Tandem supramolecular synthesis of substituted 2-aryl-2,3- dihydroquinazolin-4(1H)-ones in the presence of β-cyclodextrin in water

Article abstract of DOI:10.1016/j.tetlet.2012.08.141

Substituted 2-aryl-2,3-dihydroquinazolin-4(1H)-ones were prepared for the first time in water under neutral conditions by the reaction of aniline, isatoic anhydride, and aldehyde mediated by β-cyclodextrin in good yields. β-Cyclodextrin can be recovered a

Full text of DOI:10.1016/j.tetlet.2012.08.141

Tetrahedron Letters 53 (2012) 6095–6099
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem supramolecular synthesis of substituted
2-aryl-2,3-dihydroquinazolin-4(1H)-ones in the presence of b-cyclodextrin
in water
⇑
K. Ramesh, K. Karnakar, G. Satish, K. Harsha Vardhan Reddy, 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:
Received 4 July 2012
Revised 29 August 2012
Accepted 30 August 2012
Available online 7 September 2012
Substituted 2-aryl-2,3-dihydroquinazolin-4(1H)-ones were prepared for the first time in water under
neutral conditions by the reaction of aniline, isatoic anhydride, and aldehyde mediated by b-cyclodextrin
in good yields. b-Cyclodextrin can be recovered and reused with a little loss of catalytic activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldehydes
Aniline/ammonium acetate
Isatoic anhydride
2-Aryl-2,3-dihydroquinazolin 4(1H)-ones
b-Cyclodextrin
Water
2,3-Dihydroquinazolin-4(1H)-one derivatives are important
heterocyclic compounds, these are widely used in potential biolog-
ical and pharmaceutical activities.1 These are also valuable inter-
mediates in synthetic organic chemistry. These exhibit various
medicinal properties such as anti-tumor, anti-cancer, herbicidal,
diuretic, as well as plant growth regulation.2 Some representative
examples of drug molecules having quinazolinone skeleton are gi-
ven in Figure 1. Several synthetic protocols have been reported for
the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives by
using different catalytic systems. Wang et al. developed an eco-
friendly synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives
in water medium from anthranilamide, aldehydes, or ketones.3
Chun Cai and co-workers demonstrated a one-pot three-compo-
nent domino approach for 2-arylquinazoline-4-amines, by the acti-
vation of sp3 C–H bond in a nonmetal catalytic oxidation system by
using I2 in TBHP.4 J. K. Zaberi reported an acetic acid catalyzed reac-
tion between isatoic anhydride, aromatic amine, and aldehyde for
the preparation of 2,3-dihydroquinazolin-4(1H)-ones in a one-pot
synthesis.5 Weike Su and co-workers described an eco-friendly
synthesis of 2,3-dihydroquinazolin-4(1H)-ones in ionic liquids,
F
H
Cl
O
S
O
N
N
O
CH3
HN
N
CH3
H2N
H2N
NH
N
N
O
S
N
H2N
O
N
O
QUINETHAZONE
PROQUAZONE
AFLOQUALONE
NOLATREXED
Figure 1. Some marketed drugs with quinazolinone skeleton.
⇑
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.2012.08.141

