Ultrasound-based approach to spiro-2,3-dihydroquinazolin-4(1H)-ones: Their in vitro evaluation against chorismate mutase

Article abstract of DOI:10.1016/j.tetlet.2012.11.057

Amberlyst-15 has been identified as a green and reusable catalyst in the synthesis of spiro 2,3-dihydroquinazolin-4(1H)-ones under ultrasound irradiation at room temperature. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. The methodology was found to be general and a wide variety of spiro 2,3-dihydroquinazolin-4(1H)-ones were prepared from 2-aminobenzamides and cyclic ketones within a few minutes in quantitative yields. The products isolated do not require any chromatographic purification. This method provides advantages such as shorter reaction time, high yields of products, and simple operational procedures. Some of the compounds showed chorismate mutase inhibitory properties when tested in vitro.

Full text of DOI:10.1016/j.tetlet.2012.11.057

Tetrahedron Letters 54 (2013) 495–501
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ultrasound-based approach to spiro-2,3-dihydroquinazolin-4(1H)-ones: their
in vitro evaluation against chorismate mutase
D. Rambabu a, S. Kiran Kumar b, B. Yogi Sreenivas a, Sandhya Sandra a, Ajit Kandale a, Parimal Misra a,
a,
M. V. Basaveswara Rao c, , Manojit Pal
⇑
⇑
a Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
b Department of Chemistry, K. L. University, Vaddeswaram, Guntur 522 502, Andhra Pradesh, India
c Department of Chemistry, Krishna University, Machilipatnam 521 001, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Amberlyst-15 has been identified as a green and reusable catalyst in the synthesis of spiro 2,3-dihydro-
quinazolin-4(1H)-ones under ultrasound irradiation at room temperature. The reaction can be performed
in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric
moisture. The methodology was found to be general and a wide variety of spiro 2,3-dihydroquinazo-
lin-4(1H)-ones were prepared from 2-aminobenzamides and cyclic ketones within a few minutes in
quantitative yields. The products isolated do not require any chromatographic purification. This method
provides advantages such as shorter reaction time, high yields of products, and simple operational pro-
cedures. Some of the compounds showed chorismate mutase inhibitory properties when tested in vitro.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 October 2012
Revised 16 November 2012
Accepted 18 November 2012
Available online 28 November 2012
Keywords:
2-Aminobenzamide
2,3-Dihydroquinazolin-4(1H)-one
Amberlyst-15
Chorismate mutase
Spiroheterocycles have remained relatively less investigated
class of compounds until recent past. The development of newer
methods for their synthesis however has gained enormous atten-
tion especially in the area of organic as well as medicinal chemis-
try. This is because the in-built spiro system in a heterocyclic
structure causes structural rigidity due to conformational restric-
tions which generally influences as well as imparts enhanced activ-
ities against several pharmacological targets. Many of these
spiroheterocycles have shown interesting pharmacological proper-
ties including anticancer,1,2 antibacterial,3,4 anticonvulsant,5–7
anti-tubercular,8 and anti-Alzheimer activities.9 Among the bioac-
tive natural products the spiroindole based compounds for exam-
ple, horsfiline (A), spirotryprostatin A (B), coerulescine (C), etc,
are mention-worthy (Fig. 1).10,11 Recently, being an important class
of fused heterocycles and due to their wide range of pharmacolog-
ical properties12–14 spiroquinazolines have attracted considerable
interest in medicinal and pharmaceutical chemistry. Due to our
continuing interest in compounds of potential pharmacological
significances15 we became interested in generating a library of
structurally diverse small molecules D (Fig. 2) based on spiroqui-
nazolines for assessing their potential antibacterial properties in
vitro.
none or cyclopentanone in ethanol saturated with hydrogen chlo-
ride,16 (ii) heating monosubstituted 2-aminobenzamides with
cyclic ketones in the absence of any solvent,17–19 (iii) cyclization
of 2-aminobenzamide with ketones in absolute ethanol20–22 or in
N
O
O
Me
N
N
MeO
R'
O
O
O
N
N
N
MeO
R
H
H
C
B
A
Figure 1. Examples of spiro-heterocycle based bioactive natural products.
H or
O
halo or
alkynyl
NH
The reported methods for the synthesis of spiroquinazoline
derivatives involve (i) treating 2-aminobenzamide with cyclohexa-
N
H
diverse
groups
D
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
Figure 2. Spiroquinazoline based library of target molecules.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.057

