Nafion-H: An efficient and recyclable heterogeneous catalyst for the one-pot synthesis of 2,3-disubstituted 4-(3H)-quinazolinones under solvent-free microwave irradiation conditions

Article abstract of DOI:10.1055/s-2006-950428

A one-pot synthesis of 2,3-disubstituted 4-(3H)-quinazolinones has been carried out efficiently by the three-component coupling of isatoic anhydride/anthranilic acid, orthoesters, and amines in the presence of Nafion-H (a perfluorinated resin-supported su

Full text of DOI:10.1055/s-2006-950428

LETTER
2507
Nafion-H: An Efficient and Recyclable Heterogeneous Catalyst for the
One-Pot Synthesis of 2,3-Disubstituted 4-(3H)-Quinazolinones under Solvent-
Free Microwave Irradiation Conditions
One-Pot Synthes
.
V
H
)-Q
e
uinazolino
n
nes kat Lingaiah,a G. Ezikiel,a T. Yakaiah,a G. Venkat Reddy,b P. Shanthan Rao*a
a
Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: shanthanpp@yahoo.co.in
b
BASR Fine Chemicals Pvt. Ltd. Phase-III, D-122, Jeedimetla, Hyderabad 500007, India
Received 6 June 2006
corrosive environments and permselectivity, which
preferentially allows cations to diffuse faster through the
membranes than anions. Thus, Nafion-H was used as a
catalyst for a multi-component condensation reaction for
Abstract: A one-pot synthesis of 2,3-disubstituted 4-(3H)-
quinazolinones has been carried out efficiently by the three-compo-
nent coupling of isatoic anhydride/anthranilic acid, orthoesters, and
amines in the presence of Nafion-H (a perfluorinated resin-support-
ed sulfonic acid) as a heterogeneous catalyst. The reaction occurred the first time and found to be an efficient catalyst to obtain
within a few minutes under solvent-free microwave irradiation
4-(3H)-quinazolinones in a single pot under microwave
conditions to afford the products in good yields. The catalyst was
irradiation conditions.
recovered and recycled.
Quinazolin-4-(3H)-one derivatives possess a broad spec-
Key words: quinazolin-4-(3H)-ones, Nafion-H, one-pot reaction,
microwave irradiation
trum of biological and pharmaceutical activities.11 Several
bioactive natural products contain the quinazolinone
moiety,12 such as febrifugine and isofebrifugine, naturally
occurring 2-substituted 4-(3H)-quinazolinones, which
Multicomponent organic reactions using environmentally
exhibit high potential as anti-malarial compounds.12,13
benign catalysts are of great interest in organic synthesis.1
The synthesis of quinazolinone derivatives is achieved by
Today’s environmental legislation demands clean and
cycloaddition reactions of anthranilic acid derivatives to-
green reaction processes. Attempts have been made to de-
gether with a diverse range of substrates including
velop green technologies with maximum yield and mini-
imidates and iminohalides.14 However, some of these
mum cost whilst using non-toxic reagents, catalysts, and
methods are associated with certain drawbacks such as a
solvents, or even better, without solvents, which to some
multi-step procedure, costly reagents, harsh reaction
extent has been successful in a few transformations.2 One
conditions, complex experimental process, long reaction
of the tools to combine economic aspects with the envi-
times, and low yields. Thus, several previous methods
ronmental ones is the multicomponent reaction strategy;
have been excluded from practical application due to
this process consists of three or more synthetic steps
environmental and economic considerations. Therefore,
which are carried out without isolation of any intermedi-
there is still a need to develop appropriate efficient
ate, thus reducing time and saving energy and raw materi-
methods for the synthesis of 4-(3H)-quinazolinones.
als.3 Catalysts play an important role in organic synthesis.
