Pyrrolo[1,2-a]quinoxalines from chalcones: An alternate route

Article abstract of DOI:10.1016/j.tetlet.2021.153008

The synthesis of 2,4-disubstituted pyrrolo[1,2-a]quinoxalines from chalcones is reported. The key steps used are polyphosphoric acid (PPA) assisted acyl rearrangement of the pyrrole ring and Fe catalyzed reduction-cyclization leading to 2,4-disubstituted

Full text of DOI:10.1016/j.tetlet.2021.153008

Tetrahedron Letters 70 (2021) 153008
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pyrrolo[1,2-a]quinoxalines from chalcones: An alternate route
⇑
Uday Kumar Togiti, Adarash Kumar Shukla, Anupam Bhattacharya
Department of Chemistry, BITS-Pilani Hyderabad Campus, Hyderabad 500078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2,4-disubstituted pyrrolo[1,2-a]quinoxalines from chalcones is reported. The key steps
used are polyphosphoric acid (PPA) assisted acyl rearrangement of the pyrrole ring and Fe catalyzed
reduction-cyclization leading to 2,4-disubstituted pyrrolo[1,2-a]quinoxalines. Despite the utilization of
comparatively unreactive aromatic ketones, modest to good yields were obtained.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 21 January 2021
Revised 9 March 2021
Accepted 11 March 2021
Available online 16 March 2021
Keywords:
Pyrrolo[1,2-a]quinoxalines
Chalcones
Fe
Reduction-cyclization
Introduction
Pyrrolo[1,2-a]quinoxalines are an important synthetic target
due to their diverse bioactivities and photophysical properties
[1]. These compounds have shown potential as anti-leishmanial
and antitumor compounds as well as central dopamine antagonists
[2]. Additionally, compounds such as 1 and 2 also display 5-HT3
receptor and glucagon receptor antagonist activity, respectively
(Fig. 1) [3,4].
Our group has an ongoing interest in the synthesis of fused
heterocyclic systems and their applications [5]. With this experi-
ence, the synthesis of 2,4-disubstituted pyrrolo[1,2-a]quinoxalines
were envisaged. The synthesis of these compounds can generally
be segregated into two broad categories: (a) cyclization reactions
carried out on 1-arylpyrroles and (b) conversion of propiolates or
N-ylides to pyrrolo[1,2-a]quinoxalines via 1,3-dipolar cycloaddi-
tion [6]. Several alternative strategies have also been reported in
the literature, relying mainly on specific precursors or catalysts.
Ammermann and co-workers have demonstrated the synthesis of
1,4-disubstituted pyrrolo[1,2-a]quinoxalines via the annulation of
2-alkylquinoxalines. A unique feature of this reaction was incorpo-
rating a pyrrole ring in the last step using Ir(acac)3 as the catalyst
[7]. The synthesis of pyrrolo[1,2-a]quinoxalines was reported by
Guiffer and co-workers via the condensation of 2-methylquinoxa-
lines and ethyl bromopyruvate [8]. Wang and co-workers reported
the one-pot, three-component synthesis of 4,5-dihydropyrrolo[1,2-
a]quinoxaline under BF3.Et2O catalysis using o-phenylenediami-
Fig. 1. Pyrrolo[1,2-a]quinoxaline compounds with 5-HT3 receptor and glucagon
receptor antagonist activities.
⇑
Corresponding author.
E-mail address: anupam@hyderabad.bits-pilani.ac.in (A. Bhattacharya).
Scheme 1. Retrosynthetic analysis for the synthesis of 2,4-disubstituted pyrrolo
[1,2-a]quinoxalines.
https://doi.org/10.1016/j.tetlet.2021.153008
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Uday Kumar Togiti, Adarash Kumar Shukla and A. Bhattacharya
Tetrahedron Letters 70 (2021) 153008
of the final product is not possible. Our motivation was, therefore, to
start with a precursor that can be easily synthesized and subse-
quently converted to the target compounds. Accordingly, a retrosyn-
