An efficient synthesis, characterization and docking studies of 2-Methoxy-3-(1-substituted-1H-pyrazol-3-yl)quinoxalines

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.