Click reaction: Highly efficient synthesis of 2,3-dihydroquinazolin-4(1H)- ones

Article abstract of DOI:10.1080/00397910802213802

In this work, condensation reaction of 2-aminobenzamide with various alkyl, aryl, and alicyclic aldehydes or ketones to 2,3-dihydroquinazolin-4(1H)-one derivatives in the presence of a catalytic amount of ammonium chloride in ethanol at room temperature is described. This reaction can be classified as a click chemical synthesis because of its high yields, short reaction times, and green and efficient reaction medium. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802213802

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Click Reaction: Highly
Efficient Synthesis of 2,3-
Dihydroquinazolin-4(1H)-ones
Ahmad Shaabani a , Ali Maleki a & Hamid Mofakham a
a Department of Chemistry, Shahid Beheshti
University, Tehran, Iran
Version of record first published: 14 Oct 2008.
To cite this article: Ahmad Shaabani , Ali Maleki & Hamid Mofakham (2008): Click
Reaction: Highly Efficient Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones, Synthetic
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Synthetic Communications1, 38: 3751–3759, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802213802
Click Reaction: Highly Efficient Synthesis
of 2,3-Dihydroquinazolin-4(1H)-ones
Ahmad Shaabani, Ali Maleki, and Hamid Mofakham
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Abstract: In this work, condensation reaction of 2-aminobenzamide with various
alkyl, aryl, and alicyclic aldehydes or ketones to 2,3-dihydroquinazolin-4(1H)-one
derivatives in the presence of a catalytic amount of ammonium chloride in etha-
nol at room temperature is described. This reaction can be classified as a click
chemical synthesis because of its high yields, short reaction times, and green
and efficient reaction medium.
Keywords: 2-Aminobenzamide,
ammonium
chloride,
click
2,3-dihydroquinazolin-4(1H)-one, green chemistry, quantitative yield
chemistry,
INTRODUCTION
Quinazolinone derivatives have drawn much attention because of their
broad range of pharmacological activities,[1] such as anticancer,[2] anti-
inflammatory,[3] and anticonvulsant[4] activities. Therefore, considerable
efforts have been made to explore new, simple, and direct approaches
toward the construction of 4(3H)-quinazolinone skeletons, for example,
via amidation of 2-aminobenzonitrile followed by oxidative ring closure[5]
and Pd-catalyzed heterocyclization of nitroarenes.[6]
Recently, a number of classical methods for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones have been reported in the literature,[7–9] invol-
ving the condensation of 2-aminobenzamide with aldehydes or ketones in the
Received May 5, 2008.
Address correspondence to Ahmad Shaabani, Department of Chemistry,
Shahid Beheshti University, P. O. Box 19396-4716, Tehran, Iran. E-mail:
a-shaabani@cc.sbu.ac.ir
3751

3752
A. Shaabani, A. Maleki, and H. Mofakham
Scheme 1. Click synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives.
presence of various catalyst such as CuCl2 and TiCl4–Zn.[8] However,
[7]
most of the reported methods suffer from tedious procedures and often from
low yields. Therefore, the development of simpler, environmentally benign,
high-yielding, and clean syntheses of 2,3-dihydroquinazolin-4(1H)-ones is
in demand.
In connection with our previous work for the synthesis of pharma-
ceutically important heterocyclic compounds,[9] and using ammonium
chloride as a catalyst in organic synthesis,[10] herein we report a quantita-
tive yield click[11] condensation of 2-aminobenzamide 1 with an aldehyde
or ketone 2 to 2,3-dihydroquinazolin-4(1H)-one derivatives 3a–o in the
presence of a catalytic amount of ammonium chloridein ethanol at room
temperature with short reaction times (Scheme 1).
RESULTS AND DISCUSSION
In a pilot experiment, 2-aminobenzamide and benzaldehyde in EtOH
were stirred at room temperature using a catalytic amount of NH4Cl.
