Route to pyrrolo[1,2-a]quinoxalines via a furan ring opening-pyrrole ring closure sequence

Article abstract of DOI:10.1016/j.tetlet.2019.151532

A method was developed for the synthesis of pyrrolo[1,2-a]quinoxalines based on an acid-promoted furan ring opening of readily accessible N-(furan-2-ylmethyl)-2-nitroanilines or their heterocyclic analogues followed by a key reductive Paal-Knorr cyclization of the corresponding nitro-1,4-diketones.

Full text of DOI:10.1016/j.tetlet.2019.151532

Journal Pre-proofs
Route to Pyrrolo[1,2–a]quinoxalines via a Furan Ring Opening–Pyrrole Ring
Closure Sequence
Elena Y. Zelina, Tatyana A. Nevolina, Ludmila N. Sorotskaja, Dmitry A.
Skvortsov, Igor V. Trushkov, Maxim G. Uchuskin
PII:
S0040-4039(19)31331-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151532
TETL 151532
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 October 2019
9 December 2019
15 December 2019
Please cite this article as: Zelina, E.Y., Nevolina, T.A., Sorotskaja, L.N., Skvortsov, D.A., Trushkov, I.V., Uchuskin,
M.G., Route to Pyrrolo[1,2–a]quinoxalines via a Furan Ring Opening–Pyrrole Ring Closure Sequence, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151532
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Route to Pyrrolo[1,2-a]quinoxalines via a
Furan Ring Opening–Pyrrole Ring Closure
Sequence
Leave this area blank for abstract info.
Elena Y. Zelina,a Tatyana A. Nevolina,a Ludmila N. Sorotskaja,b Dmitry A. Skvortsov,c,d Igor V. Trushkov,e,f
and Maxim G. Uchuskina*
a Perm State University, Bukireva st. 15, Perm, 614990 Russian Federation; E-mail: mu@psu.ru
b Kuban State Technological University, Moskovskaya st. 2, Krasnodar, 350072, Russian Federation
c M. V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow, 119991 Russian Federation
d Higher School of Economics, Myasnitskaya st. 13, Moscow, 101000, Russian Federation
e N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, Leninsky pr. 47, Moscow, 119991,
Russian Federation
f D. Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela
st. 1, Moscow, 117997 Russian Federation
R1
N
NO2
NO2
H3O
[H]
X
N
R2
X
N
R2
X
N
R2
O
O
O
R1
R1
Elena Y. Zelina,a Tatyana A. Nevolina,a Ludmila N.
Sorotskaja,b Dmitry A. Skvortsov,c,d Igor V.
Trushkov,e,f and Maxim G. Uchuskina*
Tetraheda PreormnState University, Bukireva st. 15, Perm, 614990 Russian Federation;
journal homepage: www.elsevier.com
E-mail: mu@psu.ru
b Kuban State Technological University, Moskovskaya st. 2, Krasnodar,
350072, Russian Federation
c M. V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow,
119991 Russian Federation
d Higher School of Economics, Myasnitskaya st. 13, Moscow, 101000,
Russian Federation
Route to Pyrrolo[1,2-a]quinoxalines via
a Furan Ring Opening–Pyrrole Ring
Closure Sequence
e N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences,
Leninsky pr. 47, Moscow, 119991, Russian Federation
f D. Rogachev National Research Center of Pediatric Hematology, Oncology
and Immunology, Samory Mashela st. 1, Moscow, 117997 Russian
Federation
Introduction
ARTICLE INFO
ABSTRACT
Pyrrolo[1,2-a]quinoxalines and their (partially) hydrogenated
analogues belong to an important family of heterocycles found in
various natural compounds, including those possessing a broad
diversity of biological activities. For example, quinoxaline I was
recently isolated from Piper nigrum L. and Piper longum L.;1
compound II is an arginine vasopressin antagonist with
selectivity for the V2 receptor;2 carboxylic acid III and related
compounds possess anti-allergic activity;3 PPQ-102 is an
inhibitor of the cystic fibrosis transmembrane conductance
regulator;4 CGS 12066B is a potent and selective agonist for the
5-HT1B receptor;5 quinoxaline IV is an inhibitor of PARP-1.6
The diverse biological activities of pyrrolo[1,2-a]quinoxalines
Article history:
Received
Received in revised form
Accepted
A method was developed for the synthesis
of pyrrolo[1,2-a]quinoxalines based on an
acid-promoted furan ring opening of
readily accessible N-(furan-2-ylmethyl)-2-
Available online
nitroanilines
analogues followed by a key reductive
Paal-Knorr cyclization of the
corresponding nitro-1,4-diketones.
or
their
heterocyclic
Keywords:
Furan
Pyrrolo[1,2-a]quinoxaline
Paal-Knorr synthesis
1,4-Diketone
2009 Elsevier Ltd. All rights reserved.
Domino reaction

