Sulfonic acid functionalized Wang resin (Wang-OSO3H) as polymeric acidic catalyst for the eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones In memory of Dr. K. Anji Reddy, the founder of Dr. Reddy's Laboratories Ltd DRL Communication no.: IPDO IPM-00443

Article abstract of DOI:10.1016/j.tetlet.2015.06.004

Abstract An efficient and green approach has been developed for the synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones directly from corresponding substituted aromatic and aliphatic aldehyde and anthranilamide using recyclable polymer supported sulfonic acid catalyst under aqueous conditions. Environmental acceptability, operational simplicity, low cost, excellent functional group compatibility, and high yields are the important features of this protocol.

Full text of DOI:10.1016/j.tetlet.2015.06.004

Accepted Manuscript
Sulphonic acid functionalized Wang resin (Wang-OSO3H) as polymeric acidic
catalyst for the eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones
A.V. Dhanunjaya Rao, B.P. Vykunteswararao, T. Bhaskarkumar, Nivrutti R.
Jogdand, Dipak Kalita, Jaydeep kumar D. Lilakar, Vidavalur Siddaiah, Paul
Douglas Sanasi, Akula Raghunadh
PII:
S0040-4039(15)00976-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.004
TETL 46396
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 April 2015
2 June 2015
3 June 2015
Please cite this article as: Dhanunjaya Rao, A.V., Vykunteswararao, B.P., Bhaskarkumar, T., Jogdand, N.R., Kalita,
D., Lilakar, J.k.D., Siddaiah, V., Douglas Sanasi, P., Raghunadh, A., Sulphonic acid functionalized Wang resin
(Wang-OSO3H) as polymeric acidic catalyst for the eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.004
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Sulphonic acid functionalized Wang resin (Wang-OSO3H) as polymeric acidic catalyst for the eco-friendly
synthesis of 2,3-dihydroquinazolin-4(1H)-ones
A.V.Dhanunjaya Raoa, b,B.P.Vykunteswararao a, T.Bhaskarkumar a, Nivrutti R. Jogdanda,Dipak Kalitaa,,Jaydeep
kumar D. Lilakar c, Vidavalur Siddaiah b, Paul Douglas Sanasi, dAkula Raghunadh,a*

1
Tetrahedron Letters
Tetrahedron Letters
journal homepage: www.els evier.com
Sulphonic acid functionalized Wang resin (Wang-OSO3H) as polymeric acidic catalyst
for the eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones
A.V.Dhanunjaya Raoa, b,B.P.Vykunteswararaoa, T.Bhaskarkumara, Nivrutti R. Jogdanda,Dipak Kalitaa,,Jaydeep kumar D. Lilakar c,
Vidavalur Siddaiah b, Paul Douglas Sanasi d , Akula Raghunadh,a*
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India;
b Department of Organic Chemistry, Foods, Drugs and Water, Andhra University, Visakhapatnam, 530003, India.
c Research & Development, Bachupally, Dr. Reddy’s Laboratories Ltd, Hyderabad, 500049, India;
d Department Of Engineering Chemistry, College Of Engineering, Andhra University, Visakhapatnam, 530003, India,
*E-mail: raghunadha@drreddys.com
ABSTRACT
Article history:
An efficient and green approach has been developed for the synthesis of 2-substituted 2,3-
dihydroquinazolin-4(1H)-ones directly from corresponding substituted aromatic and aliphatic
aldehyde and anthranilamide using recyclable polymer supported sulphonic acid catalyst under
Received
Received in revised form
Accepted
aqueous conditions. Environmental acceptability, operational simplicity, low cost, excellent
Available online
functional group compatibility and high yields are the important features of this protocol.
2009 Elsevier Ltd. All rights reserved.
In memory of Dr. K. Anji Reddy, the founder
of Dr. Reddy’s Laboratories Ltd.
DRL Communication no.: IPDO IPM-00443
Keywords: Wang resin, 2,3-
dihydroquinazolin-4(1H)-ones, 2-
Aminobenzamide,aldehyde,water, green
chemistry.
Dihydroquinazolin-4(1H)-one skeletons constitute a class of
synthetic compounds that have pharmaceutical activities and
clinical applications. In particular a core structure of
level of interest in the current domain is clearly shown by
the number of publications.
dihydroquinazolin-4(1H)-one scaffold is present in
a
number of compounds that demonstrated anticancer,
antidiuretic, and anticonvulsant activities.1 Some
representative examples of drug molecules having
quinazolinone skeleton are given in Figure 1. They are also
useful as antihistamine, antidepressant, and vasodilating
agents. Among the several methods for the preparation of
2,3-dihydroquinazolin-4(1H)-ones,
the
most
direct
Figure 1. Examples of marketed drugs with quinazolinone
skeleton
Recently, a number of classical methods for the synthesis of
procedure involves the condensation of aryl, alkyl and
hetero aryl aldehydes with anthranilamide in the presence of
p-toluene sulphonic acid.2 In the past decade, a variety of
synthetic methods have been employed for the preparation
of functionalized 2,3-dihydroquinazolin-4(1H)-ones and the
2,3-dihydroquinazolin-4(1H)-ones have been reported in the
literature involving the condensation of 2-aminobenzamide
with aldehydes in the presence of various catalysts like

