ORGANIC

LETTERS

A Simple and Straightforward Approach

to Quinoxalines by Iron/Sulfur-Catalyzed
Redox Condensation of oNitroanilines
and Phenethylamines

2013
Vol. 15, No. 20
52385241

Thanh Binh Nguyen,* Pascal Retailleau, and Ali Al-Mourabit

Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles,
CNRS, 91198 Gif-sur-Yvette Cedex, France
[email protected]
Received August 23, 2013

ABSTRACT

In situ generated iron sulfide from elemental sulfur and ferric chloride was found to be a highly efficient catalyst for the redox condensation
cascade reaction between o-nitroanilines and 2-arylethylamines. This method constitutes a new atom-, step-, and redox-economical route to
2-arylquinoxalines.

Development of methods to transform functional groups

efficiently which respect the concept of atom, step, and
redox economy plays a crucial role in modern sustainable
organic synthesis.1 In this context, unnecessary energy
consuming steps might be avoided by the judicious choice
of catalytic chemical processes. Because of the unique
electrochemical properties of iron, its highest natural abundance, which results in low cost and ready accessibility on a
large scale, and its low toxicity compared to other transition
metals, iron seems to be a highly promising catalyst for
redox transformations.2
Iron!sulfur clusters, a subgroup of iron catalysts in the
active sites of redox proteins of all living forms, play an
important role in the electron transfer between functional
groups. Thanks to their property of storing and releasing
electrons during metabolic reactions, iron!sulfur clusters
behave as molecular capacitors and are capable of

accelerating the redox tranformations.3 Despite the ubiquity and the essential roles of iron!sulfur clusters in living
systems, only a few examples of the application of Fe/S
clusters as redox catalysts in organic synthesis have been
reported.4,5 Compared to other ligands which are expensive, with high molecular weights and/or sensitivity to
oxygen and moisture, elemental sulfur is obviously very
cheap, toxicologically benign, and potentially efficient
even under physiological systems.
Our recent investigation demonstrated that Fe/S was
catalytically active for achieving a redox condensation
between o-nitroanilines/phenols and 2- or 4-picolines and
related compounds, yielding the corresponding 2-hetaryl
benzimidazoles and benzoxazoles with the formation of
water as the only byproduct.5 In continuing our effort
in developing new applications of an Fe/S catalyst, here
we report a redox condensation between o-nitroanilines

(1) For a recent review, see: Wender, P. A. Tetrahedron 2013, 69,

7529.
(2) For selective reviews on iron-catalyzed reactions in organic
synthesis, see: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
Rev. 2004, 104, 6217. (b) Sun, C.; Li, B.; Shi, Z. Chem. Rev. 2011, 111,
1293. (c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417. (d) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009, 38, 2730. (e)
Correa, A.; Manche~
no, O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108.

(3) (a) Johnson, M. K.; Smith, A. D. Iron!Sulfur Proteins. In

Encyclopedia of Inorganic Chemistry, 2nd ed.; King, R. B., Ed.; John
Wiley & Sons: Chichester, 2005. (b) Beinert, H.; Holm, R. H.; Munck, E.
Science 1997, 277, 653.
(4) Wang, J.; Wang, S.; Wang, G.; Zhang, J.; Yu, X. Q. Chem.
Commun. 2012, 48, 11769.
(5) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. J. Am. Chem.
Soc. 2013, 135, 118.

