One-pot synthesis of pyrrolo[1,2-a]quinoxaline derivatives via iron-promoted aryl nitro reduction and aerobic oxidation of alcohols

Article abstract of DOI:10.1021/ol302006b

Here, we describe a new one-pot method to synthesize 4,7-substituted pyrrolo[1,2-a]quinoxalines and related heterocyles through a cascade of redox reactions/imine formation/intramolecular cyclization. This procedure tolerates readily available substituted 1-(2-nitrophenyl)pyrrole derivatives and aliphatic or benzylic alcohols as starting materials using iron powder and acidic conditions. This is the first example of constructing N-heterocycles via iron-mediated aryl nitro reduction and aerobic oxidation of alcohols in one pot.

Full text of DOI:10.1021/ol302006b

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4754–4757
One-Pot Synthesis of
Pyrrolo[1,2‑a]quinoxaline Derivatives via
Iron-Promoted Aryl Nitro Reduction and
Aerobic Oxidation of Alcohols
†
Maria de Fatima Pereira*,†,‡ and Valerie Thiery
ꢀ
ꢀ
ꢀ
Universite de La Rochelle, UMR CNRS 7266 -LIENSs, LIttoral ENvironnement
ꢀ ꢀ ꢀ
^
^
SocieteS, Pole Sciences et Technologie, Batiment Marie-Curie, Avenue Michel Crepeau,
ꢀ
17042 La Rochelle, France, and Universite de Caen Basse-Normandie, EA 4258
CERMN - FR CNRS 3038 INC3M, UFR des Sciences Pharmaceutiques,
14032 Caen, France
maria_de_fatima.pereira-rosenfeld@univ-lr.fr
Received July 19, 2012
ABSTRACT
Here, we describe a new one-pot method to synthesize 4,7-substituted pyrrolo[1,2-a]quinoxalines and related heterocyles through a cascade of
redox reactions/imine formation/intramolecular cyclization. This procedure tolerates readily available substituted 1-(2-nitrophenyl)pyrrole
derivatives and aliphatic or benzylic alcohols as starting materials using iron powder and acidic conditions. This is the first example of
constructing N-heterocycles via iron-mediated aryl nitro reduction and aerobic oxidation of alcohols in one pot.
The pyrrolo[1,2-a]quinoxaline skeleton is present in
various heterocyclic compounds possessing interesting
biological activities. This nucleus substituted at the C-4
position gives various derivatives with 5-HTR affinities,1
in vitro antiparasitic activities,2 potential nonpeptide glu-
cagon receptor antagonist activities,3 and fluorescence
properties for amyloid fibril detection.4 Some of these
classes of compounds are of particular interest in antipro-
liferative activity.5 They inhibit human leukemic cell lines
U937, K562 and the breast cancer cell line MCF7 (IC50
in the range of 4.5 and 8 μM). These three human cell
(2) (a) Alleca, S.; Corona, P.; Loriga, M.; Paglietti, G.; Loddo, R.;
Mascia, V.; Busonera, B.; La Colla, P. Il Farmaco 2003, 58, 639–650.
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(b) Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Leger, J.-M.;
Deprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaıtre, N.;
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Pehourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. J. Med. Chem.
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2004, 47, 1997–2009. (c) Guillon, J.; Mouray, E.; Moreau, S.; Mullie, C.;
Forfar, I.; Desplat, V.; Belisle-Fabre, S.; Pinaud, N.; Ravanello, F.;
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Le-Naour, A.; Leger, J.-M.; Gosmann, G.; Jarry, C.; Deleris, G.; Sonnet,
P.; Grellier, P. Eur. J. Med. Chem. 2011, 46, 2310–2326. (d) Guillon, J.;
Moreau, S.; Mouray, E.; Sinou, V.; Forfar, I.; Fabre, S. B.; Desplat, V.;
Millet, P.; Parzy, D.; Jarry, C.; Grellier, P. Bioorg. Med. Chem. 2008, 16,
9133–9144.
