Claisen-Schmidt, aza-Michael, cyclization via cascade strategy toward microwave promoted synthesis of imidazo[2,1-b]quinazolines

Article abstract of DOI:10.1080/00397911.2020.1757112

Imidazole blended quinazolines are having a wide run of potential applications in synthetic field. In this current investigation, we reported a modern synthesis with the help of non-conventional energy. Optimization parameters have been stabilized utilizi

Full text of DOI:10.1080/00397911.2020.1757112

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Claisen-Schmidt, aza-Michael, cyclization via
cascade strategy toward microwave promoted
synthesis of imidazo[2,1-b]quinazolines
Duraipandi Devi Priya & Selvaraj Mohana Roopan
To cite this article: Duraipandi Devi Priya & Selvaraj Mohana Roopan (2020): Claisen-Schmidt,
aza-Michael, cyclization via cascade strategy toward microwave promoted synthesis of imidazo[2,1-
b]quinazolines, Synthetic Communications, DOI: 10.1080/00397911.2020.1757112
To link to this article: https://doi.org/10.1080/00397911.2020.1757112
View supplementary material
Published online: 24 Apr 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1757112
Claisen-Schmidt, aza-Michael, cyclization via cascade
strategy toward microwave promoted synthesis of
imidazo[2,1-b]quinazolines
Duraipandi Devi Priya and Selvaraj Mohana Roopan
Department of Chemistry, Chemistry of Heterocycles and Natural Product Research Laboratory, School
of Advanced Science, Vellore Institute of Technology, Vellore, Tamilnadu, India
ABSTRACT
ARTICLE HISTORY
Received 6 November 2019
Imidazole blended quinazolines are having a wide run of potential
applications in synthetic field. In this current investigation, we
reported a modern synthesis with the help of non-conventional
energy. Optimization parameters have been stabilized utilizing RSM
(Response Surface Method) as well as Taguchi models. The yield
obtained from the proposed protocol is significantly higher com-
pared to other routine strategies. The products were explored by
implies of 1H, 13C-NMR and HR-MS investigation. Interestingly, cyc-
lization & aromatization has been influenced by KOH in a greater
extent. It is critical that the imidazo[1,2-b]quinazolines show intense
fluorescence emission, significant stokes shift, and high quantum
yield.
KEYWORDS
Fluorescence; imidazole;
microwave; non-
conventional; quinazoline
GRAPHICAL ABSTRACT
CONTACT Selvaraj Mohana Roopan
mohanaroopan.s@vit.ac.in
Department of Chemistry, Chemistry of
Heterocycles and Natural Product Research Laboratory, School of Advanced Science, Vellore Institute of Technology,
Vellore 632 014, Tamilnadu, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
D. D. PRIYA AND S. M. ROOPAN
Introduction
Broadly, a heterocyclic compound that contains nitrogen within the ring exists in nature
and it is imperative to human life. Imidazoles are significantly present in various
parts of natural sources.[1] The biological significance of the imidazole core has been
well-known in literature.[1] Among these, nitroimidazoles are being widely employed in
medical care against giardial, anaerobic, amebic, and trichomonal infections.[2] The imi-
dazoles such as Itraconazole, Ketoconazole, and Fluconazole are considered as abide
medicines which will be dynamic against Leishmania.[3] However, imidazole utilize in
skin therapy and visceral leishmaniasis have provided conflicting results.[4] In later a
long time scientist looking for imidazole as drug that can restrain central nervous sys-
tem disorders, clonidine, heart rate, phentolamine, and blood pressure.[5]Imidazole has
become an important component in numerous pharmaceuticals.[6] There are many syn-
thesized imidazoles which possess fungicides, antifungal, antiprotozoal, and antihyper-
tensive properties.[7–10] It is also present in anticancer drug (Mercaptopurine,
Tisagenlecleucel, Clofarabine) which fights leukemia.[11] The substituted imidazole
derivatives were effective in the treatment of many systemic fungal infections.[12]
Quinazolines is classes of fused heterocycles, of extraordinary concern due to their
biological characteristics.[13] It is used as an anti-malarial agent.[14] Many replaced
derivatives of quinazoline have a broad variety of bioactivities, including antimalarial,
antiviral, anticancer, anti-inflammatory, diuretic, anti-protozoan, etc.[15–20] Quinazoline
and quinazolinone are too utilized within the arrangement of utilitarian functional
materials for synthetic chemistry and are moreover display in multiple drug molecules
such as Uroxatral, Iressa, anagrelide proquazone, biarison, afatinib, gilotrif, barasertib,
dacomitinib, bunazosin, andante, gefitinib, etc.[21]
Nitrogen-bridgehead heterocyclic structures comprising an imidazole ring have an
application in therapeutic and materials chemistry. These compounds have many dis-
tinct curative effects, such as antimicrobial, anticancer, anti-inflammatory, antioxidant
etc.[22] The imidazo [4,5] dihydrobenzo [1,2-c] quinazoline ring is blending of imidazole
with pharmaceutically dynamic quinazoline core as outlined in Figure 1. Moreover,
these types of heterocycles are fluorescent in nature. Further, it has been used in
Figure 1. Pharmacutical importance of benzimidazole with a quinazoline.

