Amberlyst-15 mediated synthesis of 2-substituted 2,3-dihydroquinazolin- 4(1H)-ones and their crystal structure analysis

Article abstract of DOI:10.1016/j.tetlet.2011.12.023

An efficient and clean method has been developed for the synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones using Amberlyst-15 as a recyclable catalyst. A variety of dihydroquinazolinones were prepared from 2-aminobenzamide and aldehydes under mild conditions in excellent yields. Further structure elaboration of one compound and the crystal structure analysis and hydrogen bonding patterns of the two compounds prepared by using this methodology is presented.

Full text of DOI:10.1016/j.tetlet.2011.12.023

Tetrahedron Letters 53 (2012) 863–867
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Amberlyst-15 mediated synthesis of 2-substituted
2,3-dihydroquinazolin-4(1H)-ones and their crystal structure analysis
P. VNS Murthy a, D. Rambabu a,b, G. Rama Krishna c, C. Malla Reddy c, K.R.S. Prasad a,
M.V. Basaveswara Rao d, Manojit Pal b,
⇑
a Department of Chemistry, K L University, Vaddeswaram, Guntur 522502, AP, India
b Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, India
c Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741252, India
d Department of chemistry, Krishna University, Machilipatnam 521001, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and clean method has been developed for the synthesis of 2-substituted 2,3-dihydroquinaz-
olin-4(1H)-ones using Amberlyst-15 as a recyclable catalyst. A variety of dihydroquinazolinones were
prepared from 2-aminobenzamide and aldehydes under mild conditions in excellent yields. Further
structure elaboration of one compound and the crystal structure analysis and hydrogen bonding patterns
of the two compounds prepared by using this methodology is presented.
Received 20 October 2011
Revised 1 December 2011
Accepted 7 December 2011
Available online 13 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2,3-Dihydroquinazolin-4(1H)-ones,
Aldehydes
Amberlyst-15
2,3-Dihydroquinazolin-4(1H)-ones, an importantclass of hetero-
cyclic compounds influence numerous cellular processes. This is
exemplified by their broad range of pharmacological properties,
for example, anticancer, antitumor, antibiotic, antidefibrillatory,
antipyretic, analgesic, antihypertonic and diuretic activities.1–11
They are also useful as antihistamine, antidepressant, and vasodilat-
ing agents. A number of synthetic methods have been reported to
prepare this class of compounds in the past few years. These include
the use of iridium,12 citric acid,13 [bmim]HSO4,14 iodine,15 ammo-
nium chloride,16 gallium trifluoro methane sulfonate,17 ionic liq-
uids,18 bronsted acids,19 phosphoric acid,20 copper chloride,21 tetra
butyl ammonium bromide,22 and TiCl4/Zn.23 Many of these methods
however, suffer from drawbacks, such as low yields of products, the
requirement of longer reaction time and high temperature along
with the use of non-recyclable catalysts. Moreover, preparation of
required catalysts is cumbersome in some cases. Thus, development
of a facile, atom-efficient, and eco-friendly method is highly
desirable. In recent years, heterogeneous catalysis has played the
central role in various organic transformations.24 As an inexpensive
and commercially available heterogeneous catalyst Amberlyst-15
attracted our attention25a due to its non-hazardous nature and easy
removal from the reaction mixture, for example, via simple filtra-
tion. Due to our continuing interest in quinazolinone derivatives25b
we now report an Amberlyst-15 mediated practical and efficient
synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones 3
from 2-aminobenzamide 1 and aldehyde 2 (Scheme 1).
In our initial study, 4-chlorobenzaldehyde (2a) was reacted
with 2-aminobenzamide (1) in the presence of Amberlyst-15 in
Table 1
The reaction of 1 and 2a in the presence of Amberlyst-15 under various conditionsa
O
O
Amberlyst-15
NH
NH2
+ OHC
Cl
solvent
N
H
NH2
room temp
Cl
2a
1
3a
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
DCM
30
30
30
10
60
60
95
92
80
MeOH
Toluene
CH3CN
CH3CN
CH3CN
98 (97, 96, 95)c
30d
70e
a
Reaction and conditions: all the reactions were carried out using 2-amino-
benzamide 1 (1.0 mmol), aldehyde 2a (1.0 mmol) and Amberlyst-15 (10%, w/w) at
room temperature.
b
Isolated yield.
c
Catalyst was reused for additional three runs and figures within parentheses
indicate the corresponding yields for each run.
d
⇑
The reaction was carried out without Amberlyst-15.
The reaction was carried out without Amberlyst-15 under sonication.
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: manojitpal@rediffmail.com, palmanojit@yahoo.co.uk (M. Pal).
e
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.023