thetic approach was envisaged as shown in Scheme 1. The synthesis
was proposed to start with chalcones 1, which would be coverted
into 3,4-disubstituted pyrroles 2 using TosMIC (p-toluenesulfonyl-
methyl isocyanide). Subsequent rearrangement of the 3,4-disubsti-
tuted pyrroles would give their 2,4-disubstituted analogues. Finally,
an SNAr reaction, followed by reduction-cyclization would afford
the desired 2,4-disubstituted pyrrolo[1,2-a]quinoxalines.
Results and discussion
Our efforts towards the synthesis of 2,4-disubstituted pyrrolo
[1,2-a]quinoxalines started with the conversion of chalcones (1)
to the corresponding 2,3-disubstituted pyrroles (2) using the
well-known van Leusen synthesis [13]. The product bearing an acyl
linkage was then treated with polyphosphoric acid at 110 °C to
effect acyl rearrangement to the C-2 position of the pyrrole ring
(Scheme 2) [14]. Subsequent steps involved an SNAr reaction using
rearranged pyrrole (3) and 1-fluoro-2-nitrobenzene (4) as sub-
strates with K+–OC(CH3)3 and DMSO as the base and solvent,
respectively (Scheme 2).
Scheme 2. Synthesis of o-nitrophenyl appended 2,4-disubstituted pyrroles 5a-l
from chalcones.
nes, 2-alkoxy-2,3-dihydrofurans and ketones as substrates [9].
Zhang and co-workers reported the cyclization of 1-(N-arylpyr-
rol-2-yl)ethanone O-acetyl oximes for the synthesis of pyrrolo
[1,2-a]quinoxalines and their indole congeners [10]. A palladium-
catalyzed one-pot approach was reported by Keivanloo and
co-workers for the synthesis of trisubstituted pyrrolo[1,2-a]
quinoxalines using 3-substituted-2-chloroquinoxalines, propargyl
bromides and diverse secondary amines as precursors [11]. Finally,
Reddy and co-workers have reported the one-pot synthesis of
pyrrolo[1,2-a]quinoxalines using 1-(2-aminophenyl)pyrrole and
styrene as precursors with I2/IBX in DMSO as the oxidant [12].
A literature search revealed that most of the recent efforts utilize
precursors which are either difficult to synthesize or require expen-
sive/difficult to handle transition metal catalysts. Additionally, in the
cases with simple starting compounds, sufficient structural diversity
Next,
(1-(2-nitrophenyl)-4-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (5a) was utilized as a model substrate to optimize
the reaction conditions for the synthesis of 2,4-disubstituted pyr-
rolo[1,2-a]quinoxalines (Table 1). The main requirement of the
final step was to sequentially carry out the selective reduction of
the nitro group in the presence of a ketone functionality and imine
formation-cyclization reactions. Initial attempts (Entries 1–2) car-
ried out with NaBH4 (5 equiv.) and NiCl2Á6H2O (0.2 equiv.) in CH3-
CN-H2O [(1:2) and (9:1)] gave 2,4-diphenylpyrrolo[1,2-a]
quinoxaline (6a) in 20% and 40% yield, respectively. Increasing
the amount of NiCl2Á6H2O to 0.5 equivalents in CH3CN-H2O (9:1)
Table 1
Optimization of the reaction conditions.
Entry
Reagent [equiv.]
Solvent
Temp. (°C)
Time (h)
Yield
6a (%)a
1
2
3
4
5
6
7
8
NaBH4/NiCl2Á6H2O [5/0.2]
NaBH4/NiCl2Á6H2O [5/0.2]
NaBH4/NiCl2Á6H2O [5/0.5]
NaBH4/NiCl2Á6H2O [5/0.2]
NaBH4/NiCl2Á6H2O [5/0.2]
NaBH4/NiCl2Á6H2O [5/0.2]
Na2S2O4 [5]
CH3CN-H2O (1:2)
CH3CN-H2O (9:1)
CH3CN-H2O (9:1)
THF
THF-H2O (1:1)
THF-H2O (9:1)
EtOH-H2O (1:1)
CH3COOH
EtOH-CH3COOH-H2O (2:2:1)
CH3COOH
CH3COOH
CH3COOH
MeOH
RT
RT
RT
RT
RT
RT
RT
90
90
90
90
90
70
90
90
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
2
2
2
2
20
40
38
–
40
–
–
46
–
Fe [5]
9
Fe [5]
10
11
12
13
14
15
Fe [1]b
–
Fe [3]
Fe [7]
Fe/CaCl2 [5/0.2]
Fe/NH4Cl [5/5]
Fe/NH4Cl [5/5]
45
38
–
–
–
12
12
12
1,4-dioxane-H2O (9:1)
THF-H2O (9:1)
a
Isolated yields;
Incomplete conversion, product was not isolated.
b
2

