Efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by titanium silicon oxide nanopowder in aqueous media

Article abstract of DOI:10.1080/00397911.2016.1254801

An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives is accomplished in aqueous media by a three-component reaction of isatoic anhydride, primary amines or ammonium acetate, and aldehydes catalyzed by titanium silicon oxide nanopowder. A variety of 2,3-dihydroquinazolin-4(1H)-one derivatives were synthesized using this methodology in good to excellent yields. The catalyst was recovered and recycled up to four times without significant loss in the catalytic activity.

Full text of DOI:10.1080/00397911.2016.1254801

An Efficient Synthesis of 2, 3-dihydroquinazolin-4(1H)-ones Catalyzed by Titanium
Silicon Oxide Nanopowder in Aqueous Media
1
,2,
1
1
1
Ramamohan Mekala , M. V. Madhubabu , G. Dhanunjaya , Sridhar Regati , K. B.
2
1
Chandrasekhar , Jayaprakash Sarva
1
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy`s
Laboratories Limited, Hyderabad, Telangana, India Department of Chemistry,
2
Jawaharlal Nehru Technological University Anantapur, Ananthapuramu, Andhra
Pradesh, India
Corresponding author Ramamohan Mekala Dr. Reddy’s Laboratories Ltd.
communication no: IPDO IPM-00511. E-mail: ramamohanm@drreddys.com.
Abstract
An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives is accomplished in
aqueous media by a three-component reaction of isatoic anhydride, primary amines or
ammonium acetate, and aldehydes catalyzed by titanium silicon oxide nanopowder. A
variety of 2, 3-dihydroquinazolin-4(1H)-one derivatives were synthesized using this
methodology in good to excellent yields. The catalyst was recovered and recycled up to
four times without significant loss in the catalytic activity.
Graphical Abstract
KEYWORDS: Quinazolinones, Nitrogen heterocycles, Reusable catalyst, Green
chemistry, Nanopowder
INTRODUCTION
1

2
,3-dihydroquinazolin-4(1H)-one derivatives are an important class of fused heterocycles
[
1–8]
that exhibit a variety of biological and pharmaceutical activities
such as
[
1]
[2]
[3]
[4]
[5]
antihypertensive, antitumor, analgesic, antibacterial, anticonvulsant,
[
6]
[7]
[8]
anticancer, anti-inflammatory, and diuretic (Fig. 1). In view of their significance,
various methods for the preparation of 2, 3-dihydroquinazolin-4(1H)-one derivatives
have been developed. The most widely used approach for the synthesis of 2, 3-
dihydroquinazolin-4(1H)-one include three component reaction of isatoic anhydride,
primary amine with aldehydes or ketones in the presence of different catalysts. Use of
[9]
[10]
[11]
montmorillonite K-10, p-toluenesulfonic acid, silica-sulfuric acid (SSA), gallium
[
12]
[13]
[14]
triflate, ionic liquids (ILs), zinc (II) perfluorooctanoate [Zn(PFO2], amberlyst-15
[
15]
[16]
[17]
[18]
[19]
resin, iodine, beta-cyclodextrin, Cyanuric Chloride, Cu-CNTs
etc. have
been reported for this transformation, however most of the known methods suffer from
certain drawbacks such as longer time, tedious work up and use of volatile organic
solvents. Thus the development of more convenient and environmentally benign
synthetic methods using a recyclable catalytic system for these compounds is highly
desired.
Development of new protocols for environmentally benign synthetic methods using a
recyclable catalytic system has been in focus in recent times. In particular metal
nanoparticles have attracted considerable attention due to their superior catalytic activity,
reusability and mild nature in the context of green chemistry. As part of our ongoing
research towards the development of novel methodologies for the synthesis of
[
20]
biologically active heterocyclic compounds titanium silicon oxide nanopowder has
2

