Efficient one-pot synthesis of 2,3-dihydroquinazoline-4(1H)-ones promoted by FeCl3/neutral Al2O3

Article abstract of DOI:10.1007/s11164-018-03732-w

2,3-Dihydroquinazolin-4(1H)-one derivatives have been synthesized via one-pot reaction of isatoic anhydride, aromatic aldehyde, and ammonium acetate catalyzed by FeCl₃/neutral Al₂O₃ in tert-butanol under reflux conditions.

Full text of DOI:10.1007/s11164-018-03732-w

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-03732-w
Efcient one‑pot synthesis
of 2,3‑dihydroquinazoline‑4(1H)‑ones promoted by FeCl3/
neutral Al2O3
Suo Juan Wu1 · Zi Qiang Zhao1 · Jing Shuo Gao1 · Bao Hua Chen2 ·
Guo Feng Chen1
Received: 15 September 2018 / Accepted: 29 December 2018
© Springer Nature B.V. 2019
Abstract
2,3-Dihydroquinazolin-4(1H)-one derivatives have been synthesized via one-pot
reaction of isatoic anhydride, aromatic aldehyde, and ammonium acetate catalyzed
by FeCl3/neutral Al2O3 in tert-butanol under refux conditions. Inexpensive and eas-
ily available reagents, convenient work-up procedure, reusable catalyst, and moder-
ate to good yield are the salient features of this protocol.
Keywords 2,3-Dihydroquinazolin-4(1H)-one · FeCl3/neutral Al2O3 · One-pot
synthesis · Isatoic anhydride · Aldehydes
Introduction
2,3-Dihydroquinazolin-4(1H)-one derivatives are an important class of heterocycles
containing nitrogen atom that exhibit a wide range of pharmacological and biologi-
cal activities. Aquamox, evodiamine, fenquizone, metolazone, etc. are representa-
tive drugs containing quinazolinone core scafold (Fig. 1). These quinazolinones
can display a wide range of medicinal properties, including antibacterial [1], anti-
viral [2], antitumor [3], antihistamine [4], antiinfammatory [5–7], antiosteoporosis
[8], anticonvulsant [9], antihypertensive [10], antidefbrillatory [11], and anticancer
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-018-03732-w) contains supplementary material, which is available to authorized users.
*
Guo Feng Chen
chenguofeng@hbu.cn
1
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry
and Environmental Science, Hebei University, Wusi East Road No. 180, Baoding 071002,
People’s Republic of China
2
College of Pharmaceutical Sciences, Hebei University, Baoding 071002,
People’s Republic of China
Vol.:(0123456789)
1 3

S. J. Wu et al.
Fig. 1 Representative example quinazolinone drugs
efects [12] as well as potent human immunodefciency virus (HIV)-1 reverse tran-
scriptase inhibition [13, 14]. On the other hand, 2,3-dihydroquinazolin-4(1H)-one
derivatives can be easily oxidized to 2-substituted-4(3H)-quinazolinones, which are
important building blocks in synthesis of signifcant biologically active heterocy-
clic compounds. Hence, synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives
is currently of great interest. In recent years, protocols for preparation of these
compounds have been carried out in diferent ways [15]. Among them, the typical
procedure includes condensation of anthranilamide with structurally diverse alde-
hydes or ketones in presence of various catalysts such as 2-morpholinoethanesul-
fonic acid [16], Co-carbon nanotubes (CNTs) [17], succinimide-N-sulfonic acid
(SuSA) [18], propylphosphonic anhydride [19], poly(VPyPS)-PW [20], HgCl2 [21],
SiO2-H3PW12O40 [22], α-chymotrypsin [23], and nanocatalysts [24–28]. A more
attractive and atom-efcient strategy for preparation of these compounds is one-pot,
three-component reaction of isatoic anhydride, aldehydes, and ammonium acetate or
primary amine. A number of catalysts, such as magnetic Fe3O4 nanoparticles [29],
Al/Al2O3 nanoparticles [30], ethylenediamine diacetate [31], citric acid [32], silica-
bonded N-propylsulfamic acid [33], silica-bonded S-sulfonic acid [34], SrCl2·6H2O
[35], Cu-CNTs [36], H3PO4/Al2O3 [37], and dodecylbenzenesulfonic acid [38], have
been utilized to accomplish this transformation. These synthetic strategies are useful
to facilitate synthesis of the desired compounds in many ways. However, some of
these methodologies are associated with diferent drawbacks such as long reaction
time, tedious work-up, low yield, and toxic catalyst. Therefore, development of a
mild, simple, efcient, and general method for synthesis of 2,3-dihydroquinazolin-
4(1H)-ones from readily available reagents remains one of the major challenges fac-
ing researchers in the feld of organic synthesis.