The progress of the reaction was monitored by thin-layer chromatogra-
phy (TLC). After completion of the reaction, an aqueous workup
afforded 2,3-dihydro-2-phenylquinazolin-4(1H)-one 3a in 92% yield.
In view of the success of the reaction and to examine the scope and
limitations of this approach, we applied these optimal reaction conditions
to a variety of aromatic aldehydes carring electron-withdrawing and elec-
tron-donating substituents. They were condensed with 2-aminobenza-
mide under similar circumstances, and the products (3b–f) were
obtained in excellent yields (Table 1, entries 2–6). Aliphatic aldehydes
were also condensed with 2-aminobenzamide successfully (Table 1,
entries 7 and 8). We further investigated the synthesis of 2,3-dihydroqui-
nazolin-4(1H)-ones from various aliphatic, alicyclic, and aromatic
ketones, and they afforded the corresponding products (3i–o ) with high
yields (Table 1, entries 9–15). This reaction proceeds very cleanly, and no
undesirable side reactions were observed.

2,3-Dihydroquinazolin-4(1H)-ones
3753
Table 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–o)
Entry
Aldehyde=ketone
Benzaldehyde
4-Methylbenzaldehyde
4-Methoxylbenzaldehyde
4-Benzyloxybenzaldehyde
4-Fluorobenzaldehyde
3-Nitrobenzaldehyde
Butyraldehyde
3-Methylbutyraldehyde
3-Methyl-2-pentanone
2-Octanone
Cyclohexanone
4-tert-Butylcyclohexanone
Cyclopentanone
Product
Time (min)
Yield a(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3b
3c
3d
3e
3f
15
15
15
10
10
5
50
60
60
60
35
30
45
50
40
92
94
90
92
93
95
94
97
96
95
97
98
96
90
95
3g
3h
3i
3j
3k
3l
3m
3n
3o
2,3-Dihydroinden-1-one
Isatin
aIsolated yield.
1
The structures of the products 3a–o were deduced from their IR, H
NMR, and 13C NMR spectra. The mass spectra of these compounds
displayed molecular ion peaks at the appropriate m=z values.
In conclusion, we have developed an efficient condensation reaction
of 2-aminobenzamide with various alkyl, aryl, and alicyclic aldehydes or
ketones, which provides 2,3-dihydroquinazolin-4(1H)-one derivatives in

3754
A. Shaabani, A. Maleki, and H. Mofakham
quantitative yields. This reaction can be classified as a new click synthesis
because of its high yields, short reaction times, and green and efficient
reaction medium. This synthetic route allows us to make easily a variety
of 2,3-dihydroquinazolin-4(1H)-ones, and application of this method to
generate quinazolinone-based libraries is currently under investigation
in our laboratory.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9200 apparatus.
Mass spectra were recorded on a Finnigan-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. IR spectra were recorded on
a Shimadzu IR-470 spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker DRX-300 Avance spectrometer at 300.13 and
1
75.47 MHz, respectively. All the products were characterized by IR, H
NMR and 13C NMR spectra, and mass spectral data.
Typical Procedure for the Synthesis of 2,3-Dihydro-2-phenylquinazolin-
4(1H)-one (3a)
NH4Cl (0.027 g, 5 mol%) was added to a solution of 2-aminobenzamide
(0.136 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol) in 3 mL of ethanol.
The resulting mixture was stirred for 15 min at ambient temperature.
After completion of the reaction, as indicated by TLC (ethyl acetate=n-
hexane, 1=1), the product was precipitated by addition of 10 mL of water.
Then, the precipitate was filtered off and washed with extra water.