496
D. Rambabu et al. / Tetrahedron Letters 54 (2013) 495–501
refluxing trifluoroethanol,23 (iv) the reductive cyclization of
2-nitrobenzamides with carbonyl compounds,24–26 and (v) modifi-
cation of the Friedländler reaction of 2-aminobenzonitriles with
cyclohexanone.27 Recently, a very convenient and environmentally
benign synthesis of spiroquinazolines has been reported under
either aqueous or solvent-free conditions at room temperature
without using any catalyst or co-solvent.28 While a wide variety
of spiro compounds were prepared by using this methodology
the duration of the reaction was found to be unusually longer for
example, several days in a number of cases. We were in search of
a faster method but maintaining the green reaction conditions
for direct access to our target spiroquinazolines. In recent years,
heterogeneous catalysis has played a central role in various organic
transformations.29 As an inexpensive and commercially available
heterogeneous catalyst Amberlyst-15 attracted our attention30
due to its non-hazardous nature and easy removal from the reac-
tion mixture for example, via simple filtration. The ultrasound
mediated reactions on the other hand have become increasingly
popular and widely used methodologies in organic synthesis.31
Compared to the traditional methods, these reactions are known
to be faster, convenient, and a high yielding process. Indeed, a vari-
ety of organic reactions can be carried out within short reaction
time and under mild conditions in the presence of ultra-
sound.31d,31e Herein we report a Amberlyst-15 mediated faster
and general synthesis of spiro-2,3-dihydroquinazolin-4(1H)-ones
under ultrasound irradiation at room temperature without using
an inert or anhydrous atmosphere (Scheme 1). To the best of our
knowledge such a rapid and easy access to this class of compounds
has not been reported earlier.
O
O
O
Z
+
Z
NH
diverse
NH2
NH2
diverse Amberlyst-15
groups
CH3CN, rt
1-5 min
N
H
groups
3
2
1
Scheme 1. Amberlyst-15 mediated synthesis of spiro 2,3-dihydroquinazolin-
4(1H)-ones (3) under ultrasound.
Table 1
The reaction of 1a and 2a in the presence of Amberlyst-15 under various conditions.a
O
O
O
NH
NH2
+
N
H
Amberlyst-15
solvent, rt
NH2
3a
1a
2a
Entry
Solvent
Time (mn)
Yieldb (%)
1
2
3
4
5
6
7
8
CH2Cl2
MeOH
Toluene
H2O
CH3CN
CH3CN
CH3CN
CH3CN
8
5
10
8
92
90
80
90
1
98 (96, 94, 90)c
15
15
30
40d
70e
68f
a
All the reactions were carried out using 2-aminobenzamide 1a (1.0 mmol),
In our initial study, commercially available 2-aminobenzamide
(1a) was reacted with cyclopentanone (2a) in the presence of
Amberlyst-15 under ultrasound (using SONOREX SUPER RK 510H
model producing irradiation of 40 KHz). This reaction, selected as
a model reaction was carried out under various conditions and
the results are summarized in Table 1. The reaction was initially
carried out in dichloromethane (DCM) at room temperature for
8 min when the expected product 3a was obtained in 92% yield
(Table 1, entry 1). The use of other solvents such as methanol, tol-
uene, and water were examined but did not improve the product
yield (Table 1, entries 2–4). However, almost quantitative yield
was achieved within 1 min when the reaction was carried out in
CH3CN (Table 1, entry 5). The reaction was performed in an open
flask as the conversion was found to be not sensitive to the pres-
ence of air or atmospheric moisture. 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 yield
in each run (Table 1, entry 5). To understand the role of Amberlyst-
15 and ultrasound the reaction was performed in the absence of
both catalyst and ultrasound when 3a was isolated in only 40%
yield after 15 min (Table 1, entry 6). The use of ultrasound in the
absence of catalyst increased the product yield but did not
decrease the reaction time (Table 1, entry 7). The use of catalyst
in the absence of ultrasound increased the reaction time (Table 1,
entry 8). Thus, Amberlyst-15 seemed to have played a key role in
enhancing the reaction rate and the combination of Amberlyst-
15 and ultrasound was found to be optimum for the faster synthe-
sis of 3a in high yield at room temperature.
ketone 2a (1.2 mmol), and Amberlyst-15 (10%, w/w) under ultrasound irradiation
(40 KHz) at room temperature.
b
Isolated yield.
c
Catalyst was reused for additional three runs and figures within parentheses
indicate the corresponding yield for each run.
d
The reaction was carried out in the absence of Amberlyst-15 and ultrasound.
The reaction was carried out in the absence of Amberlyst-15.
The reaction was carried out in the absence of ultrasound.
e
f
Generally, the product was separated as a solid from the reaction
mixture and was isolated by filtration. The solid was purified by
treating with EtOAc followed by filtration (to remove the insoluble
catalyst present) and concentrating the filtrate. The residue was
triturated in diethyl ether, filtered, and dried to give the pure prod-
uct. Thus, no chromatographic purification was required to obtain
the pure spiro 2,3-dihydroquinazolin-4(1H)-one prepared by the
present process. All the compounds synthesized were character-
ized by NMR, IR, and MS spectra and their purity was determined
by HPLC method. It is worthy to mention that all the reactions
were performed in flasks that were open to air as the methodology
does not require the presence of either inert or anhydrous atmo-
sphere highlighting the simplicity of the process. The aliphatic
ketones containing a 5 or 6 or 7-membered ring participated well
in the reaction affording the corresponding products in high yields
(Table 2, entries 1–3, and 10–12). The use of cyclic ketones con-
taining aromatic ring also afforded the desired product in excellent
yield (Table 2, entries 4 and 6–9). Functional groups such as
t
-CO2 Bu, –CONH–, or alkynyl moiety present in the cyclic ketones
This observation encouraged us to extend the scope and gener-
ality of this methodology. A variety of cyclic ketones (2) therefore
were reacted with 2-aminobenzamides (1) in the presence of
Amberlyst-15 under the conditions of entry 5 of Table 1. The reac-
tions were carried out with the help of a standard ultrasonic bath
producing irradiation at 40 kHz in round-bottom flasks attached
with a condenser. The results are summarized in Table 2. The reac-
tion proceeded smoothly in all these cases to give the correspond-
ing spiro 2,3-dihydroquinazolin-4(1H)-ones (3) in excellent yields.
employed were well tolerated. The presence of substituents on
the 2-aminobenzamide ring was also well tolerated. For example
2-amino-5-iodobenzamide (1b) was reacted with a number of cyc-
lic ketones to afford the corresponding products smoothly (Table 2,
entries 10–16). Notably, the iodo group of compounds 3j–p is ame-
nable for further functionalization via transition metal mediated
C–C or C–N bond forming reactions. The use of 5-alkynyl substi-
tuted 2-aminobenzamides for example. 1c and 1d also afforded
the desired products in excellent yields (Table 2, entries 17–20).

