Synthesis of 3-Aryl-4(3H)-quinazolinones from anthranilic acid, ortho esters, and anilines using Ce(CH3SO3)3· 2H2O as catalyst

Article abstract of DOI:10.1007/s00706-010-0352-y

3-Aryl-4(3H)-quinazolinones were synthesized efficiently by the three component one-pot cyclocondensation of anthranilic acid, ortho esters, and anilines in the presence of Ce(CH₃SO₃)3·2H ₂O at room temperature under solve

Full text of DOI:10.1007/s00706-010-0352-y

Monatsh Chem (2010) 141:993–996
DOI 10.1007/s00706-010-0352-y
ORIGINAL PAPER
Synthesis of 3-aryl-4(3H)-quinazolinones from anthranilic acid,
ortho esters, and anilines using Ce(CH3SO3)3Á2H2O as catalyst
•
Min Wang Zhi-Guo Song Ting-Ting Zhang
•
Received: 2 September 2009 / Accepted: 12 June 2010 / Published online: 30 July 2010
Ó Springer-Verlag 2010
Abstract 3-Aryl-4(3H)-quinazolinones were synthesized
efficiently by the three component one-pot cycloconden-
sation of anthranilic acid, ortho esters, and anilines in the
presence of Ce(CH3SO3)3Á2H2O at room temperature under
solvent-free conditions. This method offers several
advantages, such as a simple procedure, mild reaction
conditions, short reaction time, and reusability of the
catalyst.
Owing to the importance of 3-substituted 4(3H)-quinaz-
olinones, different strategies for their synthesis have been
described in literature [9, 10]. The most direct approach
involves one-pot cyclocondensation of anthranilic acid,
ortho esters, and amines in the presence of various catalysts
such as NaHSO4 or Amberlyst-15 [11], Yb(III)-resin [12],
Yb(OTf)3 [13], Bi(TFA)3-[nbp]FeCl4 [14], La(NO3)3Á
6H2O or p-toluenesulfonic acid [15], Keggin-type hetero-
polyacids under microwave irradiation [16], SnCl4Á4H2O
[17], and SiO2–FeCl3 [18]. However, some of these
methods are associated with certain drawbacks such as
expensive catalyst, high temperature (60–80 °C), long
reaction time (20 h), and using harmful organic solvents.
These processes also generate waste-containing solvents
and catalysts, which have to be recovered, treated, and
disposed of. Therefore, there is still a need to develop green
and efficient methods for the synthesis of 3-substituted
4(3H)-quinazolinones.
Keywords 3-Aryl-4(3H)-quinazolinone Á
Methanesulfonates Á One-pot synthesis Á
Solvent-free conditions
Introduction
Compounds with biological activity are often derived from
heterocyclic structures. 4(3H)-Quinazolinones are one such
class of bioactive fused heterocycles that are widely used
as antimalarial, antitumor, anticonvulsant, antiinflamma-
tory, fungicidal, and antimicrobial agents [1–6]. In
addition, 4(3H)-quinazolinones are present in several bio-
active natural products [7, 8]. Among various types of
4(3H)-quinazolinones, 3-substituted 4(3H)-quinazolinone
derivatives form an important component because they are
associated with a wide spectrum of biological activities.
In the past decade, the increasing attention on environ-
mental protection has influenced both academic and
industrial groups to develop new chemical processes with
maximum yield and minimum cost. The organic reaction
should be carried out using non-toxic reagents, catalysts,
and solvents or even better, without solvents. Lanthanide
methanesulfonates such as water-stable Lewis acid cata-
lysts in organic synthesis have been well documented in
recent years [19, 20]. In the course of our investigation to
develop new synthetic methods in solvent-free conditions,
we found that the one-pot cyclocondensation of anthranilic
acid, ortho esters, and anilines can proceed smoothly in the
presence of cerous methanesulfonate (Ce(CH3SO3)3Á2H2O)
at room temperature under solvent-free conditions
(Scheme 1). After reaction, the catalyst can be recovered
and can be recycled at least three times without distinct
loss in its catalytic activity.
M. Wang (&) Á T.-T. Zhang
College of Chemistry and Chemical Engineering,
Bohai University, Jinzhou 121000, Liaoning, China
e-mail: minwangszg@yahoo.com.cn
Z.-G. Song
Center for Science and Technology Experiment,
Bohai University, Jinzhou, China
123