Recently, development and utilization of supported catalysts have received
increasing attention [39]. Such catalysts are efcient in organic synthesis, ofering
1 3

Efcient one‑pot synthesis of…
the advantages of noncorrosivity, high selectivity, mild reaction conditions, and easy
separation from the reaction system. As reported in previous papers, FeCl3/Al2O3
has been applied in synthesis of 1,1′-binaphthalene-2,2′-diol [40] and diphenylmeth-
ane [41], esterifcation of tert-butanol [42], synthesis of 2-amino-2-hydroxy-1,1′-
binaphthyl [43], desulfurization [44], and synthesis of 2-substituted benzimidazoles
[45], afording the target products in higher yields.
In continuation of our research interest in synthesis of N–heterocyclic compounds
with pharmacological activity using environmentally benign catalysts [45–49], we
report herein a practical method for synthesis of 2,3-dihydroquinazolin-4(1H)-ones
via one-pot three-component condensation of isatoic anhydride, aldehydes, and
ammonium acetate in presence of catalytic amount of FeCl3/neutral Al2O3 using
tert-butanol as solvent under refux conditions (Scheme 1).
Experimental
Apparatus, materials, and measurements
All chemicals were commercially available and used without further purifcation.
FeCl3/neutral Al2O3 (10 % w/w) was prepared in accordance with a previously
reported procedure [45]. All yields refer to isolated products after column chroma-
tography on silica gel (200–300 mesh). Melting points were obtained using a TECH
X-4 apparatus and are uncorrected. The reaction procedure was monitored in real
time by thin-layer chromatography (TLC) plates visualized using ultraviolet light
(254 nm). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker
Avance 600 (600 MHz for 1H and 150 MHz for 13C) instrument. Chemical shifts are
expressed in ppm using tetramethylsilane (TMS) as internal standard with dimethyl-
sulfoxide (DMSO)-d6 as solvent; coupling constants (J) are reported in Hz. Mass-
spectrometric data were collected on an Agilent Technologies 6310 ion trap LC/MS.
Infrared (IR) spectra were measured on a Bruker Tensor-27 spectrophotometer using
KBr pellets.
General procedure for synthesis of 2,3‑dihydroquinazolin‑4(1H)‑ones
To a mixture of isatoic anhydride (2 mmol), aldehyde (2.4 mmol), and ammonium
acetate (3.2 mmol) in tert-butanol (10 mL), FeCl3/neutral Al2O3 (100 mg) was
Scheme 1 One-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones
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S. J. Wu et al.
Table 1 Efect of diferent
solvents on reaction of isatoic
anhydride, benzaldehyde, and
ammonium acetate
Entry
Solvent
Time (h)
Yield (%)a
TOFb (h−1
)
1
2
3
4
5
6
7
8
Solvent-free
MeOH
n-Propanol
n-Butanol
EtOH
CH2Cl2
THF
CHCl3
H2O
1,4-Dioxane
DMF
Ethyl acetate
3
3
3
3
3
3
3
3
3
3
3
3
3
19
26
12
17
51
58
58
60
62
72
69
81
92
2.06
2.82
1.30
1.84
5.52
6.28
6.28
6.50
6.72
7.80
7.47
8.77
9.97
9
10
11
12
13
tert-Butanol
Experimental conditions: isatoic anhydride (2 mmol), benzaldehyde
(2.4 mmol), ammonium acetate (3.2 mmol), and FeCl3/neutral Al2O3
(100 mg) in 10 mL of diferent solvents under refux
aIsolated yield based on isatoic anhydride
bDefned as moles of product per mole of catalyst per hour
DMF, dimethylformamide; THF, tetrahydrofuran; TOF, turnover fre-
quency
Table 2 Efect of catalyst
amount on reaction of isatoic
anhydride, benzaldehyde, and
ammonium acetate
Entry
FeCl3/neutral Al2O3 Time (h)
(mg)
Yield (%)a
1
2
3
4
5
6
7
0
20
3
3
3
3
3
3
3
65
85
86
90
91
92
92
40
60
80
100
120
Experimental conditions: isatoic anhydride (2 mmol), benzalde-
hyde (2.4 mmol), and ammonium acetate (3.2 mmol) in 10 mL tert-
