Strontium chloride-catalyzed one-pot synthesis of 4(3H)-quinazolinones under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2010.05.021

Strontium chloride was used as an efficient and recyclable catalyst in one-pot condensation of anthranilic acid, ortho esters and amines leading to the formation of 4(3. H)-quinazolinone derivatives in good yields at room temperature under solvent-free co

Full text of DOI:10.1016/j.cclet.2010.05.021

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1167–1170
www.elsevier.com/locate/cclet
Strontium chloride-catalyzed one-pot synthesis
of 4(3H)-quinazolinones under solvent-free conditions
b
a
Min Wang a, , Zhi Guo Song , Ting Ting Zhang
*
a College of Chemistry and Chemical Engineering, Bohai University, Jinzhou 121000, China
b Center for Science & Technology Experiment, Bohai University, Jinzhou 121000, China
Received 23 February 2010
Abstract
Strontium chloride was used as an efficient and recyclable catalyst in one-pot condensation of anthranilic acid, ortho esters and
amines leading to the formation of 4(3H)-quinazolinone derivatives in good yields at room temperature under solvent-free
conditions.
# 2010 Min Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 4(3H)-Quinazolinones; One-pot synthesis; Solvent-free conditions; Strontium chloride
The synthesis of 4(3H)-quinazolinones and their derivatives has attracted considerable attention from organic and
medicinal chemists for many years because most of them showed wide pharmacological and therapeutic properties
such as antimalarial, antitumor, anticonvulsant, antiinflammatory, and antimicrobial activities [1–5]. In addition,
4(3H)-quinazolinones are present in several bioactive natural products [6,7]. Their properties turn them very
interesting targets to organic chemists, and several strategies for their synthesis were already developed: (a)
cyclocondensation of anthranilamide with aryl, alkyl or heteroaryl aldehydes in refluxing ethanol [8]; (b)
poly(ethylene glycol) supported aza-Wittig reaction [9]; (c) intramolecular cyclization of fluorine-containing S-ethyl
N-benzoylisothioureas [10]; (d) cyclocondensation of 2-fluorobenzoyl chlorides with 2-amino-N-heterocycles [11];
(e) copper-catalyzed cascade reactions of the substituted 2-halobenzoic acids with amidines [12]; (f) reaction of
polymer-bound isothiourea with isatoic anhydride [13]; (g) reaction of anthranilic acids and ammonium or
triethylammonium N-aryldithiocarbamates [14]; (h) a one-pot three-component condensation of anthranilic acid,
ortho esters and amines [15–22]. Among above methods, strategy (h) is one of the most direct procedures for the
preparation of 4(3H)-quinazolinones and their derivatives. It is a type of multi-component reactions (MCRs), which
can produce the desired products in a single step and also the diversity could be achieved simply by varying the
reacting components. Different acid catalysts like NaHSO4, Amberlyst-15, Yb(III)-resin, Yb(OTf)3, [Bi(TFA)3-
nbp]FeCl4 ionic liquid, La(NO3)3Á6H2O, p-toluenesulfonic acid, Keggin-type heteropolyacid under microwave
irradiation, SnCl4Á4H2O, and SiO2–FeCl3 are known to affect this condensation [15–22]. However, some of these
methods associated with certain drawbacks such as refluxed temperature (60–80 8C), long reaction time (20 h),
* Corresponding author.
E-mail address: minwangszg@yahoo.com.cn (M. Wang).
1001-8417/$ – see front matter # 2010 Min Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.021