D. Rambabu et al. / Tetrahedron Letters 54 (2013) 495–501
497
The compounds 1c and 1d were prepared conveniently via the
Sonogashira reaction of 1b with appropriate alkynes (Scheme 2).
All the cyclic ketones (2) used in the present reaction are com-
mercially available except 2g, 2h, and 2i that were prepared from
2f according to the procedure shown in Scheme 3.32 Thus the com-
pound 2f was reacted with propargyl bromide or benzyl chloride in
the presence of K2CO3 in DMF to give 2g or 2i in good yield.32a The
Cu-mediated coupling of 2f with PhB(OH)2 in 1,2-dichloroethane
Table 2
Synthesis of spiro 2,3-dihydroquinazolin-4(1H)-ones (3) via the reaction of 2-amino benzamides (1) and cyclic ketones (2)a (Scheme 1)
Entry
1b
2
Products (3)
Time (min); % yieldc
O
O
NH
2a
1
1a
1; 98
N
H
3a
O
O
NH
NH
2b
2
3
1a
1a
1; 98
N
H
3b
O
O
1; 98
2c
N
H
3c
O
O
NH
2d
4
1a
2; 97
N
H
3d
O
N
O
NH
5
6
1a
1a
2; 97
N
H
NCO2tBu
CO2tBu
3e
2e
O
O
O
O
O
O
O
NH
NH
NH
NH
2; 95
N
H
2f
3f
O
O
N
N
N
H
7
1a
3; 96
2g
3g
O
O
O
Ph
NH
N
Ph
N
N
H
8
1a
5; 95
2h
3h
(continued on next page)