attracted considerable attention since it is non-toxic, air and moisture stable, and easy to
store for long periods under normal laboratory conditions. As per the literature and to the
best of our knowledge, till date there are no reports on the use of titanium silicon oxide
nanopowder as a catalyst for carrying out any organic transformation. Herein we report a
simple, scalable and straightforward method for the synthesis of mono- and disubstituted
2
, 3-dihydroquinazolin-4(1H)-ones (Scheme 1) in aqueous media by a one-pot three-
component reaction of isatoic anhydride, primary amines or ammonium acetate, and
aldehydes catalyzed by titanium silicon oxide nanopowder.
RESULTS AND DISCUSSION
Initially, we studied one-pot, three-component condensation reaction of isatoic anhydride
(
1), ammonium acetate and 2-chloro benzaldehyde (2a) as the model substrates by using
titanium silicon oxide nanopowder (10 mol %) as catalyst in 1, 4-dioxane solvent (Table
, entry 1). To our delight, the corresponding 2, 3-dihydroquinazolin-4(1H)-one (4a)
1
derivative was obtained in 93 % yield after 2 h. Encouraged by this result, we further
studied the effect of different solvents and catalyst loading for the synthesis of 2, 3-
dihydroquinazolin-4(1H)-ones as shown in the table-1.
As shown in the table-1, solvents 1, 4-dioxane (entry 1) and water (entry 5) were found to
be equally effective for this transformation. However we have chosen water as solvent for
further optimization studies as water is nontoxic, inexpensive, non-flammable, and
readily available. With respect to catalyst loading there is no significant improvement in
yields when the catalyst was increased from 10 to 20 mol% while yield is decreased with
3

decreasing catalyst loading to 5 mol % from 10 mol %. In the absence of catalyst,
negligible amount of product was observed under described reaction conditions.
Reusability is one of the important properties of this catalyst. The catalytic activity of
titanium silicon oxide nanopowder was evaluated by subjecting the recovered catalyst to
fresh substrates under optimized conditions. For this purpose isatoic anhydride,
ammonium acetate and 4-chloro benzaldehyde has been chosen as model substrates. It is
evident from the Table 2 that the catalyst can be recycled up to four times without
significant drop in the yield and its catalytic activity.
EXPERIMENTAL
General Methods
Unless stated otherwise, reactions were performed under nitrogen atmosphere using oven
dried glassware. Reactions were monitored by thin layer chromatography (TLC) on silica
gel plates (60 F254), visualizing with ultraviolet light or iodine spray. Flash
chromatography was performed on silica gel (100-200 mesh) using distilled hexane, ethyl
1
13
acetate, dichloromethane. H NMR and C NMR spectra were determined in CDCl or
3
DMSO-d solution by using 400 or 100 MHz spectrometers, respectively. Proton
6
chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.00) as internal standard
and expressed in ppm. Spin multiplicities are given as s (singlet), d (doublet), t (triplet)
and m (multiplet) as well as b (broad). Coupling constants (J) are given in hertz. Melting
points were determined using melting point B-540 apparatus and are uncorrected. HRMS
was determined using waters LCT premier XETOF ARE-047 apparatus.
4