[(Scheme_1)TD$FIG]
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M. Wang et al. / Chinese Chemical Letters 21 (2010) 1167–1170
Scheme 1.
harmful organic solvent, and using microwave irradiation for accelerated synthesis. Thus, there is a need for a greener
and efficient method that might work under mild conditions.
In the course of our recent work on Lewis acid-catalyzed organic reactions, we found only 1 mol% strontium
chloride (SrCl2Á6H2O) could efficiently catalyze one-pot synthesis of 4(3H)-quinazolinones via three-component
condensation of anthranilic acid 1, ortho esters 2 and amines 3 (Scheme 1). The reaction was carried out at room
temperature under solvent-free conditions. The products 4 were formed within a few minutes in excellent yields.
1. Experimental
Typical procedure for the synthesis of 4(3H)-quinazolinones (4): a mixture of anthranilic acid (10 mmol) 1, an
orthoester (12 mmol) 2, an amine (12 mmol) 3, and SrCl2Á6H2O (0.1 mmol) was stirred at room temperature for an
appropriate time (Table 2). The reaction was monitored by TLC. After completion, 20 mL CH2Cl2 was added to
dissolve the solid product. Then, catalyst was removed by gravity filtration and dried for its next use. The organic
filtrate was evaporated to yield the crude product. The crude product was purified by recrystalization from ethanol to
1
give the corresponding pure compound 4. All the pure products were identified by their mp, IR, H NMR, MS and
elemental analysis. Analytical data for new compounds:
3-(2-Methylphenyl)quinazolin-4(3H)-one (4b). White solid. IR (KBr, cmÀ1): 1689, 1594, 1489. 1H NMR
(500 MHz, DMSO-d6): d 8.55 (s, 1H), 8.31 (d, 1H, J = 7.2 Hz), 7.75–7.50 (m, 2H), 7.24–7.07 (m, 5H), 2.31 (s, 3H).
MS (ESI) m/z: 237.0 (M+H)+. Anal. Calcd. for C15H12ON2: C, 76.26; H, 5.12; O, 6.77. Found: C, 76.35; H, 5.09; O,
6.74%.
3-(2-Methoxyphenyl)quinazolin-4(3H)-one (4e). White solid. IR (KBr, cmÀ1): 1682, 1595, 1455. 1H NMR
(500 MHz, DMSO-d6): d 8.36 (s, 1H), 8.21 (d, 1H, J = 7.7 Hz), 7.45 (d, 1H, J = 6.8 Hz), 7.24 (t, 1H, J = 7.0 Hz), 7.08–
7.03 (m, 2H), 6.93 (t, 1H, J = 7.1 Hz), 6.78 (d, 1H, J = 8.2 Hz), 6.54 (t, 1H, J = 7.3 Hz), 3.85 (s, 3H). MS (ESI) m/z:
253.0 (M+H)+. Anal. Calcd. for C15H12O2N2: C, 71.42; H, 4.80; O, 12.68. Found: C, 71.35; H, 4.81; O, 12.70%.
3-(4-Methoxyphenyl)quinazolin-4(3H)-one (4f). White solid. IR (KBr, cmÀ1): 1715, 1591, 1453. 1H NMR
(500 MHz, DMSO-d6): d 8.55 (s, 1H), 8.05 (d, 1H, J = 7.5 Hz), 7.54–7.51 (m, 2H), 7.17 (t, 1H, J = 7.5 Hz), 6.97 (dd,
4H, J = 8.5, 9.5 Hz), 3.76 (s, 3H). MS (ESI) m/z: 253.0 (M+H)+. Anal. Calcd. for C15H12O2N2: C, 71.42; H, 4.80; O,
12.68. Found: C, 71.30; H, 4.84; O, 12.73%.
3-(2-Chlorophenyl)quinazolin-4(3H)-one (4g). Yellow solid. IR (KBr, cmÀ1): 1668, 1601, 1413. 1H NMR
(500 MHz, DMSO-d6): d 8.57 (s, 1H), 8.01 (d, 1H, J = 7.7 Hz), 7.74–7.71 (m, 2H), 7.61 (t, 1H, J = 7.6 Hz), 7.25–7.16
(m, 2H), 6.76 (d, 1H, J = 8.1 Hz), 6.52 (t, 1H, J = 7.2 Hz). MS (ESI) m/z: 257.0 (M+H)+. Anal. Calcd. for
C14H9ON2Cl: C, 65.51; H, 3.53; O, 6.23; N, 10.91. Found: C, 65.42; H, 3.55; O, 6.26; N, 10.96%.
1
3-(4-Chlorophenyl)quinazolin-4(3H)-one (4h). Pale yellow solid. IR (KBr, cmÀ1): 1671, 1616, 1484. H NMR
(500 MHz, DMSO-d6): d 8.52 (s, 1H), 7.71–7.68 (m, 2H), 7.24–7.20 (m, 2H), 6.75 (d, 2H, J = 7.5 Hz), 6.52 (d, 2H,
J = 7.2 Hz). MS (ESI) m/z: 257.0 (M+H)+. Anal. Calcd. for C14H9ON2Cl: C, 65.51; H, 3.53; O, 6.23; N, 10.91. Found:
C, 65.62; H, 3.50; O, 6.19; N, 10.85%.
3-(4-Bromophenyl)quinazolin-4(3H)-one (4i). White solid. IR (KBr, cmÀ1): 1712, 1586, 1443. 1H NMR
(500 MHz, DMSO-d6): d 8.55 (s, 1H), 8.01 (d, 1H, J = 7.6 Hz), 7.60 (t, 1H, J = 7.5 Hz), 7.46–7.44 (m, 4H), 7.19 (d,
2H, J = 7.5 Hz,). MS (ESI) m/z: 302.0 (M+H)+. Anal. Calcd. for C14H9ON2Br: C, 55.84; H, 3.01; O, 5.31; N, 9.30.
Found: C, 55.75; H, 3.03; O, 5.35; N, 9.24%.
1
3-(4-Carboxylphenyl)quinazolin-4(3H)-one (4m). White solid. IR (KBr, cmÀ1): 1701, 1592, 1483. H NMR
(500 MHz, DMSO-d6): d 10.49 (s, 1H), 8.35 (s, 1H), 7.92–7.88 (m, 3H), 7.71 (t, 2H, J = 8.5 Hz), 7.63 (d, 1H,

