Quinoxaline subsidiaries are a significant class of
nitrogen-containing heterocycles, as they establish
helpful intermediates in organic synthesis. This
substructure plays a significant role as an essential
skeleton for the plan of various heterocyclic
compounds with various biological activities, hence
thesecompounds significant in the fields of
antitumor, anticonvulsant, antimalarial, antiinflammatory, antiamoebic, antioxidant,
antidepressant, antiprotozoal, antibacterial, anti-HIV
agents,[1-10] fluorescent dying agents,
electroluminescent materials, chemical switches,
cavitands and semiconductors.[11-17]
Pyrazole subsidiaries are a fascinating class of
organic compounds, which are seen as related with
different pharmacological properties, for
example,antimicrobial,[18,19] anti-inflammatory,[20]
antihypertensive,[21] antidepressant,[22] antiviral[23]
and anticancer[24] activities.
Owing biological significance of Quinoxaline
and Pyrazole subsidiaries, we herein report the
synthesis of title compounds.
2. MATERIALS AND METHODS
All the chemical, reagents and solvents used in this
work were purchased either from sd/Fluka or Merck.
The progress of the reactions was monitored by
Thin-layer chromatography (TLC) which was
performed on E. Merck AL silica gel 60 F254 plates
and visualized under ultraviolet (UV) light. 1H NMR
and 13C NMR spectra were recorded using Varian
NMR‐400 MHz and 100 MHz instruments
respectively. All the chemical shifts were reported in
δ (ppm) using TMS as an internal standard. Signals
are indicated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad); and coupling
constants in Hz. Mass spectra were recorded with a
PESciex model API 3000 mass spectrometer.
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Cite this paper: Vietnam J. Chem., 2021, 59(2), 153-158 Article
DOI: 10.1002/vjch.202000139
153 Wiley Online Library © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
An efficient synthesis, characterization and docking studies of
2-methoxy-3-(1-substituted-1H-pyrazol-3-yl)quinoxalines
Muralidhar Reddy Rachala
1
, Laxminarayana Eppakayala
2
, Giri Tharikoppula
2
,
Thirumala Chary Maringanti
3*
1
Vidya Jyothi Institute of Technology, Aziz Nagar Gate, Hyderabad-500 075, Telangana, India
2
Sreenidhi Institute of Science and Technology (Autonomous), Ghatkesar, -501301 Telangana, India
3
Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, -500 085 Telangana India
Submitted August 13, 2020; Accepted October 18, 2020
Abstract
A basic, proficient and P-TSA catalyzed synthesis of quinoxalines beginning from ethyl 3-methoxyquinoxaline-2-
carboxylate in great yields is introduced. All the compounds synthesized were analyzed by spectral analysis.
Keywords. Quinoxalines, P-TSA, pyrazole, Docking studies.
1. INTRODUCTION
Quinoxaline subsidiaries are a significant class of
nitrogen-containing heterocycles, as they establish
helpful intermediates in organic synthesis. This
substructure plays a significant role as an essential
skeleton for the plan of various heterocyclic
compounds with various biological activities, hence
thesecompounds significant in the fields of
antitumor, anticonvulsant, antimalarial, anti-
inflammatory, antiamoebic, antioxidant,
antidepressant, antiprotozoal, antibacterial, anti-HIV
agents,
[1-10]
fluorescent dying agents,
electroluminescent materials, chemical switches,
cavitands and semiconductors.
[11-17]
Pyrazole subsidiaries are a fascinating class of
organic compounds, which are seen as related with
different pharmacological properties, for
example,antimicrobial,
[18,19]
anti-inflammatory,
[20]
antihypertensive,
[21]
antidepressant,
[22]
antiviral
[23]
and anticancer
[24]
activities.
Owing biological significance of Quinoxaline
and Pyrazole subsidiaries, we herein report the
synthesis of title compounds.
2. MATERIALS AND METHODS
All the chemical, reagents and solvents used in this
work were purchased either from sd/Fluka or Merck.
The progress of the reactions was monitored by
Thin-layer chromatography (TLC) which was
performed on E. Merck AL silica gel 60 F254 plates
and visualized under ultraviolet (UV) light.
1
H NMR
and
13
C NMR spectra were recorded using Varian
NMR‐400 MHz and 100 MHz instruments
respectively. All the chemical shifts were reported in
δ (ppm) using TMS as an internal standard. Signals
are indicated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad); and coupling
constants in Hz. Mass spectra were recorded with a
PESciex model API 3000 mass spectrometer.