6096
K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6095–6099
O
O
CHO
-CD/H O
60-65 °C
NH
β
O
2
NH4OAc
+
+
N
H
N
H
O
R1
R1
R1= H, F, Br, NO2, Me, OMe, OH, Allyoxy.
Scheme 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
O
O
R1
NH2
CHO
O
-CD/H O
60-65 C
N
+
+
β
2
°
N
H
O
N
H
R2
R2
R1
R1= H, Me, OEt.
Scheme 2. Synthesis of 2,3-diphenyl-2,3-dihydroquinazolin-4(1H)-ones.
R2= H, F, Br, Me, OMe
one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones
from ortho-bromobenzamides and isothiocyanates.7 Mostafa
Baghbanzadeh et al. developed a novel synthesis of bis-2,3-dihy-
droquinazolin-4(1H)-one derivatives using p-TsOH as a catalyst
under reflux conditions.8 Recently Jiu-Xi Chen and co-workers re-
ported the synthesis of 2,3-dihydroquinazolin-4(1H)-ones, under
solvent-free conditions by grinding anthranilamides or anthra-
nilhydrazides, and aldehydes in the presence of citric acid.9
However, the above mentioned methods have been associated
with different drawbacks such as the use of hazardous organic sol-
vents, low yields, strongly acidic conditions, expensive moisture-
sensitive catalysts, or tedious work-up conditions.
Table 1
Recyclability of the catalysta
Cycle
Yieldb (%)
Catalyst recovered (%)
Fresh
84
82
81
81
90
88
86
86
1
2
3
a
Reaction conditions: ammonium acetate (1.0 mmol), Isatoic anhydride
(1.0 mmol), Aldehyde (1.0 mmol), b-Cyclodextrin (10 mol %), 60–65 °C.
b
Isolated yield.
In continuation of our efforts toward the development of novel
from anthranilamide or isatoic anhydride, ammonium acetate, and
aldehyde.6 Chanjuan Xi and co-workers used a copper-catalyzed
environ-friendly methodologies10 herein, we report a novel and
Table 2
Synthesis of 2,3-dihydroquinazolin-4(1H)-onesa
Entry
Aldehyde
Isatoic anhydride
Ammonium acetate
NH4OAc
Product
Yieldb (%)
CHO
O
O
40c
58d
84
O
NH
NH
1
N
H
O
O
N
H
CHO
O
O
O
O
O
2
3
4
NH4OAc
NH4OAc
NH4OAc
86
87
90
N
H
N
H
F
F
CHO
O
O
NH
NH
N
H
O
O
N
H
Br
Br
CHO
O
O
N
H
N
H
NO2
NO2

K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6095–6099
6097
Table 2 (continued)
Entry
Aldehyde
Isatoic anhydride
Ammonium acetate
NH4OAc
Product
Yieldb (%)
CHO
O
O
O
O
O
NH
5
6
85
84
N
H
O
O
O
N
H
CHO
O
O
OCH3
NH OCH3
NH4OAc
NH4OAc
N
H
N
H
CHO
OH
O
O
NH
7
8
82
83
N
H
N
H
OH
CHO
O
O
O
O
NH
NH4OAc
O
N
H
N
H
CHO
CHO
O
O
NH
NH
NH
9
NH4OAc
NH4OAc
82
86
N
H
N
H
O
O
O
O
O
O
O
10
NO
2
NO
OH
N
H
O
N
H
O
2
CHO
OH
11
12
NH4OAc
NH4OAc
82
84
OH
OH
N
H
N
H
CHO
O
O
O
NH
N
H
O
N
H
H
N
O
O
O
O
NH
NH
CHO
H
N
13
14
15
NH4OAc
NH4OAc
NH4OAc
81
80
N
H
O
O
O
N
H
O
H
N
N
H
N
H
CHO
NH
O
O
O
NH
78
CHO
Ph
N
H
O
N
H
Ph
(continued on next page)