†
ꢀ
Universite de La Rochelle.
‡
ꢀ
Universite de Caen Basse-Normandie.
(3) Guillon, J.; Dallemagne, P.; Pfeiffer, B.; Renard, P.; Manechez,
D.; Kervran, A.; Rault, S. Eur. J. Med. Chem. 1998, 33, 293–308.
(4) Gemma, S.; Colombo, L.; Forloni, G.; Savini, L.; Fracasso, C.;
Caccia, S.; Salmona, M.; Brindisi, M.; Joshi, B. P.; Tripaldi, P.; Giorgi,
G.; Taglialatela-Scafati, O.; Novellino, E.; Fiorini, I.; Campiani, G.;
Butini, S. Org. Biomol. Chem. 2011, 9, 5137–5148.
(5) (a) Desplat, V.; Geneste, A.; Begorre, M.-A.; Fabre, S. B.; Brajot,
S.; Massip, S.; Thiolat, D.; Mossalayi, D.; Jarry, C.; Guillon, J. J. Enzym
Inhib. Med. Chem. 2008, 23, 648–658. (b) Desplat, V.; Moreau, S.; Gay,
A.; Fabre, S. B.; Thiolat, D.; Massip, S.; Macky, G.; Godde, F.;
Mossalayi, D.; Jarry, C.; Guillon, J. J. Enzym. Inhib. Med. Chem.
2010, 25, 204–215.
(1) For selected examples, see: (a) Prunier, H.; Rault, S.; Lancelot,
J.-C.; Robba, M.; Renard, P.; Delagrange, P.; Pfeiffer, B.; Caignard,
D.-H.; Misslin, R.; Hamon, M. J. Med. Chem. 1997, 40, 1808–1819. (b)
Butini, S.; Budriesi, R.; Hamon, M.; Morelli, E.; Gemma, S.; Brindisi,
M.; Borrelli, G.; Novellino, E.; Fiorini, I.; Ioan, P.; Chiarini, A.;
Cagnotto, A.; Mennini, T.; Fracasso, C.; Caccia, S.; Campiani, G.
J. Med. Chem. 2009, 52, 6946–6950. (c) Morelli, E.; Gemma, S.; Budriesi,
R.; Campiani, G.; Novellino, E.; Fattorusso, C.; Catalanotti, B.;
Coccone, S. S.; Ros, S.; Borrelli, G.; Kumar, V.; Persico, M.; Fiorini,
I.; Nacci, V.; Ioan, P.; Chiarini, A.; Hamon, M.; Cagnotto, A.; Mennini,
T.; Fracasso, C.; Colovic, M.; Caccia, S.; Butini, S. J. Med. Chem. 2009,
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r
10.1021/ol302006b
Published on Web 09/12/2012
2012 American Chemical Society

lines exhibit an active phosphorylated form of Akt
Kinase. Therefore, the development of novel and
highly efficient methods to construct these fused angular
heterocyclic architectures is highly desirable for drug
discovery.
Scheme 1. Different Pathways for the 4-Substituted Pyrrolo[1,2-a]-
quinoxalines Formation
Many methods for syntheses of 4,5-dihydropyrrolo-
[1,2-a]quinoxalines,6 pyrrolo[1,2-a]quinoxalin-4-ones,7 and
unsubstitued pyrrolo[1,2-a]quinoxalines8 have been devel-
oped; however, to the best of our knowledge, only a few
synthetic procedures have been reported for fused aromatic
pyrrolo[1,2-a]quinoxalines substituted in C-4 by aryl or
alkyl groups. As shown in Scheme 1, all of the reported
4-substituted pyrrolo[1,2-a]quinoxaline derivatives were ob-
tained by the reduction of the 1-(2-nitrophenyl)pyrroles to
provide the amino intermediates. The main synthetic meth-
od utilized various alkyl- and aryl-acid chlorides with
the amino group to obtain the corresponding acetamides.