butanol under refux
aIsolated yield based on isatoic anhydride
added, then the reaction mixture was stirred at refux temperature for appropriate
time as indicated in Tables 1, 2, 3, and 4. After reaction completion as indicated
by TLC (dichloromethane:ethyl acetate, 4:1), the catalyst was separated by fltra-
tion and washed with ethyl acetate. The solvent was evaporated under reduced pres-
sure, and the products were further purifed by chromatography eluted with ethyl
acetate/dichloromethane (1:9) to aford 2,3-dihydroquinazolin-4(1H)-ones in good
1 3

Efcient one‑pot synthesis of…
Table 3 Efect of molar ratio on
Entry
Molar ratioa
Time (h)
Yield (%)b
model reaction
1
2
3
4
5
6
7
8
1.0:1.0:1.6
1.0:1.0:1.8
1.0:1.1:1.6
1.0:1.1:1.8
1.0:1.2:1.0
1.0:1.2:1.2
1.0:1.2:1.4
1.0:1.2:1.6
1.0:1.2:1.8
1.0:1.3:1.4
1.0:1.3:1.6
1.0:1.3:1.8
3
3
3
3
3
3
3
3
3
3
3
3
87
73
89
90
79
83
88
92
92
85
85
92
9
10
11
12
aIsatoic anhydride/benzaldehyde/ammonium acetate(mmol/mmol/
mmol)
bIsolated yield based on isatoic anhydride
Table 4 Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in presence of FeCl3/neutral Al2O3
Entry
R
Product Time (h) Isolated yield (%)a Melting point (°C)
This study Literature value
1
2
3
4
5
6
7
8
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
3
6
3
3
92
68
76
76
92
89
88
89
87
54
38
76
90
76
81
79
207–210
>300
216–218 [17]
300–302 [30]
196–198 [17]
186–188 [22]
225–227 [17]
193–195 [37]
205–206 [17]
185–187 [22]
202–204 [16]
275–277 [22]
206–207 [23]
202–204 [18]
209–212 [24]
165–167 [35]
166–167 [16]
198–200 [22]
–
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CH3C6H4
4-MeOC6H4
4-ClC6H4
199–201
187–188
225–228
192–194
200–203
188–190
204–206
272–274
202–205
198–200
214–216
169–170
163–164
163–166
189–190
197–198
4
5.5
3.5
4
4
7
5
5
3
2
4
5
4
3
2
4.5
4
3-ClC6H4
2-ClC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-OHC6H4
3-OHC6H4
4-FC6H4
4-Me2NC6H4
2,4-Cl2C6H3
Furfural
C6H5CH=CH
3,4,5-(CH3O)3C6H2 4q
3,4-Cl2C6H3
82
90
4r
–
–
–
–
2,4-(NO2)2C6H3
2,3,4-(CH3O)3C6H2
CH3(CH2)2
No product
No product
No product
No product
CH3(CH2)5
–
4
aIsolated yield based on isatoic anhydride
1 3

S. J. Wu et al.
to excellent yield. The authenticity of the products was confrmed by IR, 1H NMR,
13C NMR, and MS and comparing their melting points with literature values.
Spectral and physical data for compounds
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (4a) was isolated as white crystals;
m.p.: 207–210 °C; IR (KBr): 3302, 3183, 3062, 1658, 1612, 1509, 1484, 1389,
1
1300 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.28 (s, 1H, N–H), 7.61 (d, 1H,
J=7.08 Hz, Ar–H), 7.50–7.49 (m, 2H, Ar–H), 7.40–7.33 (m, 3H, Ar–H), 7.24 (t,
1H, J=6.90 Hz, Ar–H), 7.10 (s, 1H, N–H), 6.75 (d, 1H, J=8.04 Hz, Ar–H), 6.67
(t, 1H, J=7.14 Hz, Ar–H), 5.75 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC
163.5, 147.8, 141.6, 133.3, 128.6, 128.4, 128.3, 127.8, 127.3, 126.8, 117.1, 114.9,
114.4, 66.5; m/z (ESI), 225 [M+H]+.
2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (4b) was isolated as bright-
yellow crystals; m.p.: >300 °C; IR (KBr): 3359, 3285, 3176, 1648, 1610, 1519,
1
1482, 1347, 1157, 1009, 859, 748 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.52
(s, 1H, N–H), 8.26 (d, 2H, J=8.70 Hz, Ar–H), 7.75 (d, 2H, J=8.64 Hz, Ar–H), 7.62
(d, 1H, J=7.62 Hz, Ar–H), 7.32 (s, 1H, N–H), 7.27 (t, 1H, J=6.69 Hz, Ar–H), 6.77
(d, 1H, J=8.04 Hz, Ar–H), 6.69 (t, 1H, J=7.35 Hz, Ar–H), 5.92 (s, 1H, CH); 13C
NMR (150 MHz, DMSO-d6): δC 163.2, 149.3, 147.2, 133.5, 129.3, 128.0, 127.4,
125.9, 123.6, 123.5, 117.4, 114.9, 114.5, 65.3; m/z (ESI), 270 [M+H]+.
