A new efficient method for the three-component synthesis of 4(3H)-Quinazolinones

Article abstract of DOI:10.3987/COM-08-11437

4(3H)-Quinazolinones were efficiently synthesised by the three component cyclisation-oxidation of isatoic anhydride, ammonium acetate and aromatic aldehydes in the presence of ceric ammonium nitrate in ethanol. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11437

HETEROCYCLES, Vol. 75, No. 11, 2008
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HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2809 - 2815. © The Japan Institute of Heterocyclic Chemistry
Received, 12th May, 2008, Accepted, 20th June, 2008, Published online, 23rd June, 2008. COM-08-11437
A NEW EFFICIENT METHOD FOR THE THREE-COMPONENT
SYNTHESIS OF 4(3H)-QUINAZOLINONES
Mostafa Baghbanzadeh,a Minoo Dabiri,a,* and Peyman Salehib,*
aDepartment of Chemistry, Faculty of Science, Shahid Beheshti University, Postal
Code 1983963113, Evin, Tehran, Iran. Fax: +98-21-22431663. E-mail:
m-dabiri@sbu.ac.ir
bDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute,
Shahid Beheshti University, P.O.Box 19835-389, Evin, Tehran, Iran. Fax:
+98-21-22431783. E-mail: p-salehi@sbu.ac.ir
Abstract – 4(3H)-Quinazolinones were efficiently synthesised by the three
component cyclisation-oxidation of isatoic anhydride, ammonium acetate and
aromatic aldehydes in the presence of ceric ammonium nitrate in ethanol.
4(3H)-Quinazolinones are important class of bioactive molecules and widely used as anticonvulsant,
anticancer, antimalarial, antihypertensive and antiinflammatory agents.1 4(3H)-Quinazolinone moiety is
present in several bioactive natural products.2,3 Among them 2-substituted 4(3H)-quinazolinones reported
to possess a wide range of biological and pharmaceutical activities such as growth inhibitory against
leukemia cells,4 poly(ADP-ribose)polymerase,5 and panel of tumor cell lines.6 Some other derivatives of
this family have been used in the study of potential anthelmintics,7 antiallergic8 and antitubercular
agents.9
Due to the importance of 2-substituted quinazolinones different synthetic strategies for their synthesis
have been described in the literature.10 The most common approach involves amidation of
2-aminobenzonitrile, 2-aminobenzoic acid and 2-aminobenzamide11 and some modification of this
procedure that have also been reported.12 Other methods such as reaction of anthranilic acid with
substituted imidates,13 aldehydes,14 and reductive cylization of 2-nitrobenzamides were also reported.15
However, some of these methods are associated with certain drawbacks such as a multi-step procedure,13
costly reagents,15 harsh reaction conditions,16 complex experimental process, long reaction times,11 and
low yields.11 Therefore, there is still a need to develop appropriate efficient and versatile methods for the
synthesis of 4(3H)-quinazolinones.