In continuation of our efforts to explore the application of
Nafion-H,15 the solvent-free, three-component condensa-
tion of isatoic anhydride/anthranilic acid, orthoesters, and
aromatic amines under microwave irradiation conditions
were investigated. Accordingly, an equimolar mixture of
isatoic anhydride, triethylorthoformate, and trifluoro-
methylaniline was subjected to microwave irradiation in
the presence of Nafion-H and the progress of the reaction
was monitored by TLC once a minute. After three minutes
we observed the complete disappearance of starting mate-
rials. The reaction mixture was cooled, dissolved in ethyl
acetate, and filtered to recover the catalyst. Concentration
of the reaction mixture afforded quinazolin-4-(3H)-one in
82% yield (Scheme 1, Table 1).
The quest is always there for the development of eco-
friendly and recyclable catalysts. As part of our pro-
gramme aimed at developing new, selective, and environ-
mentally friendly methodologies4 for the preparation of
fine chemicals, we wish to report herein the catalytic
activity of Nafion-H for the one-pot synthesis of quinazo-
lin-4-(3H)-ones.
Perfluorinated resin-supported sulfonic acid (Nafion-H)5
has been extensively used as an eco-friendly catalyst in
organic synthesis for alkylation,6 acylation,7 nitration,8
acetal synthesis,9 and in the Diels–Alder reaction.10 The
Nafion-H catalyst is an insoluble resin, inert to corrosive
environments, stable up to 210 °C, easy to recover and
recycle, which attracted our attention. The utility of this
catalyst particularly depends on its relative inertness to
Encouraged by this result a wide range of structurally
varied amines 3, orthoesters 2, and isatoic anhydride 1
were reacted and the results are summarized in Table 1. In
all cases, the three-component reaction proceeded rapidly
to afford the corresponding quinazolin-4-(3H)-ones 4 in
good yields (71–86%). Most importantly, anilines having
an electron-donating group (methyl) gave a high yield
SYNLETT 2006, No. 15, pp 2507–2509
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950428; Art ID: G17006ST
© Georg Thieme Verlag Stuttgart · New York

2508
B. V. Lingaiah et al.
LETTER
Table 1 Synthesis of 2,3-Disubstituted 4-(3H)-Quinazol-
inones17 (continued)
(89%) due to the increased electron density of the aro-
matic system, whereas electron-withdrawing groups (CF3
and NO2) gave a lower yield (71%). One more important
observation is that anilines with a meta electron-with-
drawing group gave a higher yield than those with a para
electron-withdrawing group. Anilines containing two or
more electron-withdrawing groups, resulted in a decrease
in yield and prolonged reaction times compared to those
with a single electron-withdrawing group. Substituents on
the orthoester did not result in much variation in yield.
When the same reaction was carried out using anthranilic
acid instead of isatoic anhydride the yields were slightly
higher, with a slightly shorter reaction time, and the sub-
stituent effect showed the same trend as earlier (Table 1).
Entry R
R1
Starting Time
compda (min) (%)
Yieldb Mp
(°C)
II
3
5
4
6
4
3
2
3
2
3
2
4
3
5
4
6
4
3
2
3
2
3
2
4
3
5
4
6
4
3
2
82
74
78
72
75
86
94
86
88
82
87
76
79
73
77
70
75
83
91
85
89
83
87
77
80
75
79
71
78
81
92
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Me 2-NO2, 4-CF3
Me 2,6-(NO2)2, 4-CF3
Me 4-Me
I
185
II
I
156
II
I
14916f
162
II
O
Et
Et
Et
Et
Et
Et
3-CF3
I
O
II
R1
N
O
H
NH2
O
N
4-CF3
I
159
1
Nafion-H
N
+
RC(OEt)3 +
II
or
solvent-free
MW (800 W)
2–6 min
R
R1
2
2-Cl, 5-CF3
2-NO2, 4-CF3
2,6-(NO2)2, 4-CF3
4-Me
I
104
COOH
NH2
3
4
II
1a
I
167
Scheme 1
II
I
186
Table 1 Synthesis of 2,3-Disubstituted 4-(3H)-Quinazol-
inones17
II
Entry R
R1
Starting Time
compda (min) (%)
Yieldb Mp
I
16216f
128
(°C)
II
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
3-CF3
I
3
2
3
2
4
3
5
4
6
4
3
2
3
2
3
2
4
82
89
80
86
78
84
77
82
75
80
89
92
88
90
78
81
77
13516a
Ph 3-CF3
I
II
II
4-CF3
I
13216b
11816c
176
Ph 4- CF3
I
122
II
II
2-Cl, 5-CF3
2-NO2, 4-CF3
2,6-(NO2)2, 4-CF3
4-Me
I
Ph 2-Cl, 5-CF3
Ph 2-NO2, 4-CF3
Ph 2,6-(NO2)2, 4-CF3
Ph 4-Me
I
206
II
II
I
I
222
II
II
I
164
I
246
II
II
I
14716d
14016e
14616b
10816e
I
17916f
II
II
Me 3-CF3
I
a I: isatoic anhydride; II: anthranilic acid.
