Iodine-catalyzed ultrasound-assisted construction of pyridines and their glutamine synthetase molecular docking

Article abstract of DOI:10.1002/jccs.201900389

Iodine-promoted facile protocol is designed for the production of pyridines at room temperature under ultrasound irradiation. Eleven pyridine derivatives in excellent yields (91–97%) are synthesized with 2 hr reaction time. Additional advantage of the pro

Full text of DOI:10.1002/jccs.201900389

Received: 13 October 2019
DOI: 10.1002/jccs.201900389
Accepted: 7 February 2020
A R T I C L E
Iodine-catalyzed ultrasound-assisted construction of
pyridines and their glutamine synthetase molecular
docking
Ramakanth Pagadala1
| Venkatesan Kasi1
| Shyam Perugu2
1Chemistry Division, H&S Department,
CVR College of Engineering, Hyderabad,
India
2Department of Biotechnology, National
Institute of Technology, Warangal, India
Abstract
Iodine-promoted facile protocol is designed for the production of pyridines at
room temperature under ultrasound irradiation. Eleven pyridine derivatives in
excellent yields (91–97%) are synthesized with 2 hr reaction time. Additional
advantage of the proposed ultrasound-assisted eco-friendly, cost-effective pro-
tocol is easy separation of product, and our in silico studies show good binding
affinity toward binding and made strong hydrogen interactions.
Correspondence
Ramakanth Pagadala, Chemistry Division,
H&S Department, CVR College of
Engineering, Ibrahimpatnam, Hyderabad,
India.
K E Y W O R D S
Email: pagadalaramakanth@gmail.com
C
C and C N bond formation, docking study, iodine, multicomponent, pyridines, ultrasound
1 | INTRODUCTION
pyridines in particular have fascinated researchers as they
constitute either partial or complete structural motifs in
In valued added organic transformations, the development
of green and efficient synthetic methodologies is a crucial
task for sustainable growth. Multicomponent reactions
(MCRs), which react three or more reactants in one pot, pre-
cisely deal with these key synthetic challenges.[1–3] Thus,
these reactions received great attention from academia
and industry, mainly for synthesizing biologically active
compounds.[4–6] For developing “Key Challenges Methodol-
ogy” (KCM) based on the formation of C C and C N
bonds, the MCR approach will be more preferred, if the
chemistry involved could be eco- and user-friendly.
In recent times, in the framework of KCM applications,
ultrasound-promoted organic syntheses have been attracting
further attention.[7–14] As per the current synthetic necessi-
ties and from the green chemistry point of view, KCM-
employing ultrasound protocols are welcome and ideal.
Highly substituted pyridine moieties are common in
many natural products, biologically active compounds,
functional organic molecules and materials.[15–19] While the
construction of N-heterocycles is one of the focus areas in
the field of synthetic organic chemistry; aryl functionalized
many biologically active compounds (Figure 1).[20,21]
Ultrasound promoted organic synthesis, as a green
energy source and user-friendly technique. It is well
known to accelerate the chemical reactions due to the
physical phenomenon of acoustic cavitation. As an acous-
tic cavitation, wave pressure causes vast number cavita-
tion bubbles to form, oscillate, and undergo vigorous
collapses of micrometrical bubbles, which can produce
the propagation of a force wave through a liquid between
the reactants.[22,23] This effect generates high temperature
and pressure within few microseconds to increase the
rate of reactions.[24–26] Considering the importance of
ultrasound chemistry, in this work, we compare the
silent process of pyridine synthesis with the ultrasound-
promoted KCM (Scheme 1).