498
D. Rambabu et al. / Tetrahedron Letters 54 (2013) 495–501
Table 2 (continued)
Entry
1b
2
Products (3)
Time (min); % yieldc
O
O
O
O
NH
NCH2Ph
NCH2Ph
N
H
9
1a
5; 96
2i
3i
O
I
I
NH
NH
10
11
1b
1b
2a
2b
1; 98
N
H
3j
O
1; 97
N
H
3k
O
I
I
NH
NH
12
13
14
1b
1b
1b
2c
2d
2e
1; 97
2; 98
2; 97
N
H
3l
O
N
H
3m
O
I
I
NH
N
H
t
NCO2 Bu
3n
O
O
O
NH
NH
NH
N
15
1b
2f
3; 96
H
3o
O
I
NCH2Ph
N
16
1b
2i
5; 95
H
3p
O
Ph
NH
17
1c
2a
2; 98
N
H
3q

D. Rambabu et al. / Tetrahedron Letters 54 (2013) 495–501
499
Table 2 (continued)
Entry
1b
1c
2
Products (3)
Time (min); % yieldc
Ph
O
NH
18
19
2b
2; 98
N
H
3r
Ph
O
NH
O
1c
2c
2; 96
N
H
3s
NH
20
1d
2b
3; 97
N
H
3t
a
Reaction conditions: all the reactions were carried out using a 2-aminobenzamide 1 (1.0 mmol), an appropriate cyclic ketone 2 (1.2 mmol), and Amberlyst-15 (10%, w/w)
in CH3CN under ultrasound irradiation at room temperature.
b
For preparation of 1b–d see Scheme 2.
Isolated yield.
c
I
O
R
R
I2, H2O
1a
NH2
NH2
R= Ph (80%)
O
10%Pd/C,PPh3
CuI, Et3N,EtOH
70 oC, 4h
NaHCO3
rt, 12h
82%
NH2
NH2
1c;
1d; R = (CH2)3CH3 (82%)
1b
Scheme 2. Preparation of 5-alkynyl substituted 2-aminobenzamides (1c and 1d).
O
N
O
O
O
Ph
Z
OH
O
NH2
O
O
NH
PhCH2Cl
CH2Br
N
O
N
2
1
Amberlyst-15
(CHCH2)n
DMF, K2CO3
rt, 2h
DMF, K2CO3
rt, 2h
H2O
E
85%
82%
2g
2f
2i
Amberlyst-15
PhB(OH)2
O
O
Ph
N
Z
SO3H
NH2
Cu(OAc)2, Et3N
ClCH2CH2Cl
rt, 2h
3
N
H
85%
2h
Scheme 4. Proposed mechanism for the Amberlyst-15 mediated synthesis of spiro
2,3-dihydroquinazolin-4(1H)-ones (3) under ultrasound.
Scheme 3. Preparation of ketones 2g, 2h, and 2i.
was carried out according to a procedure reported earlier32c to
afford the corresponding N-phenyl derivative 2h in 85% yield.
Mechanistically,33–35 the reaction of 2-aminobenzamide (1) and
cyclic ketones (2) seemed to proceed via two steps for example, (i)
in situ generation of imine intermediate E, which subsequently
undergoes (ii) intramolecular cyclization involving the nucleo-
philic attack by the –CONH2 moiety on the –C@N– affording the
spiro derivative 3 (Scheme 4). Amberlyst-15, a macro reticular
polystyrene-based ion exchange resin possessing strongly acidic
sulfonic groups (Scheme 4) is known to catalyze various reactions
involving carbonyl group. For example, the reaction of a ketone
with an amine is greatly facilitated by Amberlyst-15.33 Results pre-
sented in Table 1 suggest that both the steps were accelerated con-
siderably by the presence of Amberlyst-15 under ultrasound
irradiation. An attempt to prepare and isolate the imine intermedi-
ate via the reaction of 1a and 2a under the condition employed
however failed, perhaps due to its rapid participation in the next
cyclization step leading to 3a.