864
P. VNS Murthy et al. / Tetrahedron Letters 53 (2012) 863–867
Table 2
Amberlyst-15 mediated synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-onesa
Entry
Aldehyde (2)
Product (3)
Time (min)
10
Yieldb (%)
O
OHC
Cl
Br
NH
NH
Cl
Br
2a
1
98
3a
O
O
OHC
NH
NH
2b
2
20
98
3b
Cl
NH
NH
3c
Cl
CHO
3
4
10
20
98
97
2c
O
O
OHC
OH
NH
OH
2d
NH
3d
HO
HO
NH
NH
OHC
OCH3
5
25
97
2e
OCH3
3e
O
CH3
NH CH3
OHC
6
7
30
15
96
98
NH
2f
3f
O
O
OHC
F
NH
NH
3g
F
2g
CHO
H3CO
NH
OCH3
8
15
97
NH
2h
3h
HO
O
O
HO
NH
OHC
9
20
15
97
98
NH
2i
3i
O2N
O2N
NH
OHC
10
NH
2j
3j
OH
O
OH
NH
NH
OHC
11
20
97
2k
3k

P. VNS Murthy et al. / Tetrahedron Letters 53 (2012) 863–867
865
Table 2 (continued)
Entry
Aldehyde (2)
Product (3)
Time (min)
Yieldb (%)
O
I
NH
12
2g
30
96c
N
H
F
3l
a
Reaction and conditions: all the reactions were carried out using 2-aminobenzamide 1 (1.0 mmol), an appropriate aldehyde 2 (1.0 mmol) and Amberlyst-15 (10%, w/w) in
CH3CN at room temperature.
b
Isolated yield.
c
2-Amino-5-iodobenzamide (4) was used in place of compound 1.
O
O
Amberlyst-15
NH
NH2
+
RCHO
CH3CN
room temp
10-30 min
N
H
R
NH2
1
2
3
Scheme 1. Amberlyst-15 mediated synthesis of 2-substituted 2,3-dihydroquinaz-
olin-4(1H)-ones.
Figure 1. ORTEP representation of the compound 3a (Thermal ellipsoids are drawn
at 50% probability level).
dichloromethane (DCM) at room temperature for 30 min when the
expected product 3a was obtained in a 95% yield (Table 1, entry 1).
The use of other solvents such as methanol and toluene was exam-
ined but did not improve the product yields (Table 1, entries 2 and
3). However, almost quantitative yields was achieved when the
reaction was carried out in CH3CN and completed within 10 min
(Table 1, entry 4). The catalyst recovered from the reaction mixture
was also tested for its recyclability at least for three times and the
desired product was isolated in good yields in each run (Table 1,
entry 4). To understand the role of Amberlyst-15 the reaction
was performed in its absence when 3a was isolated only in 30%
yield after 60 min (Table 1, entry 5). The use of sonication in-
creased the product yield but did not decrease the reaction time
(Table 1, entry 6). Thus Amberlyst-15 was identified as an efficient
and reusable catalyst for the present reaction.
Figure 2. ORTEP representation of the compound 3c (Thermal ellipsoids are drawn
This observation encouraged us to extend the scope and gener-
ality of this methodology. A variety of aryl aldehydes (2) therefore
were reacted with 2-aminobenzamide (1) in the presence of
Amberlyst-15 under the conditions26 of entry 4 of Table 1 and
the results are summarized in Table 2. The reaction proceeded
smoothly in all these cases to give the corresponding 2,3-dihydro-
quinazolin-4(1H)-ones in excellent yields. Aldehydes containing
various substituents such as electron donating F, Cl, Br, OH and
OMe and electron withdrawing NO2 were well tolerated and did
not affect the product yields (Table 2, entries 1–5 and 7–11). The
use of a cinnamaldehyde derivative also afforded the desired prod-
uct in excellent yield (Table 2, entry 6).
at 50% probability level).
the iodo derivative 3l has potential for further structural elaboration
via palladium catalyzed C–C or C–N bond forming reactions thereby
introducing diversity into the quinazolinone ring. This is exempli-
fied by alkynylation of compound 3l under Pd/C–Cu catalysis27 as
shown in Scheme 2. All the 2,3-dihydroquinazolin-4(1H)-ones
synthesized can easily be oxidized21 to their quinazolin-4(3H)-one
analogs that are known to possess pharmacological activities and
be integral part of some natural products. It is worthy to mention
that the present methodology does not require the use of microwave
irradiation and therefore amenable for scale up preparation of
compound 3.
The use of 2-amino-5-iodobenzamide (4) in place of 1 was suc-
cessful (Table 2, entry 12) and the corresponding product, that is,
OH
O
O
10%Pd/C, CuI
NH
I
OH
Et3N, EtOH
NH
+
N
H
80 oC, 4h
82%
N
H
F
F
6
5
3l
Scheme 2. Pd/C-mediated alkynylation of compound 3l.