2 | RESULTS AND DISCUSSION
From our previous investigations, we reported various
efficient synthetic methods for small heterocyclic
© 2020 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2020;1–7.
http://www.jccs.wiley-vch.de
1

2
PAGADALA ET AL.
compounds[27–31] and sonification methods for pyrazoles
and pyridines.[32,33] With continued interest in deve-
lopment of KCM, here we report a facile access of a
diverse range of polyfunctionalized pyridine-annulated
heterocyclic compounds by iodine-promoted cost-effective
protocols from aldehyde, malononitrile, aliphatic/cyclic
ketones, and ammonium hydroxide in acetonitrile/ethanol
at room temperature (RT) under ultrasound (Scheme 1).
We first conducted a trial reaction with freshly distilled
benzaldehyde (2.0 mmol), malononitrile (2.0 mmol),
ethyl methyl ketone (2.0 mmol), ammonium hydroxide
(4.0 mmol), and acetic acid (2 ml) in ethanol added to a
conical flask. The reaction mixture was irradiated under
sonochemical method at RT for 5 hr; the reaction gave no
expected product (Table 1, entry 2). However, when
iodine (25.0 mg) was used as a catalyst in refluxing aceto-
nitrile, the reactions completed within 3 hr (Table 1,
entry 3). With iodine as catalyst, under ultrasound and
RT, reaction completed in 2 hr 30 min (Table 1, entry 3)
with excellent yield. Using the selection of solvent, we
performed the reaction in ethanol (Table 1, entry 4), also
obtained excellent yields in the sonochemical method.
Choice of the solvent is an important part, in terms of
yields and in environmental point of view in chemical
industry and with impact on safety, expenditure, and
health issues.
FIGURE 1 Poly-functionalized pyridine derivatives having
diverse pharmacological properties
The idea of “green” solvents expresses the goal to
minimize the environmental impact resulting from the
use of solvents in chemical production. While ethanol is
a simple and green solvent, acetonitrile is not recom-
mendable from an environmental perspective. Using the
optimization conditions, we explored the wider scope of
substrates for the transformation in ethanol under ultra-
sound and results were promising giving good to excel-
lent yields with all the 11 different substrates investigated
(Table 2).
R
O
4
NC
CH3
CH3
H2N
N
H
O
R
6a-g
CN
Iodine, CH3CN or EtOH
)))))))), rt
O
NH4OH
R
CN
1a-g
2
3
NC
5
Ultrasound to accelerate organic synthesis has con-
firmed to be a useful tool for meeting the KCM goals of
avoiding use of expensive reagents and minimization the
waste. In addition, increasing the rate of reactions,
H2N
N
7a-g
SCHEME 1 Strategy for the Construction of Pyridines
TABLE 1 Optimization of reaction conditions for the synthesis of 6a
Conventional
Sonication
Time
Temp
(ꢀC)
Yielda
(%)
Time
(hr)
Temp
(ꢀC)
Yielda
(%)
Entry Product Catalyst Amount Solvent (hr)
1
2
3
4
5
6
6a
6a
6a
6a
6a
6a
Au/MgO 20.0 mg
Au/MgO 20.0 mg
EtOH
EtOH
CH3CN
EtOH
EtOH
EtOH
4.0
2.0
3.0
Rt
49
95
72
2.0
5.0
2.5
2.0
2.0
2.0
RT
RT
RT
RT
RT
RT
96
b
70
Iodine
Iodine
Iodine
Iodine
25.0 mg
25.0 mg
15.0 mg
35.0 mg
80
96
95
91
97
3.0
c
70
c
82
c
c
c
c
aIsolated yields.
bProducts was not found.
cReaction was not performed.
Abbreviation: RT, room temperature.

PAGADALA ET AL.
