Catalyst-free, one pot and three-component synthesis of 4′-phenyl-1′H-spiro[indoline-3,2′-quinazolin]-2-ones and 2,4-diphenyl-1,2-dihydroquinazolines

Article abstract of DOI:10.1016/j.tetlet.2015.09.125

A simple, green, efficient and three-component procedure has been developed for the synthesis of 4′-phenyl-1′H-spiro[indoline-3,2′-quinazolin]-2-ones (4a-m and 6a-g) and 2,4-diphenyl-1,2-dihydroquinazolines (8a-l) by the reaction of 2-aminobenzophenones,

Full text of DOI:10.1016/j.tetlet.2015.09.125

Accepted Manuscript
Catalyst-free, one pot and three-component synthesis of 4’-phenyl-1’H-spi-
ro[indoline-3,2’-quinazolin]-2-ones and 2,4-diphenyl-1,2-dihydroquinazolines
Ahmed Kamal, Korrapati Suresh Babu, Cheemalamarri Chandrasekhar, Burri
Nagaraju, K.N. Visweswara Sastry, C. Ganesh Kumar
PII:
S0040-4039(15)30165-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.125
TETL 46797
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 July 2015
14 September 2015
26 September 2015
Please cite this article as: Kamal, A., Babu, K.S., Chandrasekhar, C., Nagaraju, B., Visweswara Sastry, K.N., Ganesh
Kumar, C., Catalyst-free, one pot and three-component synthesis of 4’-phenyl-1’H-spiro[indoline-3,2’-
quinazolin]-2-ones and 2,4-diphenyl-1,2-dihydroquinazolines, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.09.125
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Graphical Abstract
Catalyst-free, one pot and three-component
synthesis of 4'-phenyl-1'H-spiro[indoline-
3,2'-quinazolin]-2-ones and 2,4-diphenyl-1,2-
dihydroquinazolines
Ahmed Kamal, Korrapati Suresh Babu, Cheemalamarri Chandrasekhar, Burri Nagaraju, K N Visweswara
Sastry, C Ganesh Kumar

1
Tetrahedron Letters
Catalyst-free, one pot and three-component synthesis of 4'-phenyl-1'H-
spiro[indoline-3,2'-quinazolin]-2-ones and 2,4-diphenyl-1,2-dihydroquinazolines
Ahmed Kamal*a,b Korrapati Suresh Babu,a Cheemalamarri Chandrasekhar,a Burri Nagaraju,a K N
Visweswara Sastry,a,c C Ganesh Kumara
aMedicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
bCatalytic Chemistry Chair, Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
cDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, green, efficient and three-component procedure has been developed for the synthesis
of 4'-phenyl-1'H-spiro[indoline-3,2'-quinazolin]-2-ones (4a-m and 6a-g) and 2,4-diphenyl-1,2-
dihydroquinazolines (8a-l) by the reaction of 2-aminobenzophenones, isatins or aromatic
benzaldehydes and ammonium acetate in excellent yields under catalyst-free conditions using
ethanol as solvent. This method provides several advantages such as operational simplicity,
higher yields, shorter reaction time and catalyst-free conditions with ethanol as a solvent makes
the method eco-friendly as well as economical. All the 4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-ones were tested for antimicrobial activity against both Gram-positive and Gram-
negative bacterial strains including a fungal strain Candida albicans MTCC 3017. Among these,
the compounds 4f, 6a, 6c and 6g showed appreciable antibacterial activity with MIC values 7.8
μg/ml selectively against Gram-positive bacteria, Micrococcus luteus MTCC 2470. On the other
hand, compounds 4j, 4m, 6c and 6g showed good activity with MIC values ranging between 3.9
and 7.8 μg/ml against Gram-negative bacteria, Klebsiella planticola MTCC 530.
Available online
Keywords:
Catalyst-free
Quinazoline
Spirooxindole
Antimicrobial
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Quinazolines are an important class of heterocycles found in a
wide range of natural products and pharmaceuticals and exhibit
several biological activities including antibacterial,1 antitumor,2
antiplasmodial,3 anti-inflammatory,4 antiviral5 and anti-oxidant6
activities, apart from their usage as photo-chemotherapeutic
agents,7 DNA-gyrase, PDE5, EGFR tyrosine kinase inhibitors,8
T-type calcium channel9 and CB2 receptor are familiar targets of
various quinazoline derivatives.10 This scaffold is also the
building block for many naturally occurring alkaloids such as
Bouchardatia neurococca, Bacillus cereus, Peganum nigellastrum
and Dichroa febrifuga.11
The spirooxindole unit is a privileged heterocyclic moiety present
in a large number of alkaloids and natural products such as
spirotryprostatin A and B. These two natural alkaloids isolated
from the fermentation broth of Aspergillus fumigatus, has been
identified as inhibitors of microtubule assembly,12 pteropodine
act as positive modulators of muscarinic M(1) and 5-HT(2)
receptors13 and alstonisine (figure 1). A spirooxindole system is
also a core scaffold of many synthetic pharmaceuticals with a
wide range of biological applications such as antimicrobial,14
antitumor,15 antibiotic16 and inhibitors of the human NK-1
receptor.17 Due to the significant biological activity of these
spiroxindoles, it is required to find new and simple synthetic
methods for the preparation of new substituted spirooxindoles.
Figure 1. Biologically and pharmaceutically important quinazoline
and spirocyclic oxindoles
Owing to extensive applications of diverse quinazoline
derivatives in various fields, several methods have been reported
such as copper-catalyzed cascade coupling of 2-
bromobenzaldehyde with acetamidine hydrochloride,18a copper-
catalyzed Ullmann N-arylation coupling,18b,c photochemical
method,18d tandem reaction from 2-aminobenzophenones and
benzylic amines,18e,f maltose-urea-NH4Cl mixture as a solvent
synthesis,18g copper-catalyzed alkynylation and cyclization of N-
phenylbenzamidines,18h the condensation of aldehydes with 2-
18j
aminobenzylamine using sodium hypochlorite18i or MnO2 as