2-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (4c) was isolated as bright-
yellow crystals; m.p.: 199–201 °C; IR (KBr): 3300, 3192, 3076, 1668, 1652, 1613,
1
1528, 1481, 1350, 1250, 1149, 746 cm−1; H NMR (600 MHz, DMSO-d6): δH
8.53 (s, 1H, N–H), 8.37 (s, 1H, Ar–H), 8.21 (d, 1H, J=7.14 Hz, Ar–H), 7.95 (d,
1H, J=7.68 Hz, Ar–H), 7.70 (t, 1H, J=7.95 Hz, Ar–H), 7.62 (d, 1H, J=7.56 Hz,
Ar–H), 7.34 (s, 1H, N–H), 7.28 (t, 1H, J=7.17 Hz, Ar–H), 6.79 (d, 1H, J=8.10 Hz,
Ar–H), 6.70 (t, 1H, J=7.44 Hz, Ar–H), 5.95 (s, 1H, CH); 13C NMR (150 MHz,
DMSO-d6): δC 163.3, 147.7, 147.3, 144.3, 133.5, 133.3, 130.0, 127.4, 123.2, 121.5,
117.5, 114.9, 114.6, 65.2; m/z (ESI), 270 [M+H]+.
2-(2-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (4d) was isolated as bright-
yellow crystals; m.p.: 187–188 °C; IR (KBr): 3408, 3186, 3070, 2924, 1659, 1609,
1
1536, 1504, 1457, 1390, 1352, 1297, 1173, 1128, 1029 cm−1; H NMR (600 MHz,
DMSO-d6): δH 8.21 (s, 1H, N–H), 8.06 (d, 1H, J=8.10 Hz, Ar–H), 7.86–7.85 (m,
1H, Ar–H), 7.79 (t, 1H, J=7.56 Hz, Ar–H), 7.66–7.61 (m, 2H, Ar–H), 7.26 (t, 1H,
J=7.02 Hz, Ar–H), 7.00 (s, 1H, N–H), 6.77 (d, 1H, J=8.10 Hz, Ar–H), 6.72 (t, 1H,
J=7.47 Hz, Ar–H), 6.33 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC 163.3,
147.6, 147.1, 135.9, 133.9, 133.5, 129.9, 128.9, 127.3, 124.7, 117.6, 114.9, 114.5,
62.1; m/z (ESI), 270 [M+H]+.
2-(p-Tolyl)-2,3-dihydroquinazolin-4(1H)-one (4e) was isolated as white crys-
tals; m.p.: 225–228 °C; IR (KBr): 3311, 3193, 3061, 1662, 1609, 1509, 1483, 1437,
1
1386, 1326, 1295, 1156, 1027 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.22 (s,
1H, N–H), 7.60 (d, 1H, J=7.68 Hz, Ar–H), 7.37 (d, 2H, J=7.74 Hz, Ar–H), 7.23 (t,
1H, J=7.65 Hz, Ar–H), 7.18 (d, 2H, J=7.68 Hz, Ar–H), 7.04 (s, 1H, N–H), 6.74 (d,
1H, J=8.10 Hz, Ar–H), 6.66 (t, 1H, J=7.44 Hz, Ar–H), 5.71 (s, 1H, CH), 2.29 (s,
1 3

Efcient one‑pot synthesis of…
3H, CH3); 13C NMR (150 MHz, DMSO-d6): δC 163.6, 147.9, 138.6, 137.7, 133.2,
129.2, 128.8, 127.7, 127.3, 126.7, 117.0, 115.0, 114.4, 66.3, 20.7; m/z (ESI), 239
[M+H]+.
2-(4-Methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (4f) was isolated as
white crystals; m.p.: 192–194 °C; IR (KBr): 3298, 3181, 3058, 1658, 1611, 1509,
1434, 1388, 1300, 1250, 1176, 1032 cm−1; 1H NMR (600 MHz, DMSO-d6): δH 8.17
(s, 1H, N–H), 7.61 (d, 1H, J=7.74 Hz, Ar–H), 7.42 (d, 2H, J=8.64 Hz, Ar–H),
7.23 (t, 1H, J=8.28 Hz, Ar–H), 6.99 (s, 1H, N–H), 6.94 (d, 2H, J=8.58 Hz, Ar–H),
6.74 (d, 1H, J=8.10 Hz, Ar–H), 6.67 (t, 1H, J=7.44 Hz, Ar–H), 5.70 (s, 1H, CH),
3.74 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6): δC 163.7, 159.4, 148.0, 133.5,
133.2, 129.4, 128.2, 127.3, 117.0, 115.0, 114.4, 114.0, 113.6, 66.3, 55.1; m/z (ESI),
255 [M+H]+.
2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4g) was isolated as white
crystals; m.p.: 200–203 °C; IR (KBr): 3307, 3187, 3063, 1659, 1609, 1509, 1484,
1
1433, 1386, 1294, 1156, 1092 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.32 (s,
1H, N–H), 7.61 (d, 1H, J=7.62 Hz, Ar–H), 7.51–7.50 (m, 2H, Ar–H), 7.46–7.45
(m, 2H, Ar–H), 7.25 (t, 1H, J=7.62 Hz, Ar–H), 7.13 (s, 1H, N–H), 6.75 (d, 1H,
J=8.10 Hz, Ar–H), 6.68 (t, 1H, J=7.44 Hz, Ar–H), 5.77 (s, 1H, CH); 13C NMR
(150 MHz, DMSO-d6): δC 163.4, 147.6, 140.7, 133.4, 132.9, 129.6, 128.7, 128.3,
127.3, 117.3, 114.9, 114.4, 65.7; m/z (ESI), 259 [M+H]+.