10.1021/ol402435c r 2013 American Chemical Society

Published on Web 10/08/2013

and 2-phenethylamines as a straightforward access to

2-phenylquinoxalines.6
While an oxidizing agent is generally necessary for
functionalization of sp3 C!H bonds,7 the use of a nitro
group as a nitrogen synthon inevitably requires a reducing
agent.8 Alternatively, when the nitro group plays the role
of an oxidizing agent for functionalization of sp3 C!H
bonds, no additional oxidizing or reducing agent is needed.
Such an atom-, step-, and redox-economical transformation
is highly desirable. Based on this principle, we studied a model
reaction between 2-phenethylamine and o-nitroaniline. This
six-electron transfer process would occur with the formation
of two molecules of water and one molecule of ammonia as
the only byproducts.
At the beginning of our study, o-nitroaniline 1a and
2-phenethylamine 2a (2 equiv) were chosen as model substrates for redox condensation (Table 1). When the reaction was carried out in the absence of catalysts, both
starting materials were recovered unchanged (entry 1).
Except for MnCl2, NiCl2 3 6H2O, and CuCl which were
catalytically inactive (entries 2,8 and 9), we observed a low
conversion into product with iron (entries 3!6) and cobalt
salts (entry 7). Gratifyingly, the addition of elemental
sulfur (20 mol %, entries 10!15) provided an improved conversion in most cases (except for CoCl2 3 6H2O, entry 13).
Most significantly, a high conversion into product was
observed with the FeCl3 3 6H2O/S system (entry 12). The
use of sulfur (entry 16) as the catalyst without ferric
chloride as well as the ferric chloride without elemental
sulfur (entry 4) gave only low formation of product, 7%
and 10% respectively. The almost 10-fold decrease of the
C!H/NO2 electron transfer clearly indicates the key role
of the ensemble Fe/S clusters. The conditions identified
in Table 1 (entry 12) were therefore used for further
reactions.
To explore the application of this method, the scope of
the redox condensation reaction was examined under the
optimized conditions (Tables 2 and 3).
A range of 2-arylethylamines (2 equiv) were allowed to
react with o-nitroaniline in the presence of FeCl3 3 6H2O
(5 mol %) and sulfur (20 mol %) under solvent-free
conditions (Table 2). 2-Phenethyalmines bearing differing
(6) For representative examples of synthesis of quinoxalines, see:
from o-phenylenediamines: (a) Martin, L. J.; Marzinzik, A. L.; Ley,
S. V.; Baxendale, I. R. Org. Lett. 2011, 13, 320. (b) Chen, Y.; Li, K.;
Zhao, M.; Li, Y.; Chen, B. Tetrahedron Lett. 2013, 54, 1627. (c)
Padmavathy, K.; Nagendrappa, G.; Geetha, K. V. Tetrahedron Lett.
2011, 52, 544. (d) Lian, M.; Li, G.; Zhu, Y.; Yin, G.; Wu, A. Tetrahedron
2012, 68, 9598. (e) Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.;
Chen, B. Org. Lett. 2011, 13, 4514. (f) Song, J.; Li, X.; Chen, Y.; Zhao,
M.; Dou, Y.; Chen, B. Synlett 2012, 2416. (g) Zhang, C.; Xu, Z.; Zhang,
L.; Jiao, N. Tetrahedron 2012, 68, 5258. From o-nitroanilines in the
presence of an external reducing agent: (h) Wallace, J. M.; Soederberg,
B. C. G.; Tamariz, J.; Akhmedov, N. G.; Hurley, M. T. Tetrahedron
2008, 64, 9675. (i) Blaikley, D. C. W.; Currie, D. W; Smith, D. M.;
Watson, S. A.; McNab, H. J. Chem. Soc., Perkin Trans. 1 1984, 367. (j)
Cho, C. S.; Ren, W. X.; Shim, S. C. Tetrahedron Lett. 2007, 48, 4665. (k)
Neochoritis, C.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A. Synlett
2009, 302. (l) Cho, C. S.; Oh, S. G. Tetrahedron Lett. 2006, 47, 5633. (m)
Meshram, H. M.; Santosh Kumar, G.; Ramesh, P.; Chennakesava
Reddy, B. Tetrahedron Lett. 2010, 51, 2580.
(7) Zhang, S.; Zhang, F.; Tu, Y. Chem. Soc. Rev. 2011, 40, 1937.
(8) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Yan, G.; Yang, M. Org. Biomol. Chem. 2013, 11, 2554.
Org. Lett., Vol. 15, No. 20, 2013

Table 1. Optimization of Reaction Conditionsa

metal salt
(5 mol %)

S
(mol %)b

conversion
(%)c

!
MnCl2
FeCl2 3 4H2O
FeCl3 3 6H2O
FeSO4 3 7H2O
Fe(NO3)3 3 9H2O
CoCl2 3 6H2O
NiCl2 3 6H2O
CuCl
MnCl2
FeCl2 3 4H2O
FeCl3 3 6H2O
CoCl2 3 6H2O
NiCl2 3 6H2O
CuCl
!

0
0
0
0
0
0
0
0
0
20
20
20
20
20
20
20

0
0
20
10
7
18
10
0
0
29
75
93
5
8
5
7

entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
c

a
Reaction conditions: 1a (2.5 mmol), 2a (5 mmol). b 32.1 g mol!1.
Determined by 1H NMR.

