One-pot, two-step synthesis of substituted triazoloquinoxalinone starting from 3-hydrazineylquinoxalin-2(1H)-one

Article abstract of DOI:10.1080/00397911.2021.1918171

An efficient one-pot two-step synthesis of substituted-triazolo[4,3-a]quinoxalin-4(5H)-one has been developed. The 3-hydrazineylquinoxalin-2(1H)-one reacts with respective aldehyde to afford the individual hydrazineylidene intermediate which undergoes oxidative cyclization in the presence of ferric chloride hexahydrate (FeCl₃.6H₂O) to affords various substituted- triazolo[4,3-a]quinoxalin-4(5H)-one in good to excellent yields.

Full text of DOI:10.1080/00397911.2021.1918171

Synthetic Communications
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Chemistry
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One-pot, two-step synthesis of substituted
triazoloquinoxalinone starting from 3-
hydrazineylquinoxalin-2(1H)-one
Vikas S Patil, Subba Rao Yadavalli, Ramchander Merugu, Swamy S J &
Nagaraju Devunuri
To cite this article: Vikas S Patil, Subba Rao Yadavalli, Ramchander Merugu, Swamy S J &
Nagaraju Devunuri (2021) One-pot, two-step synthesis of substituted triazoloquinoxalinone starting
from 3-hydrazineylquinoxalin-2(1H)-one, Synthetic Communications, 51:13, 1994-2000, DOI:
10.1080/00397911.2021.1918171
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https://doi.org/10.1080/00397911.2021.1918171
One-pot, two-step synthesis of substituted
triazoloquinoxalinone starting from
3
-hydrazineylquinoxalin-2(1H)-one
a
a
b
c
Vikas S Patil , Subba Rao Yadavalli , Ramchander Merugu , Swamy S J , and
a
Nagaraju Devunuri
a
Division of Chemistry, Department of Sciences & Humanities, Vignan’s Foundation for Science,
b
Technology & Research (VFSTR) Deemed University, Guntur, India; Department of Bio Chemistry,
Mahatma Gandhi University, Nalgonda, India; Department of Chemistry, Kakatiya University,
c
Warangal, India
ABSTRACT
ARTICLE HISTORY
An efficient one-pot two-step synthesis of substituted-triazolo[4,3-
a]quinoxalin-4(5H)-one has been developed. The 3-hydrazineylquinox-
alin-2(1H)-one reacts with respective aldehyde to afford the individual
hydrazineylidene intermediate which undergoes oxidative cyclization
in the presence of ferric chloride hexahydrate (FeCl .6H O) to affords
various substituted- triazolo[4,3-a]quinoxalin-4(5H)-one in good to
excellent yields.
Received 27 February 2021
KEYWORDS
Hydrazine; ferric chloride; 3-
hydrazineylquinoxalin-
3
2
2
(1H)-one
GRAPHICAL ABSTRACT
Introduction
The synthesis of heterocyclic compounds is one of the most research areas in synthetic
[
1a–e]
organic chemistry due to its high medicinal value.
cyclic molecules having nitrogen, oxygen, and Sulfur exhibits a wide variety of biological
It is well-known fact that hetero-
[
1f–i]
activities
tains in their skeleton.
and most of the marketed drug molecule has one or more nitrogen con-
[
2]
The imidazoquinoxalinone or triazoloquinoxalinone com-
pound(s) has the effect of inhibiting PDE9 and can serve as an active ingredient in a
therapeutic and prophylactic agent of urine retention disorders, urination disorders,
[
3]
bladder, and urinary tract diseases, and anti-convulsing agents, etc.
Thus, due to the diverse range of the biological activities of trizoloquainoxaline scaf-
folds, attempted to synthesize these molecules particularly by following oxidative cyc-
lization to construct the triazolo ring. These are the main synthetic schemes were used
CONTACT Nagaraju Devunuri
naag1977@gmail.com
Division of Chemistry, Department of Sciences &
Humanities, Vignan’s Foundation for Science, Technology & Research (VFSTR) Deemed University, Vadlamudi, Guntur,
Andhra Pradesh 522 213, India.
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2021.1918171
ß 2021 Taylor & Francis Group, LLC

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Scheme 1. Synthetic strategies for the generation of Substituted triazoquinaxalinone (previous
and current).
for the construction of triazolo ring after generating the hydizinoimine 3a
[
4]
(Scheme 1).
Graphical representations (Scheme 2)
Another popular method is to make the hydrzino amide 6a and then go for oxida-
[
5]
tive cyclization to get the desired product 7 (Scheme 3).
All these reported methods are used in synthesizing the variety of substituted triazo-
loquinoxalinone but they have some limitations are drawbacks for instance in catalytic
reactions mediated by copper, it becomes difficult to sometimes erase the traces of cop-
per owing to chelation and often needs multiple attempts before one can get pure
material. The other method doesn’t require the metal but it required a very high tem-
perature that is not compatible with the heat-labile functional group. Although the
IBDA method was good, it involves hypervalent iodine reagent, which is expensive, and
generating organic waste which required rigorous purification techniques material.
[
6]
Moreover, hypervalent reagents have some safety limitations. Given the facts men-
tioned above, a general and relatively safer method for the synthesis of the triazoloqui-
noxalinone has been attempted. This prompted us to design and investigate a robust
method for the synthesis of triazoloquinoxalinone. To make the synthetic process less

1
996
V. S. PATIL ET AL.
cumbersome and safer, we have demonstrated an effective approach for the one-pot
two-step synthesis of triazoloquinoxalinone.
Result and discussion
The 3-hydrazinylquinoxalin-2(1H)-one (7) has been prepared as per literature referen-
[
7]
ces which is further used for the preparation of imines derivative as an intermediate
[
7]
(6) for methodological scope and screening purpose (Scheme 4).
FeCl .6H O attracted us to investigate the oxidative cyclization of 6 because of it is
3
2
an environment friendly, operational simplicity in nature. To do the oxidative cycliza-
tion, we have decided to explore the FeCl .6H O because of its cheap, easy to handle,
3
2
Scheme 2. Synthesis of bioactive triazoloquinoxalinone.
Scheme 3. Synthesis of substituted triazoloquinoxalinone.
Scheme 4. Conversion of diaminobenzene to triazoloquinoxalinone (7a–7k).

