Iron sulfide catalyzed redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups: A straightforward atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles

Article abstract of DOI:10.1021/ja311780a

Iron sulfide generated in situ from elemental sulfur and iron was found to be highly efficient in catalyzing a redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups. This method represents a straightforward and highly atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

Full text of DOI:10.1021/ja311780a

Communication
pubs.acs.org/JACS
Iron Sulfide Catalyzed Redox/Condensation Cascade Reaction
between 2‑Amino/Hydroxy Nitrobenzenes and Activated Methyl
Groups: A Straightforward Atom Economical Approach to 2‑Hetaryl-
benzimidazoles and -benzoxazoles
Thanh Binh Nguyen,* Ludmila Ermolenko, and Ali Al-Mourabit
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
*
S Supporting Information
Scheme 1. Approaches to Benzazoles
ABSTRACT: Iron sulfide generated in situ from ele-
mental sulfur and iron was found to be highly efficient in
catalyzing a redox/condensation cascade reaction between
2
-amino/hydroxy nitrobenzenes and activated methyl
groups. This method represents a straightforward and
highly atom economical approach to 2-hetaryl-benzimida-
zoles and -benzoxazoles.
evelopment of new efficient functional group trans-
D
formations in organic synthesis plays a crucial role in
modern sustainable chemistry. For this purpose, application of
catalytic chemical processes might avoid unnecessary steps, thus
reducing material and energy waste. The Fe−S redox system is
considered among the most interesting catalysts involving
electron transfer in active centers of redox catalytic proteins.
Many types of Fe−S clusters are based on the coordination of
elemental sulfur and usually bridged to their proteins by cysteine
a
Table 1. Optimization of Reaction Conditions
1
thiolates. The chemistry of redox reactions involving organic
compounds and the sulfur/iron interaction is consequently very
interesting to investigate. Iron sulfide clusters are found in all
living forms, ranging from bacteria to man and are present at the
b
entry
catalyst (mol %)
conditions
conversion (%)
1
2
3
4
5
6
7
8
9
−
150 °C, 72 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
150 °C, 16 h
140 °C, 16 h
0
30
<5
<5
<5
<5
<5
30
95
7
2
active sites of a wide variety of redox proteins. In many of these
FeS (10)
proteins, the main role of the cluster is to accelerate electron
transfer, to act as capacitors, storing and releasing electrons to
FeCl ·6H O (10)
3
2
FeCl
(10)
3
3
metabolic reactions. Fe−S cluster formation can occur
FeSO
Fe(NO
Fe(acac)
FeSO ·7H
4
·7H
2
O (10)
spontaneously when sufficient amounts of reduced and soluble
)
3
3
·9H
2
O (10)
4
iron and sulfur are available. The prevalence of such conditions
3
(10)
early in the history of the earth could account for the presence of
4
O/Na S (10/10)
2 2
5
these groups in a wide variety of proteins. Based on these
Fe (10), S (10)
S (10)
10
11
12
13
literature reports, we reasoned that iron sulfide could be a
promising, contributing candidate in both oxidation and
reduction.
Fe (10)
<5
<5
75
S (1), Fe (1)
S (10), Fe (10)
Benzimidazoles and benzoxazoles are important building
blocks for the construction of pharmaceuticals, natural products,
functional materials, and agrochemical compounds. In the course
of our research on new strategies of C−N bond formation, we
were interested in the creation of this moiety. Typically, these
compounds are synthesized by condensing 2-amino/hydroxy
a
Reaction conditions: o-nitroaniline 1a (5 mmol), 4-picoline 2a (10
b
1
mmol). Determined by H NMR.
−
1
(6e transfer); (ii) carboxylic acids 5 from the oxidation of their
6
lower oxidation degree parent compounds 2 such as aldehydes,
anilines 4 with carboxylic acid derivatives 5 (Scheme 1). This
−
−
−
primary alcohols, or even methyl groups (2e , 4e , or 6e
approach, although extensively used, cannot be considered as an
atom economical transformation because both of the starting
materials are usually obtained by two opposite reactions: (i)
anilines 4 from the reduction of the corresponding nitrobenzenes
Received: December 5, 2012
Published: December 19, 2012
©
2012 American Chemical Society
118
dx.doi.org/10.1021/ja311780a | J. Am. Chem. Soc. 2013, 135, 118−121