2
Tetrahedron
oxidant and microwave promoted synthesis.18k,l,m,n Inspite of
Scheme 2. Synthesis of 4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-one derivatives
their remarkable biological activities, only few methods for the
synthesis of 4'-phenyl-1'H-spiro[indoline-3,2'-quinazolin]-2-one
derivatives have been reported in the literature.19 However, these
methods suffer from one or more disadvantages such as use of
catalysts, lower yields and difficult operation.
Table 2. Synthesis of 4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-one derivatives.
Entry
4a
4b
4c
R
R1
Time (min)
Yielda (%)
H
H
50
60
60
60
60
60
60
90
70
60
70
70
70
94
92
92
91
88
87
88
84
87
92
88
87
85
In the course of our interest to develop environmentally benign
methods for the synthesis of bioactive compounds20 we herein
report a facile synthesis of 4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-ones and 2,4-diphenyl-1,2-dihydroquinazolines
using 2-amino benzophenones, isatins or aromatic benzaldehydes
5-F
H
7-F
H
4d
4e
5-Cl
5-Br
5-I
H
H
and ammonium acetate in ethanol
conditions.
under catalyst-free
4f
H
4g
4h
4i
5-Me
5,7-Di Me
5-OMe
5-NO2
H
H
2. Results and discussion
H
H
4j
H
4k
4l
Benzyl
Benzyl
Benzyl
5-Cl
5-Br
4m
Scheme 1. Model Reaction
aisolated yields
For the synthesis of 4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-one (4), 2-amino benzophenone (1), isatin (2) and
ammonium acetate (3) were selected as model reactants during
the optimization process. Initially, this transformation was
carried out in water without any catalyst at room temperature and
under refluxing conditions and the reaction was monitored by
TLC (Scheme 1). It was observed that the reaction did not
proceed even until 360 min (Table 1, entries 1 and 2). When the
same reaction was carried out using various solvents such as
CH3CN, MeOH and EtOH at room temperature, the desired
transformation was accomplished in the good yields 62%, 90%
and 95%, respectively (Table 1, entries 3-5). Therefore, EtOH
was found to be a suitable solvent that provides higher yields
(95%) in 50 min at room temperature and further increase of time
did not improve the yields. The high yield obtained (95%) in
EtOH prompted its selection for catalyst-free conditions.
Scheme 3. Synthesis of 6'-nitro-4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-one derivatives
For the synthesis of 6'-nitro-4'-phenyl-1'H-spiro[indoline-3,2'-
quinazolin]-2-one (6a), a reaction was performed using 2-amino-
5-nitro benzophenone (5), isatin (2) and ammonium acetate (3) in
EtOH at room temperature, traces of the product was found even
until 6 hours. Later, this reaction was carried out under reflux
conditions and the desired transformation provided the product in
very good yield. A series of 6'-nitro-4'-phenyl-1'H-spiro[indoline-
3,2'-quinazolin]-2-one derivatives were synthesized under the
above optimized conditions (Scheme 3). In this case, the presence
of an electron withdrawing group at position 5 of the 2-
aminobenzophenone, slowed down the reaction resulting in
comparably longer reaction time and lower yields (Table 3,
entries 6a-6g).
Table 1. Optimization of reaction conditions.
Entry
Solvent
Temperature (°C)
Time (min)
Yielda (%)
1
2
3
4
5
water
360
360
60
--
--
water
reflux
CH3CN
MeOH
EtOH
rt
rt
rt
62
90
95
Table 3. Synthesis of 6'-nitro-4'-phenyl-1'H-spiro[indoline-
60
3,2'-quinazolin]-2-one derivatives.
50
Entry
R
R1
Time (min)
150
Yielda (%)
aisolated yields
6a
H
H
88
86
85
85
83
85
82
The scope and generality of the present protocol was then
examined by employing various substituted isatins (Scheme 2)
and the results are summarized in Table 2. The reaction tolerates
both electron withdrawing as well as donating substituents on the
isatin component without any significant deviation in yields
(entries 4b-j). Similarly the N-protected isatins also afforded the
corresponding products in excellent yields (entries 4k-m).
6b
5-F
H
H
150
6c
5-Cl
5-Me
5-OMe
5-NO2
5-Br
160
6d
H
170
6e
H
170
6f
H
160
6g
Benzyl
180
aisolated yields
Based on the interesting results obtained using the above
discussed method for the synthesis of 4'-phenyl-1'H-
spiro[indoline-3,2'-quinazolin]-2-one derivatives (4a-m and 6a-
g), it was considered of interest to perform the reaction using
aromatic benzaldehydes as reported by Boulcina and co-