Finally, the residue was crystallized from acetone to give 3a as white solid
(0.206 g, 92%): mp 216–218 ꢀC. IR (KBr) cmꢁ1: 3298, 3185, 3059, 2918,
1
1655, 1615, 1538, 1452. H NMR (DMSO-d6) d: 5.74 (1H, br s, CH),
6.66–6.74 (2H, m, Harom), 7.09–7.72 (8H, m, NH and Harom), 8.26
(1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 67.0 (CH), 114.9, 115.4,
117.6, 127.3, 127.8, 128.8, 128.9, 133.8, 142.1, 148.3 (Carom), 164.1
(CO). MS m=z: 224 (Mþ, 28), 147 (100), 120 (72), 91 (55), 77 (37).
2,3-Dihydro-2-p-tolylquinazolin-4(1H)-one (3b)
White solid (0.224 g, 94%): mp 232–234 ꢀC. IR (KBr) cmꢁ1: 3329, 3188,
1
3070, 2929, 1671, 1658, 1609, 1509, 1485. H NMR (DMSO-d6) d: 2.21
(s, 3H, CH3), 5.52 (1H, br s, CH), 6.47–6.52 (2H, m, Harom), 7.14–7.88
(7H, m, NH and Harom), 8.25 (1H, br s, NH-CO). 13C NMR (DMSO-
d6) d: 21.1 (CH), 66.2 (CH), 115.4, 115.9, 117.5, 126.3, 127.1, 128.8,

2,3-Dihydroquinazolin-4(1H)-ones
3755
133.7, 136.9, 137.8, 147.9 (Carom), 162.1 (CO). MS m=z: 238 (Mþ, 35), 147
(100), 120 (52), 91 (50), 77 (40).
2,3-Dihydro-2-(4-methoxyphenyl)quinazolin-4(1H)-one (3c)
White solid (0.229 g, 90%): mp 193–195ꢀC. IR (KBr) cmꢁ1: 3360, 3185, 3060,
1
2929, 1670, 1609, 1572, 1514, 1463. H NMR (DMSO-d6) d: 3.71 (s, 3H,
OCH3), 5.69 (1H, br s, CH), 6.70–7.60 (9H, m, NH and Harom), 8.19 (1H,
br s, NH-CO). 13C NMR (DMSO-d6) d: 55.5 (OCH), 66.8 (CH), 114.1,
114.9, 115.4, 117.6, 127.8, 128.7, 133.7, 133.9, 148.5, 159.9 (Carom), 164.2
(CO). MS m=z: 254 (Mþ, 32), 147 (100), 120 (62), 91 (44), 77 (28).
2-(4-(Benzyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (3d)
White solid (0.304 g, 92%): mp 253–254 ꢀC. IR (KBr) cmꢁ1: 3305, 3176,
1
3023, 2930, 1673, 1650, 1609, 1573, 1503, 1482. H NMR (DMSO-d6)
d: 5.20 (s, 2H, CH2), 6.99 (1H, br s, CH), 7.15 (2H, d, J ¼ 7.5 Hz, Harom),
7.20–7.60 (8H, m, NH and Harom), 7.69 (1H, d, J ¼ 7.8 Hz, Harom), 7.78
(1H, d, J ¼ 6.0 Hz, Harom), 8.13 (1H, d, J ¼ 8.1 Hz, NH-CO), 8.18 (2H,
d, J ¼ 7.7 Hz, Harom). 13C NMR (DMSO-d6) d: 68.1 (CH), 69.9 (CH2),
115.3, 115.5, 121.2, 125.5, 126.3, 126.6, 127.8, 128.2, 128.4, 129.9,
135.0, 137.1, 149.4, 152.3 (Carom), 162.8 (CO). MS m=z: 328 (Mþ ꢁ 2,
35), 119 (15), 91 (100), 65 (60), 41 (32).
2-(4-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e)
White solid (0.225 g, 93%): mp 202–204 ꢀC. IR (KBr) cmꢁ1: 3365, 3211,
1
3023, 2929, 1673, 1650, 1609, 1509, 1480. H NMR (DMSO-d6) d: 5.60
(1H, br s, CH), 6.47–6.57 (2H, m, Harom), 7.17–8.07 (7H, m, NH and
H
arom), 8.26 (1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 66.4 (CH),
114.4, 115.9, 117.5, 126.8, 127.1, 128.8, 133.7, 136.9, 137.8, 147.8 (Carom),
162.3 (CO). MS m=z: 242 (Mþ, 35), 147 (100), 120 (42), 91 (35), 77 (26).