3
open promising possibilities for drug discovery and development
based on this heterocyclic motif.
attractive features of these methods include the accessibility of
the starting furans, the simplicity of the synthetic procedures, and
the high structural variability of the potential products.
Various synthetic protocols have been developed for the
construction of pyrrolo[1,2-a]quinoxalines,7 mostly based on the
use of key 2-(1H-pyrrol-1-yl)anilines or their precursors.8 Such
an approach was firstly described almost 55 years ago by
Cheeseman and Tuck (a, Scheme 1).9 Subsequently, numerous
synthetic protocols based on the related construction of a
pyrazine core were reported using the Pictet–Spengler10 and
Bischler–Napieralski reactions11 (b, Scheme 1). Despite the
simplicity of such approaches, their application is restricted by
Accounting for the significance of substituted pyrrolo[1,2-
a]quinoxalines, we tried to apply the same strategy to the
synthesis of these compounds. Herein, we report an original
approach to substituted pyrrolo[1,2-a]quinoxalines based on a
domino nitroarene reduction/intramolecular Paal-Knorr reaction
(c, Scheme 1).
Results and Discussion
The starting point of our research was the synthesis of
substituted N-(furan-2-ylmethyl)-2-nitroanilines 3 (Scheme 2).
The desired products were synthesized in near quantitative yields
by heating mixtures of 1-fluoro-2-nitrobenzene (1a),
furfurylamines 2a,b and freshly calcined K2CO3 at reflux in
MeCN.
CO2H
N
Cl
Cl
N
N
N
N
n-Hex
N
H
O
n-Bu
O
O
I
III
N
H
II
O
NO2
F
NO2
K2CO3
MeCN,
H N
+
2
R1
N
Ph
O

O
R1
N
H
O
N
N
N
N
N
2a,b
3a, R1 = Me, 97%
3b, R1 = Et, 98%
1a
N
N
H
F3C
N
N
O
H
O
N
Scheme 2. Synthesis of the starting N-(furan-2-ylmethyl)-2-nitro-
anilines 3a,b. Reagents and conditions: 1a (6.5 mmol), K2CO3
(10 mmol), MeCN (10 mL), 2a,b (7.5 mmol), reflux, 4−10 h.
PPQ-102
CGS 12066B
IV
Figure. 1. Selected biologically important pyrrolo[1,2-
a]quinoxalines.
The transformation of compounds 3 to the target pyrrolo[1,2-
a]quinoxalines include three principal steps: reduction of the
nitro group to an amine, hydrolysis of the furan to the
corresponding 1,4-diketone, and the key intramolecular Paal-
Knorr reaction. In general, these reactions can be performed
either stepwise in the appropriate order or simultaneously
accounting for the fact that the reduction step can be performed
under the acidic conditions required for both the furan ring
hydrolysis and the Paal-Knorr reaction.
the low scope of substrates involved, since the synthesis and
subsequent functionalization of the desired products proceed in a
stepwise manner, and both steps impose demands on the
functionalities that can be present in the starting materials. Thus,
the development of straightforward and effective protocols for
the synthesis of substituted pyrrolo[1,2-a]quinoxalines is an
important task.
Nevertheless, we previously found that the acid-induced
recyclization of the related N-furfurylanthranilamides have
significant restrictions due to competitive side-processes.13f
These side reactions can be significantly suppressed by using a
hydrolysis/Paal-Knorr reaction sequence starting from N-
furfuryl-2-nitrobenzamides as substrates. The successful
a) Initial synthesis of pyrrolo[1,2-a]quinoxaline
HO
N
N
NH2
NH2
N
HCO2H
+ O
HO