2
Tetrahedron Letters
ammonium
iodine,10
chloride,3 fumaric acid,4 silica-HClO4,5
gallium trifluoromethanesulfonate,11 ionic
Amberlyst-15,6 iridium,7 citric acid,8 [bmim]HSO4,9
aromatic and aliphatic aldehydes and 2-aminobenzamide
under thermal condition in the presence of Wang-OSO3H as
an efficient, green, inexpensive, reusable, and polymeric
catalyst. It is pertinent to mention that this is the first report
on the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
installing Wang-OSO3H catalyzed protocol in aqueous
media (Scheme 2).
liquids,12 bronsted acids,13 phosphoric acid,14 copper
chloride,15 tetrabutylammoniumbromide,16 and TiCl4/Zn.17
However, the above mentioned methods have been
associated with different drawbacks such as the use of
hazardous organic solvents, low yields, strongly acidic
conditions, expensive moisture sensitive catalysts, or
tedious work-up conditions.
In spite of the efficiency of homogeneous acidic catalysts,
their use is associated with generation of unwanted waste
and with the corrosion of process equipment. In contrast, the
Scheme 2: Wang-OSO3H mediated synthesis of
use of heterogeneous acid catalysis often benefits from a
2-substituted 2,3-dihydroquinazolin-4(1H)-ones
18
substantial process improvement
including greater
Table 1: Optimization of the ratio of catalyst (% w/w).
catalyst stability, recovery and regeneration, and enhanced
process selectivity.
Entry
Catalyst (% w/w)
Time (hr) Yieldb (%)
The researchers continue for finding a better catalyst for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones derivatives
in terms of operational simplicity, economic viability, and
greater selectivity.
1
No Wang-OSO3H
3.0
70.0
74.0
86.0
84.5
2
3
4
5
1.2
10
15
0.45
0.40
The objective of the present study was the development of a
novel heterogeneous catalyst for efficient preparation of 2-
substituted 2,3-dihydroquinazolin-4(1H)-ones. Sulfonic acid
functionalized resin (Wang-SO3H) is an efficient
heterogeneous solid acid catalyst which can easily be
handled and removed from the reaction mixture by simple
filtration functionalized resin (Wang-SO3H) is an efficient
heterogeneous solid acid catalyst which can easily be
handled and removed from the reaction mixture by simple
filtration.
Reaction and conditions: 2-Aminobenzamide (1.0 mmol), 3-
hydroxybenzaldehyde (1.2 mmol) and Wang-OSO3H in water
at 100 °C. bYield refers to pure products after
chromatography.
We found that 2-aminobenzamide 1 readily reacts with a
variety of aldehydes 2a-2v under the catalysis with Wang-
OSO3H resin to form 2-substituted 2,3-dihydroquinazolin-
4(1H)-ones.
The reaction conditions were optimized with respect to the
quantity of catalyst (Table 1) and the solvent (Table 2) by
studying the condensation of 2-aminobenzamide (1, 1.0
mmol) with 3-hydroxybenzaldehyde (2d, 1.2 mmol). The
highest isolated yields of compound 3d were obtained by
carrying out the process in water at 100 oC for 0.5-1.5 hr. in
the presence of 10% w/w catalyst with respect to 2-
aminobenzamide.
Wang resin22 is most often used for the attachment of
organic and inorganic acids. In particular, treatment of
Wang resin with chlorosulfonic acid in the presence of N,N-
diisopropylethylamine (DIPEA) results in the formation of a
monosulfate ester (Wang-OSO3H, Scheme 1).
The recovery and reuse of Wang-OSO3H were examined in
the
reaction
of
2-aminobenzamide
with
3-
hydroxybenzaldehyde. When the reaction was completed,
ethyl acetate was added to the reaction mixture and the
catalyst was recovered by filtration.
Scheme 1: Preparation of Wang-OSO3H
In this work, we report an efficient procedure for the
preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives
through a one-step reaction between variously substituted