R
SYNTHETIC COMMUNICATIONSV
3
optoelectronics, optical lasers, and organic luminophores.[23–24] Moreover, Imidazole
blended quinazoline moiety has various utilization within the catalysis field.
To the leading of our information, until now, microwave advanced imidazo[2,1-
b]quinazoline synthesis has not however detailed. From the literature review[25], we
found some of the motifs were related to our synthesized compounds. The research in
photoluminescence revealed that a bright blue light was emitted by all benzo [4,5]-imi-
dazo[1,2-c]quinazoline compounds.[26] Synthesis of imidazo quinazolines and azole
blended with pyrimido-quinazolines via C-N coupling/C-H functionalization was
reported. The resultant compounds were exhibited interesting biological and physical
properties.[27] The synthesis of imidazo-quinazolines and imidazo-quinolines via tandem
methodology[28] are also reported. In our earlier work[29] on UV light promoted synthe-
sis of imidazole fused quinazoline, we have faced a problem that it requires 2 h continu-
ous light source. Thus, to overcome the disadvantages, minimization of energy, and
chemicals, we made an endeavor for the basic, productive, and green way to synthesize
imidazo[2,1-b]quinazoline utilizing one pot metal-free microwave illumination strategy.
Additionally, detailed fluorescence emission properties are explored. Furthermore, here
we detailed RSM (Central Composite Design/Box–Behnken Design) as well as the
Taguchi models to recognize the most excellent ideal condition to synthesize imi-
dazo[2,1-b]quinazolines.
Results and discussion
The metal-free pathway for imidazo[2,1-b]quinazolines was handled by the microwave
strategy utilizing DMF as a dissolvable medium within the presence of KOH
(Scheme I). This reaction was carried out via both aza-Michael addition (Route-I) and
cascade reaction (Route-II). During the course of study, we screened different combina-
tions of aldehydes, amines, solvents and bases to improve the yields.
Route 1: Reaction undergoes aza-Michael addition between I and 3 followed by intra-
molecular cyclization step with the loss of water molecule (Figure 2).
Route 2: Reaction proceeds in cascade pathway i.e. first transformation is
Claisen–Schmidt condensation, followed by aza-Michael addition and intramolecular
cyclization step with the loss of water molecule. (Figure 2)
Scheme 1. Synthesis of imidazo[2, 1-b] quinazolines.

4
D. D. PRIYA AND S. M. ROOPAN
Figure 2. Synthesis of imidazo[2, 1-b] quinazolines by MW method.
Authors previously[30] reported that b-amino ketones were synthesized at the yield of
92% by the reaction between acetophenone, aldehyde and amine with the help of MW
energy. The authors[31] utilized two step methodology and reported the synthesis of 7-
amino 6H-benzo[c]chromen-6-ones, with 93% of yield and recently Polo et al.[32]

R
SYNTHETIC COMMUNICATIONSV
5
Table 1. Optimization of the reaction under, various time and temperature.
Entry
Base
Solvent
Temperature (ꢁC)
Source
Time (min)
aYield (%)
1.
2.
3.
4.
5.
6.
7.
8.
–
MeOH
MeOH
MeOH
DMF
DMF
DMF
MeOH
MeOH
MeOH
EtOH
MeOH
i-PrOH
n-BuOH
ACN
60
60
60
80
80
80
60
60
60
60
60
70
80
80
80
80
80
80
80
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
30
30
30
30
30
30
30
30
30
30
18
30
30
30
30
30
12
18
25
NR
52
48
45
61
31
53
44
58
76
78
42
47
45
74
76
89
95
95.5
NaOH
Triethyl amine
pyridine
Piperidine
Methyl amine
NaOMe
NaOEt
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
9.
10.
11.
12.
13.
14.
15.
16.
17.
18
19
THF
DMSO
DMF
DMF
DMF
aIsolated yields. The optimal conditions are shown by bold letters.
reported the synthesis of Pyrazolo-pyridines via single step approach utilizing InCl3 and
water with 90% yield.
At first, a, b-unsaturated carbonyl analogs (Ia-v) were prepared using the
Claisen–Schmidt condensation of a-tetralone with various substituted benzaldehydes in
the presence of KOH with slight modifications.[29] Subsequently, a,b-unsaturated car-
bonyl analogs were confirmed by their melting point and proton NMR. Initially, reac-
tion between Ia and 3 was performed with the assistance of methanol without base
which results nonappearance of 4a (Table 1, entry 1). So we plan to introduce base
NaOH in our reaction which results in 52% yield of 4a (Table 1, entry 2). The observed
yields may not be moved forward by utilizing other bases such as Triethylamine,
Pyridine, Piperidine, Methylamine, NaOMe (Table 1, entries 3–8). In comparison with
KOH and NaOH, better result was obtained by using KOH (10 mol-%) in the presence
of DMF (Table 1, entry 9).
Response of (E)-2-((4-bromocyclohexa-2,4-dien-1-ylidene)methyl)-3,4-dihydronaph-
thalen-1(2H)-one (Ia–v) having substituted in C-4, C-3 and C-2 positions of corre-
sponding imidazo[2,1-b]quinazolines comes about in 70–95% yields (Figure 2). This
specific strategy was moreover successful within the case of bicyclic chalcones like 2-
naphthaldehydes 4g (89%) and 4s (81%), and heterocyclic chalcones such as 2-thio-
phenyl 4j (75%) and 2-pyridyl 4l (76%). In spite of the fact that the yields within the
final category got to be direct yields recorded in Table 1. The imidazo[2,1-b]quinazoline
motifs were prepared by different substituted chalcones at comparable experimental
conditions. The product obtained was characterized and affirmed by NMR (Nuclear
Magnetic Resonance spectroscopy) and HR-MS (High-Resolution Mass Spectroscopy)
analysis as displayed in Table S1. Initially, the presence of electron-donating groups
such as 4–Cl, 4–Br, 4–CH3 and 4–OCH3 on the aromatic ring gives the corresponding
product yield varying between 80 and 95% (Figure 2). The yield drop further, when the
electron-donating group (–Cl) is present in C-2, C-3, C-4 position (Entries 6ꢀ15,