Subsequently, 4-substituted pyrrolo[1,2-a]quinoxalines
were prepared by intramolecular cyclization of theses
amides according to the BischlerÀNapieralski reaction.9
The other approach involved the reaction between the
corresponding 1-(2-aminophenyl)pyrroles with aldehydes
in an acidic medium followed by oxidation of the 4,5-
dihydropyrrolo[1,2-a]quinoxaline intermediates.10 More
recently, a modified PictetÀSpengler reaction using benzo-
triazole methodology reported the one-pot synthesis of
these fused aromatic heterocycles.11 This is the firstexample
of constructing 4-aryl pyrrolo[1,2-a]quinoxalines between
aromatic aldehydes and the amino intermediates. In all
cases, these multistep syntheses led to modest overall yields
using volatile and environmentally toxic reagents such as
aliphatic aldehydes. Therefore, the use of alcohols with
nitroarenes as starting materials to form a direct CÀN bond
is highly attractive, and great progress has been made during
the past decade to develop environmentally friendly pro-
cesses toward this subject.12
Until now, whereas aryl nitro reduction with iron pow-
der as a reducing agent has already been studied, there are
only a few reports of using cheap and less toxic iron
catalysts for the oxidation of alcohols to carbonyls. In
the literature, the oxidation catalyzed by ferrous ions and
hydrogen peroxide (the Fenton reaction) has been care-
fully investigated,13 unlike oxidations with ferric ions
which have received considerably less attention. More
recently, a few methods have been developed using iron-
(III)ÀSchiff baseÀtriphenylphosphine complexes,14 iron-
(III) bromide,15 iron(III) nitrate,16 and iron(III) porphyrin
and nonporphyrin complexes,17 but all of the reagents
need the presence of hydrogen peroxide (or a peroxide) as
a reagent.
This new method provided a route for the construction
of a variety of substituted pyrrolo[1,2-a]quinoxaline deri-
vatives via iron-mediated aryl nitro reduction and aerobic
oxidation of alcohols in the one-pot procedure. Moreover,
we have extended this reaction to novel pyrido[3,2-e]-
pyrrolo[1,2-a]pyrazines.
Performed inusualreduction conditions (3 equivofiron,
6 equiv of HCl), the reaction led mainly to the expected
amino 3a besides a trace of pyrrolo[1,2-a]quinoxaline 2a
(Table 1, entry 1). In order to understand and optimize this
surprising result, we decided to reinvestigate the experi-
mental conditions to obtain the tricyclic aromatic skeleton
in one pot. When a large excess of iron powder (9 equiv)
and HCl 12 M (11 equiv) were used, only the desired
compound 2a was observed (74%) and no trace of the
amino compound 3awasidentified(entry 2). The best yield
was obtained with the same equivalents of iron and
chlorhydric acid in refluxing ethanol (80%) (entry 3). It
should be noted that when more than 14 equiv of iron, the
yield decreased to 60% because of the complex mixture of
Herein, we reported the first one-pot synthesis of 4-sub-
stituted pyrrolo[1,2-a]quinoxalines from 1-(2-nitrophenyl)-
pyrrole derivatives and various alcohols in redox conditions.
In this process, alcohols were oxidized in situ from a
nitroarene reduction step and no external oxidant reagent
was added to the reaction mixture.
(6) (a) Liu, G.; Zhou, Y.; Lin, D.; Wang, J.; Zhang, L.; Jiang, H.; Liu,
H. ACS Comb. Sci. 2011, 13, 209–213. (b) Xu, H.; Fan, L. Eur. J. Med.
Chem. 2011, 46, 1919–1925.
(7) Qiliang Yuan, D. M. J. Org. Chem. 2008, 73, 5159–62.
(8) Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.; Yee,
N. K.; Senanayake, C. H. J. Org. Chem. 2010, 75, 992–994.
(9) (a) Cheeseman, G. W. H.; Tuck, B. J. Chem. Soc. (C) 1966, 852–
855. (b) Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.;
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Saliege, M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J.-M.;
Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi, D. Bioorg. Med. Chem.