2-(3-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4h) was isolated as white
crystals; m.p.: 188–190 °C; IR (KBr): 3291, 3195, 3065, 1651, 1612, 1512, 1481,
1
1436, 1386, 1297, 1159, 1097 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.38 (s,
1H, N–H), 7.61 (d, 1H, J=7.74 Hz, Ar–H), 7.53 (s, 1H, Ar–H), 7.45–7.41 (m, 3H,
Ar–H), 7.26 (t, 1H, J=7.62 Hz, Ar–H), 7.20 (s, 1H, N–H), 6.76 (d, 1H, J=8.10 Hz,
Ar–H), 6.69 (t, 1H, J=7.44 Hz, Ar–H), 5.78 (s, 1H, CH); 13C NMR (150 MHz,
DMSO-d6): δC 163.4, 147.5, 144.4, 133.4, 132.9, 130.3, 128.2, 127.3, 126.7, 125.4,
117.3, 114.9, 114.4, 65.5; m/z (ESI), 259 [M+H]+.
2-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4i) was isolated as white
crystals; m.p.: 204–206 °C; IR (KBr): 3360, 3192, 3068, 1647, 1612, 1503, 1391,
1328, 1254, 1186, 1123, 1053, 853, 749 cm−1; 1H NMR (600 MHz, DMSO-d6): δH
8.20 (s, 1H, N–H), 7.67–7.65 (m, 2H, Ar–H), 7.50–7.48 (m, 1H, Ar–H), 7.41–7.38
(m, 2H, Ar–H), 7.26 (t, 1H, J=6.96 Hz, Ar–H), 7.01 (s, 1H, N–H), 6.76 (d, 1H,
J=8.04 Hz, Ar–H), 6.71 (t, 1H, J=7.29 Hz, Ar–H), 6.14 (s, 1H, CH); 13C NMR
(150 MHz, DMSO-d6): δC 163.6, 147.6, 137.9, 133.4, 131.8, 130.2, 129.5, 128.7,
127.4, 127.3, 117.4, 114.7, 114.5, 63.7; m/z (ESI), 259 [M+H]+.
2-(4-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (4j) was isolated as white
crystals; m.p.: 272–274 °C; IR (KBr): 3321, 3194, 1645, 1607, 1484, 1378, 1286,
1
1227, 1157, 869, 756 cm−1; H NMR (600 MHz, DMSO-d6): δH 9.49 (s, 1H, OH),
8.08 (s, 1H, N–H), 7.61 (d, 1H, J=6.96 Hz, Ar–H), 7.30 (d, 2H, J=8.46 Hz, Ar–H),
7.23 (t, 1H, J=6.93 Hz, Ar–H), 6.93 (s, 1H, N–H), 6.77–6.72 (m, 3H, Ar–H), 6.67
(t, 1H, J=7.38 Hz, Ar–H), 5.65 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC
163.7, 157.6, 148.1, 133.1, 131.6, 129.6, 128.2, 127.3, 117.0, 115.3, 114.9, 114.3,
66.6; m/z (ESI), 240 [M+H]+.
2-(3-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (4k) was isolated as
white crystals; m.p.: 202–205 °C; IR (KBr): 3324, 3190, 1644, 1611, 1485, 1466,
1 3

S. J. Wu et al.
1
1361, 1283, 1227, 1157 cm−1; H NMR (600 MHz, DMSO-d6): δH 9.49 (s, 1H,
O–H), 8.23 (s, 1H, N–H), 7.61 (d, 1H, J=7.68 Hz, Ar–H), 7.24 (t, 1H, J=7.62 Hz,
Ar–H), 7.17 (t, 1H, J=7.77 Hz, Ar–H), 7.07 (s, 1H, N–H), 6.91–6.89 (m, 2H,
Ar–H), 6.75–6.72 (m, 2H, Ar–H), 6.67 (t, 1H, J=7.44 Hz, Ar–H), 5.66 (s, 1H, CH);
13C NMR (150 MHz, DMSO-d6): δC 163.5, 157.3, 147.8, 143.2, 133.2, 129.3, 127.3,
117.4, 116.9, 115.3, 114.8, 114.3, 113.6, 66.4; m/z (ESI), 240 [M+H]+.