3
TABLE 2 Substrate scope for the synthesis of pyridines under
ultrasound irradiation in ethanol
Entry
Product
6a
R
Time (hr)
2.0
Yielda (%)
1
H
97
96
94
94
91
93
95
96
95
94
92
92
91
94
2
6b
4-OCH3
4-Br
1.5
3
6c
1.5
4
6d
6e
2-Cl
2.0
5
2-Br
2.0
6
6f
2-OCH3
4-N(CH3)2
H
2.0
7
6g
1.5
FIGURE 2 Molecular interactions of the synthesized
compound 6E with glutamine synthetase
8
7a
2.0
9
7b
4-OCH3
4-Br
1.5
10
11
12
13
14
7c
2.0
target protein file was prepared by removing the struc-
tural water molecule, heteroatoms, and co-factors by
leaving only the residues associated with protein by using
the Accelerys Discovery Studio 4.1 (ADS) tool was used
to prepare target protein file addition of polar hydrogens
to the macromolecule, an essential step to correct the cal-
culation of partial charge by keeping all other values as
default. The molecular docking was performed using
LigandFit module and obtained results were scrutinized
based on highest dock score and number of H-bonds by
SSViewer.[34] The docking studies revealed that all the
synthesized molecules exhibited excellent binding ener-
gies toward the receptor active sites.
7d
7e
2-Cl
2.0
2-Br
2.0
7f
2-OCH3
4-N(CH3)2
2.0
7g
2.0
aIsolated yields.
R
H
O
R
CN
H
CN
CN
O
CN
CN
I2
O
N
Michael addition
R
Molecular docking results are identified the finest
interacted ligands were scrutinized on the best ligand
binding poses were identified using the low binding
energy, high docking score and the number of H-bond-
ing, hydrophobic interactions at receptor site. From the
molecular docking studies, we identified that the 6E and
7G (Figures 2 and 3), made two hydrogen bond interac-
tions with less distance as shown in Table 3.
NH4OH
CN
R
R
R
CN
CN
Cyclization
N
NH2
N
NH2
N
NH2
H
6a-g
SCHEME 2 Plausible Scenario for the Reaction
3 | EXPERIMENTAL
reduction of energy requirements, and also support
cleaner reactions by improving yields and selectivity. On
the basis of the above optimal experimental results, a
plausible reaction scenario for the synthesis of pyridines
is illustrated in Scheme 2.
3.1 | Iodine promoted synthesis of
pyridine derivatives under silent
conditions (6a/7a)
A mixture of freshly distilled benzaldehyde (2.0 mmol),
malononitrile (2.0 mmol), cycloheptanone/ethyl methyl
ketone (2.0 mmol), ammonium hydroxide (4.0 mmol),
and iodine (25.0 mg) in EtOH (3 ml) at RT, were added
to a round-bottomed flask equipped with a magnetic stir-
rer and condenser. The mixture was heated at 70ꢀC
for the time specified in Table 2. Thin layer chromatogra-
phy (TLC) (EtOAc/hexane = 3:7) was used to monitor the
reaction progress. After completion of reaction, mixture
that was cooled to RT was diluted with water and organics
2.1 | Molecular modeling studies
The three-dimensional structure of glutamine synthetase
was retrieved from Protein Data Bank (PDB ID: 2BVC),
Molecular docking studies for the synthesized com-
pounds of 6A–6G and 7A–7G were performed. The prep-
aration of receptor structure and correction of protein
were performed using the Discovery Studio 4.1 suite. The

4
PAGADALA ET AL.
7.23–7.50 (5H, m); 13C NMR (100 MHz, CDCl3): δ 15.30,
23.72, 89.72, 116.80, 119.69, 128.33, 128.64, 128.77,
136.79, 153.86, 157.23, 161.57; IR (KBr, cm−1): 3,330
(NH2), 2,211 (CN); MS (ESI), m/z = 224 (M + 1, 100%);
Anal. Calcd (C14H13N3): C 75.31, H 5.87, N 18.82%.
Found: C 75.37, H 5.89, N 18.78%.