2007, 15, 194–210. (c) Kalinin, A. A.; Mamedov, V. A. Chem. Hetero-
cycl. Compd. 2011, 46, 1423–1442. (d) Lancelot, J.-C.; Rault, S.;
Laduree, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 2798–2802.
(10) Kaminskii, V. A.; Moskovkina, T. V.; Borodina, S. V. Chem.
Heterocycl. Compd. 1992, 28, 97–100.
(13) (a) Walling, C. Acc. Chem. Res. 1998, 31, 155–157. (b) MacFaul,
P. A.; Wayner, D. D. M.; Ingold, K. U. Acc. Chem. Res. 1998, 31, 159–
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(14) Rani, S.; Bhat, B. R. Tetrahedron Lett. 2010, 51, 6403–6405.
(15) Martın, S. E.; Garrone, A. Tetrahedron Lett. 2003, 44, 549–552.
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(16) Namboodiri, V. V.; Polshettiwar, V.; Varma, R. S. Tetrahedron
Lett. 2007, 48, 8839–8842.
(17) Han, J. H.; Yoo, S.-K.; Seo, J. S.; Hong, S. J.; Kim, S. K.; Kim,
C. Dalton Trans. 2005, 402.
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R. P.; Chandra, R. Eur. J. Org. Chem. 2011, 2011, 6998–7010.
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Org. Lett., Vol. 14, No. 18, 2012
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Table 1. Reactions of 1-(4-Chloro-2-nitrophenyl)pyrrole and
Ethanol under Various Conditionsa
Table 2. Reactions of 1-(2-Nitrophenyl)pyrrole Derivatives
with Various Alcoholsa
entry Fe (equiv) HCl (equiv)
solvent
EtOH
1a
2a
3a
1
3
9
9
14
9
9
9
9
9
9
9
9
9
6
0
0
0
0
0
0
0
0
0
trace 70
2
11
11
15
11
none
11
11
11
11
11
11
11
EtOH
74
80
60
0
0
3
EtOHb
EtOH
0
4
0
5
EtOHc
acetic acid
AcOEt
MeCN
dioxane
toluene
DCM
70
10d
0
6
30
58
54
0
7e
8e
9e
10e
11e
12e
13e,f
0
50d
10d
5d
75
80
0
0
Et2O
trace trace 50d
THF
0
0
0
a Conditions: solvent (15 mL), 72 h, rt, air. b Reflux, 48 h, air. c Under
N2 atmosphere. d Determined by 1H NMR analysis of the crude reaction
product. e 3 equiv of ethanol as substrate were used. f Scheme 2, 68% of
spirocyclic compound 4a.
Scheme 2. Access to Spirocyclic Compound 4a When the Re-
action Was Performed in THF as Solvent
unidentifiedbyproducts (entry 4). Interestingly, wenoticed
that only the amino compound was identified (70% yield)
when the reaction was performed under an inert atmo-
sphere (N2) (entry 5). It seems that oxygen should play a
key role in the reaction. The desired product was obtained
in 30% yield when the reaction was carried out in acetic
acid without addition of HCl 12 M and ethanol as the
substrate (entry 6).
The effect of solvents was also investigated. The use of
AcOEt and MeCN resulted in lower yields with 3 equiv of
ethanol as substrate (relative to the amount of 1-(4-chloro-
2-nitrophenyl)pyrrole) (entries 7À8). The reaction was not
efficient inother solvents suchas ether, DCM, toluene, and
dioxane; only the starting material or/and amino intermedi-
ate were isolated (entries 9À12). Interestingly, when THF
was used as solvent, none of the three compounds was
observed (entry 13). However, we identified a novel spir-
ocyclic compound 4a in good yield 68% (Scheme 2). It
supposed that THF should be oxidized and then reacted
with the amino intermediate to provide the new molecule 4a.
a Conditions: 1 (2.25 mmol), iron powder (9.0 equiv), HCl 12 M
(11.0 equiv), alcohol (15 mL), reflux, 48 h. b Isolated yield.