6098
K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6095–6099
Table 2 (continued)
Entry
Aldehyde
Isatoic anhydride
Ammonium acetate
NH4OAc
Product
Yieldb (%)
O
O
O
O
NH
NH
CHO
16
79
Ph
N
H
O
O
O
N
H
O
Ph
CHO
17
NH4OAc
84
N
H
N
H
O
O
a
Reaction conditions: ammonium acetate (1.0 mmol), isatoic anhydride (1.0 mmol), aldehyde (1.0 mmol), b-cyclodextrin (10 mol %), 60–65 °C.
Isolated yield.
Water at room temperature.
b-Cyclodextrin at room temperature.
b
c
d
Table 3
Synthesis of 2,3-diphenyl-2,3-dihydroquinazolin-4(1H)-onesa
Entry
Aldehyde
Isatoic anhydride
Ammonium acetate
Product
Yieldb (%)
CHO
O
NH2
O
34c
55d
80
O
N
N
N
N
1
N
H
O
O
O
N
H
CHO
O
NH2
NH2
NH2
O
O
O
O
2
3
83
73
N
H
N
H
CHO
O
O
Br
Br
N
H
N
H
CHO
O
O
4
72
N
H
O
O
O
N
H
OCH3
CHO
OCH3
O
NH2
O
O
O
N
N
5
6
68
84
N
H
N
H
F
F
OEt
CHO
O
NH2
OEt
O
N
H
N
H
a
b
c
Reaction conditions: Aniline (1.0 mmol), Isatoic anhydride (1.0 mmol), Aldehyde (1.0 mmol), b-Cyclodextrin (10 mol %), 60–65 °C.
Isolated yield.
Water at room temperature.
b-Cyclodextrin at room temperature.
d