Uday Kumar Togiti, Adarash Kumar Shukla and A. Bhattacharya
Tetrahedron Letters 70 (2021) 153008
Table 2
Synthesis of various 2,4-disubstituted pyrrolo[1,2-a]quinoxalines.
(Entry 3) did not improve the yield (38%). Next, the reaction with
NaBH4/NiCl2Á6H2O [5/0.2] in either THF or a THF-H2O combination
were carried out (Entries 4–6), which gave the highest yield of 40%
when the THF-H2O ratio was 1:1. The reaction was also attempted
with sodium dithionite (Entry 7) based on literature precedence,
which did not give 2,4-diphenylpyrrolo[1,2-a]quinoxaline 6a in
3

Uday Kumar Togiti, Adarash Kumar Shukla and A. Bhattacharya
Tetrahedron Letters 70 (2021) 153008
isolable yields [15]. When Fe was used to facilitate the reduction of
the nitro group in acetic acid, the desired product was obtained in
46% yield (Entry 8). However, the reaction using Fe in EtOH:CH3-
COOH:H2O (2:2:1) was not successful (Entry 9). Attempting the
reaction with a reduced concentration of Fe (Entries 10, 11) gave
2,4-diphenylpyrrolo[1,2-a]quinoxaline 6a in 45% yield when three
equivalents were used (Entry 11), while incomplete conversion
was observed when one equivalent was used (Entry 10). When
the reaction was carried out with an increased amount of Fe (Entry
12), 2,4-diphenylpyrrolo[1,2-a]quinoxaline 6a was obtained in 37%
yield. The attempted reduction with Fe in combination with either
CaCl2 or NH4Cl (Entries 13–15) did not give 2,4-diphenylpyrrolo
[1,2-a]quinoxaline 6a. Based on the screening, reduction with five
equivalents of Fe in acetic acid was identified as the optimized
reaction conditions.
Acknowledgements
The authors acknowledge BITS-Pilani for providing a PhD fel-
lowship (UKT) and for providing the necessary analytical facilities.
The authors also gratefully acknowledge the Council for Scientific
and Industrial Research (CSIR), New Delhi for the research grant
[02 (0350)/19/EMR-II].
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153008.
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The optimized reaction conditions were subsequently used on
various N-substituted pyrrole derivatives (Table 2). Initial attempts
were carried out on substrates 5b-d with an unsubstituted benzoyl
moiety at the 2-position and different para-substituted phenyl
rings at the 4-position. Compounds 6b-d were obtained in 41–
58% yield. The outcome of the reaction showed no dependence
on the electron-withdrawing or electron-donating ability of the
substituents, as comparable yields of 58% and 55% were obtained
for 6c and 6d, respectively. Substrates 5e-f with di-substituted
phenyl rings at the 4-position and an unsubstituted benzoyl moi-
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outcome indicates the suitability of the reaction conditions even
when using sterically encumbered substrates. Compounds 5g-i
containing a substituted benzoyl group at the 2-position and an
unsubstituted phenyl ring at the 4-position gave 2,4-disubstituted
pyrrolo[1,2-a]quinoxalines 6 g-i in 39–50% yield. The compara-
tively better yield of 50% in the case of substrate 5 h with a p-meth-
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In summary, an alternative strategy has been reported for the
synthesis of pyrrolo[1,2-a]quinoxalines from readily available
chalcones. The developed method allows the exclusive synthesis
of 2,4-disubstituted pyrrolo[1,2-a]quinoxalines in four simple
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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