3.2.2 | Compound 6b
Off-white solid: 1H NMR (400 MHz, CDCl3) δ = 1.97
(3H, s, CH3), 2.44 (3H, s, CH3), 3.86 (3H, s, OCH3),
5.0 (2H, s, NH2), 6.98 (2H, d, J = 8.5 Hz), 7.17 (2H, d,
J = 8.5 Hz); 13C NMR (100 MHz, CDCl3): δ 15.36, 23.78,
55.29, 89.94, 114.05, 119.95, 128.90, 129.58, 129.81,
153.68, 157.25, 159.89, 161.46; IR (KBr, cm−1): 3,320
(NH2), 2,215 (CN); MS (ESI), m/z = 254 (M + Na, 100%);
Anal. Calcd (C15H15N3O): C 71.13, H 5.97, N 16.59%.
Found: C 71.19, H 5.99, N 16.66%.
FIGURE 3 Molecular interactions of the synthesized
compound 7G with glutamine synthetase
were extracted with ethyl acetate. The extract was washed
with saturated Na2S2O3 solution and dried over anhydrous
Na2SO4. The solvent was removed to obtain a precipitate,
which was washed from ethanol to obtain the pure target
compound 6a (82% yield), as an off-white solid.
3.2.3 | Compound 6c
1
Off-white solid: H NMR (400 MHz, CDCl3) δ = 1.94
(3H, s, CH3), 2.44 (3H, s, CH3), 5.02 (2H, s, NH2),
7.11 (2H, d, J = 8.2 Hz), 7.63 (2H, d, J = 8.1 Hz); 13C
NMR (100 MHz, CDCl3): δ 15.3, 23.79, 89.94, 112.48,
119.53, 129.72, 130.07, 131.98, 132.12, 153. 68, 157.23,
161.92; IR (KBr, cm−1): 3,327 (NH2), 2,212 (CN); MS
3.2 | Iodine promoted synthesis of
pyridine derivatives under sonochemical
conditions (6a–g/7a–g)
(ESI), m/z
= 325 (M + Na, 100%); Anal. Calcd
(C14H12BrN3): C 55.65, H 4.0, N 13.91%. Found: C 55.68,
H 4.07, N 13.96.
Benzaldehyde (2.0 mmol), malononitrile (2.0 mmol),
cycloheptanone/ethyl methyl ketone (2.0 mmol), ammo-
nium hydroxide (4.0 mmol), and iodine (25.0 mg) in
EtOH (3 ml) were added to 100 ml conical flask at
RT. The flask was immersed in the ultrasonic bath, and
irradiated for the required reaction times (Table 2). Using
TLC, reaction progress was monitored. The ultrasonic
bath temperature was maintained at (25 5)ꢀC manually
by addition of small amounts cool water. After comple-
tion of the reaction, water was added and ethyl acetate
was used to extract the organic components, which were
further washed with saturated Na2S2O3 solution and
dried over anhydrous Na2SO4. The precipitate, which
recovered after the removal of ethyl acetate was washed
from ethanol and then dried under vacuum to give the
pure final product 6a (95% yield), as an off-white solid.
3.2.4 | Compound 6d
1
Off-white solid: H NMR (400 MHz, CDCl3) δ = 1.88
(3H, s, CH3), 2.46 (3H, s, CH3), 5.03 (2H, s, NH2),
7.17–7.53 (4H, m); 13C NMR (100 MHz, CDCl3): δ
14.89, 23.66, 116.20, 120.43, 127.0, 127.22, 129.81,
129.94, 130.16, 130.30, 132.45, 151.14, 157.13, 161.71;
IR (KBr, cm−1): 3,329 (NH2), 2,211 (CN); MS (ESI),
m/z = 258 (M + 1, 100%); Anal. Calcd (C14H12ClN3):
C 65.25, H 4.69, N 16.30%. Found: C 65.29, H 4.74,
N 16.36%.
3.2.5 | Compound 6e
3.2.1 | Compound 6a
Off-white solid: 1H NMR (400 MHz, CDCl3) δ = 1.94
(3H, s, CH3), 2.52 (3H, s, CH3), 5.08 (2H, s, NH2),
7.19–7.58 (4H, m); 13C NMR (100 MHz, CDCl3): δ 14.69,
19.86, 116.25, 120.63, 127.20, 127.25, 129.82, 129.93,
Off-white solid: 1H NMR (400 MHz, CDCl3) δ = 1.95
(3H, s, CH3), 2.44 (3H, s, CH3), 5.05 (2H, s, NH2),

PAGADALA ET AL.