2,3-Dihydro-2-(3-nitrophenyl)quinazolin-4(1H)-one (3f)
Yellow crystals (0.256 g, 95%): mp 163–165 ꢀC. IR (KBr) cmꢁ1: 3294,
1
3188, 3059, 2918, 1656, 1615, 1538, 1452. H NMR (DMSO-d6) d: 5.95
(1H, br s, CH), 6.69–6.71 (1H, m, NH), 6.78 (1H, d, J ¼ 7.5, Harom),
7.26 (1H, m, Harom), 7.35 (1H, br s, Harom), 7.60–7.71 (2H, m, Harom),
7.94 (1H, d, J ¼ 6.3, Harom), 8.19 (1H, d, J ¼ 6.6, Harom), 8.36 (1H, br
s, Harom), 8.54 (1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 65.6

3756
A. Shaabani, A. Maleki, and H. Mofakham
(CH), 115.0, 115.4, 118.0, 122.0, 123.7, 127.9, 130.5, 133.8, 134.0, 144.7,
147.8, 148.1 (Carom), 163.8 (CO). MS m=z: 269 (Mþ, 28), 147 (100), 120
(45), 91 (70), 77 (24).
2,3-Dihydro-2-propylquinazolin-4(1H)-one (3g)
Colorless crystals (0.179 g, 94%): mp 162–164 ꢀC. IR (KBr) cmꢁ1: 3322,
3175, 2932, 2855, 1658, 1512, 1452, 1394. 1H NMR (DMSO-d6) d:
0.80–0.90 (3H, m, CH), 1.35–1.72 (4H, m, 2CH2), 5.25 (1H, m, CH),
6.57–7.15 (5H, m, NH and Harom), 7.81 (1H, br s, NH–CO). 13C NMR
(DMSO-d6) d: 23.7 (CH3), 29.5, 33.8 (CH2), 64.5 (CH), 113.6, 114.4,
116.4, 127.3, 133.6, 146.6 (Carom), 164.2 (CO). MS m=z: 190 (Mþ, 18),
147 (100), 120 (12), 91 (45), 65 (22), 56 (30).
2,3-Dihydro-2-isobutylquinazolin-4(1H)-one (3h)
Light yellow crystals (0.198g, 97%): mp 170–172ꢀC. IR (KBr) cmꢁ1: 3312,
1
3165, 2942, 2853, 1658, 1517, 1450, 1392, 1336. H NMR (DMSO-d6) d:
0.80–0.90 (6H, m, 2CH3), 1.40–1.60 (2H, m, CH2), 1.75–1.86 (1H, m, CH),
5.55–5.66 (1H, m, CH), 6.65–7.12 (5H, m, NH and Harom), 7.88 (1H, br s,
NH–CO). 13C NMR (DMSO-d6) d: 24.5, 24.8 (CH3), 28.8 (CH), 40.6
(CH2), 66.9 (CH), 113.8, 114.2, 116.43, 127.5, 133.5, 146.4 (Carom), 164.1
(CO). MS m=z: 204 (Mþ, 10), 147 (100), 120 (14), 91 (45), 65 (15), 43 (52).