6
D. D. PRIYA AND S. M. ROOPAN
Table 2. Microwave assisted synthesis of compounds 3a–u.
Entr
y
HRMS
(m/z)
Ent
ry
%
yield
Prod
uct
HRMS
(m/z)
-R
% yield
-R’
Product
-R
-R’
1
12
92
-H
381. 1033
425.3075
77
85
-H
4a
4b
4l
336.3890
411.8820
2
3
13
14
87
91
-H
-H
-OCH3
-OCH3
4m
425.3074
78
4c
4n
456.3332
456.3332
4
15
89
92
94
-H
-H
-H
377.4370
361.4370
425.3074
96
78
77
-OCH3
-OCH3
-OCH3
4d
4e
4f
4o
4p
4q
5
6
16
17
456.3331
391.4640
7
8
9
18
19
20
397.4702
407.4630
89
87
-H
-H
81
79
-OCH3
-OCH3
4g
4h
4r
4s
407.4631
427.4960
78
75
-H
-H
337.3738
353.4390
389.4910
74
75
-OCH3
-OCH3
4i
4j
4t
4u
4v
437.4890
383.4650
10
11
21
22
76
-H
72
-H
372.4310
4k
Table 2) and the excellent yield (95%, entry 12, Table 2) was attained with KOH. In
most of the cases, the imidazo[2,1-b]quinazolines are synthesized as high purity.
Scope of the reaction was investigated with the optimized conditions. Electron defi-
cient and rich carbonyl compounds are endured in the reaction. Electron rich substrates
provide higher yields than electron-poor counterparts. The 4-pyridine carboxaldehyde
results in good process; addition to this 4-bromoaldeyde also results in good yields
which can be further utilized for coupling reactions.
One-pot three-component route is the alternate way to synthesis imidazo[2,1-b]quina-
zolines. As illustrated in Scheme 1, compound 1a reacted with 2-amino benzimidazole
2a, a-tetralone 3a and substituted aldehydes bearing ortho, meta, and para substituents

R
SYNTHETIC COMMUNICATIONSV
7
Scheme 2. Possible mechanism for the transformation.
on the aromatic ring to provide 4a–u within moderate to good yields (Table 2).
Electron donating group substituted aldehydes (Table 2, entries 2–6) gave better
yields than withdrawing groups substituted aldehydes (Table 2, entries 7–8, 20).
However, our reaction was not limited to simple aldehydes further, the imidazo[2,1-
b]quinazoline motifs were produced by similar experimental conditions with
different aldehydes and the product obtained was confirmed by NMR and HR-MS
(Table S1).
Mechanism
Mechanistically, we accept that this change is related to the imidazo[2,1-b]quinazolines
that we have been reported previously. We proposed that the reaction proceeds by for-
mation of a,b unsaturated ketones, via Claisen–Schmidt condensation route (Scheme 2).
Further 2-aminobenzimidazole react with variety of substituted a,b unsaturated ketones
to produce corresponding product via aza-Michael intermediate followed by cyclization
step. Then the intermediate eliminates the water molecules to achieve 4a as a
final product.
RSM analysis
Response surface methodology (RSM) is one of the standard methods for the optimiza-
tion of the reaction parameters using Box-Behnken design (BBD)[33–35] model. Here we
used this design for the microwave optimization of imidazo[2,1-b]quinazolines synthetic
convention. The selected independent variables where base concentration, time, MW
power and the yield of the synthetic analogs was a response of this model. The deter-
mined values (ꢀ1.0 þ 1) of the variables are recorded in Table 3. Agreeing to the BBD
second-order design; this study reveals three-level replications at the center point. Here,
totally 15 runs were performed utilizing BBD, due to varieties in parameters the

8
D. D. PRIYA AND S. M. ROOPAN
Table 3. Coded levels for independent variables for BBD.
Variables
Symbol
ꢀ1
0
1
Base concentration (mM)
Time (min)
MW Power (W)
x
y
z
2.5
12
5
18
200
7.5
24
300
100
Table 4. Experimental matrix and results for BBD.
Base concentration (mM)
Time (min)
MW power W
Experimental yield (%)
Theoretical yield (%)
2.5
5
7.5
7.5
7.5
5
5
2.5
5
7.5
2.5
5
5
2.5
18
12
18
18
24
12
24
12
24
12
24
18
18
18
18
100
300
100
300
200
100
300
200
100
200
200
200
200
300
200
57
84
81
93
92
78
92
54
82
83
79
95
94
64
91
58
81
79
90
90
75
95
55
84
86
74
94
94
65
92
7.5
obtained results were arranged in table 4. Utilizing RSM, the quadric polynomial regres-
sion equation (Y) of the yield expressed as follows,
Z ¼ 94:2391 þ 11:7446 x þ 5:75000 y þ 4:37500 z ꢀ 13:9402 x ꢂ x ꢀ 3:42935 y ꢂ y
ꢀ 6:67935 z ꢂ z ꢀ 4:00000 x ꢂ y þ 1:25000 x ꢂ z þ 1:00000 y ꢂ z
(1)
The Equation (1) represents the terms of x denotes base concentration, y denotes
time, and z denotes temperature
Based on the experimental results found ANOVA table of the different variables were
developed and displayed in Table 5. An ANOVA experimental result was utilized for
the stability and reliability of the BBD model. If the p value is less than 0.005 the model
should be significant. For the first three cases it denotes the model is significant and it
has more influence on the results. Figure 3 represent the fine relationship between the
theoretical values and the experimental values. The R2 value of the model is 96.8%;
which clearly specifies that current model should be very well fits with the total error
value. Another important parameter of the surface models was established utilizing
ANOVA (Table 5). The F-value is 16.86 of the quadratic model indicated that the
model was significant. The “Lack of Fit F-value” is 39.16, which clearly shows that the
lack of fit is not significant.
Graphical representation of BBD model
The synthesis parameters were investigated via 3D response surface diagrams and their
corresponding 2D contour diagrams. Here the diagrams represented as interaction or
relationship between yield Vs. optimized conditions. The 3D response surface graphs
and its equivalent contour graphs were employed for the optimization of base