Synthesis of 3-methoxyquinoxaline-2-carboxylic
acid (2): To a stirred solution of ethyl 3-
methoxyquinoxaline-2-carboxylate 1 (10 g, 43.08
mmol) in EtOH H2O (100 mL, 3:1) was added
LiOH.H2O (4.3 g, 86.17 mmol) and stirred the
reaction at 90
o
C for 6 h. Reaction was monitored by
TLC. After completion of reaction, solvent was
evaporated from reaction mixture up to three times,
poured the reaction mixture into ice water, acidified
with 2 N HCl (up to pH = 2) and filtered the formed
precipitate, washed the precipitate with water, dried
the product under reduced pressure to afford 3-
methoxyquinoxaline-2-carboxylic acid 2 (8 g, 91 %)
as off white solid.
1
HNMR (DMSO-d6, 400 MHz): 10.31 (brs,
1H), 8.09 (d, 2H, J = 8.2 Hz), 7.82 (t, 2H, J = 4.0
Hz), 3.78 (s, 3H); ESI-MS: m/z, 205.1 (M+H)
+
.
Synthesis of N,3-dimethoxy-N-
methylquinoxaline-2-carboxamide (3): To a stirred
solution of 3-methoxyquinoxaline-2-carboxylic acid
2 (8 g, 39.21 mmol) in DMF (40 mL) was added
Vietnam Journal of Chemistry Thirumala Chary Maringanti et al.
© 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 154
DIPEA(20.2 g, 156.8 mmol), HOBT(10.59 g, 78.43
mmol), EDC.HCl (15 g, 78.43 mmol) and stirred the
reaction at room temperature for 15 min. then added
N,O dimethyl hydroxylamine (2.87 g, 47.05 mmol)
and stirred the reaction at room temperature for 18 h.
After completion of reaction, reaction mixture was
poured into water and filtered the formed precipitate,
dried the precipitate under reduced pressure to afford
N,3-dimethoxy-N-methylquinoxaline-2-
carboxamide 3 (8 g, 83 %) as brown solid.
1
HNMR
(DMSO-d6, 400 MHz): 8.11 (d, 2H, J = 8.0 Hz),
7.81 (t, 2H, J = 8.0 Hz, 3.2 Hz);2.79 (s, 3H), 3.52 (s,
3H), 3.72 (s, 3H). ESI-MS: m/z, 247.9 (M+H)
+
.
N
N
N
N
O
N
N
O
O
N
N
N
O
O
HO
N
N
O
O
O
1 2
3
4 6 a-d
O
NH
N
N
O
O
N
O
N
N
O
O
R-NH-NH2, P-TSA
5
R
DMF-DMA
MeMgBr, THF
EtOH, 90 0C, 6 h
EDC.HCl, HOBT
DMF, DIPEA
RT, 12 h 0 0C-RT, 6 h
DMF, 90 0C, 18 h EtOH, 100
0C, 6 h
R= H, Methyl, Ethyl, Phenyl
LiOH.H2O
Scheme 1: Synthesis of 2-methoxy-3-(1-substituted-1H-pyrazol-3-yl) quinoxalines
Synthesis of 1-(2-methoxyquinoxalin-3-yl)
ethanone (4): To a stirred solution of N,3-
dimethoxy-N-methylquinoxaline-2-carboxamide 3
(6g, 24.29 mmol) in THF (60 mL) at -78
o
C was
added methyl magnesium bromide solution (16.19
mL, 3 M, 48.58 mmol) in diethyl ether as drop wise
and stirred the reaction at room temperature for 6h.
Reaction was monitored by TLC. After completion
of reaction, cooled the reaction mixture to 0
o
C and
quenched with sat. NH4Cl solution, poured the
reaction mixture into ice water, extracted with
EtOAc, combined extracts were washed with water
followed by brine solution. Dried the extracts over
anhy.Na2SO4 and evaporated the solvent to afford
crude product. Crude product was purified by silica
gel (60-120) column chromatography; product was
eluted at 70 % ethyl acetate in pet ether to afford 1-
(2-methoxyquinoxalin-3-yl) ethanone 4 (4.1 g, 85
%) as off brown solid.
1
H-NMR (DMSO-d6, 400
MHz): 8.02 (d, 2H, J = 8.0 Hz), 7.75 (t, 2H, J = 8.0
Hz), 3.78 (s, 3H), 2.24 (s, 3H); ESI-MS: m/z, 202.9
(M+H)
+
Synthesis of 3-(dimethylamino)-1-(3-
methoxyquinoxalin-2-yl)prop-2-en-1-one (5): To a
stirred solution of 1-(2-methoxyquinoxalin-3-yl)
ethanone 4 (4 g, 19.80 mmol) in DMF (20 mL) was
added DMF-DMA (2.17 g, 29.70 mmol) at room
temperature and stirred the reaction at 100
o
C for 18
h. Reaction was monitored by TLC. After
completion of reaction, reaction mixture was poured
into ice water, extracted with EtOAc, combined
extracts were washed with water, brine solution.