2-(4-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4l) was isolated as white
crystals; m.p.: 202–205 °C; IR (KBr): 3300, 3182, 3066, 1658, 1610, 1508, 1483,
1
1438, 1388, 1296, 1233, 1156 cm−1; H NMR (600 MHz, DMSO-d6): δH 8.28 (s,
1H, N–H), 7.62 (d, 1H, J=7.44 Hz, Ar–H), 7.55–7.53 (m, 2H, Ar–H), 7.26–7.21
(m, 3H, Ar–H), 7.09 (s, 1H, N–H), 6.75 (d, 1H, J=8.10 Hz, Ar–H), 6.69 (t, 1H,
J=7.44 Hz, Ar–H), 5.78–5.75 (m, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC
163.5, 162.9, 161.3, 147.8, 137.8, 137.7, 133.3, 129.0, 127.3, 117.2, 115.1, 114.4,
65.9, 54.9; m/z (ESI), 243 [M+H]+.
2-(4-(Dimethylamino)phenyl)-2,3-dihydroquinazolin-4(1H)-one (4m) was iso-
lated as canary-yellow crystals; m.p.: 214–216 °C; IR (KBr): 3291, 3188, 1656,
1
1612, 1517, 1485, 1438, 1388, 1355, 1295, 1233, 1159 cm−1; H NMR (600 MHz,
DMSO-d6): δH 8.07 (s, 1H, N–H), 7.62 (d, 1H, J=7.68 Hz, Ar–H), 7.31 (d, 2H,
J=8.58 Hz, Ar–H), 7.23 (t, 1H, J=7.62 Hz, Ar–H), 6.92 (s, 1H, N–H), 6.75–6.72
(m, 3H, Ar–H), 6.67 (t, 1H, J=7.44 Hz, CH), 2.89 (s, 6H, CH3); 13C NMR
(150 MHz, DMSO-d6): δC 163.8, 162.4, 152.3, 150.6, 148.2, 133.1, 128.9, 128.7,
127.7, 127.3, 116.9, 115.0, 114.4, 112,0, 111.2, 66.6; m/z (ESI), 268 [M+H]+.
2-(2,4-Dichlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4n) was isolated as
white crystals; m.p.: 169–170 °C; IR (KBr): 3339, 3186, 3085, 2906, 1663, 1610,
1479, 1377, 1295, 1237, 1155, 1100, 1052, 1007 cm−1; 1H NMR (600 MHz, DMSO-
d6): δH 8.23 (s, 1H, N–H), 7.67–7.65 (m, 3H, Ar–H), 7.51–7.49 (m, 1H, Ar–H), 7.27
(t, 1H, J=7.65 Hz, Ar–H), 7.02 (s, 1H, N–H), 6.76 (d, 1H, J=8.10 Hz, Ar–H), 6.73
(t, 1H, J=7.44 Hz, Ar–H), 6.12 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC
163.5, 150.1, 147.5, 137.0, 133.9, 133.5, 132.9, 130.1, 128.9, 127.6, 127.4, 117.6,
114.6, 63.3; m/z (ESI), 293 [M+H]+.
2-(Furan-2-yl)-2,3-dihydroquinazolin-4(1H)-one (4o) was isolated as yellow crys-
tals; m.p.: 163–164 °C; IR (KBr): 3301, 3178, 3064, 2939, 1658, 1611, 1514, 1483,
1
1441, 1389, 1330, 1299, 1258, 1152, 1013 cm−1; H NMR (600 MHz, DMSO-d6):
δH 8.38 (s, 1H, N–H), 7.61–7.60 (m, 2H, Ar–H), 7.23 (t, 1H, J=7.62 Hz, Ar–H),
7.20 (s, 1H, CH=), 6.75 (d, 1H, J=8.10 Hz, Ar–H), 6.67 (t, 1H, J=7.47 Hz, Ar–H),
6.37 (s, 1H, N–H), 6.26 (d, 1H, J=3.12 Hz, CH=), 5.74 (s, 1H, CH); 13C NMR
(150 MHz, DMSO-d6): δC 163.2, 154.5, 147.1, 142.7, 133.2, 127.2, 117.2, 114.9,
114.4, 110.3, 107.1, 60.2; m/z (ESI), 214 [M+H]+.
(E)-2-Styryl-2,3-dihydroquinazolin-4(1H)-one (4p) was isolated as white crys-
tals; m.p.: 163–166 °C; IR (KBr): 3287, 3182, 3058, 2929, 1648, 1612, 1515, 1486,
1
1441, 1392, 1331, 1299, 1156, 1072, 1032 cm−1; H NMR (600 MHz, DMSO-d6):
δH 8.12 (s, 1H, N–H), 7.62 (d, 1H, J=7.68 Hz, Ar–H), 7.45 (d, 2H, J=7.56 Hz,
Ar–H), 7.34 (t, 2H, J=7.47 Hz, Ar–H), 7.28–7.24 (m, 2H, Ar–H), 6.88 (s, 1H,
N–H), 6.76 (d, 1H, J=8.10 Hz, Ar–H), 6.70–6.66 (m, 2H, CH=), 6.37 (dd, 1H,
J1 =15.84 Hz, J2 =6.78 Hz, Ar–H), 5.31 (d, 1H, J=6.48 Hz, Ar–H); 13C NMR
1 3

Efcient one‑pot synthesis of…
(150 MHz, DMSO-d6): δC 163.3, 147.7, 135.7, 133.2, 131.6, 129.1, 128.7, 128.3,
128.1, 127.3, 126.6, 117.1, 114.8, 114.5, 65.8, 64.0; m/z (ESI), 251 [M+H]+.