NH2
synthesis
of
(hetero)arene-annulated
pyrrolo[1,2-
d][1,4]diazepines from the appropriate 5-(2-nitroaroyl)amino-
1,4-diketones13a supports the idea that the preferable method for
the transformation of 3 to pyrrolo[1,2-a]quinoxalines is the initial
hydrolysis of the furan ring followed by reductive cyclization of
the formed nitroanilino-1,4-diketones.
b) Related approaches to pyrrolo[1,2-a]quinoxalines
X
N
N
N
R1
R
X=NO2, NH2, NHCOR2; R1=H, COR2, CHO
Therefore, we investigated the acid-catalyzed furan ring
opening using N-[(5-methylfuran-2-yl)methyl]-2-nitroaniline
(3a) as a model compound (Scheme 3). We found that the
treatment of furan 3a with various Brønsted acids unexpectedly
led to the formation of only 2-nitroaniline (5a) in quantitative
yield. The formation of 2-nitroaniline (5a) presumably resulted
from the presence of two sites for protonation in 3: the furan core
and the amino group. The protonation of the furan core leads to
hydrolysis affording the desired 1,4-diketones (path a); on the
other hand, protonation of the amino group causes C–N bond
cleavage furnishing a furfuryl cation, which undergoes various
transformations, and 2-nitroaniline (path b).14
R1
c) This work
NO2
NO2
N
[H]
H
N
R2
N
R2
N
R2
O
O
O
R1
R1
Scheme 1. Known approaches to pyrrolo[1,2-a]quinoxalines and
the concept of this work.
Over the past decades, we have developed a general approach
to the synthesis of functionalized heterocycles that can be
referred to as “Furan Ring Opening − Heterocycle Ring
Closure”.12 In particular, a series of protocols for the synthesis of
various 1,2-annulated pyrroles has been proposed.13 The