b Isolated yields.
II
Me 4-CF3
I
Encouraged by the results we concentrated on the recycla-
bility of the Nafion-H catalyst. Accordingly, the recov-
ered catalyst was reused using a model reaction of isatoic
II
Me 2-Cl, 5-CF3
I
Synlett 2006, No. 15, 2507–2509 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 2,3-Disubstituted 4-(3H)-Quinazolinones
2509
(4) (a) Lingaiah, B. V.; Ezikiel, G.; Yakaiah, T.; Reddy, G. V.;
Rao, P. S. Tetrahedron Lett. 2006, 47, 4315. (b) Lingaiah,
B. P. V.; Reddy, G. V.; Yakaiah, T.; Narsaiah, B.; Reddy, S.
N.; Yadla, R.; Rao, P. S. Synth. Commun. 2004, 34, 4431.
(5) (a) Onaka, T. Tetrahedron Lett. 1971, 4387. (b) Kametani,
T.; Loc, C. V.; Higa, T.; Koizumi, M.; Ihara, M.; Fukumoto,
K. J. Am. Chem. Soc. 1977, 99, 2306. (c) Mori, M.;
Kobayashi, H.; Kimura, M.; Ban, Y. Heterocycles 1985, 23,
2803. (d) Sauter, F.; Frohlic, J.; Blasl, K.; Gewald, K.
Heterocycles 1985, 40, 851. (e) Majo, V. J.; Perumal, P. T.
Tetrahedron Lett. 1996, 37, 5015. (f) Prasad, M.; Chen, L.;
Repic, O.; Blacklock, T. J. Synth. Commun. 1998, 28, 2125.
(g) Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707.
(h) Wang, L.; Xia, J.; Qin, F.; Qian, C.; Sun, J. Synthesis
2003, 1241.
(6) Olah, G. A.; Iyer, P. S.; Surya Prakash, G. K. Synthesis 1986,
513.
(7) Olah, G. A.; Kaspi, J.; Bukala, J. J. Org. Chem. 1977, 42,
4187.
(8) Olah, G. A.; Malhotra, R.; Narang, S. C.; Olah, J. A.
Synthesis 1978, 672.
(9) Olah, G. A.; Narang, S. C. Synthesis 1978, 690.
(10) Olah, G. A.; Narang, S. C.; Meidar, D.; Salem, G. F.
Synthesis 1981, 282.
anhydride, triethyl orthoacetate, and 3-trifluoromethyl
aniline under solvent-free microwave irradiation condi-
tions. After completion of the reaction, ethyl acetate was
added, and the mixture was filtered to separate the cata-
lyst. The separated catalyst was used for further runs and
did not show any reduced activity even after six runs
(Table 2).
Table 2 Recycling of Nafion-H Catalyst
Run
Time (min)
Yielda (%)
1
3
88
86
85
86
88
86
2
3.5
4
3
4
4.5
6
5
6
6
a Isolated yield.
(11) (a) Wolf, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J.
A.; Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(b) Padia, J. K.; Field, M.; Hinton, J.; Meecham, K.; Pablo,
J.; Pinnock, R.; Roth, B. D.; Singh, L.; Suman-Chauhan, N.;
Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042.
(c) Khilil, M. A.; Soliman, R.; Farghaly, A. M.; Bekhit, A.
