Silica-supported sodium hydrogen sulfate and amberlyst-15 : Two efficient heterogeneous catalysts for single-step synthesis of 4(3H)-quinazolinones from anthranilic acid, ortho esters, and amines under solvent free conditions

Article abstract of DOI:10.1246/cl.2004.960

The single step synthesis of 4(3H)-quinazolinones has been carried out efficiently by coupling of the three components, anthranilic acid, ortho esters, and amines in the presence of silica-supported sodium hydrogen sulfate (NaHSO₄·SiO₂) or Amberlyst-15 as a heterogeneous catalyst. The reaction occurred within a few minutes under solvent free conditions to afford the products in excellent yields. One of the catalysts, Amberlyst-15 can be recovered and recycled.

Full text of DOI:10.1246/cl.2004.960

960
Chemistry Letters Vol.33, No.8 (2004)
Silica-supported Sodium Hydrogen Sulfate and Amberlyst-15 :
Two Efficient Heterogeneous Catalysts for Single-step Synthesis of 4(3H)-Quinazolinones
from Anthranilic Acid, Ortho Esters, and Amines under Solvent Free Conditions
Biswanath Dasꢀ and Joydeep Banerjee
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(Received May 6, 2004; CL-040510)
Table 1. Preparation of 4(3H)-quinazolinones (4a - 4r) cata-
a
The single step synthesis of 4(3H)-quinazolinones has been
carried out efficiently by coupling of the three components, an-
thranilic acid, ortho esters, and amines in the presence of silica-
.
lyzed by NaHSO4 SiO2 and Amberlyst-15
Time Isolated
/min. Yield /%
.
Entry
R
R0
Catalystb
supported sodium hydrogen sulfate (NaHSO4 SiO2) or Amber-
lyst-15 as a heterogeneous catalyst. The reaction occurred within
a few minutes under solvent free conditions to afford the prod-
ucts in excellent yields. One of the catalysts, Amberlyst-15
can be recovered and recycled.
a.
Me
H
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
5
5
5
5
5
94
96
93
97
95
98
88
90
91
92
87
90
81
82
91
92
94
96
95
98
89
92
91
93
85
86
81
82
83
85
84
86
81
85
89
90
b.
c.
d.
e.
f.
Me
Me
Me
Me
Me
Me
Et
4-Me
4-OMe
2-Cl
5
4(3H)-Quinazolinones are a class of fused heterocycles that
are of significant importance because of the broad spectrum of
their biological properties such as anticancer, anticonvulsant, an-
tihypertensive, antiinflamatory, and antimalerial activities.1 Sev-
eral bioactive natural products contain quinazolinone moiety.2
As for an example, febrifugine and isofebrifugine, which are nat-
urally occurring 2-substituted 4(3H)-quinazolinones, are highly
potential antimalerial compounds.2,3 The synthesis of quinazoli-
none derivatives is achieved by cyclo-addition reactions of an-
thranilic acid derivatives together with a diverse range of sub-
strates including imidates and iminohalides.4 However, some
of these methods are associated with certain drawbacks such
as multi-step procedure, costly reagents, harsh reaction condi-
tions, complex experimental process, long reaction times, and
low yields. The catalysts which were used earlier work mostly
under homogeneous conditions and so the recovery of these cat-
alysts is always a problem. Thus several previous methods have
been excluded from practical applications due to environmental
and economic considerations. Therefore, still there is need to de-
velop appropriate efficient methods for the synthesis of 4(3H)-
quinazolinones.
10
10
10
10
10
10
15
15
5
5
5
5
5
3-Cl
4-F
g.
h.
i.
2-NO2
H
Et
4-Me
4-OMe
2-Cl
j.
Et
5
k.
l.
Et
10
10
10
10
10
10
15
15
15
15
10
10
10
10
5
Et
3-Cl
m.
n.
o.
p.
q.
r.
Et
4-F
Multicomponent reactions are recently of practical impor-
tance due to their speed, diversty, and efficiency. We have devel-
oped an expeditious one-pot synthesis of 4(3H)-quinazolinones
(4) from the reaction of three components, anthranilic acid (1),
orthoesters (2) and anilines (3) in the presence of a heterogene-
ous catalyst, silica-supported sodium hydrogen sulphate
Et
2-NO2
4-NO2
Et
Et 2,5-di(OMe)
5
.