In light of these interesting results, we decided to study
and extend this new methodology in order to develop an
available library of pyrrolo[1,2-a]quinoxaline derivatives.
We started the reaction with readily available substituted
4756
Org. Lett., Vol. 14, No. 18, 2012

Table 3. Reactions of 3-Nitro-2-pyrrolopyridine with Various
Alcohols Leading to Pyrido[3,2-e]pyrrolo[1,2-a]pyrazines 6
under Optimal Conditionsa
Scheme 3. Proposed Mechanism
of the reaction, all alcohols were also employed to react
with 3-nitro-2-pyrrolopyridine. In general, good to mod-
erate yields were obtained under standard optimized reac-
tion conditions. Interestingly, the reaction of 3-nitro-2-
pyrrolopyridine with methanol and butyl alcohol resulted
in a much lower yield (Table 3, entries 1, 5).18
The most likely mechanism to rationalize this transfor-
mation is illustrated in Scheme 3. Inan acidicmedium, iron
could catalyze the reduction of the nitrophenylpyrrole (1)
to its amine counterpart (A) giving ferric salts (or ferrous
salts) which in turn would be able to oxidize alcohols into
aldehydes. Condensation of these latter with the amine (A)
gives the iminium salts (B) which spontaneously cyclize
leading to the dihydroquinoxalines (C) as previously de-
scribed. Finally, a final oxidation produces the 4-alkyl
or 4-phenylpyrroloquinoxalines (2) in moderate to good
yield.
Inconclusion, wehavedevelopeda rareone-potreaction
for assembling pyrrolo[1,2-a]quinoxalines from 1-(2-
nitrophenyl)pyrroles and various alcohols. The nitro re-
duction, alcohol oxidation, heterocycle formation, and
heterocycle oxidation were realized in a cascade. A wide
range of these fused heterocycles bearing in position 4
different alkyl and aryl groups have been elaborated from
suitable substrates; thereby 3-nitro-2-pyrrolopyridine was
alsocompatiblewiththis process, givingthe corresponding
fused tricyclic compounds. The synthetic applications of
this reaction are under investigation.
a Conditions: 5 (2.25 mmol), iron powder (9.0 equiv), HCl 12 M
(11.0 equiv), alcohol (15 mL), reflux, 48 h. b Isolated yield.
1-(2-nitrophenyl)pyrroles and various alcohols. As shown
in Table 2, for all combinations of 1-(2-nitrophenyl)-
pyrrole derivatives and aliphatic or benzylic alcohols, the
desired 4-substituted pyrrolo[1,2-a]quinoxaline was ob-
served as the only product. Most of the substrates exam-
ined provided good yields. The lowest yield was obtained
when substituted 1-(2-nitrophenyl)pyrroles reacted with
methanol as the substrate (entries 2, 7, 12) whereas ethanol
was the best substrate for this reaction (entries 1, 8, 13).
The reactions with 1-(2-nitrophenyl)pyrroles bearing an
electron-donating group such as a methoxy group meta to
thenitro group decreasethe productyields (entries12À15).
To our delight, besides simple aliphatic alcohols, benzyl
alcohol also reacted with the 1-(4-chloro-2-nitrophenyl)-
pyrrole to give the desired product in moderate yield
(entry 6). Furthermore, reactions between a secondary
alcohol such as isopropanol and substituted 1-(2-nitro-
phenyl)pyrroles gave 4,5-dihydropyrrolo[1,2-a]quinoxa-
line derivatives (entries 4, 10). To further explore the scope
ꢀ
Acknowledgment. We are grateful to the “Comite 17
de la Ligue Nationale contre le Cancer” and CPER for
financial support.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all the
products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) It should be noted that byproduct was identified in the reaction
when methanol, ethanol, and butyl alcohol were used as starting
materials. Characterization data confirmed the presence of trace
amounts of the 2-chloropyrido[3,2-e]pyrrolo[1,2-a]pyrazine derivatives.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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