Synthesis of 2-substituted-2,3-dihydro-4(1 H)-quinazolinones using sodium bisulfate as a catalyst by the grinding technique

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Synthesis of 2-Substituted-2,3-
dihydro-4(1H)- quinazolinones using
Sodium Bisulfate as a Catalyst by the
Grinding Technique
Min Wang a , Jing-Jing Gao a , Zhi-Guo Song b & Lei Wang a
a College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou, 121000, P. R. China
b Center for Science & Technology Experiment, Bohai University,
Jinzhou, 121000, P. R. China
Version of record first published: 30 Mar 2012.
To cite this article: Min Wang, Jing-Jing Gao, Zhi-Guo Song & Lei Wang (2012): Synthesis of 2-
Substituted-2,3-dihydro-4(1H)- quinazolinones using Sodium Bisulfate as a Catalyst by the Grinding
Technique, Organic Preparations and Procedures International: The New Journal for Organic Synthesis,
44:2, 159-163
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Organic Preparations and Procedures International, 44:159–163, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.657563
Synthesis of 2-Substituted-2,3-dihydro-4(1H)-
quinazolinones using Sodium Bisulfate as a Catalyst
by the Grinding Technique
Min Wang,1 Jing-Jing Gao,1 Zhi-Guo Song,2 and Lei Wang1
1College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou 121000, P. R. China
2Center for Science & Technology Experiment, Bohai University,
Jinzhou 121000, P. R. China
2,3-Dihydro-4(1H)-quinazolinones are a class of heterocycles that have drawn much
attention due to their biological activities.1–3 However, the conventional methods for
their synthesis require drastic conditions. For example, in 1960 Bo¨hme and Bo¨ing re-
ported 2-substituted-2,3-dihydro-4(1H)-quinazolinones could be prepared by stirring 2-
anthranilamide and aldehydes or ketones in the presence of conc. HCl in absolute ethanol.4
Recently, the synthesis of 2-substituted-2,3-dihydro-4(1H)-quinazolinones using Lewis
acids and heteropoly acids such as SmI2,5 Sc(OTf)3,6 NH4Cl,7 and H3PW12O408 as catalysts
has been described and their catalyst-free synthesis in ionic liquids or 2,2,2-trifluoroethanol
has also been reported.9,10 However, certain drawbacks such as costly reagents, harmful
solvents, large excess of raw material and catalysts, and low yields are associated with some
of these procedures. Moreover, all these reactions proceeded with mechanical stirring. We
now describe a simple, novel and efficient protocol for the preparation of 2-substituted-
2,3-dihydro-4(1H)-quinazolinones in the presence of NaHSO4 and water by the grinding
technique (Scheme 1).
In a mortar, an equimolar mixture of 2-anthranilamide and the aldehyde (or ketone),
NaHSO4 (2 mol %) and water (1 mL) were added. The mixture was ground well at
room temperature for 10 min, and then heated at 60◦C for the appropriate period of
time (Table 1). Aromatic aldehydes carrying either electron-withdrawing (NO2 and Cl)
or electron-donating groups (CH3, OCH3, OH and N(CH3)2) were all suitable for use
(3a–3m). The position of the substituents on the aromatic ring had no effect on this con-
version. The cyclocondensation of 2-anthranilamide with ketones required comparatively
longer reaction time than that with aromatic aldehydes (3n and 3o). Aliphatic aldehydes
failed to give the corresponding 2,3-dihydro-4(1H)-quinazolinones (3p and 3q). The same
Submitted June 6, 2011.
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou 121000, P. R. China. E-mail: minwangszg@yahoo.com.cn
159

160
Wang et al.
O
C
O
O
NH2
NH2
NH
NaHSO4, water
R1
R2
+
R1
grinding at r.t.
R2
N
H
then heat at 60 oC
1
3a~3q
2
Scheme 1
reaction with ammonium chloride7 as acid catalyst gave lower or no yield at all in some
cases.