Dried the extracts over anhy.Na2SO4 and evaporated
the solvent to afford crude product. Crude product
was purified by silica gel (60-120) column
chromatography; product was eluted at 3 % MeOH
in DCM to afford 2-methoxy-3-(1-alkyl-1H-pyrazol-
3-yl) quinoxaline 5 (3.75 g, 75 %) as gummy liquid.
1
H-NMR (DMSO-d6, 400 MHz): 8.02 (d, 2H, J
= 7.8 Hz), 7.78 (t, 2H, J = 7.8 Hz), 7.22 (d, 1H, J =
8.0 Hz), 6.73 (d, 8 Hz), 3.78 (s, 3H), 2.8 (s, 3H),
2.68 (s, 3H); ESI-MS: m/z, 257.9 (M+H)
+
Synthesis of 2-methoxy-3-(1-alkyl-1H-pyrazol-3-
yl) quinoxaline (6): To a stirred solution of 3-
(dimethylamino)-1-(3-methoxyquinoxalin-2-
yl)prop-2-en-1-one 5 (1 g, 3.88 mmol) in EtOH (10
mL) was added hydrazine derivatives (3.88 mmol),
P-TSA (134 mg, 0.77 mmol) at room temperature
and stirred the reaction at 100
o
C for 18 h. Reaction
was monitored by TLC. After completion of
reaction, reaction mixture was poured into water and
filtered the formed precipitate, dried the precipitate
under reduced pressure to afford crude product.
Crude product was purified by silica gel (60-120)
column chromatography, product was eluted at 2-3
% MeOH in DCM to afford 2-methoxy-3-(1-alkyl-
Vietnam Journal of Chemistry An efficient synthesis, characterization and docking
© 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 155
1H-pyrazol-3-yl) quinoxaline 6(a-d) and yields of
the products varied between 80-95 %. By adapting
this procedure the compounds 6(a-d) were
synthesized.
2-methoxy-3-(1H-pyrazol-3-yl)quinoxaline (6a):
Yield: 89 %;
1
H-NMR (DMSO-d6, 400 MHz):
10.26 (brs, 1H), 8.11 (d, 2H, J = 7.8 Hz), 7.94 (d,
1H, J = 9.8 Hz), 7.82 (t, 2H, J = 8.0 Hz), 7.63 (d,
1H, J = 9.8 Hz), 3.75 (s, 3H); ESI-MS: m/z 227
(M+H)
+
2-methoxy-3-(1-methyl-1H-pyrazol-3-
yl)quinoxaline (6b): Yield: 80 %;
1
H-NMR
(DMSO-d6, 400 MHz): 8.13 (d, 2H, J = 7.8 Hz),
7.93 (d, 1H, J = 9.8 Hz), 7.80 (t, 2H, J = 4.0 Hz),
7.62 (d, 1H, J = 9.8 Hz), 3.74 (s, 3H), 2.61 (s, 3H);
ESI–MS: m/z, 241 (M+H)+.
2-methoxy-3-(1-ethyl-1H-pyrazol-3-
yl)quinoxaline (6c): Yield: 85 %;
1
H-NMR
(DMSO-d6, 400 MHz): 8.10 (d, 2H, J = 7.8 Hz),
7.91 (d, 1H, J = 9.8 Hz), 7.79 (t, 2H, J = 8.0 Hz),
7.64 (d, 1H, J = 9.8 Hz), 3.75 (s, 3H), 2.62 (m, 2H),
1.31 (t, 3H, J = 3.5 Hz); ESI-MS: m/z, 255 (M+H)
+
.
2-methoxy-3-(1-phenyl-1H-pyrazol-3-
yl)quinoxaline (6d): Yield 95 %;
1
H-NMR (DMSO-
d6, 400 MHz): 8.12 (d, 2H, J = 7.8 Hz), 7.95 (d,
1H, J = 9.8 Hz), 7.80 (t, 2H, J = 8.0 Hz), 7.61 (d,
1H, J = 9.8 Hz), 7.40 (m, 5H), 3.78 (s, 3H);
13
C
NMR (DMSO-d6, 100 MHz): 155.02, 148.08,
142.01, 139.01, 138.0, 137.8, 132.2, 131.2, 128.8,
126.2, 122.05, 119.8, 110.80, 56.10; ESI-MS: m/z,
302.9 (M+H)
+
.