K. Ramesh et al. / Tetrahedron Letters 53 (2012) 6095–6099
6099
efficient one-pot protocol for the synthesis of 2,3-dihydroquinazo-
Acknowledgements
lin-4(1H)-one derivatives for the first time by a three-component
reaction, involving amino compounds, isatoic anhydride, and alde-
hyde promoted by recyclable b-CD in aqueous medium (Scheme 1
and 2). Presently organic reactions in aqueous phase have attracted
the attention of researchers because of the added advantages of
water, as an environ-friendly and economically affordable solvent.
However, the fundamental 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 for-
mation of host–guest complexes, activate the organic molecules
and catalyze the reactions. As a part of our ongoing program to-
ward the development of greener chemical approaches for the syn-
thesis of novel reaction intermediates and heterocyclic moieties,
we envisaged one-pot protocol for the synthesis of 2,3-dihydroqui-
nazolin-4(1H)-ones by using b-CD as a recyclable supramolecular
catalyst in aqueous medium. In the present study, a model reaction
was conducted by reacting aromatic amines and isatoic anhydride
with aldehyde in water medium at room temperature to obtain the
corresponding 2,3-dihydroquinazolin-4(1H)-one (40%). The poor
solubility of aniline in water at elevated temperatures did not re-
sult in the exclusive formation of the expected product. When
the same reaction was conducted using b-CD at room temperature
the product was obtained in moderate yield (58%). However by a
controlled experiment using b-CD, as a supramolecular catalyst,
at 60–65 °C the product was obtained in excellent yield (84%)
(Scheme 1). In general, all the reactions were clean, and the 2,3-
dihydroquinazolin-4(1H)-ones were obtained in excellent yields
(68–90%) (Table 2 and 3). All the products were characterized by
1H, 13C NMR, IR, and mass spectrometry.12,13 The catalytic activity
of b-CD was established by the fact that 2,3-dihydroquinazolin-
4(1H)-one formation was not observed in satisfactory yield in the
absence of b-cyclodextrin. The evidence for the formation of 2,3-
dihydroquinazolin-4(1H)-one in the presence of b-CD was sup-
ported by 1H NMR studies of inclusion complex between aniline
and b-CD.11 All the reactions were carried out with a catalytic
amount (10 mol %) of b-CD in water. In all these reactions b-CD
can be recovered and reused. After the reaction, 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 catalytic activity of the recovered catalyst (b-CD),
as shown in Table 1. It was observed that the yields of 2,3-dihydro-
quinazolin-4(1H)-ones diminished slightly after two to three
recycles.
We thank CSIR, New Delhi, India, for fellowships to K. K., G. S., K.
H. V. R., and UGC for fellowship to K. R.
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.
08.141.
References and notes
1. Erlanson, D. A.; McDowell, R. S.; Brien, T. O. J. Med. Chem. 2004, 47, 3463.
2. Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H.; Lee, K.; Paull, K. D. Biochem.
Pharmacol. 1996, 51, 53.
3. Wang, M.; Zhang, T. T.; Song, Z. G. Chin. Chem. Lett. 2011, 22, 427.
4. Zeng, L.-Y.; Yi, W.-B.; Cai, C. Eur. J. Org. Chem. 2012, 559.
5. Jaberi, Z. K.; Arjmandi, R. Monatsh. Chem. 2011, 142, 631.
6. Chen, J.; Su, W.; Wu, H.; Liu, M.; Jin, C. Green Chem. 2007, 9, 972.
7. Wang, F.; Zhao, P.; Xi, Ch. Tetrahedron Lett. 2011, 52, 231.
8. Baghbanzadeh, M.; Salehi, P.; Dabiri, M.; Kozehgary, G. Synthesis 2006, 2, 344.
9. Ding, Q.-S.; Zhang, J.-L.; Chen, J.-X.; Liu, M.-C.; Ding, J.-C.; Wu, H-Y. J. Heterocycl.
Chem. 2012, 49, 375.
10. (a) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D. Helv.
Chim. Acta 2009, 92, 2118; (b) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K.
R.; Nageswar, Y. V. D. Tetrahedron 2009, 65, 525; (c) Madhav, B.; Murthy, S. N.;
Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D. Tetrahedron Lett. 2009, 50, 6025; (d)
Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett.
2010, 51, 3649; (e) Shankar, J.; Karnakar, K.; Srinivas, B.; Nageswar, Y. V. D.
Tetrahedron Lett. 2010, 51, 3938; (f) Murthy, S. N.; Madhav, B.; Nageswar, Y. V.
D. Tetrahedron Lett. 2010, 51, 5252; (g) Ramesh, K.; Murthy, S. N.; Karnakar, K.;
Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 3937; (h) Ramesh, K.; Murthy, S.
N.; Karnakar, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 4734; (i) Anil
Kumar, B. S. P.; Madhav, B.; Harsha Vardhan Reddy, K.; Nageswar, Y. V. D.
Tetrahedron Lett. 2011, 52, 2862; (j) 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, 44, 1126; (k) Ramesh, K.; Madhav, B.; Murthy, S. N.;
Nageswar, Y. V. D. Synth. Commun. 2012, 42, 258; (l) Ramesh, K.; Murthy, S. N.;
Nageswar, Y. V. D. Synth. Commun. 2012, 42, 2471.
11. Ramesh, K.; Murthy, S. N.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 2362.
12. 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, aniline/ammonium acetate (1.0 mmol) was
added, stirred for 15 min, followed by the addition of isatoic anhydride
(1.0 mmol) and aldehyde (1.0 mmol). The reaction mixture was heated at 60–
65 °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 (3 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 (4:6) as an eluent. The identity and purity of the
product were confirmed by 1H, 13C NMR, and mass spectra.
13. Data of representative examples synthesized compounds 2-phenyl-2,3-
dihydroquinazolin-4(1H)-one (Table 2, Entry 1); IR (KBr): 1H NMR (300 MHz,
CDCl3) d = 7.94 (d, 1H, J = 7.5 Hz), 7.61–7.58 (m, 2H), 7.47–7.44 (m, 2H), 7.37–
7.31 (m, 1H), 7.26 (s, 1H), 6.91 (t, 1H, J = 6.7 Hz), 6.66 (d, 1H, J = 7.5 Hz), 5.91 (s,
1H), 5.78 (s, 1H, br s), 4.39 (s, 1H, br s); 13C NMR (50 MHz, CDCl3) d = 164.76,
147.20, 138.50, 134.03, 130.15, 129.11, 128.71, 127.38, 119.68, 114.56, 69.06;
MS (ESI): m/z = 225 [M+H]+.
Conclusion
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 catalyzed by b-cyclodextrin
in aqueous medium.