Table 2. Substrate Scope of the Fe/S-Catalyzed Redox Condensation Reaction of Ethylamines 2 with o-Nitroaniline 1aa

entry

yield (%)b

1
2
3
4
5
6
7
8
9
10
11

2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k

Ph
3-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-FC6H4
3,4-(MeO)2C6H3
n-hexyl

3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak

75
78
94
73
75
56
78
58
63
56
48

a
Reaction conditions: 1a (2.5 mmol), 2 (5 mmol), FeCl3 3 6H2O
(0.125 mmol, 34 mg), S (0.5 mmol, 16 mg). b Isolated yield.

substitution patterns and electronic properties were proven

to be suitable substrates, providing products in good
yields. While electron-poor 2-phenethylamine 2c was particularly reactive (Table 2, entry 3), electron-rich substrates
2f, 2h, and 2j (Table 2, entries 6, 8, and 10) gave products in
lower yields. An ortho substituent of the 2-phenethylamines
5239

was well-tolerated (Table 2, entries 8, 9), although the yield

was slightly lower. A long chain aliphatic amine such as
n-octylamine only gave a moderate yield (Table 2, entry 11).
We then applied these reaction conditions to the conversion of 2-phenethylamine 2a with various o-nitroanilines
into 2-phenylquinoxalines (Table 3). The reaction of monosubstituted o-nitroanilines 1c!g resulted in a mixture of
two possible regioisomers in good yields. These regioisomers were readily separable by column chromatography
in most cases (entries 3!6).

A subsequent two-electron transfer process would occur intramolecularly via complex imine-nitroso C with removal of one
molecule of water and ammonia. Further four-electron transfer and dehydration would furnish quinoxaline 3 and regenerate the starting complex A to complete the catalytic cycle.

Scheme 1. Proposed Mechanism

Table 3. Substrate Scope of the Fe/S-Catalyzed Redox

Condensation Reaction of Phenethylamine 2a with Various
o-Nitroanilines 1a

The formation in variable ratios of both possible regioisomers of 3 from 2-nitroanilines 1c!g monosubstitued at the
4, 5, or 6 position of the aromatic ring (entries 2!6, Table 3)
could suggest that o-phenylenediamines corresponding to
the reduced products of 1 as the intermediate were generated
prior to the cyclization into quinoxaline 3. Indeed, minor
amounts of the o-phenylenediamines corresponding reduced
products of 1 were isolated in some instances.
To confirm this hypothesis, we carried out a control
experiment using o-nitroaniline 1a (0.5 equiv), 4-methyl-ophenylenediamine (0.5 equiv), and 2-phenethylamine (2 equiv)
under standard conditions (Scheme 2). We observed a full
conversion of 1, the formation of a mixture of 2-phenylquinoxaline 3aa, 6- and 7-methyl-2-phenylquinoxaline
3ca (3aa:3ca = 1:2), and a mixture of o-phenylenediamine
and 4-methyl-o-phenylenediamine (2:1).
a
Reaction conditions: 1 (2.5 mmol), 2a (5 mmol), FeCl3 3 6H2O
(0.125 mmol, 34 mg), S (0.5 mmol, 16 mg). b Isolated yield. c Determined
by 1H NMR. d Yield of the mixture of both regioisomers. e Structure
determined by X-ray crystallography.

Although the details regarding the nature of the clusters

involved in the present method are not yet known, we propose a possible reaction mechanism in Scheme 1. The formation of iron!sulfur cluster A can occur spontaneously when
sufficient amounts of soluble iron and sulfur are available in
the presence of a reducing agent (2-phenethylamine in this
case).9 Iron!sulfur cluster A is presented arbitrarily as
cube A. The next step could be the fixation of o-nitroaniline
1 on A by chelation and 2-phenthylamine 2 by coordination.
(9) Berg, J. M.; Holm, R. H. In Iron-Sulfur Proteins; Spiro, T. G., Ed.:
John Wiley and Sons: 1981; pp 1!66.
5240

Scheme 2. Control Experiment

In summary, the above developed method of redox

condensation of o-nitroanilines and 2-arylethylamines to
2-arylquinoxalines provides a beautiful example of atom-,
step-, and redox-economical transformation. The use of
a catalytic amount of iron sulfide generated in situ from
Org. Lett., Vol. 15, No. 20, 2013

nontoxic FeCl3 3 6H2O and elemental sulfur under solventfree conditions makes the method very interesting
for preparative purposes and sustainable development.
Mechanistic studies aimed at identifying the reaction
intermediates, expansion of the scope, and exploration of
the related reactions are in progress.

Org. Lett., Vol. 15, No. 20, 2013

Supporting Information Available. Experimental procedures, product characterization, and copies of the 1H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.

5241