(NaHSO4 SiO2) or Amberlyst-15. Various 4(3H)-quinazoli-
Et
Et
2,6-di(Me)
4-Br
nones (4) were prepared (Table 1) using different substitued ani-
lines (3) and trimethyl or triethyl orthoformate (2). The reaction
was carried out under solvent free conditions. The products (4)
were formed within a few minutes in excellent yields. Most of
the reactions proceeded at room temperature but when an aniline
contains a nitro group the reaction mixture was refluxed at 60 ꢁC
and the times required were somewhat more (15 min). For 2,5-
dimethoxyaniline also heating of the mixture for 10 min was
necessary. This may be due to the steric reason. The products de-
rived from aniline containing electron donating groups were
formed in somewhat higher yields than those from anilines hav-
II
I
II
5
aThe structures of the products were settled from their
1H NMR and MS data.
b
.
Catalyst I : NaHSO4 SiO2; II : Amberlyst-15
ing electron withdrawing groups. The reaction could tolerate dif-
ferent functionalities, e.g., alkyl, halogen, ether, and nitro pres-
ent in the anilines. Trimethyl and triethyl orthoformates
reacted almost similarly.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.8 (2004)
961
R'
3
4
C. S. Jang, F. Y. Fu, C. Y. Wang, K. C. Huang, G. Lu, and
T. C. Thou, Science, 103, 59 (1946).
O
N
NH2
NaHSO4.SiO2
or Amberlyst-15
5 - 15 min
COOH
NH2
N
a) T. Onaka, Tetrahedron Lett., 1971, 4387. b) T. Kametani,
C. V. Loc, T. Higa, M. Koizumi, M. Ihara, and K. Fukumoto,
J. Am. Chem. Soc., 99, 2306 (1977). c) M. Mori, H.
Kobayashi, M. Kimura, and Y. Ban, Heterocycles, 23,
2803 (1985). d) F. Sauter, J. Frohlic, K. Blasl, and K.
Gewald, Heterocycles, 40, 851 (1985). e) V. J. Majo and
P. T. Perumal, Tetrahedron Lett., 37, 5015 (1996). f) M.
Prasad, L. Chen, O. Repic, and T. J. Blacklock, Synth.
Commun., 28, 2125 (1998). g) D. J. Connolly and P. J. Guiry,
Synlett, 2001, 1707. h) L. Wang, J. Xia, F. Qin, C. Qian and
J. Sun, Synthesis, 2003, 1241.
HC(OR)3
+
+
R'
1
3
4
2
(81 - 98%)
.
The catalysts, NaHSO4 SiO2 and Amberlyst-15 work under
heterogeneous conditions. In recent years heterogeneous cata-
lysts have attracted more attention as they catalyze the chemical
processes under eco-friendly manner and with satisfactory yields
and low cost. Both the presently used catalysts can conveniently
be handled and removed from the reaction mixture after comple-
6
.
tion of the reaction. NaHSO4 SiO2 can be prepared easily from
the readily available ingredients, NaHSO4 and silica gel. The ac-
tivity and efficiency of both the catalysts for the present conver-
sion are comparable. However, Amberlyst-15 can be recovered,
activated and recycled.
5
General experimental procedure: To a mixture of anthranilic
acid (1 mmol), an orthoester (1.2 mmol), and an amine
.
(1.2 mmol) NaHSO4 SiO2 (100 mg, the ratio of NaHSO4
and SiO2 was 2:5) or Amberlyst-15 (50 mg) was added.
The mixture was stirred at room temperature. The reaction
was monitored by TLC. After completion CH2Cl2 (10 mL)
was added to the reaction mixture and filtered. The filtrate
was washed with aq HCl (5%) (3 ꢂ 5 mL) and subsequently
with H2O (3 ꢂ 10 mL). The organic layer was dried and the
solvent was evaporated to get 4(3H)-quinazolinone. When
the reaction was carried out with a nitroaniline or with 2,5-
dimethoxyaniline the reaction mixture was refluxed at
60 ꢁC. Amberlyst-15 was recovered from the residue of fil-
tration of the reaction mixture by washing throughly with
CH2Cl2, activated and recycled. The efficiency of the recov-
ered Amberlyst-15 was verified with the reaction of anthra-
nilic acid, trimethyl orthoformate and aniline (Entry a). Us-
ing the fresh catalyst the yield of the product, 3-phenyl-
4(3H)-quinazolinone (4a) was 94% while with the recovered
catalyst in the three subsequent recyclization the yields were
92, 89, and 88%. The spectral properties of some representa-
tive 4(3H)-quinazolinones are given below.: 3-Phenyl-
In conclusion, we have developed a simple and efficient
three-component coupling reaction of anthranilic acid, orthoest-
.