4
Tetrahedron
NO2
NO2
NO2
dihydroquinoxaline B, its tautomerization to enamine C and the
b
second amine–carbonyl condensation accomplishing construction
of the target pyrrolo[1,2-a]quinoxalines 8 (Scheme 5).
..
O
path a
path b
N
H
O
NH
NH2
H
a
O
O
5a
, 99%
4a
, N.D.
3a
R1
Scheme 3. Acid-catalyzed hydrolysis of N-[(5-methylfuran-2-
yl)methyl]-2-nitroaniline (3a).
NO2
N
NH2
- H2O
H2O
R1
Fe
AcOH
R1 
O
O
N
R2
7
O
N
R2
B
N
O
R2
A
To suppress the undesirable C-N bond cleavage leading to the
formation of 2-nitroaniline (5a), we protected the nitrogen atom
by reacting the starting amines 3a,b with various acyl chlorides
under typical reaction conditions (Table 1). Indeed, we found that
O
R1
R1
R1
acid-catalyzed hydrolysis of N-protected furfurylamines
6
HO
H
produced the desired 1,4-diketones 7 in high yields. The
exception was furfurylamine 6c, which gave rise to 1,4-diketone
7c in only 43% yield; 4-methoxy-N-(2-nitrophenyl)benzamide 5b
was formed as a side product in this process. This result was
presumably associated with the easier protonation of the amide
moiety in 6c due to the electron-releasing effect of a donor para-
methoxy group providing efficient stabilization of the O-
protonated amide moiety. In other cases, we observed the
formation of side benzamides only in 5–10% yield.
N
N
N
- H2O
N
N
N
R2
R2
R2
8
C
Scheme 5. Plausible reaction pathway to pyrrolo[1,2-
a]quinoxalines 8.
The moderate yields of products 8 presumably resulted from
the competitive enolization/cyclodehydration of intermediate
amino-1,4-diketone A providing the corresponding furans, which
under acidic conditions undergo decomposition. In order to
increase the yields of the desired pyrrolo[1,2-a]quinoxalines, we
studied other commonly used reduction conditions. In particular,
we tested sodium dithionite, tin(II) chloride, Zn, and catalytic
hydrogenation in the presence of Pd/C or Ni Raney. However, in
all cases we did not observe significantly increased yields.
Table 1. Synthesis of 1,4-diketones 7.
NO2
NO2
NO2
a
b
O
O
R1
R1
N
H
N
N
R2
R2
O
7a-d
O
R1
3a,b
6a-d
Yield (%)
Entry
R1
R2
6
7
Next, we applied the developed approach to the synthesis of
heterocyclic analogues of pyrrolo[1,2-a]quinoxalines (Scheme 6).
As the starting material, we chose commercially available 2-
chloro-3-nitropyridine (1b), which was transformed into N-[(5-
methylfuran-2-yl)methyl]-3-nitropyridin-2-amine (3c) and then
to the corresponding N-protected amine 6e.
a
b
c
Me
Me
Me
Et
Ac
Bz
83
92
88
98
81a
81a
43b
74a
4-MeOC6H4CO
Bz
d
Reagents and conditions: (a) 3 (5 mmol), TEA (10 mmol),
MeCN (10 mL), R2Cl (10 mmol), reflux, 2–11 h; (b) 6 (3
mmol), AcOH (16 mL), HCl (12 M, 3.2 mL), rt, 7−24 h.
a5–10% of the corresponding benzamide was also isolated.
b20% of 4-methoxy-N-(2-nitrophenyl)benzamide was also
isolated.
NO2
NO2
NO2
Cl
a
b
O
O
N
N
H
N
N
Bz
N
Finally, we studied the reductive Paal-Knorr cyclization of
1,4-diketones 7 aiming to synthesize pyrrolo[1,2-a]quinoxalines
8 (Scheme 4).
3c, 99%
6e, 72%
1b
Scheme 6. Synthesis of substituted furfurylamine 6e. Reagents
and conditions: (a) 1b (6.5 mmol), K2CO3 (10 mmol), MeCN (10
mL), 2a (7.5 mmol), reflux, 3 h; (b) 3c (5 mmol), TEA (10
mmol), MeCN (10 mL), BzCl (10 mmol), reflux, 11 h.
R1
NO2
N
Fe
AcOH

However, the acid-catalyzed hydrolysis of furan 6e led to
tarring of the reaction mixture, and only N-(3-nitropyridin-2-
yl)benzamide 9a was isolated (Scheme 7). The C–N bond
cleavage in this case is facilitated by preferential protonation of
the pyridine core yielding an amidinium-type cation.
N
N
R2
R2
O
O
N
R1
7a-d
8a-d
NO2
NO2
N
N
N
HCl
AcOH
rt
6e
O
N
H
N
N
NH
Ph
N
O
N
Ac
8a, 36%
N
Bz
8b, 25%
N
Bz
8d, 30%
OMe
Me
O
Ph
O
9a, 49%
8c, 20%
Scheme 7. Acid-catalyzed hydrolysis of furfurylamine 6e.
Reagents and conditions: 6e (3 mmol), AcOH (16 mL), HCl (12
M, 3.2 mL), rt, 6 h.
Scheme 4. Synthesis of pyrrolo[1,2-a]quinoxalines 8a-d.
Reagents and conditions: 7a-d (1.5 mmol), AcOH (6 mL), Fe
(22.5 mmol), reflux, 3−5 min.
We suggested that in this case we could expect to promote an
acid-catalyzed hydrolysis of the furan ring without using a
protecting group on the amine moiety (Scheme 8). Indeed, we
found that the furfurylamine 3c was transformed into the
corresponding 1,4-diketone 4b in good yield; the 3-nitropyridin-
We found that the treatment of 5-(2-nitroanilino)-1,4-
diketones 7 with iron in acetic acid induced the domino reaction
including reduction of the nitro group to aniline A, its
condensation with the nearest carbonyl group affording

