A simple and straightforward approach to quinoxalines by iron/sulfur-catalyzed redox condensation of o-nitroanilines and phenethylamines

Article abstract of DOI:10.1021/ol402435c

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.

Full text of DOI:10.1021/ol402435c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Simple and Straightforward Approach
to Quinoxalines by Iron/Sulfur-Catalyzed
Redox Condensation of o‑Nitroanilines
and Phenethylamines
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
nguyen@icsn.cnrs-gif.fr
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 abun-
dance, 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
IronÀsulfur 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, ironÀsulfur clusters
behave as molecular capacitors and are capable of
accelerating the redox tranformations.3 Despite the ubi-
quity and the essential rolesof ironÀsulfur clusters inliving
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 expen-
sive, 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
(3) (a) Johnson, M. K.; Smith, A. D. IronÀSulfur Proteins. In
Encyclopedia of Inorganic Chemistry, 2nd ed.; King, R. B., Ed.; John
Wiley & Sons: Chichester, 2005. (b) Beinert, H.; Holm, R. H.; M€unck, E.
Science 1997, 277, 653.
(4) Wang, J.; Wang, S.; Wang, G.; Zhang, J.; Yu, X. Q. Chem.
Commun. 2012, 48, 11769.
(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)
(5) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. J. Am. Chem.
Soc. 2013, 135, 118.
~
Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108.
r
10.1021/ol402435c
XXXX American Chemical Society

and 2-phenethylamines as a straightforward access to
2-phenylquinoxalines.6
Table 1. Optimization of Reaction Conditionsa
While an oxidizing agent is generally necessary for
functionalization of sp3 CÀH 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 CÀH
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 sub-
strates for redox condensation (Table 1). When the reac-
tion was carried out in the absence of catalysts, both
starting materials were recovered unchanged (entry 1).
metal salt
(5 mol %)
S
conversion
(%)c
entry
(mol %)b
1
À
0
0
2
MnCl2
0
0
3
FeCl2 4H2O
0
20
10
7
3
4
FeCl3 6H2O
0
3
5
FeSO4 7H2O
0
3
6
Fe(NO3)3 9H2O
0
18
10
0
3
7
CoCl2 6H2O
0
3
8
NiCl2 6H2O
0
3
9
CuCl
0
0
10
11
12
13
14
15
16
MnCl2
20
20
20
20
20
20
20
29
75
93
5
Except for MnCl2, NiCl2 6H2O, and CuCl which were
3
FeCl2 4H2O
3
catalytically inactive (entries 2,8 and 9), we observed a low
conversion into product with iron (entries 3À6) and cobalt
salts (entry 7). Gratifyingly, the addition of elemental
sulfur (20 mol %, entries 10À15) provided an improved con-
FeCl3 6H2O
3
CoCl2 6H2O
3
NiCl2 6H2O
8
3
CuCl
5
À
7
version in most cases (except for CoCl2 6H2O, entry 13).
3
a Reaction conditions: 1a (2.5 mmol), 2a (5 mmol). b 32.1 g molÀ1
.
Most significantly, a high conversion into product was
observed with the FeCl3 6H2O/S system (entry 12). The
c Determined by 1H NMR.
3
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
CÀH/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.
Table 2. Substrate Scope of the Fe/S-Catalyzed Redox Con-
densation Reaction of Ethylamines 2 with o-Nitroaniline 1aa
To explore the application of this method, the scope of
the redox condensation reaction was examined under the
optimized conditions (Tables 2 and 3).
entry
2
R
3
yield (%)b
A range of 2-arylethylamines (2 equiv) were allowed to
react with o-nitroaniline in the presence of FeCl3 6H2O
3
1
2a
2b
2c
2d
2e
2f
Ph
3aa
3ab
3ac
3ad
3ae
3af
75
78
94
73
75
56
78
58
63
56
48
(5 mol %) and sulfur (20 mol %) under solvent-free
conditions (Table 2). 2-Phenethyalmines bearing differing
2
3-MeC6H4
4-FC6H4
3
4
4-ClC6H4
5
4-BrC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-FC6H4
(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.
6
7
2g
2h
2i
3ag
3ah
3ai
8
9
10
11
2j
3,4-(MeO)2C6H3
n-hexyl
3aj
2k
3ak
a Reaction conditions: 1a (2.5 mmol), 2 (5 mmol), FeCl3 6H2O
3
(0.125 mmol, 34 mg), S (0.5 mmol, 16 mg). b Isolated yield.
substitution patternsandelectronicpropertieswereproven
to be suitable substrates, providing products in good
yields. While electron-poor 2-phenethylamine 2c was par-
ticularly 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 orthosubstituent of the 2-phenethylamines
(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.
B
Org. Lett., Vol. XX, No. XX, XXXX

was well-tolerated (Table 2, entries 8, 9), although the yield
was slightly lower. A long chain aliphatic amine such as
n-octylamineonlygaveamoderateyield(Table2, entry11).
We then applied these reaction conditions to the conver-
sion of 2-phenethylamine 2a with various o-nitroanilines
into 2-phenylquinoxalines (Table 3). The reaction of mono-
substituted o-nitroanilines 1cÀg resulted in a mixture of
two possible regioisomers in good yields. These regio-
isomers were readily separable by column chromatography
in most cases (entries 3À6).
A subsequent two-electron transfer process would occur intra-
molecularly via complex imine-nitroso C with removal of one
molecule of water and ammonia. Further four-electron trans-
fer and dehydration would furnish quinoxaline 3 and regen-
erate 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 regioi-
somers of 3from 2-nitroanilines 1cÀgmonosubstitued at the
4, 5, or 6 position of the aromatic ring (entries 2À6, 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-o-
phenylenediamine (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-phenyl-
quinoxaline 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 6H2O
3
(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.
Scheme 2. Control Experiment
Although the details regarding the nature of the clusters
involved in the present method are not yet known, we pro-
pose a possible reaction mechanism in Scheme 1. The forma-
tion of ironÀsulfur 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 IronÀsulfur 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.
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
(9) Berg, J. M.; Holm, R. H. In Iron-Sulfur Proteins; Spiro, T. G., Ed.:
John Wiley and Sons: 1981; pp 1À66.
Org. Lett., Vol. XX, No. XX, XXXX
C

nontoxic FeCl3 6H2O and elemental sulfur under solvent-
Supporting Information Available. Experimental pro-
1
cedures, product characterization, and copies of the H
3
free 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.
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.
D
Org. Lett., Vol. XX, No. XX, XXXX