994
M. Wang et al.
R1
Scheme 1
NH2
O
COOH
NH2
(1 mol%)
Ce(CH3SO3)3 2H2O
r.t.
HC(OR)3
R1
N
3
4a-4m
2
1
Results and discussion
trimethyl or triethyl orthoformate 2 and different substi-
tuted anilines 3 in the presence of Ce(CH3SO3)3Á2H2O,
and the results are summarized in Table 2. In all cases,
the reactions proceeded very efficiently with anilines
carrying electron-donating or electron-withdrawing
groups, and steric effects did not influence the yield sig-
nificantly. However, in previous studies anilines having
electron-withdrawing substitutes, e.g., Cl and NO2, gave
generally no products at room temperature due to the
decreased electron density of the aromatic system. In this
study, the reaction could tolerate different functional
groups, such as Me, MeO, Cl, Br, and NO2, present in the
anilines. Moreover, the reaction conditions are mild
enough not to produce any undesirable side products. The
condensation yield with trimethyl orthoformate was lower
than with triethyl orthoformate. Furthermore, trimethyl
orthoformate required a comparatively longer reaction
time. In addition to aniline derivatives, alkyl amines such
as benzyl amine and butylamine were also investigated,
and few products were detected. This is probably due to
the inductive effect of the aromatic ring that results in the
hydrogen atom of aromatic amino groups being released
more easily than that of alkyl amines. Therefore, aromatic
amines are more active than alkyl amines in this type of
reaction.
First, we compared the catalytic activity of Ce(CH3SO3)3Á
2H2O with protonic acids, conventional Lewis acids, and
other lanthanide methanesulfonates in the model conden-
sation of anthranilic acid with triethyl orthoformate and
aniline (Table 1). The results revealed that Ce(CH3SO3)3Á
2H2O was the most effective catalyst for this transforma-
tion since it resulted in the highest conversion to the
desired product. Although lanthanide methanesulfonates
have similar properties, the catalytic activity of Ce(CH3-
SO3)3Á2H2O in this case is higher than that of other lan-
thanide methanesulfonates, and Ce(CH3SO3)3Á2H2O
produced almost quantitative yields of the product. We
next sought to probe whether the catalyst could be recy-
cled. After the reaction, CH2Cl2 was added to the reaction
mixture, and Ce(CH3SO3)3Á2H2O could be recovered by
simple phase separation and then reused for the next con-
densation without any treatment. The synthesis of product
4a under the conditions described in Table 1 with
Ce(CH3SO3)3Á2H2O as catalyst was run for three consec-
utive cycles, furnishing the corresponding 3-phenyl-
quinazolin-4(3H)-one with 99, 96, and 92% isolated yields
(entry 9). The feasibility of the catalyst for recycling may
be attributed to the insolubility of rare earth methanesulf-
onates in the reaction mixture.
A mechanism for this reaction can be postulated as
shown in Scheme 2. The first step in this reaction involves
the Ce(CH3SO3)3Á2H2O catalyzed formation of imidic ester
5, which is stabilized by Ce(CH3SO3)3Á2H2O. The imidic
ester 5 may be very prone to react with an aniline 3, thus
leading to the amidine intermediate 6. Then, the amidine
intermediate 6 cyclizes to form the quinazolinone 4 and
releases the catalyst for the next run. A similar mechanism
had also been described by Wang et al. [13] and Ighilahriz
et al. [16].
To explore the scope and limitations of this reaction,
we extended the condensation of anthranilic acid (1) with
Table 1 One-pot reaction of anthranilic acid, triethyl orthoformate,
and aniline catalyzed by various catalysts
Entry
Catalyst
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
None
1
5
HOAc
1
56
CuCl2Á2H2O
AlCl3Á6H2O
La(CH3SO3)3Á2H2O
Pr(CH3SO3)3Á2H2O
Yb(CH3SO3)3Á2H2O
Nd(CH3SO3)3Á2H2O
Ce(CH3SO3)3Á2H2O
1
50
In conclusion, we have demonstrated that 3-aryl-4(3H)-
quinazolinones can be synthesized easily in short reaction
time (0.1–4 h) with excellent yields (42–99%) starting
from an anthranilic acid, orthoesters, and anilines in the
presence of Ce(CH3SO3)3Á2H2O at room temperature.
After reaction, the catalyst could be recovered and reused
for successive reactions. The method is environmentally
benign. We believe our procedure will find important
application in the synthesis of 3-aryl-4(3H)-quinazolinones
and their derivatives.
0.5
1
67
84
1
91
1
92
1
94
99, 96, 92a
1
Reaction conditions: anthranilic acid (10 mmol), triethyl orthofor-
mate (12 mmol), aniline (12 mmol), catalyst (0.1 mmol), r.t.
a
Catalyst was reused for three runs
123