5
4.
5.
L. Tradtrantip, N. D. Sonawane, W. Namkung, A. S. Verkman,
J. Med. Chem. 52 (2009) 6447−6455.
2-amine side product was isolated in only 17% yield. Finally, we
performed the intramolecular reductive Paal-Knorr cyclization of
1,4-diketone 4b, and the desired pyrido[2,3-e]pyrrolo[1,2-
a]pyrazine 8e was formed in 13% yield.
R. F. Neale, S. L. Fallon, W. C. Boyar, J. W. F. Wasley, L. L.
Martin, G. A. Stone, B. S. Glaeser, C. M. Sinton, M. Williams,
Eur. J. Pharmacol. 136 (1987) 1−9.
6.
J. Miyashiro, K. W. Woods, C. H. Park, X. Liu, Y. Shi, E. F.
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4050−4054.
Me
N
NO2
Fe
AcOH

HCl
AcOH
rt
3c
7.
8.
A. A. Kalinin, L. N. Islamova, G. M. Fazleeva, Chem. Heterocycl.
Compd. 55 (2019) 584−597.
N
N
H
N
N
H
O
(a) S. Dhole, W. J. Chiu, C. M. Sun, Adv. Synth. Catal. 361
(2019) 2916−2925; (b) B. Budke, W. Tueckmantel, K. Miles, A.
P. Kozikowski, P. P. Connell, ChemMedChem 14 (2019)
1031−1040; (c) Y.-F. Gong, X.-Y. Tang, H.-R. Huo, Synthesis 50
(2018) 2727−2740; (d) A. Kamal, K. S. Babu, J. Kovvuri, V.
Manasa, A. Ravikumar, A. Alarifi, Tetrahedron Lett.56 (2015)
7012−7015.
O
Me
4b, 64%
8e, 13%
Scheme 8. Synthesis of pyrido[2,3-e]pyrrolo[1,2-a]pyrazine 8e.
Reagents and conditions: 3c (1.5 mmol), AcOH (6 mL), Fe (22.5
mmol), reflux, 3−5 min.
9.
G. W. H. Cheeseman, B. Tuck, Chem. Ind. (1965) 1382−1386.
The cytotoxicity of 8c and 8d was investigated against
MCF10A, VA13, MCF7, and A549 cell lines (Table 2). Both
10. (a) D. K. Singh, I. Kim, Arkivoc (2019) 8−21; (b) W. You, D.
Rotili, T. M. Li, C. Kambach, M. Meleshin, M. Schutkowski, K.
F. Chua, A. Mai, C. Steegborn, Angew. Chem. Int. Ed. 56 (2017)
1007−1011; (c) W. Lv, B. Budke, M. Pawlowski, P. P. Connell,
A. P. Kozikowski, J. Med. Chem. 59 (2016) 4511−4525.
11. (a) S.-B. Hu, X.-Y. Zhai, H.-Q. Shen, Y.-G. Zhou, Adv. Synth.
Catal. 360 (2018) 1334−1339; (b) V. Desplat, M. Vincenzi, R.
Lucas, S. Moreau, S. Savrimoutou, S. Rubio, N. Pinaud, D. Bigat,
E. Enriquez, M. Marchivie, S. Routier, P. Sonnet, F. Rossi, L.
Ronga, J. Guillon, ChemMedChem 12 (2017) 940−953; (c) M.
Brindisi, S. Brogi, S. Maramai, A. Grillo, G. Borrelli, S. Butini, E.
Novellino, M. Allarà, A. Ligresti, G. Campiani, V. Di Marzo, S.
Gemma, RSC Adv. 6 (2016) 64651−64664.
compounds
contain
a
2,5-dimethyl-1-phenyl-1H-pyrrole
fragment, which is a commonly found substructure in toxic
ligands. The cytotoxicity (CC50) of 8d was in low micromolar
concentrations, whereas, in contrast, the CC50 of 8c was in
nanomolar concentrations. These compounds may be compared
with structurally related pyrrolo[1,2-d][1,4]diazepines13a that
have a diazepine ring instead of a pyrazine ring, and the same
predicted cytotoxic substructure. The cytotoxicity of 8d was an
order of magnitude higher than its nearest homologue; the
cytotoxicity of 8c was 2–3 orders of magnitude higher than that
for the corresponding pyrrolodiazepine. This substrate can be