Tetrahedron Letters
Table 2: Screening of solvent.
The experimental details captured in the table (Table 4,
entries 1–3) clearly indicate that the yields obtained in the
optimized reaction conditions using Dowex 50 and
Amberlyst 15 are low compared to Wang-OSO3H. The
highest isolated yields of compound were obtained by
carrying out the process in water at 100 oC for 0.5 hr. in
presence of 10% w/w wang-SO3H catalyst with respect to 2-
aminobenzamide. The reaction time is also comparatively
very less.
Entry
Solvent (Temp. °C) Time (hr) Yieldb (%)
1
2
DMSO (100)
DMF (100)
1.5
1.5
4.0
1.0
1.0
5.0
7.0
1.0
0.45
5.0
4.0
75
72
78
80
81
82
83
82
86
73€
68¥
3
1,4-Dioxane (100)
Ethanol (78)
DCM (38)
4
5
6
Acetonitrile (80)
Methanol (64)
Toluene (110)
Water (100)
7
Spiroheterocycles have remained relatively less investigated
class of compounds until recent past. The development of
newer methods for their synthesis however has gained
enormous attention especially in the area of organic as well
8
9
10
11
Water (100)
Water (100)
as medicinal chemistry.
The condensation of 2-
Reaction and conditions: 2-Aminobenzamide (1.0 mmol), 3-
hydroxybenzaldehyde (1.2 mmol) and Wang-OSO3H (10%,
w/w) in solvent at respective temperature. bYield refers to pure
aminobenzamide (1, 1.0 mmol) with cyclohexnone (4, 1.2
mmol) to furnish spiro 2,3-dihydroquinazolin-4(1H)-ones
(5) in 85% yield were obtained by carrying out the process
in water at 100 oC for 0.5-1.0 hr in the presence of 10% w/w
catalyst with respect to 2-aminobenzamide.
€
products after chromatography. Dowex50 used as catalyst.
¥Conc. H2SO4 used as catalyst.
The recovered catalyst was washed, dried and reused. It was
found that the catalytic activities and pH of the subsequent
reaction mass of the recovered catalyst were almost the same
as that of fresh catalyst over four runs (Table 3, entries 1–5).
The scope and the utility of the suggested synthetic protocol
was demonstrated by reacting compound 2 (2a-2v, Table 5)
with a wide variety of aliphatic, aromatic, heteroaromatic,
and α,β-unsaturated aldehydes to result in the target 2,3-
dihydroquinazolin-4(1H)-ones (3a-3v, Table 5) in invariably
high yields (78-88%).
Table 3: Recyclability of the catalyst
pH of
Entry Cycle Time (hr)
Yieldf (%)
reaction
mass
2.4
In conclusion, we have reported a highly efficient and
ecofriendly method for the synthesis of novel 2-substituted
2,3-dihydroquinazolin-4(1H)-ones products with good yield
using Wang–OSO3H as an inexpensive, biodegradable and
recyclable catalyst. Prominent advantages of this method are
broad scope, operational simplicity, practicability, economic
viability, good yield of the products in shorter reaction time,
easy work-up, and reusability of the catalyst.
1
2
3
4
5
Fresh 0.45
86.0
85.0
85.5
84.5
84.0
1
2
3
4
0.45
0.50
0.55
0.55
2.5
2.5
2.7
2.7
Reaction and conditions: 2-Aminobenzamide (1.0 mmol), 3-
hydroxybenzaldehyde (1.2 mmol) and Wang-OSO3H (10%,
f
w/w) in water at 100 °C. Yield refers to pure products after
chromatography.
Table 4: Comparison of catalytic activity of different
catalysts
Entry
Catalyst
Wang-SO3H
Dowex 50
Time (hr) Yield* (%)
1
2
3
0.5
5
88
73
71
Scheme 3: Wang-OSO3H mediated synthesis of spiro 2,3-
dihydroquinazolin-4(1H)-ones (5)
Amberlyst 15
7
Reaction and conditions: 2-Aminobenzamide (1.0 mmol), 3-
hydroxybenzaldehyde (1.2 mmol) and Catalyst (10%, w/w) in
water at 100 °C. *Yield refers to pure products after
chromatography.

