A practical and versatile approach toward a one-pot synthesis of 2,3-disubstituted 4(3H)-quinazolinones

Article abstract of DOI:10.1007/s00706-010-0341-1

An effective one-pot three-component route to 4(3H)-quinazolinones from commercially available starting materials is reported. Thus, isatoic anhydride reacted with ammonium acetate or primary amines and aldehydes in the presence of iodine to produce the corresponding quinazolinone derivatives in moderate to good yields. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-010-0341-1

Monatsh Chem (2010) 141:877–881
DOI 10.1007/s00706-010-0341-1
ORIGINAL PAPER
A practical and versatile approach toward a one-pot synthesis
of 2,3-disubstituted 4(3H)-quinazolinones
•
Minoo Dabiri Peyman Salehi
•
•
Mahboobeh Bahramnejad Mohsen Alizadeh
Received: 6 April 2010 / Accepted: 4 June 2010 / Published online: 22 July 2010
Ó Springer-Verlag 2010
Abstract An effective one-pot three-component route to
4(3H)-quinazolinones from commercially available starting
materials is reported. Thus, isatoic anhydride reacted with
ammonium acetate or primary amines and aldehydes in the
presence of iodine to produce the corresponding quinaz-
olinone derivatives in moderate to good yields.
efficiently generated. In fact, MCRs have been extensively
employed in combinatorial and parallel diversity oriented
synthesis [2, 3].
The quinazolinone moiety is a building block for
approximately 150 naturally occurring alkaloids [4], such
as glycosminine [5], luotonin [6], deoxyvasicinone [7], and
drugs like methaqualone [8, 9] and piriqualone [10]
(Fig. 1).
Keywords Quinazolinone Á Heterocycle Á Iodine Á
Multicomponent reaction Á Aldehyde Á Amine
In addition, quinazolinone analogues are an important
class of heterocyclic compounds and used as antimalarial
[11], anticonvulsant [12], antibacterial [13], antidiabetic
[14], and anticancer drugs [15].
Introduction
According to the valuable biological and diverse range
of the pharmacological activities of quinazolinones, their
synthesis is in demand. Consequently many research
groups work on synthesis of this priceless heterocycles
[16–18]. The most common synthesis route involves the
amidation of 2-aminobenzoic acid or its derivatives, i.e.
2-aminobenzonitrile, 2-aminobenzoate, and 2-arylnitrilium
salts, followed by ring closure with carboxylic acid
derivatives [19, 20] or orthoesters [21–25]. Other synthesis
pathways include the cyclization–oxidation of anthranila-
mides with aldehydes [26–30], which is only useful for the
synthesis of 2-substituted quinazolinones, and reductive
cyclization of nitro-aromatic compounds [31]. Reports on
solid-phase synthesis [32], palladium-catalyzed cyclo-
carbonylation of o-iodoanilines [33], base-promoted ring
closure of o-fluorobenzoylguanidines [34], ring closure of
the N-protected guanidines [35], and a-functionalization
reaction of cyclic amines [36] are some additional inputs
to explore the quinazolinone multifaceted importance.
However, there are few reports on one-pot synthesis of 2,3-
disubstituted quinazolinones using aldehydes as a starting
material in which only preparation of 2-substituted ana-
logues has been reported [26–30]. In this contribution, we
The construction of complex molecules through multi-
component reactions (MCRs) constitutes a very attractive
strategy in organic synthesis [1]. In a multicomponent
reaction three or more reactants are involved in a cascade
of bond-forming individual steps to provide a complex
molecule without isolation of intermediates or modification
of the reaction conditions. Attractive features of MCRs are
simplicity of operation, reduction of isolation and purifi-
cation steps, and minimization of costs, time, energy,
solvents, and waste production. Moreover, by employing
an array of diverse reagents, molecular diversity is
M. Dabiri (&) Á M. Bahramnejad Á M. Alizadeh
Department of Chemistry, Faculty of Science,
Shahid Beheshti University, G. C., Evin,
1983963113 Tehran, Iran
e-mail: m-dabiri@sbu.ac.ir
P. Salehi (&)
Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, G. C., Evin,
1983963113 Tehran, Iran
e-mail: p-salehi@sbu.ac.ir
123