2,3-Dihydro-2-isobutyl-2-methylquinazolin-4(1H)-one (3i)
Colorless crystals (0.209 g, 96%): mp 173–175 ꢀC. IR (KBr) cmꢁ1: 3326,
1
3170, 2932, 2858, 1650, 1512, 1452, 1390, 1326. H NMR (DMSO-d6)
d: 0.86–0.90 (6H, m, 2CH3), 1.34 (3H, s, CH3), 1.42–1.59 (2H, m,
CH2), 1.78–1.90 (1H, m, CH), 6.55–6.63 (3H, m, NH and Harom), 7.18
(1H, td, J ¼ 7.6, 1.5 Hz, Harom), 7.54 (1H, dd, J ¼ 6.4, 1.2, Harom), 7.88
(1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 23.8, 24.7, 24.9 (CH3),
29.1 (CH), 40.8 (CH2), 69.8 (C–NH), 113.8, 114.4, 116.4, 127.5, 133.6,
147.6 (Carom), 163.5 (CO). MS m=z: 219 (Mþ þ 1, 25), 161 (100), 120
(30), 92 (30), 65 (22), 44 (25).
2-Hexyl-2,3-dihydro-2-methylquinazolin-4(1H)-one (3j)
Colorless crystals (0.234 g, 95%): mp 157–159 ꢀC. IR (KBr) cmꢁ1: 3329,
1
3176, 3070, 2930, 2847, 1638, 1613, 1516, 1486, 1421, 1398, 1334. H

2,3-Dihydroquinazolin-4(1H)-ones
3757
NMR (DMSO-d6) d: 0.80–0.84 (3H, m, CH3), 1.20–1.27 (6H, m, 3CH2),
1.32 (5H, m, CH2 and CH3), 1.54–1.61 (2H, m, CH2), 6.54–6.64 (3H, m,
NH and Harom), 7.18 (1H, td, J ¼ 7.6, 1.4 Hz, Harom), 7.54 (1H, d, J ¼ 6.7,
H
arom), 7.88 (1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 14.4, 22.4
(CH3), 23.8, 28.4, 29.3, 31.7, 41.8 (CH2), 69.5 (C–NH), 114.0, 114.4,
116.5, 127.5, 133.6, 147.6 (Carom), 163.6 (CO). MS m=z: 247 (Mþ þ 1,
12), 231 (48), 161 (100), 120 (46), 92 (46), 65 (26), 43 (35).
2-Spirocyclohexyl-2,3-dihydroquinazolin-4(1H)-one (3k)
Colorless crystals (0.215 g, 97%): mp 217–219 ꢀC. IR (KBr) cmꢁ1: 3365,
3188, 3035, 2924, 2847, 1644, 1610, 1505, 1484, 1421, 1382, 1334.
1H NMR (DMSO-d6) d: 1.24–1.72 (10H, m, 5CH2), 6.61 (1H, br s,
NH), 6.80 (1H, d, J ¼ 7.9 Hz, Harom), 7.20 (1H, t, J ¼ 7.3 Hz, Harom),
7.56 (1H, d, J ¼ 7.4 Hz, Harom), 7.89 (1H, br s, NH–CO). 13C NMR
(DMSO-d6) d: 21.3, 25.1, 37.6 (CH2), 68.2 (Cspiro), 114.9, 115.0, 116.9,
127.5, 133.6, 147.2 (Carom), 163.7 (CO). MS m=z: 216 (Mþ, 18), 173
(100), 160 (24), 120 (64), 57 (5), 45 (10).
2-Spiro(40-tert-butylcyclohexyl)-2,3-dihydroquinazolin-4(1H)-one (3l)
Colorless crystals (0.266 g, 98%): mp 274–276 ꢀC. IR (KBr) cmꢁ1: 3386,
3200, 3059, 2956, 2870, 1652, 1613, 1507, 1487, 1431, 1393, 1342.
