A novel method for the synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1002/jccs.200800168

Different metal perchlorates were screened to catalyze the three-component reaction of anthranilic acid, triethyl orthoformate and amines to afford quinazolin-4(3H)-ones in solvent-free conditions. Ni(ClO₄) ₂ or Zn(ClO₄)

Full text of DOI:10.1002/jccs.200800168

Journal of the Chinese Chemical Society, 2008, 55, 1145-1149
1145
A Novel Method for the Synthesis of 4(3H)-Quinazolinones
Xiao-Bi Jing* (
Xin Pan (
College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China
), Zhen Li (
),
) and Yao-Cheng Shi (
)
Different metal perchlorates were screened to catalyze the three-component reaction of anthranilic
acid, triethyl orthoformate and amines to afford quinazolin-4(3H)-ones in solvent-free conditions.
Ni(ClO4)2 or Zn(ClO4)2 was demonstrated to be efficient to catalyze the reaction.
Keywords: Perchlorates; Quinazolin-4(3H)-ones; Amine; One-pot reaction.
INTRODUCTION
4(3H)-Quinazolinones have emerged as an important
another procedure for the synthesis of these compounds
through a two-step reaction in the presence of (PhO)3P/an-
hydrous pyridine under microwave irradiation at 250 °C.7
The second strategy seems to be more flexible but toxic re-
agents and harsh reaction conditions are required. More re-
cently, Khosropour8 and Narasimhulu9 reported separately
that Bi(TFA)3-[nbp]FeCl4 or La(NO3)3·6H2O can promote
to synthesis 4(3H)-quinazolinones. These catalysts also
seem to be more flexible and a little expensive.
class of nitrogenated heterocycles that have attracted sig-
nificant synthetic interest because of their pharmacological
and therapeutic properties such as antibacterial, antifungal,
antimalarial, antihypertensive, anticonvulsant, anti-Par-
kinsonism, antihistaminic and local anaesthetic, analgesic,
anti-inflammatory antiviral and anticancer activities.1 A
small number of quinazolinones have been reported as po-
tent chemotherapeutic agents in the treatment of tuberculo-
sis. For example, 3-aryl-6,8-dichloro-2H-1,3-benzoxa-
zine-2,4-(3H)-diones, 3-arylquinazoline-2,4(1H,3H)-di-
ones as antimycobacterial agents2 and quinazolinone deriv-
atives as antitubercular agents.3 The antihyperlipidemic ac-
tivities of these compounds were also investigated.4 There
are several methods for the synthesis of 4(3H)-quinazo-
linones.5 However, most of these procedures have signifi-
cant drawbacks such as long reaction time, low yields,
harsh reaction conditions, difficult work-up and use of en-
vironmentally toxic reagents or media. In 2004, Das and
his co-workers have demonstrated a green process for the
synthesis of 4(3H)-quinazolinones, which is limited in that
only phenyl groups are tolerated.6 In 2005, Liu reported
The demand for increasingly clean and efficient chem-
ical synthesis is important for both economic and environ-
mental points of view. One commonly used method is to
perform reactions without use of harmful organic solvents
and in solvent-free conditions. Herein, we want to present a
high yield condensation of anthranilic acid, triethyl ortho-
formate and amines to synthesize 4(3H)-quinazolinones in
solvent-free conditions.
First of all, we occasionally found that perchlorate,
such as Mn(ClO4)2, can perform very well the condensation
of anthranilic acid, triethyl orthoformate and amines to
4(3H)-quinazolinones in moderate yields. Screening of se-
ries of perchlorate catalysts for this reaction revealed that
Ni(ClO4)2 and Zn(ClO4)2 are better than other perchlorates.
Scheme I
* Corresponding author. E-mail: jingxiaobi@yahoo.com.cn

1146 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Jing et al.
Scheme II
(Scheme II). The results are summarized in Table 2.
Table 1. One-pot reaction of anthranilic acid (1), triethyl
orthoformate (2) and aniline (3a) catalyzed by various
perchlorates under different reaction conditionsa
(Scheme I)
From Table 2, we come to realize that either aromatic
amines or aliphatic amines work very well in this reaction,
4f, 4h and 4j are unknown compounds whose structures
are fully supported by 1H, 13C NMR, GC-MS, EA and IR
spectroscopy. The other compounds are also confirmed by
1H, 13C NMR, EA and IR spectroscopy. The structure of 4k
was confirmed by a single crystal X-ray analysis (Fig. 1).
Crystal data and structure refinement are given in Table 3.
We propose a methanism similar to that of Wang5f for
the reaction. The first step in this reaction involves the
zinc-catalyzed formation of imidic ester 5 by reaction of
ortho ester with anthranilic acid; meanwhile the intermedi-
ate 5 was stabilized by zinc species. The imidic ester is very
prone to react immediately with amine and to form an ami-
dine intermediate 6 stabilized by zinc complex, which is
the key rate-limiting step. Subsequently, the reaction pro-
ceeds via the amidine intermediate 6 by intramolecular at-
tack of the nitrogen nucleophile at carbonyl carbon, which
is activated by zinc salt to produce the corresponding
Amount of
Catalyst (%)
Yield of 4a
Entry
Catalyst
Time (h)
(%)b
1
2
3
4
5
6
7
8
Mn(ClO4)2
Co(ClO4)2
Cu(ClO4)2
Cd(ClO4)2
Ni(ClO4)2
Zn(ClO4)2
Ni(ClO4)2
Zn(ClO4)2
Ni(ClO4)2
Zn(ClO4)2
5
5
5
5
5
3
3
3
3
3
3
3
3
3
3
43
80
52
44
92
92
90
94
66
58
5
2.5
2.5
1
9
10
1
a Refluxed at 70 °C for 3 h under solvent-free conditions.
b Isolated yield.
The results are summarized in Table 1.
From Table 1, we know that when reducing the amount
of catalyst to 2.5%, the yields were slightly effected (en-
tries 7 and 8). When the amount of catalyst was reduced to
1%, the yields were significantly reduced from good to
moderate (entries 9 and 10). Then a wide range of structur-
ally varied amines, including aromatic amines and aliphatic
amines were examined in the presence of a catalytic amount
(2.5% mol.) of Zn(ClO4)2 under solvent-free conditions
Scheme III
Fig. 1. X-ray crystal structure of 4k.