R
SYNTHETIC COMMUNICATIONSV
9
Table 5. ANOVA analysis of variance for yield.
Analysis of variance for yield
Source
DF
Seq SS
Adj SS
Adj MS
F
p
Regression
Linear
Square
Interaction
Residual error
Lack-of-fit
Pure error
Total
9
3
3
3
5
4
1
14
2392.12
1645.51
672.36
74.25
78.82
78.32
2392.12
1626.20
672.36
74.25
78.82
78.32
265.791
542.066
224.121
24.750
15.763
19.579
0.500
16.86
34.39
14.22
1.57
0.003
0.001
0.007
0.307
39.16
0.119
0.50
2470.93
0.50
Figure 3. The relationship between the theoretical and experimental values.
concentration (x), time (y), MW power (z), and its plots existed in Figures 4(a–c) and
5(a–c). The influence of the base concentration (x) and time (y) explains in the
Figure 4. A contour plot represent that base concentration increases the reaction con-
vention and yield were. Figure 4b and 4c also explains the interaction between the MW
Power (z) Vs. base concentration (x) and time (y) Vs MW Power (z). Here also when
the power increases automatically the yield got increased, as well as when the time
increases, the yield increased. The yield convention was greater than 90%. The response
3 D plots also explain the effect of interaction between the reactants. Figure 5(a–c) rep-
resents the yield variation with respect to all independent variables.
Form this observation the yield% might be increased due to the increases of, x in
5 mMol%, y in 18 min, and z in 200 W. The results clearly matched with the experimen-
tal method of imidazo[1,2-b]quinazoline analogs.
CCD design and statistical analysis
CCD method is considered as an important design in RSM model which was also uti-
lized to study the effect of variables. Here also, we utilized Yield as response with

10
D. D. PRIYA AND S. M. ROOPAN
Figure 4. Contour plots for different parameters on the conversion of yield (%). (a) Effect of x and y.
(b) Effect of z and x. (c) Effect of z and y.
respect to base concentration, time, and MW power. Table 3, denotes the range of the
variables, as well as 20 experiments, which were analyzed in the CCD model (Table 6).
The regression equation is as follows,
Yield ¼ 94:23 þ 5:200 x þ 5:900 y þ 7:500 z ꢀ 2:37 x ꢂ x ꢀ 9:87 y ꢂ y
ꢀ6:87 z ꢂ z ꢀ 1:00 x ꢂ y ꢀ 0:50 x ꢂ z ꢀ 1:25 y ꢂ z
From this model, Table 7 illustrates the analysis of variance using Fisher’s statistical
analysis which was utilized to investigate the significance and capability of the model.
The F and p-value of this model 69.45 and 0, respectively implies that, it is a highly sig-
nificant model. The R2 value also shows that 97.36% of this model is a good statis-
tical model.
The 3D plot and 2D contour plots represents that, corresponding interactions
between base concentration (x) and time (y) fixed at MW power (z) (Figure 6A and
6B), MW power (z), base concentration (x), fixed at time (y) (Figure 6C and 6D) and
time (y) and MW power (z) fixed at base concentration (x) (Figure 6E and 6F) point
out that all the factors examined are interconnected.
Influence of base concentration (x) on product yield
The Microwave synthesis of the imidazo[1,2-b]quinazoline yield was investigated by the
effect of base concentration. Here the base concentration varying from 2.5 mM to

R
SYNTHETIC COMMUNICATIONSV
11
Figure 5. 3D surface plots for different parameters on the conversion of yield (%). (a) Effect of y and
x. (b) Effect of z and x. (c) Effect of z and y.
Table 6. CCD matrix of the three factors in coded units along with the experimental and pre-
dicted responses.
Std Order
RunOrder
PtType
x
y
z
Experimental yield (%)
Theoretical yield (%)
18
13
17
16
20
15
14
19
3
5
6
1
2
4
7
11
10
12
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
ꢀ1
ꢀ1
ꢀ1
ꢀ1
0
ꢀ1
ꢀ1
0
1
0
0
1
1
1
1
0
1
0
1
1
0
0
0
0
1
0
1
89
85
78
86
95
75
91
95
88
95
95
56
83
87
67
95
92
95
72
69
92
83
77
87
96
75
94
91
86
96
96
56
81
86
67
94
91
94
72
70
ꢀ1
0
ꢀ1
0
0
0
0
0
1
0
0
0
0
0
1
0
1
0
0
ꢀ1
0
0
ꢀ1
0
0
0
ꢀ1
ꢀ1
ꢀ1
ꢀ1
1
1
1
ꢀ1
1
0
1
0
1
ꢀ1
ꢀ1
0
0
1
0
1
0
1
ꢀ1
ꢀ1
ꢀ1
8
ꢀ1
1
7.5 mM using, different time (12–24 min) and MW (microwave) power (100–300 W)
have been applied for the current synthesis method. A remarkable increase in product
yield (95%) was noted at the base concentration of 5 mM. Based on these observations,
the concentration of KOH (5 mM) has been thought as an appropriate condition for the
reaction method.