5
TABLE 3 Represents the docking score, hydrogen bond distance, and interacting atoms
Analog
6A
Receptor (2bvc) (interacting atoms)
GLY272-O
Ligand (atoms)
NH
O
H-bond distance (Ao)
Docking energy (kcal/mol)
2.51
2.60
3.43
2.60
2.70
2.57
2.95
2.52
2.60
2.43
2.60
3.01
3.25
3.53
2.48
3.30
3.74
3.33
2.45
3.51
2.52
2.60
2.72
2.44
3.06
3.20
3.09
3.51
3.56
2.69
3.12
3.11
3.20
3.22
3.14
3.33
3.38
2.23
2.59
−95.184
GLU219-OE1
GLU335-OE2
GLY272-O
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
6B
6C
6D
6E
6F
−94.349
−92.966
−94.534
−93.012
−89.354
GLY272-O
GLY272-O
GLY272-O
GLY272-O
GLU219-OE1
GLY272-O
GLY272-O
GLU219-OE1
ASP54-OD2
SER57-OG
6G
GLY272-O
−86.356
GLU135-OE1
GLU135-OE2
GLU335-OE2
GLU219-OE1
GLU219-OE2
GLU219-OE1
ARG368-NH2
GLY272-NH
GLU219-OE1
GLU135-OE2
GLU135-OE1
GLU335-O
7A
7B
−84.323
−91.221
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
7C
7D
7E
−83.787
−82.016
−88.387
GLU219-OE1
GLU135-OE2
GLU335-OE2
GLU335-OE2
ASP54-OD2
ARG368-NH2
GLU219-OE1
ASP54-OD2
7F
NH
NH
NH
O
−80.885
−94.379
SER57-OG
ARG368-NH2
GLU219-OE1
GLY272-O
7G
NH
NH
130.21, 130.30, 132.45, 151.14, 157.13, 161.73; IR (KBr,
cm−1): 3,324 (NH2), 2,209 (CN); MS (ESI), m/z = 325 (M
+ 1, 100%); Anal. Calcd (C14H12BrN3): C 55.65, H 4.00, N
13.91%. Found: C 55.69, H 4.06, N 13.98%.
3.2.6 | Compound 6f
Off-white solid: 1H NMR (400 MHz, CDCl3) δ = 1.89
(3H, s, CH3), 2.49 (3H, s, CH3), 3.79 (3H, s, OCH3),

6
PAGADALA ET AL.
5.08 (2H, s, NH2), 7.09–7.52 (4H, m); 13C NMR (100 MHz,
CDCl3): δ 14.69, 19.86, 55.51, 116.25, 120.68, 127.22,
127.26, 129.84, 129.93, 130.21, 130.30, 132.45, 151.14,
157.13, 161.73; IR (KBr, cm−1): 3,296 (NH2), 2,211 (CN);
MS (ESI), m/z = 276 (M + 1, 100%); Anal. Calcd
(C15H15N3O): C 71.13, H 5.97, N 16.59%. Found: C 71.18,
H 6.02, N 16.65%.
J = 5.4 Hz), 2.92 (2H, t, J = 5.4 Hz), 5.14 (2H, s, NH2),
7.10 (2H, d, J = 8.3), 7.60 (2H, d, J = 8.3); 13C NMR
(100 MHz, CDCl3): δ 26.14, 27.99, 28.97, 31.92, 39.67,
88.90, 116.76, 123.13, 126.26, 130.10, 131.93, 135.68,
151.73, 157.26, 168.25; IR (KBr, cm−1): 3,307 (NH2), 2,213
(CN); MS (ESI), m/z = 365 (M + Na, 100%); Anal. Calcd
(C17H16BrN3): C 59.66, H 4.71, N 12.28%. Found: C 59.74,
H 4.77, N 12.35%.