Organic Synthesis
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1147
Table 2. One-pot synthesis of different quinazolin-4(3H)-ones catalyzed by Zn(ClO4)2 under
solvent-free conditionsa (Scheme II)
Time
(h)
Yield
(%)b
Entry
1
R
Product
3
2
3
3
94
95
92
93
4a
2
3
4
4b
4c
4d
5
6
2.5
3
91
86
4e
4f
7
8
9
3
84
87
94
4g
3.5
1.5
4h
4i
10
11
2
88
90
4j
2.5
4k

1148 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Jing et al.
12
13
2
1
95
98
4l
4m
a Refluxed at 70 °C for the time given under solvent-free conditions.
b Isolated yield.
operation, which make it a useful and attractive process for
Table 3. Crystal data and structure refinement
the synthesis of 4(3H)-quinazolinones.
Formula
C16H14N2O
250.29
0.30 ´ 0.30 ´ 0.20 mm
Triclinic
Formula weight
Crystal size (mm)
Crystal system
Space group
Unit cell dimensions
a (Å)
b (Å)
c (Å)
a (°)
b (°)
EXPERIMENTAL
Melting points were obtained on a hot-plate micro-
scope apparatus and were uncorrected. H and 13C NMR
1
P-1
spectroscopies were recorded with a Bruker AV-600 spec-
trophotometer. IR spectra were obtained on a Nicolet FT-IR
740 spectrometer (KBr disc). Mass spectra were performed
using FINIGAN Trace DSQ instrument. Elemental analy-
sis was determined on Perkin Elmer 1102b Instrument. X-
ray data were collected on a Bruker Smart APEX-2 dif-
fractometer. The structures were refined by full-matrix
least square method using SHELXL97. In the final step of
refinement procedure, all nonhydrogen atoms were refined
with anisotropic displacement parameters.
5.8843(11)
9.3707(18)
11.762(2)
92.312(2)
97.266(2)
94.253(2)
640.8(2)
2
1.297
264
296(2)
0.083
-7 £ h £ 6, -11 £ k £ 12,
-15 £ l £ 15
g (°)
V (Å3)
Z
Dc (g cm-1)
F (000)
T (K)
m (MoKa) (mm-1)
Limiting indices
Typical procedure for the synthesis of 3-(pyridin-2-yl)-
quinazolin-4(3H)-one (4g)
To a mixture of anthranilic acid (1 mmol), triethyl
orthoformate (1.5 mmol) and pyridin-2-amine (1 mmol),
Zn(ClO4)2 (0.025 mmol) was added. The reaction mixture
was stirred at 70 °C for 3 h. After completion of the reac-
tion (monitored by TLC), the mixture was washed with wa-
ter (3 ´ 10 mL). The residue was chromatographed on silica
gel to afford pure (4g): White needle; Mp: 131-132 °C; 1H
NMR (600 MHz, CDCl3) d: 8.64 (t, J = 7.3 Hz, 2H), 8.39 (s,
1H), 7.90-7.91 (m, 2H), 7.78-7.83 (m, 2H), 7.54-7.57 (m,
1H), 7.39-7.41 (m, 1H); 13C NMR (150 MHz, CDCl3) d:
160.4, 149.6, 149.2, 147.5, 144.9, 138.1, 134.8, 127.7,
127.2, 123.6, 122.2, 121.5; IR (KBr): 3061, 1684, 1608,
1474, 1435, 1328, 1290, 1256, 915, 870, 771 cm-1; Anal.
Calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found:
C, 69.81; H, 3.92; N, 18.97.
Completeness to theta = 27.63
q range (°)
Absortion crrection
Reflections collected/unique
Refinement method
97.4%
1.8 to 27.6
None
5653/2900 [R(int) = 0.026]
Full-matrix least-squares on
F2
Data/restraints/parameters
Final R indices [I > 2s(I)]
R indices (all data)
GoF
2900/0/173
R1 = 0.0461, wR2 = 0.1259
R1 = 0.0645, wR2 = 0.1424
1.024
Largest diff. peak and hole (e Å-3) 0.201 and -0.272
cyclized product 4 (Scheme III).
In summary, we have demonstrated an efficient pro-
cedure for the synthesis of 4(3H)-quinazolinones. The no-
table features of this procedure are mild reaction condi-
tions, clear reaction profiles, improved yields for both ani-
lines and primary amines, enhanced rates and simplicity in
ACKNOWLEDGEMENT
This research was supported by National Natural Sci-

Organic Synthesis
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1149
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