12
D. D. PRIYA AND S. M. ROOPAN
Table 7. Analysis of variance for CCD model.
Source
DF
Seq SS
Adj SS
Adj MS
F-value
p-Value
Model
Blocks
Linear
x
y
z
11
2
3
1
1
1
3
1
1
1
3
1
1
1
8
5
3
2386.01
89.97
2386.01
77.14
216.910
38.571
393.667
270.400
348.100
562.500
364.180
15.109
261.623
126.780
7.500
8.000
2.000
12.500
8.099
12.959
26.78
4.76
0.000
0.043
0.000
0.000
0.000
0.000
0.000
0.209
0.000
0.004
0.471
0.349
0.633
0.249
1181.00
270.40
348.10
562.50
1092.54
511.53
454.23
126.78
22.50
8.00
2.00
12.50
64.79
1181.00
270.40
348.10
562.50
1092.54
15.11
261.62
126.78
22.50
8.00
2.00
12.50
64.79
48.61
33.39
42.98
69.45
44.96
1.87
32.30
15.65
0.93
Square
ꢂ
x x
ꢂ
y y
ꢂ
z z
2-Way interaction
ꢂ
x y
0.99
0.25
1.54
ꢂ
x z
ꢂ
y z
Error
ꢂ
ꢂ
Lack-of-fit
Pure error
Total
64.79
0.00
2450.80
64.79
0.00
0.000
19
Influence of MW time (y) on product yield
In this study, the reaction time (12–24 min) has been varied for the investigation of
product yield; keeping the other independent variables (i.e.), the base concentration and
MW (microwave) power as constant. The yield was improved by enhancing the time of
irradiation. According to the experiment, results afford a 95% yield in 18 min of the
reaction time. From the above results, 18 min irradiation time was instructed for the
reaction process.
Influence of MW power (z) on product yield
One of the important variables for this model is the MW power, which has been varied
in order to influence the reaction yield. As a result, the product yield was increased as
the MW power increased. Here, microwave power (100–300 W) was used for the opti-
mization of yield. From all the observation, the yield of the product was maximized at
200 W of microwave power.
Optimization using taguchi approach
Taguchi method[36–38] is one of the earlier statistical techniques utilized to optimize var-
iables by a highly fractional design called an orthogonal design matrix. Compared to all
the optimization methods, this method required minimum amount of data for identify-
ing suitable reaction condition. In this model, we analyze 3 level of array which was
applied for 3 different parameters. For the L9 orthogonal array, experiments were car-
ried out to optimize the yields of the product. In common, quality loss or signal to
noise (S/N) ratio (g) is utilized to speak the quality characteristics for the observed
response parameters during analysis of the experimental data. In this model there are
quality characteristics naming ‘‘higher is better,” ‘‘smaller is better” and ‘‘nominal is
better.” In present study, the quality characteristic, ‘‘higher is better” was applied for the

R
SYNTHETIC COMMUNICATIONSV
13
Figure 6. CCD/3D response surface plots and 2 D contour plots for all independent variables.
imidazo[1,2-b]quinazoline analogs yield. The product yield of S/N ratio is represents as
eqn 2,
ꢂ
ꢃ
X
ꢀ
ꢁ
S=N ¼ ꢀ10 log 10
1=y2 =n
(2)
Y denotes the response, and n denotes observation of the trails.
S/N ratio and ANOVA
With the L9 designed orthogonal array, the nine experiments were carried out and the
product of the yield was calculated, which are given in Table 8. The synthesis of the

14
D. D. PRIYA AND S. M. ROOPAN
Table 8. Calculated reaction yields and their S/N ratios.
X
y
z
Yield-1
Yield-2
Mean
S/N ratio
2.5
2.5
2.5
5.0
5.0
5.0
7.5
7.5
7.5
12
18
24
12
18
24
12
18
24
100
200
300
200
300
100
300
100
200
72
78
84
92
89
64
86
73
87
71
80
82
91
88
63
89
72
89
71.5
79.0
83.0
91.5
88.5
63.5
87.5
72.5
88.0
36.8445
38.3997
38.1714
39.0198
38.6975
36.5039
39.2855
36.9979
38.6470
Figure 7. Main effects plot of design parameters through the product yield.
Imidazo[2,1-b]quinazolines using three optimization conditions (base concentration,
reaction time and MW power) for 9 trial runs were shown in Figure 7. In this
analysis, the S/N ratios for product yield are calculated using the formulae given in
Equation (2).
The optimum condition of Imidazo[2,1-b]quinazolines yield was 92%, at 5 mM of
base concentration at 12 min of reaction time, 200 W of MW power. When the base
concentration increased from 2.5 to 5 mM, simultaneously the product yield increased.
Also, with an increase in the reaction time and MW power product yield also increased.
Figure 7 shows the plots of the main effects (i.e.) the three factors x, y and z from
which the S/N ratios (larger-is-better) are calculated (obtained from Table 8). Analysis
of variance is calculated for individual responses after the normalizing process of data,
as shown in Table 9. As shown from the ANOVA table, the p-value for all variables
>0.05 is significant.

R
SYNTHETIC COMMUNICATIONSV
15
Table 9. Analysis of variance for SN ratios.
Source
DF
Seq SS
Adj SS
Adj MS
F
p
x
y
z
2
2
2
2
8
0.3830
0.5611
7.3848
0.9096
9.2384
0.3830
0.5611
7.3848
0.9096
0.1915
0.2805
3.6924
0.4548
0.42
0.62
8.12
0.00704
0.00619
0.00110
Residual error
Total
Figure 8. Fluorescence emission spectra of synthesized motifs.
The R2 value of the S/N ratio, 90.2%, represents, the good optimum condition for
multiple performance characteristics in product yield. The maximum S/N ratio is calcu-
lated to be 39.01. As a result of the MW assisted synthesis of Imidazo[2,1-b]quinazo-
lines motifs, is considerably influenced by all optimum parameters.
Fluorescence property
The absorption and fluorescence spectra of compounds 4a–u were investigated via
numerous solvents as illustrated in Figures 8 and 9. The absorption and emission wave-
length ranges from 200 to 1200 nm. The observed absorption maxima (kmax), emission
maxima (kem), stokes shift and quantum yield (u) are listed in Table 10. The values of
extinction coefficient (Ɛ) were calculated from the graph of absorption vs concentration
in Figure 9. Here, we used a wavelength of 350 nm for fluorescence excitation (kem).
The quantum yields of synthesized motifs (4a–u) were decided by using tryptophan as

16
D. D. PRIYA AND S. M. ROOPAN
Figure 9. Absorption spectrum of compound 4a–s.
Table 10. Photo physical properties of imidazo[2,1-b]quinazoline analogs.
Entry
kmax (abs,nm)
kmax (em,nm)
Stokes shift (nm)
OD
I
/
Tryptophan
280
274
277
277
277
352
278
298
278
276
290
278
276
262
278
276
274
278
278
355
517
523
521
516
517
518
516
516
411
538
516
537
516
510
517
516
517
510
75
243
246
244
239
165
240
218
238
135
248
238
261
254
232
241
242
239
232
0.384
1.0907
0.6356
0.5040
0.5255
1.142
1.063
1.316
1.442
0.266
0.671
0.253
0.626
0.236
0.468
0.214
0.468
0.504
0.148
158517
55096.09
34922.27
31938.10
61655.98
58965.28
47428.08
7588131
64313.04
9093.39
14627.76
70773.16
20102.08
35284.51
72076.15
28383.92
42896.68
41788.86
82372.39
0.130
0.018
0.019
0.022
0.042
0.018
0.015
0.020
0.015
0.012
0.007
0.100
0.011
0.058
0.055
0.047
0.032
0.029
0.199
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
standard. Fluorescence intensity of compounds (4a–u) can be justified by an effective
intramolecular charge transfer (ICT). ICT explains endocyclic N acted as a donor site to
donate the electrons to the aliphatic ring which turns it as an acceptor moiety.
Consistently photo prompted charge exchange scheme contains a donor (D) and
acceptor (A) which is coupled, which have different chromophores inside a huge