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Recently, multi-component condensation reactions have become a powerful method for the synthesis of
small-molecule libraries, due to the fact that products are formed in a single step by simultaneous
reactions of several reagents and the molecular diversity required for such combinatorial libraries can be
achieved by simply varying each component.17
Ceric ammonium nitrate (CAN), was first investigated in 1936.18 CAN has received considerable
attention as an inexpensive and easily available catalyst for various organic reactions such as oxidation,
oxidative addition, nitration, photo-oxidation, deprotection, graft polymerization, etc.19
In continuation of our interest in finding convenient methods for the synthesis of quinazolinone
derivatives,20 we wish to report a novel and effective method for the synthesis of these class of
compounds.
When CAN was added to a mixture of isatoic anhydride, ammonium acetate and aldehyde in ethanol
under reflux condition the desired products (1a-1q) were afforded after an appropriate time (Scheme 1).
O
O
X
X
NH
CAN (1 equiv)
EtOH, reflux
O
+
CHO
NH4OAc
R
+
N
1a-1q
R
N
O
H
Scheme 1
The results are summarised in Table 1. The reaction of different aromatic and aliphatic aldehydes and two
derivatives of isatoic anhydride were conducted in ethanol and in all cases the desired products were
obtained successfully. Another advantage of this method is the use of easily available aldehydes for the
installation of C2 substituents. Therefore, a wide range of 2-substituted 4(3H)-quinazolinones could be
synthesized by a one-pot three-component reaction that is very important in view of combinatorial
chemistry in drug discovery. It is worthy to note that there are some reports on the application of
aldehydes in the synthesis of 4(3H)-quinazolinones, but they took place through two or three step
reaction.14 Aliphatic aldehydes work well under reaction condition and afforded the corresponding
products in good yields (Table 1, Product 1l and 1m). Furthermore, the heterocyclic aldehydes such as
furfural also worked well without the formation of any side products (Table 1, product 1k). Work up
procedure was so simple including isolation of products by simple aqueous work-up followed by
filtration.
In conclusion a novel one-pot procedure for the synthesis of 2-substituted 4(3H)-quinazolinones was
introduced. The reaction has been shown to display good functional group tolerance and is high yielding
and the product isolation is very straightforward. We hope that this approach may be of value to others
seeking novel synthetic fragments with unique properties for medicinal chemistry programs.

HETEROCYCLES, Vol. 75, No. 11, 2008
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Table 1. Synthesis of 2-substituted 4(3H)-quinazolinones (1)
Mp (°C)
Reportedb
Product
X
R
Time(h)
Yield(%)a
Found
1a
1b
1c
1d
H
H
H
H
C6H5
3
85
75
78
75
233-234
250 (dec.)
>300
23512f
-
2-HO-C6H4
3-O2N-C6H4
4-O2N-C6H4
3.5
4
>30014f
>30014f
245-24614g
>300
5
246-247
1e
1f
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
4-MeO-C6H4
2,4-(MeO)2-C6H3
3,4-(MeO)2-C6H3
4-Cl-C6H4
2,4-(Cl)2-C6H3
4-Me-C6H4
2-Furyl
3.5
4
80
79
83
82
75
86
73
60
55
86
83
87
83
206-207
220-222
>300
206-20714g
-
1g
1h
1i
3
30412f
3.5
5
250 (dec.)
240-242
220-222
235-236
205-206
208-209
219-221
>300
-
24112f
1j
3
221-22214c
238-23920a
206-20720a
21012f
22212f
30312f
1k
1l
4
Me
7
1m
1n
1o
1p
1q
n-Pr
9
C6H5
2.5
4
2-Cl-C6H4
4-Cl-C6H4
2-Me-C6H4
3
267-269
26812f
3
aIsolated yield based on isatoic anhydride.
bThe products were characterised by comparison of their spectroscopic and physical data with authentic
samples synthesised by reported procedures.
EXPERIMENTAL
Melting points were obtained in open capillary tubes and also were measured on the electrothermal 9100
apparatus and are uncorrected. Mass spectra were recorded on a Shimadzu QP 1100 BX Mass
Spectrometer.
CHN Elemental analysis was performed using a Heracus CHN-O-Rapid analyser. IR spectra were
1
recorded on KBr pellets on a Shimadzu IR-470 Spectrophotometer. H and 13C NMR spectra were
determined on a Bruker 300 DRX AVANCE instrument at 300 and 75 MHz, respectively.
General procedure for the synthesis of 2-substituted 4(3H)-quinazolinones
Isatoic anhydride (1 mmol), ammonium acetate (1.2 mmol, 0.1 g), aldehyde (1 mmol) and EtOH (5 mL)
were mixed in a round bottom flask. CAN (1 mmol, 0.548 g) was added and the mixture was stirred at 70

