Tris(hydrogensulfato)boron catalysed rapid synthesis of 2-substituted-2,3-dihydroquinazolin-4(1H)-ones under solvent-free conditions

Article abstract of DOI:10.3184/174751912X13310556980246

Aldehydes or ketones react readily in one-pot with isatoic anhydride and ammonium salts in the presence of tris-(hydrogensulfato)boron to produce the corresponding 2,3-dihydroquinazolin-4(1H)-ones in high yields under solventfree conditions. The use of tr

Full text of DOI:10.3184/174751912X13310556980246

194 RESEARCH PAPER
APRIL, 194–196
JOURNAL OF CHEMICAL RESEARCH 2012
Tris(hydrogensulfato)boron catalysed rapid synthesis of 2-substituted-
2,3-dihydroquinazolin-4(1H)-ones under solvent-free conditions
Zahed Karimi-Jaberi* and Leila Zarei
Department of Chemistry, Firoozabad Branch, Islamic Azad University, P.O. Box 74715-117 Firoozabad, Fars, Iran
Aldehydes or ketones react readily in one-pot with isatoic anhydride and ammonium salts in the presence of tris-
(hydrogensulfato)boron to produce the corresponding 2,3-dihydroquinazolin-4(1H)-ones in high yields under solvent-
free conditions. The use of tris(hydrogensulfato)boron makes this process quite simple, more convenient and envir-
onmentally friendly. 2,3-Dihydroquinazolin-4(1H)-one derivatives have interesting biological and pharmacological
activities.
Keywords: dihydroquinazolinones, isatoic anhydride, tris(hydrogensulfato)boron, solvent-free conditions
Heterocyclic structures form the basis of many pharmaceuti-
cal, agrochemical and veterinary products. Recently, the
synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives
have attracted great interest due to their biological and
pharmacological activities.1,2 They have been useful biological
and pharmacological properties, such as anticancer,3 anti-
inflammatory,4 and anticonvulsant5 activities. Quinazolinones
are also important building blocks in the synthesis of natural
products.6–8 Therefore, considerable efforts have been made
to explore new, simple, and direct approaches towards the
construction of quinazolin-4(1H)-one skeleton, for example,
via Pd-catalysed heterocyclisation of nitroarenes9 solid-phase
synthesis of 2-arylamino-substituted quinazolinones.10 One of
the most common approaches is the cyclisation of anthranil-
amides with aldehyde in the presence of various catalysts.11–15
Recently, three-component one-pot condensation of isatoic
anhydride, aldehydes and ammonium salts has been reported
for the construction of 2,3-dihydroquinazolin-4(1H)-one deriva-
tivesunderdifferentconditions.16–21 Although, theseapproaches
are satisfactory for synthesis of 2,3-dihydroquinazolin-4(1H)-
ones, the harsh reaction conditions, expensive reagents, use of
toxic organic solvents and long reaction times limit the use of
these methods.
amounts of tris(hydrogensulfato)boron as a solid heteroge-
neous catalysts under solvent-free conditions (Scheme 1).
Tris(hydrogensulfato)boron (B(HSO4)3) was easily prepared
by addition of chlorosulfonic acid to boric acid under N2 atmo-
sphere at room temperature. This reaction was easy and clean,
because HCl gas was immediately evolved from the reaction
vessel. This catalyst is safe and easy to handle (Scheme 2).26
Investigations were initiated with benzaldehyde being
chosen as a model compound. It was condensed with isatoic
anhydride and ammonium acetate in the presence of tris(hydro
gensulfato)boron under different conditions. The best yield of
80%, was obtained at 110 °C after 5 minutes using 0.036 g of
tris(hydrogensulfato)boron.
Using the optimised conditions, we explored the scope of
the one-pot three-component cyclocondensation reaction.
As shown in Table 1, arrays of aldehydes bearing either elec-
tron-donating or electron-withdrawing groups on the aromatic
ring were successfully reacted with isatoic anhydride and
ammonium acetate to produce their corresponding 2,3-
dihydroquinazolin-4(1H)-one in high yields with short reac-
tion times. The substitution group on the phenyl ring did not
make any difference to this reaction. The work-up procedure is
very straightforward; that is, the products were isolated and
purified by simple filtration. Our protocol avoids the use
of organic solvents during the reaction process, making it
superior to the previous methods.
Due to our interest in the development of practical, safe, and
environmentally friendly procedures for important organic
transformations22–25, we now describe a simple and efficient
protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-
ones based on a three-component reaction of isatoic anhydride,
aldehydes/ketones and ammonium salts using catalytic
The reaction can also proceed with ammonium chloride and
provide the target products in reasonable yield (Table 1). In all
Scheme 1
Scheme 2
* Correspondent. E-mail: z.karimi@iauf.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2012 195
Table 1 Synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-one
Entry
Aldehyde/Ketone
X
Time /min
Yield/%
M.p. /°C (found)
M.p. /°C (lit.)
1
2
Benzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
2-Chlorobenzaldehyde
4-Methylbenzaldehyde
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Bromobenzaldehyde