R
SYNTHETIC COMMUNICATIONSV
17
Figure 10. Fluorescence emission spectrum of compounds 4m, 4u, 4t.
molecule, ruling to intramolecular charge transfer (ICT). The synthesized core motifs
have less charge and ionic mesomeric structures. The shoulder peak on the left side of
the emission spectra indicates two nitrogen donor atoms present in analogs which is
shown in Figure 8. The motifs 4s showed a great response to the fluorescence in the
polar solvent medium. The compounds 4m, 4u, and 4t showed an absorption and emis-
sion peak at 510–516 and 506–510 nm, respectively and exhibited an excellent quantum
yield which is given in Figure 10. In polar solvents, synthesized compounds, 4a–u
showed a hypsochromic shift in emission spectra. Thus imidazo[2, 1-b]quinazoline com-
pound may act as very good fluorophores for variety of applications in various fields.
Solvatochromism effects of compound 4a were investigated in different solvents
(Figure 11). It is portrayed in this Figure that, the absorption, as well as the emission
spectra of 4a in polar solvents, experience a redshift. High dissolvable polarity balances
out the ICT excited-state molecule, which is identified with redshift of the absorption
maximums which were analytically noticed.
Experimental
A common technique for the production of imidazo[2,1-b]quinazoline fused
heterocycles (3a–u)
Route-1
1 mM of chalcones and 1 mM of amine were dissolved in 10 mL of DMF following with
the addition of 1 mM of KOH under continuous stirring for 2 min. The reaction

18
D. D. PRIYA AND S. M. ROOPAN
Figure 11. Absorption spectrum of compound 4a in various solvents.
mixture was kept it in a microwave chamber at a fixed rate for 1 min at 50 ꢁC. From
that point onward, the temperature was raised to 80 ꢁC and kept in for 18 min. The
reaction was examined by TLC, the solvent was distilled off and the residual unrefined
product was purified by silica gel supported column chromatography (eluent 15–30%
ethyl acetate/pet. ether).
Route-2
A mixture of 2-amino benzimidazole, (1 mmol), aldehydes (1 mmol) and a-tetralone
(1 mmol) were added in 5 mL of DMF followed by KOH (2.2 mmol) at room tem-
perature. The reaction mixture was heated to 80 ꢁC for 1 h using MW. Once the
reaction is completed the reaction mixture has slowly added into ice. The product
was extracted from the reaction mixture using organic solvent (ethyl acetate). To
obtain the pure compound, the extract was subjected into column chromatography.
1
Each of the derivatives (4a–u) was additional verified by H NMR, 13C NMR, and
HR-MS spectral investigations.
Fluorescence spectroscopy
The absorption and emission fluorescence spectra of prepared motifs (4a–u) were noted
down at 10ꢀ5 M concentration in ethyl acetate solvent medium. The fluorescence

R
SYNTHETIC COMMUNICATIONSV
19
spectra were recorded utilizing maximum excitation of the extensive wavelength absorp-
tion spectra. The fluorescence of the solution was estimated in a 1 cm3 cuvette in right
angle prearrangement. The quantum yield of the fluorescence compounds was calcu-
lated, using
/ ¼ /R ꢃ I=IR ꢃ AR=A ꢃ g2=gR2
(3)
Where /R is standard, we are using tryptophan[19] as a reference standard, I is the
area of the samples under fluorescence curve, IR is the standard curve, AR is the stand-
ard absorbance at the excitation wavelength, A is the sample absorbance at the excita-
tion wavelength, g2 is the refractive index of samples and gR2 is the standard
refractive index.
Conclusions
To conclude, we have synthesized highly substituted imidazo fused quinolines using
efficient microwave irradiation method under mild conditions. Here we have used vari-
ous optimization methods for the synthesis parameters which were also discussed.
Moreover, the product was obtained in a good amount of yield and the reaction com-
pleted within a short span of time. The synthesized analogs showed intense luminance
property and possessed excellent quantum yield.
Acknowledgments
The author thanks VIT for providing a lab facility.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The author thanks CSIR-SRF funding provided to Devi Priya.
References
[1] Zhang, L.; Peng, X. M.; Damu, G. L. V.; Geng, R. X.; Zhou, C. H. Comprehensive Review
in Current Developments of Imidazole Based Medicinal Chemistry. Med. Res. Rev. 2014,
34, 340–437. DOI: 10.1002/med.21290.
[2] Jacqueline, A. U.; Campbell, R. W.; Benakli, K.; Upcroft, P.; Vanelle, P. Efficacy of New 5-
Nitroimidazoles against Metronidazole-Susceptible and -Resistant Giardia, Trichomonas,
and Entamoeba Spp. Antimicrob. Agents Chemother. 1999, 43, 73–76. DOI: 10.1128/AAC.
43.1.73.
[3] Gangneux, J. P.; Dullin, M.; Sulahian, A.; Garin, Y. J. F.; Derouin, F. Experimental
Evaluation of Second-Line Oral Treatments of Visceral Leishmaniasis Caused by
Leishmania infantum. Antimicrob. Agents Chemother. 1999, 43, 172–174. DOI: 10.1128/
AAC.43.1.172.