4
Tetrahedron Letters
Table 5: Synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by Wang-OSO3H
Entry
1
Aldehyde (2)
2,4-Dimethylbenzaldehyde, 2a
4-Methoxybenzaldehyde, 2b
Product (3) Time (hr)
Yieldi (%)
87
M.P (°C)
161-163
198-201
209-210
215-217
186-187
193-194
206-208
205-206
202-203
160-162
188-190
155-157
163-164
264-266
Pasty solid
269-271
270-272
267-268
274-275
278-279
275-277
264-265
0.50
0.45
0.45
0.50
0.55
0.40
0.45
0.45
0.50
1.00
0.50
0.50
0.45
0.45
0.45
1.05
1.00
1.00
0.55
0.50
0.55
1.10
3a
3b
3c
3d
3e
3f
2
88
3
4-Hydroxybenzaldehyde, 2c
86
4
3-Hydroxybenzaldehyde, 2d
88
5
3,4,5-Trimethoxybenzaldehyde, 2e
4-Chlorobenzaldehyde, 2f
81
6
84
7
2-Chlorobenzaldehyde, 2g
83
3g
3h
3i
8
4-Bromo-2,6-difluorobenzaldehyde, 2h
4-Nitrobenzaldehyde, 2i
83
9
85
10
11
12
13
14
15
16
17
18
19
20
21
22
Hexanal, 2j
80
3j
Pivalaldehyde, 2k
81
3k
3l
Cinnamaldehyde, 2l
81
Furan-2-carbaldehyde, 2m
80
3m
3n
3o
3p
3q
3r
3s
Isonicotinaldehyde, 2n
78
5-Fluoro-1H-indole-3-carbaldehyde, 2o
2-Chloro-8-methylquinoline-3-carbaldehyde, 2p
2-Chloro-7-methylquinoline-3-carbaldehyde, 2q
2-Chloro-6-methylquinoline-3-carbaldehyde, 2r
2-Chloro-6-ethoxyquinoline-3-carbaldehyde, 2s
2-Chloro-7-methoxyquinoline-3-carbaldehyde, 2t
2-Chloro-6-methoxyquinoline-3-carbaldehyde, 2u
2-Chloro-6-fluoroquinoline-3-carbaldehyde, 2v
84
86
84
85
82
80
3t
83
3u
3v
82
Reaction and conditions: 2-Aminobenzamide 1 (1.0 mmol), aldehyde 2 (1.2 mmol) and Wang-OSO3H (10%, w/w) in water
1
at100 °C. All products were characterized by H NMR, IR and Mass spectroscopy. iYield refers to pure products after
chromatography.
33, 161; (f) Bridges A. J.; Zhou H.; Cody D. R.;
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Acknowledgments:
The authors would like to thank Dr. Vilas Dahanukar, Dr.
Upadhya Timmana, Dr. Rama Mohan, Dr. Rashid Abdul
Rehman Khan and the analytical group of CPS-DRL for
spectral data. Mr A.V.Dhanunjaya Rao thanks the CPS-
DRL, Hyderabad, India for encouragement.
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Tetrahedron Letters
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Wang-OSO3H was prepared by adding freshly distilled
ClSO3H (2.0 mmol) to wang resin (1.0 mmol), DIPEA
(5.0 mmol) in DCM (10 volumes) and the resulting
solution was stirred at 25-35 °C for 2 hr. The reaction
mass was filtered and washed with DMF (5 x 10
volumes), DCM (5 x 10 volumes) and Isopropanol (5 x
10 volumes) and the wang catalyst was dried at 130 0C
for 3 hr.
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aldehyde 2 (2a-2v) or ketone 4 (1.2 mmol) was
dissolved in 5 ml of water and Wang-OSO3H (10%
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°
w/w) was added under stirring condition at 100 C.
Stirring was continued in for the stipulated period of
time (Table 5). The progress of the reaction was
monitored with TLC. After completion of the reaction,
the reaction mixture was diluted with 1:9 mixture of
methanol: ethyl acetate to dissolve the precipitated
product and the catalyst was removed simply by
filtration. The residual catalyst was repeatedly washed
with ethyl acetate (3 x 5 volumes). The combined
filtrate and washings, on evaporation, gave the desired
product. This was further purified by column
chromatography using silica gel (60-120 mesh) with
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Macqquarrie, D. J. Chem. Soc. Rev. 1996, 25, 310; (e)

6
Tetrahedron Letters
ethyl acetate and hexane (4:6) as eluent to afford the
desired product 3(3a-3v) or 5.