3. RESULTS AND DISCUSSION
3.1. Chemistry
The target compounds 6a-d was prepared as outlined
in scheme 1. The compound ethyl 3-
methoxyquinoxaline-2-carboxylate 1 was reacted
with LiOH.H2O in presence EtOH:Water to afford 3-
methoxyquinoxaline-2-carboxylic acid 2 as 90 %
yield. The resulting product was treated with N,O
dimethyl hydroxylamine in presence of EDC.HCl,
HOBT and afford N,3-dimethoxy-N-
methylquinoxaline-2-carboxamide 3 as 87 % yield.
Resulted amide was treated with methyl magnesium
bromide in THF then formed corresponding 1-(2-
methoxyquinoxalin-3-yl)ethanone 4 as 85 % yield.
This ketone was further treated with DMF-DMA and
get 2-methoxy-3-(1-alkyl-1H-pyrazol-3-yl)
quinoxaline 5 as 80 % yield. This compound 5 was
treated with different hydrazine derivatives in EtOH
in presence of P-TSA to afford corresponding
substituted pyrazole products 6(a-d) in excellent
yield. The structures of synthesized compounds were
confirmed by spectral analysis.
The
1
H NMR spectrum of compound 6d showed
a doublet peak at δ 8.12, 7.95, 7.80, 7.61
corresponding to quinoxaline and pyrazole rings,
multiplet at 7.40 indicating phenyl group and 3.78
singlet for three protons suggested the presence of
methyl group. In the
13
C NMR spectrum of
compound 8a peak at δ 56.1 indicated the presence
of ether group and the other signals corresponding to
aromatic carbons. Further support was also obtained
from the mass spectrum which showed peak at m/z =
302.9 corresponding to [(M+H)
+
] of the compound
6d.
3.2. Docking studies
The protein 1jff (tubulin) was downloaded from
RSC PDB and was docked.
[25]
Compound 6d was
the most efficient for inhibiting the structural protein
as shown in tables 1 and 2. The major aminoacids
which were involved in the binding of the
compounds were tyrosine, asparagines, alanine,
glutamine, glutamic acid, leucine, serine (figure 1).
Table 1: Docking results for Free energy of Binding
Rank
Est. Free
Energy
of
Binding
Est. Inhibition
Constant, Ki
vdW + Hbond
+ desolv Energy
Electrostatic
Energy
Total Intermolec.
Energy
Frequency
Interact.
Surface
1.
-4.45
kcal/mol
547.79 M -5.21 kcal/mol
-0.07
kcal/mol
-5.28 kcal/mol 50 % 586.527
Vietnam Journal of Chemistry Thirumala Chary Maringanti et al.
© 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 156
Table 2: Docking results of hydrogen bonding
Hydrogen bonds Polar Hydrophobic pi-pi Other
N2 ()
[3.27]
–
SER38
(O, OG)
N4 ()
[3.63]
–
SER38
(OG)
C14 ()
[3.39]
–
PRO35
(CB)
C13 ()
[3.31]
–
TYR55
(CD1,
CE1)
C7 ()
[3.90]
–
SER38
(CB)
N3 ()
[2.66]
–
SER38
(CB,
OG)
C9 ()
[3.89]
–
PRO40
(CG)
C14 ()
[3.79]
–
TYR55
(CD1)
C8 ()
[3.53]
–
SER38
(CB,
OG)
C10 ()
[3.46]
–
TYR55
(CE1,
CZ)
C18 ()
[3.64]
–
SER38
(CB)
C12 ()
[3.78]
–
TYR55
(CE1)
C9 ()
[3.35]
–
SER38
(OG)
C13 ()
[3.89]
–
SER38
(OG)
N2 ()
[3.67]
–
PRO40
(CB,
CG)
N3 ()
[3.83]
–
PRO40
(CG)
C2 ()
[3.04]
–
GLN42
(CD,
NE2,
OE1)
C1 ()
[3.31]
–
GLN42
(OE1)
N4 ()
[3.74]
–
TYR55
(CE1)
C11 ()
[3.76]
–
TYR55
(OH)
C10 ()
[3.51]
–
TYR55
(OH)
C2 ()
[3.87]
–
LYS468
(NZ)
Figure 1: Bonding involved in the binding of the ligand to the tubulin
Vietnam Journal of Chemistry An efficient synthesis, characterization and docking
© 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 157
Acknowledgements. The authors are thankful to
JNT University Hyderabad and Vidya Jyothi
Institute of Technology for providing the research
facilities to carry out this work.
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Corresponding author: M. Thirumala Chary
Jawaharlal Technological University Hyderabad
Hyderabad, Telangana State, India
Email: mtcharya@yahoo.com.