500
D. Rambabu et al. / Tetrahedron Letters 54 (2013) 495–501
Figure 3. Assay results of compound 3 at the concentration of 30 lM against chorismate mutase (S = substrate and E = enzyme).
Prompted by the antitubercular activities shown by the spiro
Acknowledgements
derivatives8 of oxindole and isoxazole-5-one against Mycobacterium
tuberculosis H37Rv we tested some of our compounds synthesized
for their antitubercular properties in vitro. Thus compounds
were tested for their inhibitory potential against Mycobacterium
tuberculosis H37Rv chorismate mutase (CM). Due to its absence in
animals but not in bacteria CM is considered as a promising target
for the identification of new antitubercular agents.36 However, only
a few small molecules have been reported as inhibitors of CM.32c,37
The assay38,39 involved determination of activity of enzyme CM
which catalyzes the conversion of chorismate to prephenate. Thus
the determination of activity of CM is based on the direct observa-
tion of conversion of chorismic acid to prephenate spectrophoto-
metrically at OD274. This reaction was performed in the presence
of test compounds to determine their CM inhibiting activities. A
known inhibitor of CM that is, 4-(3,5-dimethoxyphenethylamino)-
3-nitro-5-sulfamoylbenzoic acid37a was prepared and used as a
reference compound the IC50 value of which was found to be less
The authors thank Professor Seyed E. Hasnain and Professor J.
Iqbal for encouragement and DBT, New Delhi, India for financial
support (Grant NO BT/01/COE/07/02).
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.
11.057.
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M. Compounds 3c and 3m showed 30–35% inhibition of
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In conclusion, we have described a practical synthesis of spiro
2,3-dihydroquinazolin-4(1H)-ones of potential synthetic and phar-
maceutical importance. Amberlyst-15 was identified as an effec-
tive, green, and reusable catalyst and the methodology worked
under ultrasound irradiation at room temperature. The reaction
can be performed in an open flask as the methodology does not
require the presence of inert or anhydrous atmosphere. The
methodology was found to be general and a wide variety of spiro
2,3-dihydroquinazolin-4(1H)-ones were prepared from 2-aminob-
enzamides and cyclic ketones within a few minutes in high yields.
Additionally, the products isolated do not require any chromato-
graphic purification. To the best of our knowledge this is the first
example of synthesizing spiro 2,3-dihydroquinazolin-4(1H)-ones
using Amberlyst-15 as a catalyst under ultrasound. Some of the
compounds showed antibacterial properties when tested against
chorismate mutase in vitro indicating that an appropriately substi-
tuted spiro 2,3-dihydroquinazolin-4(1H)-one framework can be
explored as a new scaffold for the development of novel inhibitors
of chorismate mutase. Overall, due to (i) the simple operational
procedure, (ii) the use of an inexpensive and heterogeneous there-
by recyclable catalyst, (iii) shorter reaction time, and (iv) high
yields of products, the present method may have advantages over
the previously reported methods. We believe that this methodol-
ogy would find wide usage in the rapid synthesis of spiro 2,3-dihy-
droquinazolin-4(1H)-ones based library of structurally diverse
small molecules useful for medicinal chemistry/drug discovery.
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