A novel and efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the reaction of (het)arylmethanamines with isatoic anhydride

Article abstract of DOI:10.1016/j.tetlet.2016.07.025

A novel and straightforward method for the synthesis of quinazolin-4(3H)-ones is described. The one-pot reaction between isatoic anhydride and (het)arylmethanamines led to the formation of N-substituted anthranilamides, which under aerobic conditions in the presence of CuBr undergo an in situ oxidation–cyclization reaction to produce quinazolin-4(3H)-ones in good yields.

Full text of DOI:10.1016/j.tetlet.2016.07.025

Accepted Manuscript
A novel and efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the
reaction of (het)arylmethanamines with isatoic anhydride
Mohammad Mahdavi, Rasool Hassanzadeh, Mehdi Soheilizad, Shiva Golshani,
Setareh Moghimi, Loghman Firoozpour, Abbas Shafiee, Alireza Foroumadi
PII:
S0040-4039(16)30858-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.025
TETL 47887
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 April 2016
2 July 2016
7 July 2016
Please cite this article as: Mahdavi, M., Hassanzadeh, R., Soheilizad, M., Golshani, S., Moghimi, S., Firoozpour,
L., Shafiee, A., Foroumadi, A., A novel and efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the
reaction of (het)arylmethanamines with isatoic anhydride, Tetrahedron Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2016.07.025
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A novel and efficient synthesis of 2-substituted
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quinazolin-4(3H)-ones by the reaction
of (het)arylmethanamines with isatoic anhydride
Mohammad Mahdavi, Rasool Hassanzadeh, Mehdi Soheilizad, Shiva Golshani, Setareh Moghimi, Loghman

Firoozpour, Abbas Shafiee, Alireza Foroumadi

1
Tetrahedron Letters
A novel and efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the
reaction of (het)arylmethanamines with isatoic anhydride
a
b
b
b
b
Mohammad Mahdavi, Rasool Hassanzadeh, Mehdi Soheilizad, Shiva Golshani, Setareh Moghimi,
a
b
a,b
Loghman Firoozpour, Abbas Shafiee, Alireza Foroumadi
a
Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran,
b
Iran.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and straightforward method for the synthesis of quinazoline-4(3H)-ones is
described. The one-pot reaction between isatoic anhydride and (het)arylmethanamines led
to the formation of N-substituted anthranilamides, which under aerobic conditions in the
presence of CuBr undergo an in situ oxidation-cyclization reaction to produce quinazoline-
4(3H)-ones in good yields.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Quinazoline
One-pot
Isatoic anhydride
Aerobic conditions
CuBr
—
——

Corresponding author. Tel.: +98-21-66954708; fax: +98-21-66461178; e-mail: aforoumadi@yahoo.com