878
M. Dabiri et al.
reaction. In recent years, molecular iodine has received
considerable attention as an inexpensive and readily
available catalyst for various organic transformations under
very mild and convenient conditions to afford the corre-
sponding products in excellent yields with high selectivity
[37].
O
N
O
N
R2
R1
N
N
N
Quinazolinone core
Luotonin
O
N
N
O
N
Results and discussion
Isatoic anhydride, benzaldehyde, and aniline were chosen
as the model substrates to optimize the reaction conditions
including the solvents, amount of iodine, and catalyst. As
shown in Table 1, five different solvents were tested under
reflux conditions using 1 equivalent of iodine and 10 mol%
of acetic acid as the catalyst (relative to the amount of
isatoic anhydride) (Table 1, entries 1–5). As can be seen,
acetonitrile was the best choice (Table 1, entry 2). No
quinazolinone 4 was formed in the absence of acetic acid
(Table 1, entry 6), and no improvement in yield was
observed using higher amounts of the acid (Table 1, entry
7). When the reaction was run in the presence of lower
amounts of iodine the yield of product decreased and
increasing the amount of iodine had no obvious effect on
N
Deoxyvasicinone
Methaqualone
Fig. 1 Quinazolinone core and some well-known quinazolinone
derivatives
report the one-pot three-component synthesis of 2,3-
disubstituted quinazolinones starting from aldehydes for
the first time. This will allow the method to be used for the
production of ensembles, as different isatoic anhydrides,
amines, and aldehydes could be used in the reaction.
The use of molecular iodine in organic synthesis has
been known for a long time, such as in the Grignard
Table 1 Optimization of reaction conditions
O
O
X
Ph
Ph
O
N
Different conditions
Ph CHO
+
+ Ph NH2
N
O
N
H
Entry
Solvent
Iodine (eq)
AcOH (mol%)
Time (h)
Yield (%)a
1
CHCl3
1
1
10
10
10
10
10
–
12
12
12
12
12
12
12
12
12
12
10
8
10
62
50
50
–
2
CH3CN
CH3OH
C2H5OH
C6H5CH3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3
1
4
1
5
1
6
1
–
7
1
20
10
10
10
10
10
10
10
10
61
–
8
–
9
0.5
2
30
62
60
61
60
50
30
10
11
12
13
14
15
CH3CN:H2O (3:1)
CH3CN:H2O (2:1)
CH3CN:H2O (1:1)
CH3CN:H2O (1:2)
CH3CN:H2O (1:3)
1
1
1
5
1
12
12
1
Reaction conditions: a mixture of isatoic anhydride (1 mmol), benzaldehyde (1 mmol), aniline (1.1 mmol), I2, acetic acid, and 5 cm3 solvent was
stirred in a round bottom flask under reflux
a
Isolated yield
123