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˚C under reflux condition for the appropriate time (see Table 1). After completion of the reaction was
confirmed by TLC (eluent: EtOAc/n-hexane: 1/2), the solvent was evaporated. Water was added and the
precipitated product was filtered. Finally, the crude quinazolinone was recrystallised from EtOH.
2-(2-Hydroxyphenyl)quinazolin-4(3H)-one (1b). Pale yellow powder, mp 250 ̊C (decomp.). IR (KBr)
1
υ/cm: 3440, 3098, 1673, 1610, 1563, 1506, 1397, 1333. H NMR (DMSO-d6, 300 MHz) δ (ppm):
6.93-7.01 (m, 2H, Ar-H), 7.42-7.56 (m, 2H, Ar-H), 7.70-8.23 (m, 4H, Ar-H), 12.47 (s, 1H, NH), 13.79 (s,
13
1H, OH). C NMR (DMSO-d6, 75 MHz) δ (ppm): 114.13, 118.33, 119.24, 121.16, 126.48, 127.36,
128.36, 134.15, 135.42, 138.08, 146.54, 154.19, 160.55, 161.86. MS (EI, 70 eV) (m/z, %): 238 (M+, 100),
199(20), 119 (70), 92 (50), 63 (35), 39 (25). Anal. Calcd for C14H10N2O2 (238): C, 70.58; H, 4.23; N,
11.76%. Found: C, 70.44; H, 4.21; N, 12.01%.
2-(3-Nitrophenyl)quinazolin-4(3H)-one (1c). White powder, mp >300 ̊C. IR (KBr) υ/cm: 3448, 3075,
1
2928, 1678, 1608, 1531, 1464. H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.55-7.58 (m, 1H, Ar-H),
7.73-7.86 (m, 3H, Ar-H), 8.16 (d, J = 7.5 Hz, 1H, Ar-H), 8.41 (d, J = 7.4 Hz, 1H, Ar-H), 8.59 (d, J = 7.5
13
Hz, 1H, Ar-H), 9.00 (s, 1H, Ar-H), 12.87 (s, 1H, NH). C NMR (DMSO-d6, 75 MHz) δ (ppm): 121.65,
123.13, 126.25, 126.36, 127.61, 128.06, 130.39, 134.43, 134.76, 135.21, 148.4, 148.72, 150.96, 162.61.
MS (EI, 70 eV) (m/z, %): 267 (M+, 100), 221 (85), 192 (25), 166 (10), 119 (25), 92 (20). Anal. Calcd for
C14H9N3O3 (267.24): C, 69.92; H, 3.39; N, 15.72%. Found: C, 69.94; H, 3.31; N, 15.51%.
2-(4-Nitrophenyl)quinazolin-4(3H)-one (1d). Yellow powder, mp >300 ̊C. IR (KBr) υ/cm: 3425, 3085,
1
2925, 1676, 1593, 1473, 1346. H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.54-7.99 (m, 5H, Ar-H),
13
8.15-8.21 (m, 5H, Ar-H), 12.82 (s, 1H, NH). C NMR (DMSO-d6, 75 MHz) δ (ppm): 124.02, 126.34,
127.75, 128.15, 128.46, 129.68, 135.17, 137.95, 148.68, 149.36, 151.05, 162.49. MS (EI, 70 eV)
(m/z, %): 267 (M+, 40), 220 (35), 192 (40), 119 (50), 76 (100), 50 (80). Anal. Calcd for C14H9N3O3
(267.24): C, 69.92; H, 3.39; N, 15.72%. Found: C, 69.89; H, 3.31; N, 15.53%.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (1e). White powder, mp 245-246 ̊C. IR (KBr) υ/cm: 3444,
1
3182, 3093, 2961, 2841, 1681, 1605, 1597, 1522, 1483, 1310. H NMR (DMSO-d6, 300 MHz) δ (ppm):
3.83 (s, 3H, OMe), 7.07 (br.s, 2H, Ar-H), 7.47-7.92 (m, 3H, Ar-H), 8.11-8.17 (m, 3H, Ar-H), 12.56 (s, 1H,
13
NH). C NMR (DMSO-d6, 75 MHz) δ (ppm): 55.85 (OMe), 114.39, 121.12, 125.22, 126.26, 126.49,
127.6, 129.88, 134.82, 147.4, 149.29, 152.33, 162.29. MS (EI, 70 eV) (m/z, %): 252 (M+, 100), 197 (50),
119 (50), 90 (25), 63 (35). Anal. Calcd for C15H12N2O2 (252.27): C, 71.42; H, 4.79; N, 11.10%. Found: C,
71.54; H, 4.61; N, 11.31%.
2-(2,4-Dimethoxyphenyl)quinazolin-4(3H)-one (1f). White powder, mp 206-207 ̊C. IR (KBr) υ/cm:
3432, 3094, 3061, 1662, 1610, 1509, 1485, 1438, 1386. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 3.85 (s,
3H, OMe), 3.89 (s, 3H, OMe), 6.46-6.77 (m, 2H, Ar-H), 7.46-8.19 (m, 5H, Ar-H), 11.82 (s, 1H, NH). 13C
NMR (DMSO-d6, 75 MHz) δ (ppm): 55.548, 55.98, 114.51, 118.43, 120.65, 122.23, 125.73, 126.12,