2
Tetrahedron
26
1.Introduction
anhydride, ortho esters and primary amines,
the CuO
nanoparticle-catalysed three-component reaction of isatoic
anhydride, aldehydes and amine or ammonium under ultrasonic
irradiation, and the reaction between 2-aminobenzamides and
The development of novel approaches and the use of
inexpensive and efficient reagents or catalysts are key areas of
organic synthesis for the preparation of valuable heterocyclic
compounds.
27
aryl
halides
via
a
palladium-catalysed
isocyanide
28
29
insertion/cyclization sequence, as well as other methods.
Quinazoline-4(3H)-ones are an important class of nitrogen-
However, some of these procedures have drawbacks such as
long reaction times, low yields, harsh reaction conditions,
difficult work-up and the use of expensive and/or toxic catalysts,
reagents or reaction media. Furthermore, some of the starting
materials need to be synthesized and purified which is time-
consuming. Therefore, the development of simple and efficient
methods for the synthesis of quinazoline-4(3H)-ones are
desirable.
containing heterocyclic compounds exhibiting a number of
1
important biological and pharmacological properties such as
2
3
4
5
anticancer, anti-microbial, anti-inflammatory, anticonvulsant,
6
7
8
9
anti-ulcer, anti-bacterial, antidiabetic, anti-virus, and anti-
1
0
cytotoxin activities. Illustrative examples of pharmacologically
active quinazolinones are shown in Figure 1. Additionally, a
1
1
number of natural products containing the quinazolin-4(3H)-one
12
moiety, such as the alkaloids tryptanthrin 1, deoxyvasicinone
1
3
14
15
2
,
antimalarials febrifugine 3, and isofebrifugine 4 are
Taking into account the pharmacological importance of
quinazoline-4(3H)-ones, and as a part of our continued efforts
regarding the development of straightforward routes for the
known (Figure 2).
This broad range of applications has made the development of
new and efficient quinazoline-4(3H)-ones syntheses valuable.
Therefore, a number of synthetic routes have been reported for
the preparation of quinazoline-4(3H)-one derivatives including:
30
preparation of heterocyclic compounds, herein, we report a
novel and efficient protocol for the synthesis of 2-substituted
quinazoline-4(3H)-ones by the reaction of (het)arylmethanamines
with isatoic anhydride, in the presence of CuBr and K CO , in
2 3
DMSO at 120 C under aerobic conditions (Scheme 1).
the FeCl
3
catalysed reaction of isatoic anhydride with
16
amidoximes, the CuBr catalysed domino reaction of alkyl
halides and anthranilamides, the p-TSA-catalysed cyclization of
17
2
-aminobenzamides and aldehydes followed by oxidative
18
dehydrogenation with PhI(OAc)
2
,
the reaction of 2-
nitrobenzamides with aldehydes via in-situ reduction of the nitro
19
group using Na
2 2
S O
4
,
the C–C bond cleavage of 2,2-
Scheme 1. Synthesis of 2-substituted quinazoline-4(3H)-ones
disubstituted-1,2,3,4-tetrahydroquinazolinone by a CuBr/air
In order to optimize the reaction conditions, benzyl amine (1
mmol), isatoic anhydride (1 mmol), tetra-butyl ammonium
bromide (TBAB) (0.5 mol%) and K CO , were used as a model
2 3
reaction. To evaluate the catalyst effect, the reaction was first
examined in the presence of different copper catalysts (Table 1,
entries 1-4), and without a copper catalyst (Entry 5). The best
yield was obtained using CuBr (Entry 2). Performing the reaction
under a nitrogen atmosphere led to the desired product in trace
amounts (Entry 6). We observed that only in the presence of the
copper catalyst and under aerobic condition was the desired
product formed. The model reaction was also carried out in the
presence of various bases, solvents and temperatures. Compared
3 4 2 3 2 3 2 3
to K PO , Na CO and Cs CO , the reaction with K CO gave the
Figure 1. Representative pharmacologically active quinazoline-4(3H)-ones
highest yield (Entries 7-9). Switching the solvent from DMSO to
DMF and toluene resulted in poor reactivity (Entries 10-11).
Finally, the highest yield was obtained when the reaction was
conducted at 120 °C (Entries 12-14).
Table 1. Optimization of the reaction conditions
Figure 2. Representative quinazoline-4(3H)-one containing natural products.
2
0
catalytic system, the three-component reaction of isatoic
anhydride, primary amines and benzyl halides under Kornblum
b
Entry
Catalyst
Base
Solvent
Temp.
Yield
(%)
21
o
a
(
C)
oxidation conditions, the copper-catalysed domino Ullmann-
type coupling and aerobic oxidative C-H amidation of 2-
1
2
3
4
5
CuI
CuBr
K
2
CO
CO
CO
CO
CO
3
3
3
3
3
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
44
70
51
48
-
22
halobenzamides and (aryl)methanamines, the CuI catalysed
coupling/condensative cyclization of 2-haloarylcarboxamides
K
2
23
with imidamides, the Pd-catalysed cyclocarbonylation of 2-
Cu(OAc)
2
K
2
24
iodoanilines with imidoyl chlorides, the condensation of
anthranilic acids, carboxylic acids, and amines under microwave
CuBr
-
2
K
2
25
K
2
condition, the silica sulfuric acid catalysed reaction of isatoic