2-(3,4,5-Trimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (4q) was isolated
as white crystals; m.p.: 189–190 °C; IR (KBr): 3322, 3212, 3066, 2937, 1649, 1608,
1
1495, 1460, 1420, 1357, 1326, 1299, 1126, 1040, 1004 cm−1; H NMR (600 MHz,
DMSO-d6): δH 8.19 (s, 1H, N–H), 7.62 (d, 1H, J=7.68 Hz, Ar–H), 7.26 (t, 1H,
J=8.22 Hz, Ar–H), 7.03 (s, 1H, N–H), 6.85 (s, 2H, Ar–H), 6.77 (d, 1H, J=8.10 Hz,
Ar–H), 6.69 (t, 1H, J=7.47 Hz, Ar–H), 5.71 (s, 1H, CH), 3.77 (s, 6H, CH3), 3.65 (s,
3H, CH3); 13C NMR (150 MHz, DMSO- d6): δC 163.7, 163.6, 152.7, 148.0, 137.6,
136.6, 133.2, 127.3, 117.2, 115.0, 114.4, 104.4, 104.3, 66.8, 59.9, 55.9; m/z (ESI),
315 [M+H]+ .
2-(3,4-Dichlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4r) was isolated as
white crystals; m.p.: 197–198 °C; IR (KBr): 3258, 3180, 3060, 2929, 1650, 1610,
1
1515, 1468, 1387, 1317, 1248, 1186, 1153, 1128, 1030 cm−1; H NMR (600 MHz,
DMSO-d6): δH 8.41 (s, 1H, N–H), 7.72 (s, 1H, Ar–H), 7.67 (d, 1H, J=8.34 Hz,
Ar–H), 7.61 (d, 1H, J=7.62 Hz, Ar–H), 7.47 (d, 1H, J=6.72 Hz, Ar–H), 7.27 (d,
1H, J=7.65 Hz, Ar–H), 7.23 (s, 1H, N–H), 6.77 (d, 1H, J=8.10 Hz, Ar–H), 6.70
(t, 1H, J=7.44 Hz, Ar–H), 5.80 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δC
163.3, 147.3, 143.0, 133.5, 130.9, 130.8, 130.6, 128.9, 127.4, 127.0, 117.5, 114.9,
114.5, 65.0; m/z (ESI), 293 [M+H]+.
Results and discussion
To evaluate the efect of diferent solvents on the condensation, the three-compo-
nent one-pot reaction of isatoic anhydride, benzaldehyde, and ammonium acetate
was chosen as model reaction in presence of FeCl3/neutral Al2O3 (Table 1). We
examined the reaction in diferent solvent systems (solvent free, MeOH, EtOH,
n-propanol, n-butanol, CH2Cl2, THF, CHCl3, H2O, 1,4-dioxane, DMF, ethyl acetate,
and tert-butanol) as depicted in Table 1. Among the tested conditions, solvent-free,
MeOH, n-propanol, and n-butanol gave 2-phenyl-2,3-dihydroquinazolin-4(1H)-one
(4a) in poor yield with low turnover frequency (TOF) (Table 1, entries 1–4). Use of
EtOH, CH2Cl2, THF, CHCl3, H2O, 1,4-dioxane, and DMF gave moderate yield with
obviously increased TOF (Table 1, entries 5–11). When the experiment was carried
out in ethyl acetate, the yield of 4a was 81 % and the TOF was 8.77 h−1 (Table 1,
entry 12). The best conversion was observed when the reaction was performed in
tert-butanol, with 4a being obtained in 92 % yield with TOF of 9.97 h−1 (Table 1,
entry 13). Therefore, tert-butanol was selected as solvent for this reaction.
Moreover, we also found that the yield of the product 4a was obviously afected by
the amount of catalyst used in this reaction (Table 2). Without any catalyst, the product
was obtained in 65 % yield (Table 2, entry 1). When the amount of catalyst was 20, 40,
60, 80, and 100 mg, formation of the product was observed in 85 %, 86 %, 90 %, 91 %,
and 92 % yield (Table 2, entries 2–6), respectively. Using lower amounts of catalyst
resulted in lower yield, while increasing the amount of catalyst above 100 mg did not
improve the reaction yield (Table 2, entry 7). From these results, it can be concluded
1 3

S. J. Wu et al.
that the optimum amount of the catalyst was 100 mg, giving 4a in yield of 92 %
(Table 2, entry 6).