The effect of water on the product yields was investigated using a model reaction
between 2-anthranilamide and benzaldehyde. In the presence of 2 mL water, 92% yield
was obtained but required 1 h longer. Furthermore, we observed that a much lower yield
(78%) was produced under solvent-free conditions.
Table 1
Reaction of 2-Anthranilamide with Aldehydes and Ketones in the Presence of NaHSO4
mp (◦C)
Found lit.
Heating
time (h) Yield (%)
Product
R1
R2
3a
C6H5-
H
H
H
H
H
H
H
H
H
H
H
H
H
0.5
1.0
1.0
1.0
1.5
1.5
1.5
2.0
1.5
2.0
1.5
1.0
2.0
3.0
7.0
8.0
8.0
94
95
97
90
92
96
93
71
84
85
73
75
82
83
54
0
225–227 224–22611
191–193 191–19411
200–202 see Table 2
198–200 see Table 2
202–204 see Table 2
204–206 205–20610
174–176 181–18512
224–225 225–2275
182–184 180–1825
222–224 see Table 2
210–212 see Table 2
219–221 see Table 2
205–207 see Table 2
224–226 225–2265
222–224 225–22911
3b
3ca
3da
3e
3f
3g
3h
3i
3j
3k
3l
3ma, b
3n
3oc
3p
3q
2-NO2C6H4-
3-NO2C6H4-
4-NO2C6H4-
2-ClC6H4-
4-ClC6H4-
2,4-Cl2C6H3-
4-CH3C6H4-
4-CH3OC6H4-
2-HOC6H4-
4-HOC6H4-
4-HO-3-CH3OC6H3-
4-(CH3)2NC6H4-
-(CH2)5-
C6H5-
CH3CH2-
C6H5CH2-
CH3
H
H
—
—
—
—
0
a) Yellow solid. b) p-Dimethylaminobenzaldehyde (6.5 mmol) was used. c) Acetophenone
(6.5 mmol) was used.

2-Substituted-2,3-dihydro-4(1H)-quinazolinones
161
Table 2
Spectral Data of Compounds 3c–3e, 3j–3m
Elemental Analysis
(Found)
C mpd mp (◦C)
C
H
N
IR (cm−1
)
1H NMR (δ)
3c
3d
3e
3j
200–202 62.45
4.12
15.61
3337
3147
1673
8.76 (d, J = 7.4 Hz, 2H, ArH), 8.42 (t,
J = 7.5 Hz, 2H, ArH), 7.97 (brs, 1H,
NH-CO), 7.87 (dt, J = 6, 7.5 Hz, 2H,
ArH), 7.62 (brs, 1H, NH), 7.57 (t, J =
6.2 Hz, 1H, ArH), 7.39 (t, J = 7.5 Hz,
1H, ArH), 7.26
(62.56) (4.08) (15.50)
(s, 1H, CH)
198–200 62.45
4.12
15.61
3363
3291
1661
8.53 (s, 1H, NH-CO), 8.27 (d, J =
8.6 Hz, 2H, ArH), 7.76 (d, J = 8.6 Hz,
2H, ArH), 7.64 (d, J = 7.6 Hz, 1H,
ArH), 7.33 (s, 1H, NH), 7.29 (t, J =
7.4 Hz, 1H, ArH), 6.79 (d, J = 8.1 Hz,
1H, ArH), 6.71 (t, J = 7.4 Hz, 1H,
ArH), 5.93 (s, 1H, CH)
(62.33) (4.08) (15.70)
202–204 65.00
4.29
10.83
3362
3196
1647
8.21 (s, 1H, NH-CO), 7.67 (d, J =
7.8 Hz, 2H, ArH), 7.50–7.47 (m, 1H,
ArH), 7.41–7.38 (m, 2H, ArH), 7.27 (t,
J = 6.8 Hz, 1H, ArH), 7.01
(64.88) (4.34) (10.75)
(s, 1H, NH), 6.78 (d, J = 7.8 Hz, 1H,
ArH), 6.73 (dd, J = 6.8, 7.9 Hz, 1H,
ArH), 6.14 (s, 1H, CH)
222–224 69.99
5.04
11.66
3410
3157
1647
9.85 (s, 1H, NH-CO), 7.93 (s, 1H, NH),
7.64 (d, J = 7.0 Hz, 1H, ArH), 7.36 (d,
J = 7.5 Hz, 1H, ArH), 7.24 (t, J =
7.1 Hz, 1H, ArH), 7.16
(70.10) (4.98) (11.57)
(t, J = 7.5 Hz, 1H, ArH), 6.88 (d, J =