Typical Procedure For The Synthesis Of 2-(2-Chlorophenyl)-2, 3-
Dihydroquinazolin-4(1H)-One (4a)
A mixture of isatoic anhydride 1 (500 mg, 3.06 mmol.), 2-chlorobenzaldehyde 2a (473
mg, 3.37 mmol.), ammonium acetate 3 (260 mg, 3.37 mmol.) and titanium silicon oxide
nanopowder (42.89 mg, 0.306 mmol.) in water (5 ml) was stirred at 100°C for 2 h. After
completion of the reaction as indicated by TLC, cooled to room temperature, ethyl
acetate (30 ml) was added and filtered, washed the catalyst with additional ethyl acetate
(10 ml). The filtrate was collected and the layers were separated, organic layer was
concentrated under vacuum to get crude product, which was further purified by silica-gel
column chromatography (hexane–EtOAc, 3:2) to afford 4a as a white color solid; m.p:
1
2
01-203 ºC (lit. 202-204 ºC); H NMR (400 MHz, DMSO-d ): δ = 8.18 (s, 1 H), 7.65 (d, J
6
=
1
6.4 Hz, 2 H), 7.48-7.50 (m, 1 H), 7.39-7.41 (m, 2 H), 7.25 (t, J = 8.4 Hz, 1 H), 6.99 (s,
1
3
H), 6.69-6.76 (m, 2 H), 6.13 (s, 1 H); C NMR (100 MHz, DMSO-d ): δ = 163.6,
6
1
47.6, 137.9, 133.4, 131.8, 130.3, 129.6, 128.7, 127.5, 127.3, 117.4, 114.7, 114.5, 63.7;
MS (ESI): m/z = 259.1 (M + H); HRMS (ESI): m/z [M + H] calcd for C H N OCl:
1
4
12
2
2
59.0638; found: 259.0627.
Synthesis Of Various Mono-And Di-Substituted 2, 3-Dihydroquinazolin-4(1H)-Ones
Derivatives
To verify the generality of this methodology, variety of electronically differing aldehydes
were evaluated under the optimized reaction conditions (Table-3). Irrespective of the
electron withdrawing or releasing substituent on aldehydes underwent reactions
5

efficiently and afforded the desired products in good to excellent yields (Table-3, entry 1-
1). Hetero aromatic aldehydes (Table-3, entry 12-15) also readily reacted giving desired
1
products in high yields. More importantly, aliphatic aldehydes (Table-3, entry 16-18)
were also reacted, and the corresponding products were isolated in good yields.
1
Formation of the products was confirmed by comparing their physical data and H NMR,
1
3
C NMR, mass and HRMS spectroscopic data with those of authentic samples reported
in the literature.
To investigate the effectiveness of this protocol, reactions of isatoic anhydride (1),
aliphatic amines (Table-4, entry 1), aromatic amines (Table-4, entry 2-4) and aldehydes
(2) were examined under optimized conditions. Aromatic and aliphatic amines were also
found to be successful and afforded the corresponding disubstituted-2, 3-
dihydroquinazolin-4(1H)-ones in high yields.
To extend the application of this methodology to synthesize spiro dihydroquinazolinones
derivatives, reactions of isatoic anhydride, (1), ammonium acetate and isatin was also
studied under optimized reaction conditions. We are delighted to find the desired spiro-2,
3
-dihydroquinazolin-4(1H)-one (6) was obtained in good yields (Table-5).
Proposed Mechanism
[
12,21]
Based on the literature reports
a plausible mechanism for the formation of 2,3-
dihydroquinazolin-4(1H)-ones is given in Scheme 2.
6

Isatoic anhydride is activated by titanium silicon oxide nano powder (A), followed by the
N-nucleophilic amine attacks on the carbonyl to form transition state B. Elimination of
CO from B leads to the formation of anthranilamide derivative C. Intermediate C reacts
2
with aldehydes in the presence of titanium silicon oxide nano powder, which upon
intramolecular cyclization afforded the final product 4. Titanium silicon oxide nano
powder might activate the aldehyde through coordination with the oxygen of the carbonyl
group which facilitates the subsequent nucleophilic attack by the nitrogen atom on the
carbonyl carbon.
CONCLUSION
In conclusion, we have successfully developed for the first time titanium silicon oxide
nanopowder catalyst as an efficient and recyclable catalyst for synthesis of 2, 3-
dihydroquinazolin-4(1H)-ones by the one-pot three component condensation of isatoic
anhydride, ammonium acetate or primary amines and various aldehydes in good to
excellent yields. To the best our knowledge, application of titanium silicon oxide
nanopowder is reported for the first time to carry out any organic transformation. The
advantage of this methodology is avoiding use of organic solvents, ideal for large scale
synthesis, ease of product isolation, and catalyst recovered up to four times without any
significant impact on the yield of the products.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Vilas Dahanukar, Dr. H. Rama Mohan, and the
management of Dr. Reddy’s Laboratories Limited for giving support to carry out this
7