HETEROCYCLES, Vol. 75, No. 11, 2008
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127.11, 127.84, 131.79, 134.34, 137.16, 151.92, 158.73, 162.89. MS (EI, 70 eV) (m/z, %): 282 (M+, 50),
252 (25), 225 (30), 199 (100), 171 (30), 119 (85). Anal. Calcd for C16H14N2O3 (282.29): C, 68.07; H,
5.00; N, 9.92%. Found: C, 68.14; H, 4.91; N, 10.01%.
2-(3,4-Dimethoxyphenyl)quinazolin-4(3H)-one (1g). White powder, mp 220-222 ̊C. IR (KBr) υ/cm:
3444, 3182, 3093, 2841, 1671, 1605, 1567, 1522, 1483. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 3.84 (s,
3H, OMe), 3.88 (s, 3H, OMe), 7.11 (d, J = 9.1 Hz, 1H, Ar-H), 7.45-7.51 (m, 1H, Ar-H), 7.63-7.95 (m, 4H,
Ar-H), 8.12 (d, J = 9.1 Hz, 1H, Ar-H), 12.43 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 56.11
(2 OMe), 111.09, 111.78, 121.13, 121.58, 125.17, 126.28, 126.58, 127.76, 135.00, 148.98, 149.35, 152.02,
152.28 162.81. MS (EI, 70 eV) (m/z, %): 282 (M+, 100), 251 (M+, 25), 236 (30), 119 (40), 90 (35), 90
(25). Anal. Calcd for C16H14N2O3 (282.29): C, 68.07; H, 5.00; N, 9.92%. Found: C, 68.14; H, 4.91; N,
10.02%.
2-(2,4-Dichlorophenyl)quinazolin-4(3H)-one (1i). Pale yellow powder, mp 250 ̊C (decomp.). IR (KBr)
υ/cm: 3446, 3205, 1692, 1594, 1466, 1333, 1298. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 7.56-7.88 (m,
5H, Ar-H), 7.99-8.26 (m, 2H, Ar-H), 12.86 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 125.82,
127.18, 127.48, 127.96, 129.17, 129.85, 132.20, 132.64, 132.70, 134.60, 137.46, 147.41, 151.91, 160.28.
MS (EI, 70 eV) (m/z, %): 290 (M+, 30), 197 (55), 136 (25), 119 (100), 90 (35). Anal. Calcd for
C14H8Cl2N2O (291.13): C, 57.76; H, 2.77; N, 9.62%. Found: C, 57.81; H, 2.71; N, 9.71%.
ACKNOWLEDGEMENTS
The authors would like to acknowledge financial support from the Research Council of Shahid Beheshti
University.
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