A concise aqueous phase supramolecular synthesis of 2-phenyl-2,3- dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.10.029

2-Phenyl-2,3-dihydroquinazolin-4(1H)-one derivatives were synthesized for the first time in water under neutral conditions by the reaction of aldehyde, and anthranilamide mediated by β-cyclodextrin in high yields. β-Cyclodextrin can be recovered and reused with a small loss of catalytic activity.

Full text of DOI:10.1016/j.tetlet.2012.10.029

Tetrahedron Letters 53 (2012) 6936–6939
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A concise aqueous phase supramolecular synthesis of
2-phenyl-2,3-dihydroquinazolin-4(1H)-one derivatives
⇑
K. Ramesh, K. Karnakar, G. Satish, B. S. P. Anil Kumar, Y. V. D. Nageswar
CSIR-Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one derivatives were synthesized for the first time in water under
neutral conditions by the reaction of aldehyde, and anthranilamide mediated by b-cyclodextrin in high
yields. b-Cyclodextrin can be recovered and reused with a small loss of catalytic activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 September 2012
Revised 4 October 2012
Accepted 6 October 2012
Available online 16 October 2012
Keywords:
Aldehydes
Anthranilamide
2-Phenyl-2,3-dihydroquinazolin 4(1H)-ones
b-Cyclodextrin
Water
Heterocyclic compounds acquired significance, as these are
associated with a wide range of potential biological and pharma-
ceutical activities.1 These N-containing heterocyclic compounds
play a crucial role in the context of drug scaffolds, synthetic organic
chemistry, and medicinal chemistry as well as material sciences.2
2,3-Dihydroquinazolinone derivatives act as important intermedi-
ates in the synthesis of drug molecules, and natural products.3
These also exhibit various activities such as anti-cancer, anti-tumor,
diuretic, herbicidal, as well as plant growth regulation.4 Moreover,
these derivatives can be easily oxidized to their quinazolin-4(3H)-
one analogues,5 which occur in several natural products.6
Numerous protocols have been developed for the synthesis of 2,3-
dihydroquinazolinones, using silica sulfuric acid,7 montmorillonite
K-10,8 Amberlyst-15,9 molecular iodine,10 zinc(II) perfluorooctano-
ate [Zn(PFO)2],11 gallium(III) triflate,12 KAl(SO4)2. 12H2O,13Al(H2
PO4)3,14 MCM-41-SO3H,15 and 1-butyl-3-methylimidazolium
tetrafluoroborate ([bmim]BF4).16a Recently Wang and co-workers
demonstrated the eco-friendly synthesis of 2-substituted-2,
3-dihydroquinazolin-4(1H)-ones from anthranilamide and differ-
ent aldehydes/ketones in water.16b These methods suffer from
one or more disadvantages such as the use of hazardous organic
solvents, low yields, strongly acidic conditions, expensive
moisture-sensitive catalysts, and tedious work-up conditions.
There are some drugs with quinazolinone skeleton (Fig. 1). In con-
tinuation of our efforts toward the development of novel environ-
friendly methodologies,17–27 herein, we report a mild and efficient
one-pot protocol for the synthesis of 2,3-dihydroquinazolin-
4(1H)-one derivatives by a two component reaction, involving
aromatic/aliphatic aldehydes and anthranilamide mediated by
recyclable b-CD in water (Scheme 1). Presently organic reactions
in aqueous phase have attracted the attention of researchers
because of the added advantages of water, as an environmentally
benign and economically affordable solvent. However, the funda-
mental problem in performing the reactions in water is that many
organic substrates are hydrophobic and are insoluble in water.
Cyclodextrins, possessing hydrophobic cavities, are well known
supramolecular catalysts, which by reversible formation of host–
guest complexes, activate the organic molecules and catalyze the
reactions. As part of our ongoing program toward the development
of greener chemical approaches for the synthesis of novel reaction
intermediates and heterocyclic moieties, we report herein the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones by the reaction of
aromatic/aliphatic aldehydes and anthranilamide, using b-
cyclodextrin, as a recyclable supramolecular catalyst, in aqueous
medium.
In this study, a model reaction was conducted by reacting
benzaldehyde, and anthranilamide in water medium at room
temperature to obtain the corresponding 2,3-dihydroquinazolin-
4(1H)-one in low yields (55%). The poor solubility of benzaldehyde
in water at elevated temperatures resulted in the formation of
undesired products. When the same reaction was conducted using
b-CD at room temperature the product was obtained in moderate
yield (68%). However by a controlled experiment using b-CD, as a
supramolecular catalyst, at 55–60 °C the product was obtained in
excellent yield (86%) (Scheme 1). In general, all the reactions were
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.029

