ease of reusability and excellent thermal and chemical stability. It is therefore of interest to examine
the behavior of TBAB as catalyst in the synthesis of quinazolinone derivatives. To the best of our knowledge,
cyclocondensation of 2-aminobenzamide with aromatic aldehydes for the synthesis of 2-aryl-2,3-dihydroquinazolin-
4(1H)-ones and 2-arylquinazolin-4(3H)-ones using TBAB as catalyst has not been reported in the literature.
Prompted by these findings and in continuation of our previous works on the applications of reusable catalysts in the
synthesis of heterocyclic compounds [19,20], in this paper we wish to report a new green approach for the synthesis of
2-aryl-2,3-dihydroquinazolin-4(1H)-ones 2a–g (Table 1) and 2-arylquinazolin-4(3H)-ones 3a–g (Table 2) through
cyclocondensation of 2-aminobenzamide 1 with aromatic aldehydes using TBAB as catalyst under solvent-free neat
conditions (Scheme 1).
Initially, to find the optimal conditions, the synthesis of 2-phenylquinazolin-4(3H)-one 3a was used as a model
reaction. A mixture of 2-aminobenzamide 1 (4 mmol), benzaldehyde (5 mmol), TBAB and CuCl2 was heated under
various reaction conditions. The best results have been obtained at 100 8C with an amount of 1.6 mmol (40 mol%) of
TBAB in the presence of 1.4 mmol (35 mol%) CuCl2 in solvent-free conditions. In the absence of TBAB, the product
3a was obtained in trace amount after 120 min.
Next, treatment of 2-aminobenzamide 1 with various aromatic aldehydes in molten TBAB (40 mol%) at 100 8C in
the presence of CuCl2 (35 mol%) as oxidizing agent was investigated (Table 2, Method A). Under these conditions,
the products 2-arylquinazolin-4(3H)-ones 3a–g were formed and attempts to isolate the intermediates 2-aryl-2,3-
dihydroquinazolin-4(1H)-ones 2a–g failed when we carefully monitored the reactions. The formation of the products
3a–g was assumed to proceed via a cyclocondensation reaction followed by oxidation of the intermediates 2a–g
(Scheme 1). In the absence of CuCl2, heating the same reaction mixture afforded a mixture of the products 2a–g and
3a–g after 1 h in low yields but after prolonged heating (72 h) the products 3a–g were formed in good yields. In the
absence of CuCl2, the formation of the products 3a–g was assumed to proceed via the air oxidation of the
Table 2
Synthesis of 2-arylquinazolin-4(3H)-ones 3a–g.
Productsa
Ar
Method A
Method B
Method C
Mp (8C)
Time (min)
Yield (%)b
Time (min)
Yield (%)b
Time (min)
Yield (%)b
Found
Reported
3a
3b
3c
3d
3e
3f
C6H5
90
120
75
87
79
88
83
91
86
82
60
90
60
75
60
60
75
95
84
91
92
91
89
86
2
3
3
2
3
3
4
96
81
85
85
92
86
84
235–236
209–212
247–249
240–242
315–316
305–308
358–360
235–237 [8]
208–210 [8]
248–249 [8]
241–243 [8]
315–316 [8]
305–307 [8]
363–364 [8]
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-O2NC6H4
95
60
60
3g
90
a
All products were characterized by 1H NMR and IR spectral data and comparision of their melting points with those of authentic samples.
Isolated yields.
b

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552
A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 550–553
Scheme 1.
intermediates 2a–g because when the same reaction mixture was heated under a nitrogen atmosphere and in the
absence of CuCl2, the reaction did not proceed to form compounds 3a–g and the intermediates 2a–g were isolated
(Table 1). When these intermediates were heated in molten TBAB containing CuCl2, oxidation reaction occurred and
the products 3a–g were obtained (Scheme 1 and Table 2, Method B). In the absence of TBAB, the yields of the
products were poor.
Finally, due to our interest in the utilization of microwave irradiation for the synthesis of heterocyclic compounds
[21,22], we tried to extend this non-conventional synthetic method for the synthesis of compounds 2a–g and 3a–g.
Therefore, 2-aminobenzamide 1 was allowed to interact with aromatic aldehydes under microwave irradiation in
TBAB media and in solvent-free conditions. All of the reactions were carried out using a Milestone microwave oven
(MicroSYNTH) at 800 W and 120 8C.