work. We also thank the analytical department of Dr. Reddy’s Laboratories for providing
timely support.
SUPPLEMENTAL MATERIAL
1
13
Full experimental details, copies of H and C NMR spectra, mass and HRMS data can
be found via the “supplementary content” section of this article’s webpage.
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1
0

a
Table 1. Optimization of reaction conditions.
b
Entry Catalyst (mol %) Solvent
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
10
1,4-Dioxane 100
2
4
4
6
3
3
2
6
93
10
Ethanol
80
86
10
CH CN
80
85
3
10
THF
65
80
10
Water
Water
Water
water
100
100
100
100
93
5
87
20
94
8
No catalyst
< 10
a
Reaction conditions: 1 (1.53 mmol), ammonium acetate (1.68 mmol), 2a (1.68 mmol),
and solvent (5 mL).
b
Yield of isolated product.
1
1

a
Table 2. Recyclability of the catalyst.
b
Entry Cycle Time (h) Yield (%)
1
2
3
4
Fresh 3
94
94
93
91
91
1st
3
5
5
6
2nd
3rd
4th
5
a
Reaction conditions: 1 (3.06 mmol), ammonium acetate (3.4 mmol), 4-chloro
benzaldehyde 2b (3.4 mmol), and water (5 mL) at 100 °C
b
Yield of isolated product.
1
2

Table 3 Synthesis of mono-substituted 2, 3-dihydroquinazolin-4(1H)-ones derivatives
a
under the optimized conditions.
Entry Aldehyde (2)
Product (4)
Time
h)
Yield
b
(
(%)
1
2
3
2
93
94
94
2
3
4
5
2
2
91
95
1
3

6
2
95
7
8
9
3
4
4
90
89
90
1
1
0
1
3
8
94
95
1
4

1
1
1
2
3
4
5
3
4
90
91
88
1
5
4
86
1
1
1
6
7
8
2
2
3
91
90
88
1
5

a
Reaction conditions: Isatoic anhydride 1 (3.06 mmol), ammonium acetate (3.4 mmol),
aldehyde 2 (3.4 mmol), and water (5 mL) at 100 °C;
b
Yield of isolated product.
1
6

Table 4. Synthesis of di-substituted 2, 3-dihydroquinazolin-4(1H)-ones derivatives under
a
the optimized conditions.
Entry Amine (3)
Aldehyde (2)
Product (5)
Time
h)
Yield
b
(
(%)
1
2
91
2
4
90
3
4
4
5
89
87
a
Reaction conditions: 1 (3.06 mmol), ), aldehyde 2 (3.4 mmol primary amine 3 (3.4
mmol), and water (5 mL) at 100 °C;
b
Yield of isolated product.
1
7

Table 5. Synthesis of spiro-2, 3-dihydroquinazolin-4(1H)-one derivative under the
a
optimized conditions.
b
Entry Isatin
1
Product (6)
Time (h) Yield (%)
6
90
a
Reaction conditions: Isatoic anhydride 1 (3.06 mmol), Ammonium acetate (3.4 mmol),
Isatin (3.4 mmol), and water (5 mL) at 100 °C;
b
Yield of isolated product.
1
8

Scheme 1. Synthesis of 2, 3-dihydroquinazolin-4(1H)-ones catalyzed by titanium silicon
oxide nanopowder.
1
9

Scheme 2. Plausible mechanism for the formation of the 2, 3-dihydro quinazolinones
2
0

Figure 1. Examples of biologically active 2, 3-dihydroquinazolin-4(1H)-one derivatives.
2
1