8.0 Hz, 1H, OH), 6.81–6.74 (m, 3H,
ArH), 6.68 (t, J = 7.5 Hz, 1H, ArH),
6.01 (s, 1H, CH)
3k
3l
210–212 69.99
5.04
11.66
3338
3184
1670
9.52 (s, 1H, NH-CO), 8.14 (s, 1H, NH),
7.64 (d, J = 7.5 Hz, 1H, ArH), 7.33 (d,
J = 8.5 Hz, 2H, ArH), 7.26 (t, J =
7.5 Hz, 1H, ArH), 6.94
(70.12) (5.11) (11.57)
(t, J = 8.5 Hz, 1H, OH), 6.79–6.67 (m,
4H, ArH), 5.67 (s, 1H, CH)
219–221 66.66
5.22
10.36
3389
3354
1650
9.06 (s, 1H, NH-CO), 8.09 (s, 1H, NH),
7.62 (d, J = 6.5 Hz, 1H, ArH), 7.25
(dd, J = 7.2, 8.0 Hz, 1H, ArH), 7.09
(s, 1H, ArH), 6.94 (s, 1H, OH), 6.89
(d, J = 6.5 Hz, 1H, ArH), 6.77 (t, J =
8.1 Hz, 2H, ArH), 6.69 (t, J = 7.4 Hz,
1H, ArH), 5.65 (s, 1H, CH), 3.76 (s,
3H, OCH3)
(66.53) (5.17) (10.45)
3m
205–207 71.89
6.41
15.72
3295
3192
1655
8.07 (s, 1H, NH-CO), 7.62 (d, J =
7.5 Hz, 1H, ArH), 7.31 (d, J = 8.6 Hz,
2H, ArH), 7.24 (dd, J = 7.2, 8.0 Hz,
1H, ArH), 6.92 (s, 1H, NH), 6.75–6.65
(m, 4H, ArH), 5.64 (s, 1H, CH), 2.87
(s, 6H, N(CH3)2)
(72.01) (6.47) (15.65)

162
Wang et al.
A method for the synthesis of 2-substituted-2,3-dihydro-4(1H)-quinazolinones from
2-anthranilamide and various aldehydes or ketones by aqueous grinding technique has been
elaborated, and it possesses the advantages of inexpensive catalyst, mild reaction conditions
and clean procedure.
Experimental Section
Mps were determined using an RY-1 micromelting point apparatus. Infrared spectra were
recorded on a Scimitar 2000 series Fourier Transform instrument of VARIAN.1H NMR
spectra were obtained on a Bruker AV-500 spectrometer in DMSO-d6 using TMS as an
internal standard. Mass spectra were determined on an Agilent 1100 series LC/MSD VL
ESI instrument. Elemental analyses were carried out on EA 2400II elemental analyzer
(Perkin Elmer).
General Procedure
An equimolar mixture of 2-anthranilamide (1, 0.68 g, 5 mmol) and an aldehyde (or ketone)
(5 mmol), NaHSO4 (0.012 g, 0.1 mmol) and water (1 mL) in a mortar were ground well
with a pestle at room temperature for 10 minutes. Then the mixture in the mortar was
placed in an oven and kept at 60◦C for the appropriate time until the completion of reaction
(checked by TLC using CHCl3:MeOH, 95: 5). The reaction mixture was cooled to room
temperature and the precipitated solid was collected and washed thoroughly with water.
The products were purified further by crystallization from ethanol. The pure products were
identified by mp, IR, 1H NMR, MS, and elemental analysis. The procedure was carried out
on 100 mmol scale of anthranilamide with essentially no change in the yield.
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