During monitoring of the reaction mixture by TLC (CHCl3:MeOH, 95:5), we observed that the products 3a–g were
forming (Scheme 1 and Table 2, Method C). The formation of these products was assumed to proceed via a
cyclocondensation reaction followed by air oxidation. Under microwave irradiation, attempts to isolate the
intermediates 2-aryl-2,3-dihydroquinazolin-4(1H)-ones 2a–g failed.
In conclusion, we have reported a new efficient catalyst for the synthesis of 2-arylquinazolin-4(3H)-ones and 2-
aryl-2,3-dihydroquinazolin-4(1H)-ones through cyclocondensation of 2-aminobenzamide with aromatic aldehydes
using TBAB, a novel neutral IL. The catalyst can be reused after a simple work-up, with a gradual decline of its activity
being observed. High yields, relatively short reaction times, simplicity of operation and easy work-up are some
advantages of this protocol.
1. Experimental
All chemicals were commercially available and used without further purification. Melting points were recorded
on an electrothermal type 9100 melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu
spectrophotometer as KBr disks. The 1H NMR (100 MHz) spectra were recorded on a Bruker AC 100
spectrometer.
1.1. Preparation of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones 2a–g. General procedure
A mixture of 2-aminobenzamide (4 mmol), aromatic aldehyde (5 mmol) and TBAB (1.6 mmol) was heated on the
oil bath at 100 8C under a nitrogen atmosphere for 45–90 min. The reaction was monitored by TLC. After completion
of the reaction, the reaction mixture was cooled to room temperature and then water was added. The precipitate was
filtered off and recrystallized from acetonitrile to give compounds 2a–g in high yields. All products were known and
characterized by 1H NMR and IR spectral data and comparision of their melting points with those of authentic samples
[13] (Table 1).

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A. Davoodnia et al. / Chinese Chemical Letters 21 (2010) 550–553
553
1.2. Preparation of 2-arylquinazolin-4(3H)-ones 3a–g. General procedures
1.2.1. Method A
A mixture of 2-aminobenzamide (4 mmol), aromatic aldehyde (5 mmol) and TBAB (1.6 mmol) in the presence of
CuCl2 (1.4 mmol) was heated on the oil bath at 100 8C for 60–120 min. The progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was
added. The precipitate was filtered off and recrystallized from acetonitrile to give compounds 3a–g in high yields. All
products were known and characterized by 1H NMR and IR spectral data and comparision of their melting points with
those of authentic samples [8] (Table 2).
1.2.2. Method B
A mixture of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones 2a–g (1 mmol) and TBAB (0.4 mmol) in the presence of
CuCl2 (0.35 mmol) was heated on the oil bath at 100 8C for 60–90 min. The progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added.
The precipitate was filtered off and recrystallized from acetonitrile to give compounds 3a–g in high yields (Table 2).
1.2.3. Method C
A mixture of 2-aminobenzamide (4 mmol), aromatic aldehyde (5 mmol) and TBAB (1.6 mmol) was subjected to
microwave irradiation at 800 W and 120 8C for 2–4 min. After completion of the reaction (monitored by TLC), the
reaction mixture was cooled to room temperature and then water was added. The precipitate was filtered off and
recrystallized from acetonitrile to give compounds 3a–g in high yields (Table 2).
1
1.3. Selected H NMR data
2d: 1H NMR (DMSO-d6): d 2.31 (s, 3H, CH3), 5.72 (s, 1H, CH), 6.60–6.85 (m, 2H, arom-H), 7.06 (s, 1H, NH),
7.15–7.40 (m, 5H, arom-H), 7.62 (d, J = 7.6 Hz, 1H, arom-H), 8.26 (s, 1H, NH).
2e: 1H NMR (DMSO-d6): d 5.75 (s, 1H, CH), 6.60–6.95 (m, 2H, arom-H), 7.02 (s, 1H, NH), 7.10–7.85 (m, 6H,
arom-H), 8.22 (s, 1H, NH).
1
3d: H NMR (DMSO-d6): d 2.37 (s, 3H, CH3), 7.20–8.25 (m, 8H, arom-H), 12.27 (br, 1H, NH).
1
3e: H NMR (DMSO-d6): d 7.35–8.70 (m, 8H, arom-H), 12.15 (br, 1H, NH).
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