3
c
6
7
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K
2
CO
PO
CO
CO
3
DMSO
DMSO
DMSO
DMSO
DMF
120
120
120
120
120
120
80
Trace
K
3
4
57
60
54
17
0
Na
Cs
2
3
2
3
1
0
1
2
3
4
K
2
CO
CO
CO
CO
CO
3
1
1
1
1
K
2
3
Toluene
DMSO
DMSO
DMSO
K
2
3
3
3
20
56
63
K
2
100
140
K
2
a
b
c
Isolated yields.
0 mol% catalyst.
Reaction performed under N
1
Scheme 2. Proposed reaction mechanism for the preparation of 2-substituted
quinazoline-4(3H)-ones
2
.
Acknowledgments
Having obtained the optimized conditions, the formation of 2-
phenylquinazolin-4(3H)-ones was examined using various aryl
and heteroaryl methaneamines, affording products 7a-7k in 66-
This study was funded and supported by the Research Council of
Tehran University of Medical Sciences (TUMS), Grant no. 95-
31
7
7% yield (Table 2).
02-92-32295; and Iran National Science Foundation (INSF).
Table 2. Synthesis of quinazoline-4(3H)-ones 7a-k
Compound Ar
Yield
%)
References and notes
(
7
7
a
C
6
H
5
70
72
73
73
77
74
66
70
68
70
72
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2-MeOC
3-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
2
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7
c
(
7
d
3
4
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7
e
f
4-Me
2
NC
6
H
4
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4-MeC
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7
i
2-O
3-O
2
2
NC
6
6
H
H
4
4
j
NC
7
k
2-thienyl
6
7
8
.
.
.
A suggested mechanism for the formation of quinazoline-
(3H)-ones 7 is depicted in Scheme 2. First, N-substituted
4
anthranilamide 8, prepared through nucleophilic addition of
amine 5 to isatoic anhydride 6, undergoes a copper-catalysed
aerobic oxidation to give the imine intermediate 9. Then,
intramolecular attack of the imine bond and subsequent copper-
catalysed aerobic oxidation led to the formation of quinazoline-
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1
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4
(3H)-ones 7 (Scheme 2).
In conclusion, we have developed a novel and efficient
2
011, 2, 22-28.
approach for the preparation of quinazoline-4(3H)-ones via the
reaction of isatoic anhydride and (het)arylmethanamines in
DMSO, followed by aerobic oxidation in the presence of CuBr
and K CO at 120 C. Use of commercially available starting
2 3
materials, ligand-free metal catalysis and aerobic oxidative
conditions are the main advantages of this method.
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4
Tetrahedron
1
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2
2
0. Hu, B.Q.; Wang, L.X.; Yang, L.; Xiang, J.F.; Tang, Y.L. Eur. J.
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2
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2
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4. Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829-832.
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3
1. General procedure for the synthesis of 7: A mixture of the benzyl
amine (1 mmol) and isatoic anhydride (1 mmol, 163 mg) in
DMSO (1 mL) was stirred for 2 h at 120 °C. Next, CuBr (10
mol%, 14.3 mg), TBAB (0.5 mol%, 1.4 µL) and K
38 mg) were added to the reaction mixture and stirring was
continued for 6 h at 120 °C under air. Upon reaction completion
TLC) the reaction mixture was cooled, quenched with water (3
mL), and stirring continued for 15 min at ambient temperature.
The resulting precipitate was filtered, washed with H O, and the
2 3
CO (1 mmol,
1
(
2
residue purified by column chromatography using n-
hexane‒EtOAc (4:1) as eluent. 2-(4-Methylphenyl)quinazolin-
4
(3H)-one (7f) : White solid; yield: 0.174 g (74%); mp: 260-262
o
22 –1
C; Lit. mp: 261-263 °C; IR (KBr) (νmax/cm ): 3319 (NH), 1658
1
(C=O); H NMR (500 MHz, DMSO-d
6 3
): δ 2.39 (s, 3H, CH ), 7.35
(d, J = 8.5 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz,
1
8
2
1
5
H), 7.82 (t, J = 8.0 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.14 (d, J =
13
.0 Hz, 1H), 12.39 (s, NH). C NMR (125 MHz, DMSO-d
0.9, 120.8, 125.7, 126.2, 127.2, 127.6, 129.0, 129.8, 134.4, 141.3,
48.1, 152.2, 162.2. Anal. Calcd. for C15 : C, 76.25; H,
.12; N, 11.86. Found: C, 76.19; H, 5.17; N, 11.90.
6
): δ
12 2 2
H N O

5
Graphical abstract
A novel and efficient synthesis of 2-substituted quinazolin-4(3H)-ones by the reaction
of (het)arylmethanamines with isatoic anhydride
Mohammad Mahdavi, Rasool Hassanzadeh, Mehdi Soheilizad, Shiva Golshani, Setareh Moghimi,
Loghman Firoozpour, Abbas Shafiee, Alireza Foroumadi

6
Tetrahedron
Highlights



Quinazoline-4(3H)-ones were synthesized in a one-pot reaction.
The reaction proceeded in the presence of catalytic CuBr under aerobic conditions.
Good yield and broad substrate scope are the advantageous features.