1H NMR (DMSO-d6) d: 0.80–0.89 [9H, m, C(CH3)3], 0.95–0.96 (2H,
m, CH2), 1.29–1.51 (7H, m, 3CH2 and CH), 6.51 (1H, br s, NH), 6.58–
6.66 (2H, m, Harom), 7.20 (1H, td, J ¼ 7.6, 1.5 Hz, Harom), 7.50 (1H, dd,
J ¼ 7.6, 1.2 Hz, Harom), 8.11 (1H, br s, NH–CO). 13C NMR (DMSO-
d6) d: 22.1, 22.2 (CH2), 28.1 (3CH3), 31.2 [C(CH3)3], 32.6, 38.1 (CH2),
47.5 (CH), 68.0 (Cspiro), 114.7, 114.8, 116.9, 127.7, 133.6, 147.8 (Carom),
163.6 (CO). MS m=z: 272 (Mþ, 12), 215 (36), 173 (100), 160 (64), 72
(20), 58 (20), 43 (34).
2-Spirocyclopentyl-2,3-dihydroquinazolin-4(1H)-one (3m)
Colorless crystals (0.215 g, 96%): mp 257–260 ꢀC. IR (KBr) cmꢁ1: 3292,
3155, 3029, 2945, 2851, 1643, 1611, 1516, 1484, 1430, 1382, 1325.
1H NMR (DMSO-d6) d: 1.65–1.79 (8H, m, 4CH2), 6.62–6.74 (3H,
m, NH and Harom), 7.20 (1H, m, Harom), 7.56 (1H, d, J ¼ 6.5 Hz,
H
arom), 8.10 (1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 22.4
(4CH2), 77.5 (Cspiro), 114.8, 115.0, 117.0, 127.7, 133.5, 148.0 (Carom),
163.9 (CO). MS m=z: 202 (Mþ, 10), 173 (100), 119 (25), 92 (20), 65 (15).

3758
A. Shaabani, A. Maleki, and H. Mofakham
2-Spiro(2,3-dihydroinden-1-one)-2,3-dihydroquinazolin-4(1H)-one (3n)
Green crystals (0.225 g, 90%): mp 224–226 ꢀC. IR (KBr) cmꢁ1: 3294,
1
3180, 3026, 2937, 2853, 1644, 1611, 1518, 1481, 1421, 1376. H NMR
(DMSO-d6) d: 2.34 (2H, m, CH2), 2.95 (2H, m, CH2), 6.64–6.67 (2H,
m, NH and Harom), 7.15–7.26 (6H, m, Harom), 7.65 (1H, d, J ¼ 6.9 Hz,
H
arom), 8.40 (1H, br s, NH–CO). 13C NMR (DMSO-d6) d: 28.2, 41.5
(CH2), 79.0 (Cspiro), 114.5, 114.6, 117.2, 122.9, 125.6, 127.2, 127.6,
129.3, 133.8, 141.9, 146.6, 147.4 (Carom), 163.5 (CO). MS m=z: 250
(Mþ, 80), 221 (25), 173 (20), 120 (100), 92 (40), 45 (20).
2-Spiro(3-indolin-2-one)-2,3-dihydroquinazolin-4(1H)-one (3o)
Yellow solid (0.252 g, 95%): mp 214–216 ꢀC. IR (KBr) cmꢁ1: 3315, 3300,
1
3180, 3025, 2988, 1715, 1707, 1656, 1616, 1520, 1473, 1327. H NMR
(DMSO-d6) d: 6.61–6.71 (2H, m, Harom), 6.86 (1H, d, J ¼ 7.1 Hz, Harom),
7.05–7.34 (4H, m, NH and Harom), 7.49 (1H, d, J ¼ 7.0 Hz, Harom), 7.61
(1H, d, J ¼ 7.1 Hz, Harom), 8.37 (1H, br s, NH-CO), 10.31 (1H, br s,
NH–CO). 13C NMR (DMSO-d6) d: 71.4 (Cspiro), 110.6, 114.3, 114.8,
117.6, 122.8, 125.8, 127.3, 129.9, 131.3, 133.8, 142.6, 147.3 (Carom),
164.4, 176.5 (CO). MS m=z: 265 (Mþ, 24), 221 (25), 173 (26), 120
(100), 91 (60), 55 (30).
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Research
Council of Shahid Beheshti University.
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