20
D. D. PRIYA AND S. M. ROOPAN
[4] Khalil, E. A. G.; Nur, N. M.; Zijlstra, E. E.; El Hassan, A. M.; Davidson, R. N. Failure of a
Combination of Two Antifungal Drugs, Terbinafine plus Itraconazole, in Sudanese Post-
Kala-Azar Dermal Leishmaniasis. Trans. R. Soc. Trop. Med. Hyg. 1996, 90, 187–188. DOI:
10.1016/S0035-9203(96)90134-0.
[5] Shallal, A. H.; Muhammed, M. A. Literature Review on the Imidazole. International J.
Multidiscip. Res. Rev. 2019, 5, 1–11.
[6] Verma, A.; Joshi, S.; Singh, D. Imidazole: Having Versatile Biological Activities. J. Org.
Chem. 2013, 2013, 1–329412. DOI: 10.1155/2013/329412.
[7] Bedi, P. M. S.; Kumar, V.; Mahajan, M. P. Synthesis and Biological Activity of Novel
Antibacterial Quinazolines. Bioorg. Med. Chem. Lett. 2004, 14, 5211–5213. DOI: 10.1016/j.
bmcl.2004.07.065.
[8] Yang, W.-C.; Li, J.; Li, J.; Chen, Q.; Yang, G.-F. Novel Synthetic Methods for N-Cyano-
1H-Imidazole-4-Carboxamides and Their Fungicidal Activity. Bioorg. Med. Chem. Lett.
2012, 22, 1455–1458. DOI: 10.1016/j.bmcl.2011.11.115.
ꢀ
[9] Aguirre, G. 1.; Boiani, M.; Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Sainz, Y. F.; Denicola,
ꢀ
A.; De Ocariz, C. O.; Nogal, J. J.; Montero, D.; et al. Novel Antiprotozoal Products:
Imidazole and Benzimidazole N-Oxide Derivatives and Related Compounds. Arch. Pharm.
Pharm. Med. Chem. 2004, 337, 259–270. DOI: 10.1002/ardp.200300840.
[10] Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price,
W. A.; Santella, J. B.; Wells, G. J.; Wexler, R. R. Nonpeptide Angiotensin II Receptor
Antagonists: The Discovery of a Series of N-(Biphenylylmethyl) Imidazoles as Potent,
Orally Active Antihypertensives. J. Med. Chem. 1991, 34, 2525–2547. DOI: 10.1021/
jm00112a031.
[11] Yang, J. J.; Landier, W.; Yang, W.; Liu, C.; Hageman, L.; Cheng, C.; Pei, D.; Chen, Y.;
Crews, K. R.; Kornegay, N.; et al. Inherited NUDT15 Variant is a Genetic Determinant of
Mercaptopurine Intolerance in Children with Acute Lymphoblastic Leukemia. JCO. 2015,
33, 1235–1242. DOI: 10.1200/JCO.2014.59.4671.
[12] Samira, I.; Patel, S.; Hasmin, M.; Patel, S. Biological Profile of Quinazoline. Int. J. Pharm.
Chem. 2012, 1, 1863–1872.
[13] Singh, V. K.; Singh, S. K.; Gangwar, L. Synthesis and Antimicrobial Activity of Novel
Fused 4-(3H) Quinazolinone Derivatives. Int. J. Recent Sci. Res 2013, 2, 425–428.
[14] Paul, R. G.; Cyrus, T.; Kate, E. J.; Kym, N. L.; Joan, M. C.; William, N.; Adrian, E. D.;
Hayley, E. B.; Boris, P.; Sandra, D.; Jonathan, B. B.; Craig, A. H..; et al. Optimization of 2-
Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral
in Vivo Activity. J. Med. Chem. 2017, 60, 1171–1188.
[15] Ghorab, M. M.; Ismail, Z.; Radwan, A. A.; Abdalla, M. Synthesis and Pharmacophore
Modeling of Novel Quinazolines Bearing a Biologically Active Sulfonamide Moiety. Acta
Pharmacol. Sin. 2013, 63, 1–18. DOI: 10.2478/acph-2013-0006.
[16] Al-Amiery, A. A.; Kadhum, A. A. H.; Shamel, M.; Satar, M.; Khalid, Y.; Mohamad, A. B.
Antioxidant and Antimicrobial Activities of Novel Quinazolinones. Med. Chem. Res. 2014,
23, 236–242. DOI: 10.1007/s00044-013-0625-1.
[17] Alagarsamy, V.; Solomon, V. R.; Dhanabal, K. Synthesis and Pharmacological
Evaluation of Some 3-Phenyl-2-Substituted-3H -Quinazolin-4-One as Analgesic, Anti-
Inflammatory Agents. Bioorg. Med. Chem. Lett. 2007, 15, 235–241. DOI: 10.1016/j.bmc.
2006.09.065.
[18] Baba, A.; Kawamura, N.; Makino, H.; Ohta, Y.; Taketomi, S.; Sohda, T. Studies on
Disease-Modifying Antirheumatic Drugs: Synthesis of Novel Quinoline and Quinazoline
Derivatives and Their Anti-Inflammatory Effect. J. Med. Chem. 1996, 39, 5176–5182. DOI:
10.1021/jm9509408.
[19] Jafari, E.; Khajouei, M. R.; Hassanzadeh, F.; Hakimelahi, G. H.; Khodarahmi, G. A.
Quinazolinone and Quinazoline Derivatives: Recent Structures with Potent Antimicrob.
Cytotoxic Act. Res. Pharm. Sci. 2016, 11, 1–14.