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[
8,9]
its consideration as green reagents,
Figure 1).
To validate the usage of FeCl 6H O at the oxidative cyclization step, we have decided
and ease to remove from the reaction mixture
(
3
.
2
to synthesize the intermediate (6) starting from diaminobenzene (1). After preparing
the imine intermediate (6), FeCl .6H O was added to the same reaction mixture and
3
2
stirred for 16 h at room temperature. To our delight, we observed the formation of
desired cyclized compound (7) with a 96% isolation yield. This result encouraged us to
optimize the reaction conditions we have screened the various solvents to as summar-
ized in Table 1.
It observed that solvent has a great influence on yield, in polar solvent reaction worked
better in compression to nonpolar solvent. Moreover, the protic polar solvent much bet-
ter may be due to the high degree of solubility of FeCl .6H O. In both methanol and
3
2
acetonitrile yields are comparable, but for optimization, purpose methanol was the choice
of solvent due to low cost. After selecting the solvent, we have also screened the different
mole ratios of FeCl . 6H O. The results are summarized in Table 1 (entry 8,9,10).
3
2
It is observed that by using the 5 equivalents of FeCl .6H O the reaction works very
3
2
well, and 96% of isolated yield is acquired. After this, we have also tried to reduce the
reaction time by increasing the temperature, but it was observed that increasing the
temperature does not have much effect on the rate of reaction. Finally, we have applied
the optimized condition to synthesize a variety of substituted triazoloquinoxalinone.
The results are summarized in Table 2.
Figure 1. Plausible reaction mechanism.
Table 1. Screening of Various solvents with FeCl .6H O acting as a reagent.
3
2
S.NO
Reagent
Equivalents
Solvents
Yield (%)
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
3
3
3
3
3
3
3
3
3
.6H
.6H
.6H
.6H
.6H
.6H
.6H
.6H
.6H
.6H
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.0
5.0
6.0
Dichloromethane
Isopropanol
Tetrahydrofuran
Methanol
Acetone
Acetonitrile
N, N-Dimethylformamide
Methanol
Methanol
Methanol
0%
27%
61%
74%
52%
66%
45%
85%
96%
96%
1
0

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V. S. PATIL ET AL.
Table 2. Conversion of Aldehydes to substituted triazoloquinoxalinone
Conclusion
In conclusion, we have developed a very efficient one-pot two-step method for the syn-
thesis of substituted-triazolo[4,3-a]quinoxalin-4(5H)-one. This reaction required
FeCl .H O, which less toxic and relatively more enviro-friendly. Moreover, workup and
3
2
purification are very easy; therefore, they will be very useful for large-scale synthesis.
Experimental section
General procedure for the synthesis of triazoloquinoxalinone (7)
A solution of 3-hydrazinylquinoxalin-2(1H)-one (1.0 equivalent) in methanol (35 V),
followed by the addition of a catalytic amount of acetic acid (1–2 drops) and aldehyde
ꢀ
(
1.1 eq) was heated at 45–50 C for 1–3 h, the reaction progress monitored by TLC,
after consumption of starting compound to in situ imine product then added ferric
chloride hexahydrate (5-mole eq) and stirred resulting dark greenish mixture at room

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temperature, as reaction progress the dark solutions turn into light brown color, again
the reaction progress monitored by TLC, after consumption of imine compound, dis-
tilled the methanol under reduced pressure to obtained residue then added water and
stirred for 15–20 min. The yellow solid precipitated was filtered and washed with water
till the filtrate pH is getting neutral, then the further product was recrystallized to afford
the triazoloquinoxalinone.
[
4c]
1-Phenyl-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (7a)
[
4 ]
–1
Yield: 357 mg (96%), Light yellow solid; m.p.: 322–324 c ; FT-IR (KBr): 1673.48 cm
–1
1
-
1
C ¼ O stretching, 3125.35 cm : -N-H stretching; H NMR (400 MHz, DMSO-d6):
w
13
2.11 (s, 1H), 7.27–7.67 (m, 5H), 7.37–7.39 (m, 2H) & 7.00–7.05 (m, 2H); C NMR
151.91, 150.62, 144.26, 130.99, 129.84, 129.43, 129.18, 128.16,
(100 MHz, DMSO-d6):
w
1
27.11, 122.54, 120.84, 117.17 & 116.06; LC-MS Purity: 99.79%; Mass: 263.02 (M þ 1);
þ
HRMS found: ESI m/z 263.0918 (M þ H) , [M.F: C H ON requires 263.0927].
15
11
4
Supporting information
Supplementary data of compounds synthesized: Full characterization data, H, and
1
13
C
NMR spectra, LCMS traces IR spectra, and HRMS. This material can be found via the
supplementary content section of this article’s webpage.
Acknowledgment
We are extremely thankful to VFSTR University for financial support and analytical facilities for
the execution of this research work. My special thanks to Dr. Arunendra Pathak for helping us
whenever we required.
Funding
The present research was financially supported by Vignan’s Foundation for Science, Technology
and Research.
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