One-pot synthesis of 2,3-disubstituted 4(3H)-quinazolinones
879
conversion (Table 1, entries 8–10). Based on our knowl-
edge in using water in the synthesis of quinazolinones
[38–40], a mixture of water and acetonitrile was utilized as
the solvent (Table 1, entries 11–15). Different ratios were
examined and in 1:1 ratio the best result was provided
(Table 1, entry 13). A wide range of structurally diverse
amines 3, aldehydes 2, and isatoic anhydrides 1 were
reacted under the optimum conditions (Scheme 1). The
results are summarized in Table 2. In all cases, the three-
component reaction proceeded smoothly to afford the
corresponding quinazolin-4(3H)-ones in good yields. Ani-
lines having an electron-donating group (methyl) gave a
higher yield (65%) (Table 2, entry 3) due to the increased
electron density of the aromatic system, whereas electron-
withdrawing groups (Cl) gave a lower yield (54%)
(Table 2, entry 6). Heteroaromatic aldehydes also under-
went cyclocondensation reaction successfully (Table 2,
entries 11, 20). The results also showed that aliphatic
aldehydes were cyclized to give the corresponding qui-
nazolinone in lower yields and longer reaction time. Using
ammonium acetate instead of amine in the reaction pro-
duced 2-substituted quinazolinones successfully in higher
yield and shorter time compared to disubstituted analogues.
It was found that by using ammonium acetate there was no
need to use acetic acid in the reaction (Table 2, entries
18–24). Although the 2-substituted quinazolinone nucleus
has been synthesized via condensation of anthranilamides
with aldehydes followed by oxidation reaction using
Scheme 1
O
O
I2 (1 equiv.)
AcOH (10 mol%)
X
X
R2
R1
O
N
R1 CHO
+
+ R2 NH2
N
O
CH3CN:H2O (1:1)
Reflux
N
H
1
2
3
4
Table 2 Synthesis of quinazolinone derivatives
Entry
Product
X
R1
R2
Ph
Time (h)
Yield (%)a
Mp (°C) [Ref.]
1
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Cl
H
H
H
H
Cl
Cl
Cl
Cl
Ph
Ph
Ph
7
5
60
71
65
63
60
54
58
60
70
73
57
45
68
71
65
40
45
65
50
55
74
72
74
60
156–157 [33]
198–200 [33]
178–179 [33]
171–173 [33]
168–169 [33]
198–200 [33]
175–176 [33]
182–183 [33]
130–131 [33]
114–115 [33]
202–204 [33]
231–232 [42]
172–174
2
4-CH3OC6H4
3
4-CH3C6H4
7
4
4-CH3C6H4
4-CH3C6H4
Ph
Ph
7
5
4-CH3C6H4
7
6
4-ClC6H4
7
7
4g
4h
4i
4-ClC6H4
4-ClC6H4
Ph
Ph
6
8
4-ClC6H4
6
9
i-Pr
6
10
11
12
13
14
15
16
17
18b
19b
20b
21b
22b
23b
24b
a
4j
Ph
n-Bu
7
4k
4l
2-Furyl
Me
Ph
6
Me
10
7
4m
4n
4o
4p
4q
4r
4s
4-HOC6H4
Ph
4-CH3C6H4
PhCH2
7
137–139 [43]
176–178
4-BrC6H4
3-O2NC6H4
2-Pyridyl
4-HOC6H4
Me
4-CH3C6H4
7
4-CH3C6H4
10
8
252–254
4-CH3C6H4
206–207 [20]
302–303 [30]
335–337 [22]
220–221 [30]
247–248 [44]
208–210 [44]
213–215 [44]
230–232 [44]
H
H
H
H
H
H
H
5
5
4t
2-Furyl
4-CH3C6H4
Ph
5
4u
4v
4w
4x
5
5
4-ClC6H4
4-O2NC6H4
5
5
Isolated yield
b
The reaction was carried out using NH4OAc instead of AcOH and amine
123