ers, and amines using NaHSO4 SiO2 or Amberlyst-15 for the
preparation of 4(3H)-quinazolinones in single step. The mild
and solvent free heterogeneous reaction conditions, short reac-
tion times (5–15 min), simple experimental procedure, excellent
yields (81–98%) and reusability of one of the catalysts (Amber-
lyst-15) are of great advantages of the present protocol. The
process is associated with the combined benefits derived from
multicomponent reaction and heterogeneous catalyst. We feel
that the developed procedure will find important practical appli-
cations for the synthesis of 4(3H)-quinazolinones.
The authors thank CSIR, New Delhi for financial assistance.
References and Notes
1
a) J. F. Wolfe, T. L. Rathman, M. C. Sleevi, J. A. Campbell,
and T. D. Greenwood, J. Med. Chem., 33, 161 (1990). b) K.
Tereshima, H. Shimamura, A. Kawase, Y. Tanaka, T.
Tanimura, T. Kamisaki, Y. Ishizuka, and M. Sato, Chem.
Pharm. Bull., 43, 2021 (1995). c) Y. Kurogi, Y. Inoue, K.
Tsutsumi, S. Nakamura, K. Nagao, H. Yohsitsugu, and Y.
Tsuda, J. Med. Chem., 39, 1443 (1996). d) N. J. Liverton,
D. J. Armstong, D. A. Claremon, D. C. Remy, J. J. Baldwin,
R. J. Lynch, G. Zhang, and R. Gould, Bioorg. Med. Chem.
Lett., 8, 483 (1998). e) D. Gueyrard, V. Gurnel, O. Leoni,
S. Palmieri, and P. Rollin, Heterocycles, 52, 827 (2000).
a) J. B. Koepfly, J. F. Mead, and J. A. Brockman, Jr., J. Am.
Chem. Soc., 69, 1837 (1947). b) F. Ablondi, S. Gordon,
J. Morton, II, and J. H. Williams, J. Org. Chem., 17, 14
(1952). c) S. Kobayashi, M. Ueno, R. Suzuki, and H. Ishitani,
Tetrahedron Lett., 40, 2175 (1999).
1
4(3H)-quinazolinone (4a), H NMR (CDCl3, 200 MHz): d
8.68 (1H, d, J ¼ 8:0 Hz), 8.31 (1H, s), 7.52 (2H, d,
J ¼ 8:0 Hz), 7.38–7.22 (5H, m), 7.16 (1H, m); EIMS: m=z
(%) 222 (Mþ, 5), 221 (Mþ ꢃ 1, 4) 121 (92), 93 (100).
3-(3-Chlorophenyl)-4(3H)-quinazolinone (4e), 1H NMR
(CDCl3, 200 MHz): d 8.32 (1H, d, J ¼ 8:0 Hz), 8.12 (1H,
s), 7.89–7.61 (2H, m), 7.61–7.53 (4H, m), 7.40 (1H, m);
EIMS: m=z (%) 257 (Mþ þ 1, 22), 256 (Mþ, 23), 221 (12),
149 (78), 111 (22). 3-(2,6-Dimethyl phenyl)-4(3H)-quina-
1
2
zolinone (4q), H NMR (CDCl3, 200 MHz): d 8.38 (1H, d,
J ¼ 8:0 Hz), 7.88–7.72 (2H, m), 7.55 (1H, t, J ¼ 8:0 Hz),
7.36–7.20 (3H, m), 7.02 (1H, m), 2.18 (6H, s); EIMS: m=z
(%) 250 (Mþ, 62), 233 (91), 149 (46), 125 (12), 103 (38).
G. W. Breton, J. Org. Chem., 62, 8952 (1997).
6
Published on the web (Advance View) June 28, 2004; DOI 10.1246/cl.2004.960