To determine the optimum molar ratio of the substrates, the yields of the model
reaction in tert-butanol using diferent molar ratios of isatoic anhydride, benzaldehyde,
and ammonium acetate were obtained and compared (Table 3). As seen from Table 3,
the best result was obtained using a ratio of 1:1.2:1.6 of isatoic anhydride, benzalde-
hyde, and ammonium acetate in presence of FeCl3/neutral Al2O3 (Table 3, entry 8).
With the optimized conditions in hand, the reactions of diferent aromatic aldehydes
with either electron-donating or electron-withdrawing groups were screened to explore
the scope and generality of this protocol for synthesis of various 2,3-dihydroquinazo-
lin-4(1H)-ones. The results are summarized in Table 4. As indicated in Table 4, aro-
matic aldehydes with electron-donating substituents performed well with isatoic anhy-
dride and ammonium acetate in presence of FeCl3/neutral Al2O3 in tert-butanol under
refux conditions, afording the desired products in excellent yield (Table 4, entries 5,
6, 13). However, aldehydes with strongly electron-withdrawing groups on aromatic
ring gave the products in moderate yield under the similar reaction conditions (Table 4,
entries 2–4). These observations indicate that the electronic efect and the position of
the substituent group on the phenyl ring had some impact on this conversion.
We also examined the reaction of furfuraldehyde with isatoic anhydride and ammo-
nium acetate, which gave the desired product 2-(furan-2-yl)-2,3-dihydroquinazolin-
4(1H)-one (4o) in good yield (81 %) (Table 4, entry 15). 3,4,5-Trimethoxybenzalde-
hyde was also condensed with isatoic anhydride and ammonium acetate successfully;
the corresponding 2-3,4,5-trimethoxyphenyl-2,3-dihydroquinazolin-4(1H)-one (4q)
was obtained in good yield within 4 h (Table 4, entry 17).
No product was obtained when 2,4-dinitrobenzaldehyde and 2,3,4-trimethoxyben-
zaldehyde (Table 4, entries 19, 20) were used in this experiment. The reactions of ali-
phatic aldehydes could not aford the corresponding products even when prolonging
the reaction time (Table 4, entries 21, 22). It seems that this protocol has limitations
with respect to these substrates.
Recovery and reusability are the most important features of supported catalysts. The
recyclability of the catalyst was investigated using a model reaction (Table 5). After
reaction completion, the catalyst was separated by simple fltration and washed with
ethyl acetate, air-dried, and reused directly in the same reaction. The experimental
results revealed that the catalyst can be reused, albeit accompanied by appreciable loss
of activity.
Based on the observations in the progress of the experiments and other mecha-
nisms reported in literature [29, 30, 33, 35, 36], a plausible mechanism for the
synthesis of 4a is proposed in Scheme 2. Firstly, isatoic anhydride is activated by
FeCl3/neutral Al2O3 to produce reactive intermediate I, followed by attack of NH3
Table 5 Synthesis of 2-phenyl-2,3-dihydroquinazolin-4(1H)-one with recovered FeCl3/neutral Al2O3
Number of cycles
Fresh
Recycle I
Recycle II
Recycle III
Isolated yield (%)
92
87
82
78
1 3

Efcient one‑pot synthesis of…
Scheme 2 Proposed mechanism for synthesis of 2-phenyl-2,3-didihydroquinazolin-4(1H)-one
on the carbonyl to form intermediate II, which in turn is converted to 2-amino-
N-substituted-amide (III) by decarboxylation and proton transfer reaction. Subse-
quently, reaction of benzaldehyde activated by FeCl3/neutral Al2O3 with III gives
imine intermediate IV. The amide part of IV could be converted into tautomer
in the presence of FeCl3/neutral Al2O3. Meanwhile, intermediate V is obtained
by intermolecular nucleophilic attack of the amide nitrogen on imine carbon.
Finally, 2-phenyl-2,3-dihydroquinazolin-4(1H)-one (4a) can form by 1,5-proton
transfer of V.
Conclusions
We developed an ecofriendly method to synthesize 2,3-dihydroquinazolin-4(1H)-
one derivatives by three-component reaction of isatoic anhydride, aromatic alde-
hyde, and ammonium acetate using FeCl3/neutral Al2O3 as catalyst in tert-butanol
under refux condition. The advantages of this methodology are milder condi-
tions, shorter reaction time, good yield, and environmentally benign catalyst.
Acknowledgements The project was supported by the Education Department of Hebei Province Founda-
tion for Youths (QN2015039) and the Foundation of Hebei University (no. 799207217002).
1 3

S. J. Wu et al.
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