880
M. Dabiri et al.
Scheme 2
H
O
O
O
H2N R2
NHR2
N
NHR2
R1 CHO
O
3
NH2
N
H
O
CO2
1
6
5
R1
H
I2
O
O
O
N
R2
R1
R2
R1
NHR2
R1
N
N
N
N
I
HI
I
4
7
8
General procedure for the one-pot synthesis
of 2,3-disubstituted quinazolin-4(3H)-ones
different oxidant [26–30] in good yields, our present
method has the capability to adapt for the synthesis of 2,3-
disubstituted quinazolinones which are important com-
pounds in biological and pharmaceutical chemistry (Fig. 1)
[8–15].
Isatoic anhydride (1 mmol, 0.16 g), 1.2 mmol primary
amine or 0.1 g ammonium acetate (1.2 mmol), 1 mmol
aldehyde, and 5 cm3 solvent (CH3CN:H2O/1:1) were
mixed in a round bottom flask. Then 0.25 g iodine
(1 mmol) and 6 cm3 AcOH (10 mol%) were added and the
mixture was stirred under reflux condition for the appro-
priate time (see Table 2). After completion of the reaction
confirmed by TLC (eluent: ethyl acetate/n-hexane: 1/2), the
solvent was evaporated. To the resulting solid was added
15 cm3 H2O and the mixture was stirred for 10 min. The
resulting precipitate was filtered and washed with 10%
aqueous Na2S2O3 solution, water, and cold MeOH. Finally,
the crude quinazolinone was recrystallised from ethanol.
In view of these results, we assume the reaction mech-
anism to be working as shown in Scheme 2. At first, the
reaction starts through condensation of isatoic anhydride 1
and amine followed by decarboxylation to yield the cor-
responding 2-aminobenzamide 5 [21–25]. Condensation of
the aromatic aldehyde with the amino group of 5 then gives
imine 6 [26–30]. Electrophilic activation of imine via a
cyclic iodonium ion [8, 9, 41] opens the way for nucleo-
philic cyclization of the amide. Finally, when the
intermediate 8 loses HI [37], the quinazolinone 4 is formed.
In conclusion, we developed a general and efficient
method for the synthesis of quinazolinone derivatives via
iodine-catalyzed cyclization–oxidation coupling of isatoic
anhydride with aldehydes and amines under mild condi-
tions. The present method shows simple, economical, and
practical advantages over the previous methods, so it can
provide a procedure for one-pot synthesis of diverse mol-
ecules for organic and medicinal chemistry.
2-(4-Hydroxyphenyl)-3-(4-methylphenyl)quinazoline-
4(3H)-one (4m, C21H16N2O2)
Pale yellow solid; m.p: 172–174 °C; 1H NMR
(300.13 MHz, DMSO-d6): d = 2.29 (s, 3H), 3.47–3.40
(m, 1H), 6.59 (d, J = 7.4 Hz, 2H), 7.21–7.15 (m, 6 H),
7.58–7.56 (m, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.87–7.85
(m,1 H), 8.17 (d, J = 7.5 Hz, 1H) ppm; 13C NMR
(75.47 MHz, DMSO-d6): d = 21.1, 114.8, 120.9, 126.9,
127.2, 127.7, 129.5, 129.6, 131.2, 135.1, 136.1, 137.8,
Experimental
ꢀ
147.8, 155.8, 158.4, 162.1 ppm; IR (KBr): m = 1,678
[(C=O)] cm-1; MS (70 eV): m/z = 328 (M? 60), 327
(100), 256 (25), 221 (20), 192 (20), 160 (40), 128 (35), 96
(25), 64 (75).
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
75.47 MHz. The structures of the isolated products were
confirmed by elemental analyses and from spectral data
2-(4-Bromophenyl)-3-(4-methylphenyl)quinazoline-4(3H)-
one (4o, C21H15BrN2O)
1
White solid; m.p.: 176–178 °C; H NMR (300.13 MHz,
DMSO-d6): d = 2.27 (s, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.23
(d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.46 (d,
J = 8.4 Hz, 2H), 7.63–7.58 (m, 1H), 7.77 (d, J = 8.1 Hz,
1H), 7.92–7.87 (m, 1H), 8.19 (d, J = 7.9 Hz, 1H) ppm; 13
1
(mass, H, and 13C NMR spectra) and by comparison of
C
their melting points with those of authentic samples.
123

One-pot synthesis of 2,3-disubstituted 4(3H)-quinazolinones
881
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NMR (75.47 MHz, DMSO-d6): d = 21.2, 121.3, 122.9,
127.0, 127.7, 127.9, 129.7, 131.1, 131.5, 135.2, 135.4,
ꢀ
135.5, 138.2, 147.6, 154.8, 161.9 ppm; IR (KBr): m = 1,659
[(C=O)] cm-1; MS (70 eV): m/z = 392 (60), 391 (M? 100),
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2-(3-Nitrophenyl)-3-(4-methylphenyl)quinazoline-4(3H)-
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1
White solid; m.p.: 252–254 °C; H NMR (300.13 MHz,
DMSO-d6): d = 2.23 (s, 3H), 7.13 (d, J = 8.1 Hz, 2H),
7.28 (d, J = 8.1 Hz, 2H), 7.56–7.49 (m, 1H), 7.66–7.63
(m, 1H), 7.75–7.72 (m, 1H), 7.86–7.79 (m, 2H), 8.15–8.12
(m, 1H), 8.31 (d, J = 3 Hz, 1H) ppm; 13C NMR
(75.47 MHz, DMSO-d6): d = 21.2, 118.5, 124.3, 124.4,
127.6, 129.7, 129.8, 130.3, 133.4, 135.1, 135.2, 135.7,
137.3, 138.5, 147.3, 150.0, 154.5, 159.8, 170.8; IR (KBr):
m = 1,663 [(C=O)] cm-1; MS (70 eV): m/z = 393 (10),
ꢀ
391 (M? 30), 366 (20), 256 (25), 192 (25),160 (50), 128
(50), 96 (25), 64 (100).
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Acknowledgments The authors would like to acknowledge
financial support from the Research Council of Shahid Beheshti
University.
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