3
workers19b (Scheme 4). In this regard, benzaldehydes possesing
both electron donating as well as electron withdrawing
substituents have been employed. It was observed that the
synthesis of 2,4-diphenyl-1,2-dihydroquinazoline derivatives (8a-
f) using this method requires slightly longer times when
compared to the synthesis of 4a-4m. Whereas 6-nitro-2,4-
diphenyl-1,2-dihydroquinazolines (8g-l) were obtained under
reflux conditions and the time required is similar to that for the
synthesis of 6a-6g. Interestingly, the aromatic benzaldehydes
with both electron donating as well as electron withdrawing
substituents reacted well to provide excellent yields of the
corresponding products and similar to the isatins, benzaldehydes
afford the dihydro product exclusively.
is outlined in the Figure 2. The reaction is presumed to proceed
with the formation of a ketoimine (I) from 2-aminobenzophenone
and isatin. Later ammonium acetate reacts with the keto group of
2-aminobenzophenone to form a diimine (II) with the expulsion
of water and acetic acid. The imine carbon which is susceptible
for a nucleophilic attack was then attacked by the adjacent
nitrogen atom to form carbanion intermediate (III) which
undergoes intramolecular cyclization to form 4a.
The synthesized 4'-phenyl-1'H-spiro[indoline-3,2'-quinazolin]-2-
one derivatives were evaluated for their antibacterial activity
using well diffusion method against both Gram-positive bacterial
strains such as Staphylococcus aureus MTCC 96, Bacillus
subtilis MTCC 121, Staphylococcus aureus MLS16 MTCC 2940
and Micrococcus luteus MTCC 2470 as well as Gram-negative
bacterial strains such as Klebsiella planticola MTCC 530,
Escherichia coli MTCC 739 and Pseudomonas aeruginosa
MTCC 2453. The minimum inhibitory concentration (MIC)
values are summarized in Table 5 and were compared with
ciprofloxacin. From the results it is evident that, some of the
compounds were selectively active against one Gram-positive
bacteria, Micrococcus luteus MTCC 2470 and one Gram-
negative bacteria, Klebsiella planticola MTCC 530. Compounds
4j and 6c exhibited potent antimicrobial activity with MIC value
3.9 μg/ml and 4m and 6g showed good antimicrobial activity
with MIC value 7.8 µg/mL against Klebsiella planticola MTCC
530. Compounds 4f, 6a, 6c and 6g showed appreciable
antibacterial activity with MIC values 7.8 μg/ml against
Micrococcus luteus MTCC 2470. Compounds 4b, 4d and 6a
showed the MIC value of 15.6 μg/mL against Klebsiella
planticola MTCC 530. The compounds 4a, 4b, 4d, 4e, 4h and 4j
exhibited moderate activity with MIC values 31.2 μg/ml against
Micrococcus luteus MTCC 2470. In addition, all the compounds
were evaluated for their antifungal potential against the fungal
strain Candida albicans MTCC 3017 in comparison with
miconazole as standard drug. In this case, only compound 6c
showed appreciable MIC value of 31.2 μg/mL against the tested
fungal strain.
Scheme 4. Synthesis of 2,4-diphenyl-1,2-dihydroquinazoline
derivatives.
Table 4. 2,4-diphenyl-1,2-dihydroquinazoline derivatives.
Time
(min)
Yielda
(%)
Entry
X
R2
Condition
8a
8b
8c
8d
8e
8f
H
H
4-Cl
4-Br
90
90
rt
rt
89
87
92
85
90
88
81
80
85
78
82
79
H
4-NO2
3-NO2
4-OMe
3,4-DiOMe
4-Cl
70
rt
H
90
rt
H
80
rt
H
90
rt
8g
8h
8i
NO2
NO2
NO2
NO2
NO2
NO2
150
150
130
160
140
150
reflux
reflux
reflux
reflux
reflux
reflux
4-Br
4-NO2
3-NO2
4-OMe
3,4-DiOMe
Table 5. Antimicrobial activity of the compounds against
different microbial strains
8j
Compound
Minimum Inhibitory Concentration (MIC, μg/ml)
8k
8l
M.la
K.pb
C.ac
4a
31.2
31.2
31.2
31.2
7.8
31.2
31.2
-
62.5
15.6
15.6
-
-
aisolated yields
4b
62.5
After employing isatins and benzaldehydes, we turned our
attention towards the use of activated ketones like benzil and
ethyl pyruvate. It was observed that the reaction did not proceed
until 6 hours even under refluxing conditions.
4d
-
4e
-
4f
-
-
4h
-
-
4j
3.9
7.8
15.6
3.9
-
-
4m
-
-
6a
7.8
7.8
-
6c
6d
31.2
62.5
-
6g
7.8
-
7.8
-
Figure 2. Plausble mechanism for the formation of 4'-phenyl-1'H-
spiro[indoline-3,2'-quinazolin]-2-one
Miconazole
Ciprofloxacin
7.8
-
0.9
0.9
The plausible mechanism for the formation of 4'-phenyl-1'H-
spiro[indoline-3,2'-quinazolin]-2-one from a three component
reaction of isatin, 2-aminobenzophenone and ammonium acetate
aMicrococcus luteus MTCC 2470, bKlebsiella planticola MTCC 530,
cCandida albicans MTCC 3017.