used as a lead compound for the search of new anticancer drugs.
12. I. V. Trushkov, M. G. Uchuskin, A. V. Butin, Eur. J. Org. Chem.
(2015) 2999−3016; (b) V. T. Abaev, I. V. Trushkov, M. G.
Uchuskin, Chem. Heterocycl. Compd. 52 (2017) 973−995.
13. (a) E. Y. Zelina, T. A. Nevolina, D. A. Skvortsov, I. V. Trushkov,
M. G. Uchuskin, J. Org. Chem. 84 (2019) 13707−13720; (b) E. Y.
Zelina, T. A. Nevolina, L. N. Sorotskaja, D. A. Skvortsov, I. V.
Trushkov, M. G. Uchuskin, J. Org. Chem. 83 (2018)
11747−11757; (c) I. V. Trushkov, T. A. Nevolina, V. A.
Shcherbinin, L. N. Sorotskaya, A. V. Butin, Tetrahedron Lett. 54
(2013) 3974−3976; (d) T. A. Nevolina, V. A. Shcherbinin, O. V.
Serdyuk, A. V. Butin, Synthesis (2011) 3547−3551; (e) A. V.
Butin, T. A. Nevolina, V. A. Shcherbinin, M. G. Uchuskin, O. V.
Serdyuk, I. V. Trushkov, Synthesis (2010) 2969−2678; (f) A. V.
Butin, T. A. Nevolina, V. A. Shcherbinin, I. V. Trushkov, D. A.
Table 2. The cytotoxicity (CC50, M) of quinoxalines 8c,d.
Entry
8c
MCF10A
MCF7
A549
VA13
0.0044±0.0015 0.0033±0.0015 0.035±0.029 0.47±0.26
8d
doxoru-
bicin
2±0.3
2.4±0.5
2.29±0.12
0.11±0.01
5.21±1.34
0.25±0.02
0.08±0.02
0.12±0.02
In conclusion, we have developed a simple route for the
synthesis of functionalized pyrrolo[1,2-a]quinoxalines starting
from furfurylamines and 1-fluoro-2-nitrobenzene (or their
heterocyclic analogues). The key step of the developed method is
based on reductive Paal-Knorr cyclization of the corresponding
nitro-1,4-diketones. The commercially available and inexpensive
starting materials and mild reaction conditions are attractive
features of the developed method.
Cheshkov, G. D. Krapivin, Org. Biomol. Chem.
8 (2010)
3316−3627; (g) T. A. Stroganova, A. V. Butin, V. K. Vasilin, T.
A. Nevolina, G. D. Krapivin, Synlett (2007) 1106−1108.
14. (a) C. Piutti, F. Quartieri, Molecules 18 (2013) 12290−12312; (b)
A. A. Merkushev, V. N. Strel’nikov, M. G. Uchuskin, I. V.
Trushkov, Tetrahedron 73 (2017) 6523−6529; (c) M. G. Uchuskin,
N. V. Molodtsova, S. A. Lysenko, V. N. Strel’nikov, I. V.
Trushkov, A. V. Butin, Eur. J. Org. Chem. (2014) 2508−2515.
Acknowledgments
 Route for the synthesis of
We thank the Ministry of Science and Higher Education of the
Russian Federation (project № 4.5371.2017/8.9) for the financial
support. We also thank Dr. Aleksandr E. Rubtsov (Perm State
University) for the preparation of single-crystal X-ray data.
functionalized
pyrrolo[1,2-
a]quinoxalines was developed
 The hydrolysis of N-protected
Appendix A. Supplementary data
furfurylamines
produced
1,4-
diketones in high yields
Supplementary data to this article can be found online at
 The reductive Paal-Knorr reaction
afforded the target pyrrolo[1,2-
a]quinoxalines
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 The cytotoxicity of obtained
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pyrrolo[1,2-a]quinoxalines
was
investigated