R
SYNTHETIC COMMUNICATIONSV
21
[20] Rahman, M. U.; Jeyabalan, G.; Saraswat, P.; Parveen, G.; Khan, S.; Yar, M. S. Quinazolines
and Anticancer Activity: A Current Perspectives. Synth. Commun. 2017, 47, 379–408.
DOI: 10.1080/00397911.2016.1269926.
[21] Eryılmaz, E.; Canpolat, C. Novel Agents for the Treatment of Childhood Leukemia: An
Update. OTT. 2017, 10, 3299–3306. DOI: 10.2147/OTT.S126368.
[22] Bansal, Y.; Silakari, O. The Therapeutic Journey of Benzimidazoles: A Review. Bioorg.
Med. Chem. 2012, 20, 6208–6236. DOI: 10.1016/j.bmc.2012.09.013.
[23] Itoh, T. Fluorescence and Phosphorescence from Higher Excited States of Organic
Molecules. Chem. Rev. 2012, 112, 4541–4568. DOI: 10.1021/cr200166m.
[24] Hirano, K.; Oderaotoshi, Y.; Minakata, S.; Komatsu, M. Unique Fluorescent Properties of
1-Aryl-3,4-Diphenylpyrido[1,2-a]Benzimidazoles. Chem. Lett. 2001, 30, 1262–1263. DOI:
10.1246/cl.2001.1262.
[25] Xie, C.; Huang, N. Y.; Ding, M. W. New Efficient Synthesis of Imidazo [2, 1-b]
Quinazoline-2,
5 (1H, 3H)-Diones by a Consecutive Aza-Wittig/Heterocumulene-
Mediated Annulation. ARKIVOC. 2009, 10, 220–232.
[26] Hasan, H. A.; Abdulmalek, E.; Saleh, T. A.; Rahman, A.; Basyaruddin, M.; Shaari, K. B.;
Yamin, B. M.; Chan, K. W. Synthesis of Novel 6-Substituted-5,6-Dihydrobenzo[4,5]
Imidazo[1,2-c] Quinazoline Compounds and Evaluation of Their Properties. J. Mol.
Struct. 2019, 1193, 482–494. DOI: 10.1016/j.molstruc.2019.04.111.
[27] Chen, D.; Huang, L.; Yang, J.; Ma, J.; Zheng, Y.; Luo, Y.; Shen, Y.; Wu, J.; Feng, C.; Lv, X.
Copper-Catalyzed C–N Coupling/C–H Functionalization: A Tandem Approach to Azole-
Fused Quinazoline Derivatives. Tetrahedron Lett. 2018, 59, 2005–2009. DOI: 10.1016/j.tet-
let.2018.04.020.
[28] Kumar, N.; Shiv, N.; Kumar, D. H.; Kumar, S. I.; Kumar, A. Synthesis of Quinazolinones,
Imidazo[1,2c]Quinazolines and Imidazo[4,5c]Quinolines through Tandem Reductive
Amination of Aryl Halides and Oxidative Amination of C(sp3)–H Bonds. Eur. J. Org.
Chem. 2017, 2017, 514–522. DOI: 10.1002/ejoc.201601329.
[29] Devipriya, D.; Roopan, S. M. UV-Light Intervened Synthesis of Imidazo Fused
Quinazoline and Its Solvatochromism, Antioxidant, Antifungal and Luminescence
Properties. J. Photochem. Photobiol. B. 2019, 190, 42–49. DOI: 10.1016/j.jphotobiol.2018.
11.003.
[30] Yuvaraj, P.; Kathirvelan, D.; Reddy, B. S. R. Synthesis of b-Aminoketone by Reaction of
Amine and Activated Chalcone in Microwave Irradiation. Indian J Chem B. 2015, 46, 828.
DOI: 10.1002/chin.201546122.
[31] Yaragorla, S.; Dada, R. Amine-Triggered Highly Facile Oxidative Benzannulation Reaction
for the Synthesis of Anthranilates under Solvent-Free Calcium(II) Catalysis. ACS Omega.
2017, 2, 4859–4869. DOI: 10.1021/acsomega.7b00753.
ꢀ
[32] Polo, E.; Ferrer-Pertuz, K.; Trilleras, J.; Quiroga, J.; GutıErrez, M. Microwave-Assisted
One-Pot Synthesis in Water of Carbonylpyrazolo[3,4-b]Pyridine Derivatives Catalyzed by
InCl3 and Sonochemical Assisted Condensation with Aldehydes to Obtain New Chalcone
Derivatives Containing the Pyrazolopyridinic Moiety. RSC Adv. 2017, 7, 50044–50055.
DOI: 10.1039/C7RA10127A.
[33] Bezerra, M. A.; Santelli, R. E.; Oliveira, E. P.; Villar, L. S.; Escaleira, L. A. Response
Surface Methodology (RSM) as a Tool for Optimization in Analytical Chemistry. Talanta.
2008, 76, 965–977. DOI: 10.1016/j.talanta.2008.05.019.
[34] Mason, R. L.; Gunst, R. F.; Hess, J. L. Statistical Design and Analysis of Experiments.
2003, 1–760, ISBN: 978-0-471-37216-5.
[35] Lizotte, D. J.; Greiner, R.; Schuurmans, D. An Experimental Methodology for Response
Surface Optimization Methods. J. Glob. Optim. 2012, 53, 699–736. DOI: 10.1007/s10898-
011-9732-z.
[36] Ghoreishi, S. M.; Moein, P. Biodiesel Synthesis from Waste Vegetable Oil via
Transesterification Reaction in Supercritical Methanol. J. Supercrit. Fluids. 2013, 76,
24–31. DOI: 10.1016/j.supflu.2013.01.011.

22
D. D. PRIYA AND S. M. ROOPAN
[37] Sivaraos, K. R.; Milkey, A. R.; Samsudin, A. K.; Dubey, P. The Mechanical Properties of
Fly Ash-Based Geopolymer Concrete with Alkaline Activators. Kidd. J. Mech. Ind. Eng.
2014, 8, 35–42.
[38] Varatharajulu, M.; Jayaprakash, G.; Baskar, N.; Suresh Kumar, B. Application of RSM and
Taguchi Methods for Optimizing the Transesterification of Waste Cooking Oil Catalyzed
by Solid Ostrich and Chicken-Eggshell Derived CaO. Asian J. Res. Soc. Sci. Humanit.
2017, 7, 1237–1251.