Synthesis of 3-aryl-4(3H)-quinazolinones
995
Table 2 Ce(CH3SO3)3Á2H2O-catalyzed synthesis of 3-aryl-4(3H)-quinazolinones 4a–4m
Cpd.
R1
R = Et
R = Me
Mp (°C)
Time (h)
Yield (%)
Time (h)
Yield (%)
Found
Reported
4a
4b
4c
4d
4e
4f
H
1
99
93
67
95
87
97
78
82
98
59
98
98
84
2
67
72
45
91
60
92
62
62
76
42
88
83
57
138–140
158–159
137–139
145–147
150–152
135–137
118–120
125–126
145–147
149–151
151–153
166–168
240–242
139–140 [13]
158–189 [21]
136–137 [13]
146–147 [13]
151–153 [21]
132–134 [21]
117–120 [21]
122–124 [21]
149–151 [21]
156–158 [13]
154–156 [13]
165–166 [13]
240–242 [21]
2-Me
3-Me
4-Me
2-MeO
4-MeO
2-Cl
1.1
2
1.5
3.5
1
0.5
0.9
0.4
0.2
0.3
0.2
4
4
1
4g
4h
4i
0.3
0.6
0.4
0.2
0.1
0.1
0.3
4-Cl
4-Br
4j
2-NO2
3-NO2
4-NO2
4-COOH
4k
4l
0.2
0.2
0.2
4m
The structures of the products were determined from spectral and analytical data (IR, 1H NMR, 13C NMR, and elemental analysis) and by
comparison with reported data
Scheme 2
COOH
H
N
(CH3SO3)3Ce
5
NH2
OR
COOH
NH2
R1
HC(OR)3
3
1
2
(CH3SO3)3Ce
Ce(CH3SO3)3
O
C
OH
H
R1
N
R1
N
H
(CH3SO3)3Ce
O
6
N
N
4
General procedure for the synthesis of 3-aryl-4(3H)-
quinazolinones 4
Experimental
Melting points were determined using an RY-1 micro-
melting point apparatus. Infrared spectra were recorded on
a VARIAN Scimitar 2000 series Fourier transform instru-
ment. 1H NMR spectra were recorded on a Bruker AV-500
spectrometer in DMSO-d6 using TMS as an internal stan-
dard. 13C NMR spectra were performed on a Bruker
AV-500 spectrometer at 125 MHz using DMSO-d6 as an
internal standard. Elemental analyses were carried out on
EA 2400II elemental analyzer (Perkin-Elmer).
Ce(CH3SO3)3Á2H2O (0.1 mmol) was added to a mixture of
anthranilic acid (10 mmol), an orthoester (12 mmol), and
an aniline (12 mmol). The mixture was stirred at room
temperature (monitored by TLC). After completion,
CH2Cl2 was added to dissolve the solid product. Then, the
catalyst was removed by gravity filtration and dried for its
next use. The organic filtrate was evaporated to yield the
crude product. The crude product was recrystallized from
123

996
M. Wang et al.
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ethanol to give the pure products. The pure products were
identified by IR, 1H NMR, 13C NMR, and elemental
analysis.
9. Szczepankiewicz W, Suwinski J (2000) Chem Heterocycl Compd
36:809
Acknowledgments We are grateful to the Committee of Science
and Technology of Liaoning Province, China, for financial support
(no. 20091001).
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