K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6936–6939
6937
O
O
H
N
Cl
O
S
N
N
HN
N
H
HN
NH2
N
O
O
N
H
N
H3C
O
O
BENZOURACIL
FENQUIZONE
EVODIAMINE
PROQUAZONE
Figure 1. Some marketed drugs with quinazolinone skeleton.
Table 1
O
Recyclability of the catalysta
O
CHO
NH
β-CD/H2O
Cycles
Yieldb (%)
Catalyst recovered (%)
NH2
NH2
55-60 OC
+
N
Fresh
1
86
85
83
80
95
94
92
90
H
2
3
R
R
a
R= H, F, Br, NO2, CH3, OCH3,O-allyloxy
Scheme 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
Reaction conditions: Benzaldehyde (1.0 mmol), Anthranilamide (1.0 mmol),
b-Cyclodextrin (10 mol %), 55–60 °C, 1.5 h.
b
Isolated yield.
Table 2
Synthesis of 2,3-dihydroquinazolin-4(1H)-onesa
Entry
Aldehyde
Product
Yieldb (%)
86
CHO
O
NH
NH
1
N
H
O
CHO
2
3
4
92
89
88
85
N
H
NO2
NO2
CHO
O
NH
NH
NH
NH
N
H
Br
Br
F
CHO
O
N
H
F
CHO
O
5
6
N
H
OH
OH
CHO
O
OCH3
OCH3
87
86
N
H
CHO
CHO
O
NH
NH
7
8
N
H
O
83
N
H
(continued on next page)

6938
K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6936–6939
Table 2 (continued)
Entry
Aldehyde
Product
Yieldb (%)
CHO
O
NH
9
85
N
H
CHO
O
NH
N
10
11
82
88
N
H
O
N
CHO
NH
NO2
N
H
NO2
CHO
O
NH
12
13
84
81
OH
OH
OH
N
H
OH
S
O
CHO
NH
NH
S
N
H
CHO
O
14
15
85
82
N
H
H
N
O
CHO
NH
NH
H
N
N
H
H
N
O
16
80
84
N
H
CHO
NH
CHO
O
O
NH
17
18
N
H
O
O
CHO
CHO
NH
NH
Ph
78
79
N
H
O
Ph
Ph
19
Ph
N
H
a
Reaction conditions: aromatic aldehyde (1.0 mmol), anthranilamide (1.0 mmol), b-cyclodextrin (10 mol %), 55–60 °C, 1.5–7 h.
Isolated yield.
b
clean, and the 2,3-dihydroquinazolin-4(1H)-ones were obtained in
yields in the absence of b-cyclodextrin. The evidence of the forma-
tion of 2,3-dihydroquinazolin-4(1H)-one in the presence of b-CD
was supported by 1H NMR studies of the inclusion complex
between benzaldehyde and b-CD.28 All the reactions were carried
out with a catalytic amount (10 mol %) of b-CD in water. b-CD
excellent yields (78–92%) (Table 2). All the products were charac-
terized by 1H, 13C NMR, IR, and mass spectrometry.29,30 The
catalytic activity of the b-CD was established by the fact that 2,3-
dihydroquinazolin-4(1H)-one formation was observed in low