4-Fluorobenzaldehyde
Cyclohexanone
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
CH3CO2−
Cl−
5
5
80
81
79
80
86
78
76
79
82
80
83
79
76
73
78
82
70
71
72
74
216–218
204–206
189–191
205–207
227–230
216–218
206–208
200–202
205–206
223–225
250–252
216–218
204–206
189–191
205–207
227–230
216–218
206–208
200–202
205–206
218–22019
205–20616
192–19317
208–21022
233–2342o
216–21717
213–21417
200–20016
205–20616
217–21921
257–2621
3
3
4
5
5
3
6
8
7
15
5
8
9
5
10
11
12
13
14
15
16
17
18
19
20
5
Cyclopentanone
5
Benzaldehyde
5
218–22019
205–20616
192–19317
208–21022
233–2342o
216–21717
213–21417
205–20616
205–20616
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
2-Chlorobenzaldehyde
4-Methylbenzaldehyde
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Bromobenzaldehyde
4-Fluorobenzaldehyde
Cl−
5
Cl−
5
Cl−
5
Cl−
5
Cl−
10
5
Cl−
Cl−
5
5
Cl−
Table 2 Comparison the results of tris(hydrogensulfato)boron with other catalysts reported in the literature
Entry
Conditions
Time /min
Yield/%
Ref.
1
2
3
4
5
Ga(OTf)3 (1 mol%), EtOH, 70 oC
35–70
5–7 h
55–75
4–7 h
3–15
71–91
70–94
77–90
70–95
70–86
17
Copolymer-PTSA (0.3 g), EtOH, reflux
18
19
[Bmim]BF4 (3.0 ml), H2O, 80 oC
Montmorillonite K-10 (0.3 g), EtOH, reflux
B(HSO4)3 (0.036 g), solvent-free, 110 oC
20
This paper
Shimadzu spectrophotometer as KBr disks. The NMR spectra were
recorded on a Bruker250MHz spectrometer. Tris(hydrogensulfato)
boron has been prepared according to reported method.26
these cases, the corresponding 2,3-dihydroquinazolin-4(1H)-
ones were obtained in good yields at 110 °C under solvent-
free conditions without formation of any side products. It is
important to note that the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones could not be achieved in the absence of catalyst.
Moreover, the condensation of ketones with isatoic anhy-
dride and ammonium salts was also successfully carried out
under the same conditions and the corresponding 2,3-dihydro-
4(1H)-quinazolinones were obtained in high yields and short
reaction times (Table 1, entries 10–11). All products are known
compounds and structures of them were confirmed by com-
parison with their known physical and spectral (NMR and IR)
data.16–21
In order to compare the current protocol with previously
published methods for the synthesis of 2,3-dihydroquinazolin-
4(1H)-one, we carried out the studies described in Table 2.
These results, clearly demonstrate that tris(hydrogensulfato)
boron is a good catalyst with respect to reaction times and
yields of the obtained products.
In conclusion, we have described a successful strategy for
the efficient and rapid synthesis of 2-substituted 2,3-dihydro-
quinazolinones in a one-pot, three-component cyclocondensa-
tion reaction of isatoic anhydride, aldehydes or ketones and
ammonium salts using tris(hydrogensulfato)boron as catalyst
at 110 °C under solvent-free conditions. The notable features
of this procedure are high yields of products, operational
simplicity, enhanced reaction rates, cleaner reaction profiles
and ease of isolation of products, which make this process
quite simple, more convenient and environmentally benign for
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones; general procedure
A mixture of isotoic anhydride (1 mmol), aldehyde/ketone (1 mmol),
ammonium acetate or chloride (1 mmol) and tris(hydrogensulfato)bor
on (0.036 g) was stirred at 110 °C for the appropriate time indicated
in Table 1. The progress of reactions was monitored by TLC (ethyl
acetate/n-hexane). After completion of the reaction, a solid was
obtained. It was washed with water and purified by recrystalisation
from ethanol to afford pure products.
2-(4-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one: IR(KBr):
3424, 3300, 3184, 2924, 1655, 1611, 1515 cm−1; 1H NMR (250 MHz,
DMSO-d6): δ = 5.74 (1H, s, CH), 6.65–6.73 (2H, m, ArH), 7.08 (2H,
s, NH), 7.16–7.24 (3H, m, ArH), 7.48–7.60 (3H, m, ArH), 8.27 (1H, s,
N-CO).
2-(4-Nitrophenyl)-2,3-Dihydroquinazolin-4(1H)-one: IR(KBr):
3445, 3280, 2922, 2854, 1647, 1610, 1519, 1519 cm−1; 1H NMR
(250 MHz, DMSO-d6): δ = 5.88 (1H, s, CH), 6-63–6.75 (2H, m, ArH),
7.21–7.27(1H, m, ArH), 7.33 (1H, s, NH), 7.58(1H, d, J = 7.75 Hz,
ArH), 7.71 (2H, d, J = 7.5, ArH), 8.23 (2H, d, J = 7.5 Hz, ArH), 8.53
(1H, s, NH–CO).
2-(4-Methylphenyl)-2,3-Dihydroquinazolin-4(1H)-one: IR(KBr):
3312, 3194, 3062, 2934, 1658, 1610 cm−1, 1H NMR (250 MHz,
DMSO-d6): δ = 2.26 (3H, s, CH3), 5.67 (1H, s, CH), 6.60–6.72 (2H, m,
ArH), 7.04 (1H, s, NH), 7.14–7.23 (3H, m, ArH), 7.34 (2H, d, J =
7.75 Hz, ArH), 7.57 (1H, d, J = 7.5 Hz, ArH), 8.23 (1H, s, NH–CO).
2-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one: IR(KBr):
3361, 3194, 3064, 2922, 1646, 1615, 1503 cm−1, 1H NMR (250 MHz,
DMSO-d6): δ = 6.11 (1H, s, CH), 6.69–6.75 (2H, m, ArH), 7.0 (1H, s,
NH), 7.20–7.23 (1H, m, ArH),7.36–7.40 (3H, m, ArH), 7.63 (2H, d,
J = 6.25 Hz, ArH), 8.21 (1H, s, NH–CO).
Experimental
Received 6 January 2012; accepted 17 February 2012
Paper 1201086 doi: 10.3184/174751912X13310556980246
Published online: 17 April 2012
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

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