A. Arch. Pharm. (Weinhem, Ger.) 1994, 32, 27.
(12) Cohen, E.; Klarberg, B.; Vaughan, J. R. J. Am. Chem. Soc.
1960, 82, 2731.
(13) (a) Koepfly, J. B.; Mead, J. F.; Brockman, J. A. Jr. J. Am.
Chem. Soc. 1947, 69, 1837. (b) Ablondi, F.; Gordon, S.;
Morton, J. II; Williams, J. H. J. Org. Chem. 1952, 17, 14.
(c) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175.
(14) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.;
Thou, T. C. Science (Washington, D.C.) 1946, 103, 59.
(15) Rama Rao, V. V. V. N. S.; Reddy, G. V.; Maitraie, D.; Ravi
Kanth, S.; Yadla, R.; Narsaiah, B.; Shanthan Roa, P.
Tetrahedron 2004, 60, 12231.
(16) (a) Allias, A.; Meier, J. Fr 1520743, 1968; Chem. Abstr.
1969, 71, 49975b. (b) Keiichi, K.; Atsushi, N.; Mashashi,
H.; Tamotsu, M.; Hiroto, N.; Hisashi, T. JP o7258224, 1995;
Chem. Abstr. 1996, 124, 176144t. (c) Janiak, S. Ger. Offen.
1908097, 1969; Chem. Abstr. 1969, 71, 124484. (d) Wang,
L.; Xia, J.; Qin, F.; Qian, C.; Sun, J. Synthesis 2003, 1241.
(e) Lietz, W.; Matthies, H. Acta Biol. Med. Ger. 1964, 13, 4–
591. (f) Dabiri, M.; Salehi, P.; Mohammadi, A. A.;
Baghbanzadeh, M.; Kozehgiry, G. J. Chem. Res., Synop.
2004, 570.
In conclusion, we have demonstrated that eco-friendly
Nafion-H catalyst could be used efficiently for the synthe-
sis of quinazolinones with good yields under solvent-free
microwave irradiation conditions in short reaction times.
The notable factors of this reaction are: (a) reasonably
good yields; (b) solvent-free conditions; (c) choice of
appropriate substituents on the aniline; (d) microwave
irradiation conditions; (e) the catalyst Nafion-H can be
easily recovered; (f) green synthesis avoiding toxic sol-
vents; and (g) recyclability of the catalyst. Thus, we
believe that, the developed procedure will find important
practical applications for the synthesis of 4-(3H)-
quinazolinones.
Acknowledgment
The authors are thankful to Dr. J. S. Yadav, Director of IICT and
Shri. S. Narayan Reddy, Head of the Fluoroorganic Division, IICT,
Hyderabad for their constant encouragement. We are grateful for
financial support from an industry sponsored project.
References and Notes
(1) (a) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R.
J.; Steele, J. Tetrahedron 1995, 51, 8135. (b) Armstrong, R.
W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T.
A. Acc. Chem. Res. 1996, 29, 123. (c) Thomson, L. A.;
Ellman, J. A. Chem. Rev. 1996, 96, 555. (d) Tietze, L. F.;
Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363.
(e) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168.
(2) Green Chemistry, ACS Symposium Series 626; Anastas, P.
T.; Williamson, T. C., Eds.; American Chemical Society:
Washington D.C., 1996, ; and references therein.
(3) Hall, N. Science (Washington, D.C.) 1994, 32, 266.
(17) General Procedure: A mixture of isatoic anhydride (1.8
mmol) or anthranilic acid (1.8 mmol), triethyl orthoester (1.8
mmol), aromatic aniline (1.8 mmol), and a catalytic amount
of Nafion-H was irradiated in a domestic microwave oven at
800 W in an open tube for 2–6 min. After completion of the
reaction the reaction mixture was allowed to cool to ambient
temperature, dissolved in EtOAc, and the catalyst was
separated by filtration. The organic layer was dried with
Na2SO4 and concentrated. The solid was passed through a
silica gel column (n-hexane–CHCl3, 1:1) to furnish the title
compound in sufficiently pure form.
Synlett 2006, No. 15, 2507–2509 © Thieme Stuttgart · New York