K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6936–6939
6939
13. Dabiri, M.; Salehi, P.; Otokesh, S.; Baghbanzadeh, M.; Kozehgary, G.;
Mohammadi, A. A. Tetrahedron Lett. 2005, 46, 6123.
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15. Rostamizadeh, S.; Amani, A. M.; Mahdavinia, G. H.; Sepehrian, H.; Ebrahimi, S.
Synthesis 2010, 1356.
16. (a) Dabiri, M.; Salehi, P.; Baghbanzadeh, M. Monatsh. Chem. 2007, 138, 1191; (b)
Min Wang, M.; Zhang, T. T.; Song, Z. G. Chin. Chem. Lett. 2011, 22, 427.
17. Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D. Helv.
Chim. Acta 2009, 92, 2118.
18. Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D.
Tetrahedron 2009, 65, 525.
19. Madhav, B.; Murthy, S. N.; Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D.
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was observed to be recoverable in these reactions. After the reac-
tion, the reaction mass was cooled to room temperature and b-
CD was filtered and washed with ice-cold water and dried. The
recovered b-CD was further used in the reaction with the same
substrates and checked for the yields and the catalytic activity of
the recovered catalyst
(b-CD), as shown in Table 1. It was observed that the yields of 2,3-
dihydroquinazolin-4(1H)-ones diminished slightly after two to
three recycles.
In summary, we have developed an eco-friendly method to
synthesize 2,3-dihydroquinazolin-4(1H)-ones in excellent yields
under neutral conditions in one-pot involving catalysis by b-
cyclodextrin in water.
22. Murthy, S. N.; Madhav, B.; Nageswar, Y. V. D. Tetrahedron Lett. 2010, 51, 5252.
23. Ramesh, K.; Murthy, S. N.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 2362.
24. Ramesh, K.; Murthy, S. N.; Karnakar, K.; Nageswar, Y. V. D. Tetrahedron Lett.
2011, 52, 3937.
Acknowledgements
25. Ramesh, K.; Murthy, S. N.; Karnakar, K.; Nageswar, Y. V. D. Tetrahedron Lett.
2011, 52, 4734.
26. Anil Kumar, B. S. P.; Madhav, B.; Harsha Vardhan Reddy, K.; Nageswar, Y. V. D.
Tetrahedron Lett. 2011, 52, 2862.
We thank CSIR, New Delhi, India, for fellowships to K.K., G.S.,
B.S.P., and UGC for fellowship to K.R.
27. Ramesh, K.; Murthy, S. N.; Karnakar, K.; Nageswar, Y. V. D.; Vijayalakhshmi, K.;
Prabhavathi Devi, B. L. A.; Prasad, R. B. N. Tetrahedron Lett. 2012, 53, 1126.
28. Ramesh, K.; Madhav, B.; Murthy, S. N.; Nageswar, Y. V. D. Synth. Commun. 2012,
42, 258.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.029.
29. General experimental procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-
ones using b-cyclodextrin: b-Cyclodextrin (10 mol %) was dissolved in water
(15 ml), and to this clear solution, benzaldehyde (1.0 mmol) was added, and
stirred for 15 min, followed by the addition of anthranilamide (1.0 mmol). The
reaction mixture was heated at 55–60 °C until completion of the reaction as
indicated by TLC. The reaction mixture was cooled to 5 °C and b-cyclodextrin
was filtered. The aqueous layer was extracted with ethyl acetate (4 Â 10 ml).
The combined organic layers were washed with water, saturated brine
solution, and dried over anhydrous Na2SO4. The combined organic layers
were evaporated under reduced pressure and the resulting crude product was
purified by column chromatography by using ethyl acetate and hexane
mixture (3:7) as an eluent. The identity and purity of the product were
confirmed by 1H, 13C NMR, and mass spectra.
References and notes
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30. Data of representative examples synthesized compounds.
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry 1)1; IR: 3302, 3184,
3061, 2924, 1658, 1612 cmÀ1 1H NMR (300 MHz, CDCl3) d = 7.95 (d, 1H,
;
J = 7.5 Hz), 7.60–7.57 (m, 2H), 7.48–7.45 (m, 2H), 7.36–7.30 (m, 1H), 7.27 (s,
1H), 6.92 (t, 1H, J = 6.7 Hz), 6.65 (d, 1H, J = 7.5 Hz), 5.92 (s, 1H), 5.79 (s, 1H, br),
4.38 (s, 1H, br); 13C NMR (50 MHz, CDCl3) d = 164.75, 147.22, 138.51, 134.02,
130.16, 129.12, 128.72, 127.39, 119.67, 114.55, 69.07; MS (ESI): m/z = 225
[M+H]+.
2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry 2)1; IR: 3278,
3174, 3032, 2922, 2855, 1647, 1608, 1520, 1461, 1345 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d = 8.32 (d, 1H, J = 8.3 Hz), 7.97 (m, 1H), 7.84–7.80 (m, 2H),
7.42–7.36 (m, 1H), 7.28 (s, 1H), 6.99–6.91 (m, 1H), 6.71 (d, 1H, J = 7.5 Hz), 6.16
(s, 1H, br), 6.04 (s, 1H), 4.42 (s, 1H, br); 13C NMR (50 MHz, CDCl3) d = 162.97,
147.61, 146.51, 145.96, 132.45, 126.79, 126.50, 122.26, 116.71, 113.72, 64.88;
MS (ESI): m/z = 270 [M+H]+.
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