3.2.7 | Compound 6g
3.2.11 | Compound 7d
Off-white solid: 1H NMR (400 MHz, CDCl3) δ = 1.89
(3H, s, CH3), 2.47 (3H, s, CH3), 3.04 (6H, s,
N
Off-white solid: 1H NMR (400 MHz, CDCl3)
δ = 1.39–2.96 (10H, m), 5.18 (2H, s, NH2), 7.15–7.52 (4H,
m); 13C NMR (100 MHz, CDCl3): δ 26.11, 27.57, 29.27,
32.01, 39.77, 89.24, 116.34, 126.78, 127.12, 129.87, 129.91,
130.20, 132.58, 135.81, 150.33, 157.21, 168.07; IR (KBr,
cm−1): 3,313 (NH2), 2,214 (CN); MS (ESI), m/z = 320 (M
+ Na, 100%); Anal. Calcd (C17H16ClN3): C 68.57, H 5.42,
N 14.11%. Found: C 68.65, H 5.46, N 14.18%.
[CH3]2), 5.02 (2H, s, NH2), 6.98 (2H, d, J = 8.5 Hz), 7.17
(2H, d, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3): δ 15.49,
22.84, 40.28, 88.94, 113.86, 118.25, 128.84, 129.61, 129.86,
153.58, 157.27, 159.82, 161.42; IR (KBr, cm−1): 3,319
(NH2), 2,215 (CN); MS (ESI), m/z = 289 (M + Na, 100%);
Anal. Calcd (C16H18N4): C 72.15, H 6.81, N 21.04%.
Found: C 72.19, H 6.89, N 21.09%.
3.2.8 | Compound 7a
3.2.12 | Compound 7e
1
Off-white solid: 1H NMR (400 MHz, CDCl3)
δ = 1.47–1.52 (2H, m), 1.69–1.82 (4H, m), 2.46 (2H, t,
J = 5.4 Hz), 2.92 (2H, t, J = 5.5 Hz), 5.11 (2H, s, NH2),
7.21–7.49 (5H, m); 13C NMR (100 MHz, CDCl3): δ 26.18,
28.03, 28.97, 31.98, 39.67, 89.33, 116.94, 126.42, 128.38,
128.60, 128.68, 136.85, 153.11, 157.22, 167.96; IR (KBr,
cm−1): 3,316 (NH2), 2,212 (CN); MS (ESI), m/z = 286 (M
+ Na, 100%); Anal. Calcd (C17H17N3): C 77.54, H 6.51, N
15.96%. Found: C 77.67, H 6.58, N 15.98%.
Off-white solid: H NMR (400 MHz, CDCl3) δ = 1.38–3.0
(10H, m), 5.14 (2H, s, NH2), 7.14–7.70 (4H, m); 13C NMR
(100 MHz, CDCl3): δ 26.11, 27.54, 29.27, 32.01, 39.80,
89.17, 116.28, 122.30, 126.58, 127.71, 129.79, 130.29,
133.03, 137.91, 151.86, 157.13, 168.14; IR (KBr, cm−1):
3,312 (NH2), 2,214 (CN); MS (ESI), m/z = 365 (M + Na,
100%); Anal. Calcd (C17H16BrN3): C 59.66, H 4.71, N
12.28%. Found: C 59.69, H 4.76, N 12.34%.