4
Tetrahedron
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3,2'-quinazolin]-2-ones
and
2,4-diphenyl-1,2-
dihydroquinazolines has been developed without using any
catalyst in ethanol. The advantages of this method include its
simplicity of operation, cleaner reactions, absence of side
products and higher yields. Furthermore, the spiroquinazolines
have been screened for their antimicrobial activities. Among
these, compounds 4f, 6a, 6c and 6g showed selective activity
against Gram-positive bacteria. Whereas compounds 4j, 4m, 6c
and 6g showed potent antimicrobial activity against Gram-
negative bacteria.
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2,4-diphenyl-1,2-dihydroquinazoline (8a-f)
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ethanol (5 mL) was stirred at room temperature. The progress of
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Acknowledgements
K.S.B thankful to CSIR-New Delhi for the award of senior
research fellowship and BN thanks DST for the award of
fellowship under DST-Inspire Scheme. We acknowledge funding
received from the project entitled “Affordable Cancer
Therapeutics (ACT)” (CSC0301) under XIIth five year plan. This
project was also supported by King Saud University, Deanship of
Scientific Research, Research Chair.
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2010, 14, 507; (b) Chamseddine, D.; Raouf, B.; Gilbert, K.;
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A. B. RSC. Adv. 2014, 4, 46369; (b) Kamal, A.; Babu, K. S.;
Vishnu Vardhan, M. V. P. S.; Hussaini, S. M. A.; Mahesh, R.;
Shaik, S. P.; Alarifi, A. Bioorg. Med. Chem. Lett. 2015, 25, 2199;
(c) Kamal, A.; Babu, K. S.; Hussaini, S. M. A.; Mahesh, R.;
Alarifi, A. Tetrahedron Lett. 2015, 56, 2803. (d) Kamal, A.; Babu,
K. S., Hussaini, S. M. A.; Srikanth, P. S.; Balakrishna, M.; Alarifi,
A. Tetrahedron Lett. 2015, 56, 4619.
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