M. Wang et al. / Chinese Chemical Letters 21 (2010) 1167–1170
1169
Table 1
Screening of different Lewis acid catalystsa.
Entry
Catalyst
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
None
1
5
CuCl2Á2H2O
Cu(o-CH3C6H4SO3)2Á4H2O
AlCl3Á6H2O
La(CH3SO3)3Á2H2O
I2
1
50
0.8
0.5
1
62
67
84
1
90
ZnCl2
0.8
0.6
0.6
92
(NH4)2Ce(NO3)6
SrCl2Á6H2O
94
99, 97, 94, 91b
a
Reaction conditions: anthranilic acid (10 mmol), triethyl orthoformate (12 mmol), aniline (12 mmol), catalyst (0.1 mmol), room temperature.
Catalyst was reused four times.
b
J = 5.5 Hz), 7.31 (d, 1H, J = 8.5 Hz), 6.56 (d, 1H, J = 5.5 Hz). MS (ESI) m/z: 267.0 (M+H)+. Anal. Calcd. for
C15H10O3N2: C, 67.67; H, 3.79; O, 18.03. Found: C, 67.59; H, 3.78; O, 18.06%.
3-Benzylquinazolin-4(3H)-one (4n). White solid. IR (KBr, cmÀ1): 1678, 1620, 1459. 1H NMR (500 MHz, DMSO-
d6): d 8.52 (s, 1H), 8.00 (d, 1H, J = 7.5 Hz), 7.54–7.46 (m, 2H), 7.41–7.37 (m, 4H), 7.32 (t, 1H, J = 6.8 Hz), 7.14 (t, 1H,
J = 7.0 Hz), 4.63 (s, 2H). MS (ESI) m/z: 237.0 (M+H)+. Anal. Calcd. for C15H12ON2: C, 76.26; H, 5.12; O, 6.77.
Found: C, 76.35; H, 5.09; O, 6.75%.
2. Results and discussion
First, we compared the catalytic activity of SrCl2Á6H2O with other Lewis acids in the model condensation of
anthranilic acid, triethyl orthoformate and aniline (Table 1). A controlled experiment was carried out first; the results
show that little product was produced after 1 h (Entry 1). Screening of different catalysts revealed that SrCl2Á6H2O was
the most effective catalyst for this transformation since it resulted in the highest yield in short reaction time. Only
1 mol% SrCl2Á6H2O was enough to catalyze the transformation. The recyclability of SrCl2Á6H2O was also
investigated, and it could be recycled four times without distinct loss of activity (Entry 9).
In order to explore the generality and scope of the new procedure, three-component one-pot reaction of anthranilic
acid with triethyl orthoformate or trimethyl orthoformate and different substituted aryl amines or alkyl amine was
tested and the results were listed in Table 2. Most reactions proceeded smoothly in the presence of 1 mol% SrCl2Á6H2O
Table 2
SrCl2Á6H2O-catalyzed one-pot reaction of anthranilic acid with ortho esters and aminesa.
Product (4)
R1
Isolated yield (%) (time (h))
Mp (8C)
HC(OEt)3
HC(OMe)3
Found
Reported [17]
4a
4b
4c
4d
4e
4f
Ph
99 (0.6)
83 (0.4)
74 (2.5)
83 (0.3)
96 (0.6)
91 (0.2)
88 (0.2)
69 (0.2)
77 (0.15)
62 (2)
58 (3)
140–142
157–159
138–140
145–148
150–153
133–135
117–119
122–124
147–149
155–157
153–156
165–167
239–241
154–155
–
139–140
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
4-BrC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-COOHC6H4
PhCH2
94 (1.5)
55 (5.5)
85 (1)
–
136–137
146–147
79 (2.5)
98 (1)
–
–
4g
4h
4i
82 (0.3)
74 (0.5)
82 (0.4)
62 (4.5)
81 (0.3)
90 (0.2)
59 (0.1)
14 (0.35)
0 (24)
–
–
–
4j
156–158
4k
4l
84 (0.25)
94 (0.1)
76 (0.1)
29 (0.03)
0 (24)
154–156
165–166
4m
4n
4o
–
–
–
n-C4H9
aThe purity and the identity of the products were determined by mp, IR, 1H NMR, MS and elemental analysis.

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M. Wang et al. / Chinese Chemical Letters 21 (2010) 1167–1170
at room temperature to give the corresponding 3-substituted 4(3H)-quinazolinones in moderate to high yields. Triethyl
orthoformate and trimethyl orthoformate are found to be equally effective for this transformation. The yields of
products from trimethyl orthoformate were lower than those from triethyl orthoformate. Aryl amines carrying either
electron-donating groups (–Me and –OMe) or electron-withdrawing groups (–Cl, –Br and –NO2) were all suitable for
use with this new procedure. Furthermore, the position of the substituents on the aromatic ring of amines has no
obvious effects on this conversion. It is worth mentioning that aniline having strong electro-withdrawing substitutes,
e.g., Cl and NO2, gave generally no product at room temperature in previous reports, also yielded the corresponding
4(3H)-quinazolinones in moderate yields when our method was used. Besides aryl amines, alkyl amines such as
benzyl amine and n-butyl amine were also investigated. However, low and zero yields were provided (4n, 4o). In
conclusion, SrCl2Á6H2O is an efficient catalyst for the preparation of 4(3H)-quinazolinones and their derivatives from
aryl amines. The method offers several advantages including simple work-up, mild reaction conditions, commercially
available and reusable catalyst, and the relatively clean procedure.
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