3.2.13 | Compound 7f
3.2.9 | Compound 7b
Off-white solid: 1H NMR (400 MHz, CDCl3)
δ = 1.42–2.94 (10H, m), 3.78 (3H, s, OCH3), 5.03 (2H, s,
NH2), 6.99–7.43 (4H, m); 13C NMR (100 MHz, CDCl3): δ
26.18, 27.65, 29.40, 32.13, 39.76, 55.46, 90.08, 111.11,
117.03, 120.74, 125.59, 127.36, 130.0, 130.39, 150.33,
156.11, 157.16, 167.37; IR (KBr, cm−1): 3,296 (NH2), 2,210
(CN); MS (ESI), m/z = 316 (M + Na, 100%); Anal. Calcd
(C18H19N3O): C 73.69, H 6.53, N 14.32%. Found: C 73.75,
H 6.58, N 14.39%.
Off-white solid: 1H NMR (400 MHz, CDCl3)
δ = 1.48–1.53 (2H, m), 1.70–1.84 (4H, m), 2.49 (2H, t,
J = 5.4 Hz), 2.91 (2H, t, J = 5.4 Hz), 3.85 (3H, s, OCH3),
5.07 (2H, s, NH2), 6.98 (2H, d, J = 8.6), 7.15 (2H, d,
J = 8.6); 13C NMR (100 MHz, CDCl3): δ 26.20, 28.06,
28.91, 32.0, 39.69, 55.28, 89.59, 114.03, 117.21, 126.69,
128.97, 129.82, 152.94, 157.24, 159.82, 167.86; IR (KBr,
cm−1): 3,318 (NH2), 2,213 (CN); MS (ESI), m/z = 294 (M
+ 1, 100%); Anal. Calcd (C18H19N3O): C 73.69, H 6.53, N
14.32%. Found: C 73.78, H 6.57, N 14.39%.
3.2.14 | Compound 7g
3.2.10 | Compound 7c
Light yellow solid: 1H NMR (400 MHz, CDCl3)
δ = 1.52–1.81 (6H, m), 2.56 (2H, t, J = 5.3 Hz), 2.91 (2H,
t, J = 5.4 Hz), 3.01 (6H, s, N[CH3]2), 4.96 (2H, s, NH2),
6.76 (2H, d, J = 8.6), 7.11 (2H, d, J = 8.6); 13C NMR
Off-white solid: 1H NMR (400 MHz, CDCl3)
δ = 1.48–1.51 (2H, m), 1.70–1.84 (4H, m), 2.44 (2H, t,

PAGADALA ET AL.
7
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(100 MHz, CDCl3): δ 26.25, 28.15, 28.90, 32.06, 39.73,
40.26, 88.90, 111.77, 123.13, 124.04, 126.79, 129.63,
135.68, 150.42, 153.68, 157.28, 167.58; IR (KBr, cm−1):
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100%); Anal. Calcd (C19H22N4): C 74.48, H 7.24, N
18.29%. Found: C 74.55, H 7.28, N 18.35%.
4 | CONCLUSIONS
In conclusion, we have developed new iodine-promoted
sonochemical domino reaction for the construction of
poly-substituted pyridines from readily available mate-
rials and cost-effective catalyst. In comparison with ear-
lier reported methods, this green protocol is attractive, as
a wider range of biologically important substrates can be
easily introduced in this ultrasound method. This proto-
col proceeded under KCM conditions and afforded the
preferred products in good to excellent yields (91–97%).
Our in silico studies revealed that strong binding of recep-
tor with compounds of 6E and 7G, made two hydrogen
bond interactions with less distance.
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S. B. Jonnalagadda, Cat. Comm. 2014, 45, 148.
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Adv. 2014, 4, 6602.
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ACKNOWLEDGMENTS
The authors are grateful to CVR College of Engineering
for encouraging and providing necessary facilities for car-
rying out this work.
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Int. 2014, 46, 261.
ORCID
Ramakanth Pagadala https://orcid.org/0000-0002-
9248-1846
Venkatesan Kasi https://orcid.org/0000-0001-8010-0009
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Pagadala R, Kasi V,
Perugu S. Iodine-catalyzed ultrasound-assisted
construction of pyridines and their glutamine
synthetase molecular docking. J Chin Chem Soc.
2020;1–7. https://doi.org/10.1002/jccs.201900389
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