866
P. VNS Murthy et al. / Tetrahedron Letters 53 (2012) 863–867
Figure 3. Showing the packing patterns in compound 3a.
Figure 4. Showing the packing patterns in compound 3c.
molecules. The torsion angles of the phenyl ring and dihydroquinaz-
olin-4-one moieties are (C8–C9–C10–C11 178.6(2), C8–C9–C14–
C13 178.9(2) and C7–N2–C8–C9 162.6(2), C8–N2–C7–O1 163.9(2).
The two molecules in the asymmetric unit form same hydrogen
bonding patterns in the crystal structure. These molecules are con-
formationally different which were showed in Figure 5. Here two
molecules have formed hydrogen bonding with amide as functional
group present in dihydroquinazolin-4-one, and formed dimer syn-
thon via O–Hꢀ ꢀ ꢀN. These interactions propagate in 3D corrugated
layered structure.
In conclusion, we have described Amberlyst-15 mediated prac-
tical and general synthesis of 2,3-dihydroquinazolin-4(1H)-ones
from 2-aminobenzamide and aldehydes under mild conditions.
The notable advantages of this protocol include (i) simple opera-
tional procedure, (ii) the use of an inexpensive and heterogeneous
thereby recyclable catalyst, (iii) shorter reaction time and (iv) high
yields of products. The crystal structure analysis and hydrogen
bonding patterns of two compounds prepared by using this meth-
odology are presented. We believe that this methodology would
find wide usage in the preparation of dihydroquinazolinone based
library of small molecules useful not only for medicinal chemistry/
drug discovery but also for studying their solid state properties.
Figure 5. (a) Showing the hydrogen bonding patterns in two molecules of
asymmetric unit in compound 3c; (b) Showing the overlay diagram of compound
3c conformer-a (Red), conformer-b (purple) color.
All the compounds synthesized were well characterized by
spectral data (NMR, MS and IR). Additionally, the molecular struc-
ture of two representative compounds, for example, 3a and 3c was
established unambiguously by single crystal X-ray diffraction (Figs.
1 and 2).28,29 Further crystal structure analysis were carried out to
understand the packing and/or hydrogen bonding patterns in crys-
tals of these molecules and results are summarized in the following
sections.
Compound 3a crystallizes in Monoclinic P2 (1)/c space group
with one molecule in the asymmetric unit (Z: 4 Z0: 0) (Fig. 3).
Two p-chlorophenyl rings of the molecules in the asymmetric unit
are not in coplanar with dihydroquinazolin-4-one of the two mol-
ecules. The torsion angles of the phenyl ring and dihydroquinazo-
lin-4-one moieties are (C8–C9–C10–C11 175.4(2), C8–C9–C14–C13
176.5(2) and C7–N2–C8–C9 159.54(19), C8–N2–C7–O1 170.3(2).
Here one molecule present in the asymmetric unit forms the dimer
synthon with amide functional group present in dihydroquinazo-
lin-4-one, and formed dimer synthon via O–Hꢀ ꢀ ꢀN and weak Van-
der Waal Clꢀ ꢀ ꢀCl interactions. These interactions propagate 3D
corrugated layered structure.
Acknowledgment
The authors sincerely thank the management of Institute of Life
Sciences for continuous support and encouragement.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.023.
References and notes
Compound 3c crystallizes in Orthorhombic Pca2 (1) space group
with two molecules in the asymmetric unit (Z: 8 Z0: 0) (Fig. 4).The
two m-chlorophenyl rings of the molecules in the asymmetric unit
are not in coplanar with dihydroquinazolin-4-one of the two
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26. General procedure for the preparation of compound 3:
A mixture of 2-
aminobenzamide 1 or 4 (1.0 mmol), aldehyde 2 (1.0 mmol) and Amberlyst-15
(10%, w/w) in acetonitrile (5 mL) was stirred at room temperature for the time
indicated in Table 2. After completion of the reaction (indicated by TLC) the
solid separated was filtered, washed by diethyl ether (2 ꢁ 5 mL), dried and
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28. Crystal data of 3a: Molecular formula = C14H11ClN2O, Formula weight = 258.21,
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b = 8.9167(6) Å, c = 11.2545(7) Å, V = 1237.07(14) Å3, T = 296(2) K, Z = 4,
Dc = 1.405 Mg mꢂ3 (Mo-K ) = 0.30 mmꢂ1, 1974 reflections measured, 2578
, l
a
independent reflections, 1986 observed reflections [I > 2.0
r
(I)],
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29. Crystal data of 3c: Molecular formula = C14H11ClN2O, Formula weight = 258.21,
Crystal system = Orthorhombic, space group = Pca2(1), a = 10.9794(6) Å,
b = 9.1619(6) Å, c = 23.5375(16) Å, V = 2367.7(18) Å3, T = 296(2) K, Z = 8,
Dc = 1.488 Mg mꢂ3 (Mo-K ) = 0.31 mmꢂ1, 1440 reflections measured, 3816
, l
a
independent reflections, 3522 observed reflections [I > 2.0
r
(I)],
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