Journal of the American Chemical Society
Communication
a
Table 2. Iron Sulfide Catalyzed Reaction between 2-Amino/Hydroxy Nitrobenzenes and Methyl Hetarenes
a
Reaction conditions: nitrobenzene 1 (5 mmol), methyl hetarene 2 (10 mmol), Fe (0.5 mmol), S (0.5 mmol), 150 °C, 24 h unless otherwise noted.
af-2:3af-4 ratio of the crude mixture determined by H NMR = 2:1. Reaction performed at 160 °C. ∼90% purity by H NMR.
b
1
c
d
1
3
7
transfer respectively). A catalyst capable of effecting a direct H-
transfer from 2 to 1 would be highly desirable because three
processes, oxidation, reduction, and condensation, are carried
out in only one operation.
has been reported. Although efficient in some cases, this method
suffered from a major intrinsic drawback. Because benzyl alcohol
can transfer only four electrons while the reduction of o-
nitrophenols requires six electrons, the use of excess benzyl
alcohol and the formation of its side products are obviously
unavoidable. Moreover, the use of an expensive, high molecular
weight dppf catalyst hindered practical application.
Recently, the formation of 2-arylbenzoxazoles from o-
nitrophenols and benzylic alcohols using 1,1′-bis-
(
diphenylphosphino)ferrocene (dppf) as a H-transfer catalyst
1
19
dx.doi.org/10.1021/ja311780a | J. Am. Chem. Soc. 2013, 135, 118−121

Journal of the American Chemical Society
Communication
Scheme 2. Proposed Mechanism
To investigate the scope and limitation of this catalytic system,
we next applied the optimized conditions to different substrates
(
Table 2). Pyridine and quinoline derivatives possessing a methyl
group at the 2- or 4-position, 2a−g, were all suitable substrates in
the reaction with o-nitroaniline providing the corresponding
benzimidazole products 3aa−3ag in yields ranging from 56% to
9
1% (entries 1−7, Table 2). In the case of 2,4,6-trimethylpyr-
idine, no remarkable difference in reactivity of the 2- and 4-
methyl groups was observed. Both regioisomers 3af-2 and 3af-4
were obtained in a 2:1 ratio. However, 3-picoline 2h failed to
react with 1a (entry 8, Table 2) and both starting materials were
recovered unchanged. This result is in agreement with earlier
observed reactivities of the methyl groups of picolines in
1
1
elemental sulfur-mediated oxidation. This difference in
reactivity was demonstrated clearly when 3,4-lutidine 2g reacted
12
with o-nitroaniline 1a and afforded only one product, 3ag. o-
Nitroanilines 1b−h having electron-donating and -withdrawing
substituents on the benzene ring were all capable of reacting with
4
3
-picoline 2a to afford the corresponding benzimidazoles 3ba−
ha in high to excellent yields (entries 9−15, Table 2).
In this context, a reaction between o-amino/hydroxy nitro-
benzenes 1 and methylhetaryl 2 catalyzed by efficient, low-cost,
readily available, and nontoxic catalysts such as iron sulfide would
provide a new straightforward approach to benzazoles 3.
Herein, we report an extremely simple iron sulfide based
catalytic system for a direct condensation between 2-hydroxy/
amino nitrobenzenes with a methylhetarene without any added
oxidizing or reducing agent.
Moreover, the reaction displayed high functional group
tolerance. Chloride, bromide, and methoxy functionalities are
all tolerated. Interestingly even a reaction between dinitroaniline
1
h and 2a could be achieved, leaving the other nitro group at the
para position to aniline intact (entry 15, Table 2). Although 1i is
a highly sterically demanding substrate, the H-transfer process
was successfully carried out with 2a (entry 16, Table 2).
In addition, 2-methylbenzimidazoles (2i−j) can be oxidized
and converted to the desired product 3ai−aj in 66−85% yields
As an exploratory study, we chose the reaction between o-
nitroaniline 1a and 4-picoline 2a as a model reaction under
solvent-free conditions (Table 1). This reaction has been
reported by using a large excess of elemental sulfur at high
temperature (up to 185 °C) and resulting in benzimidazole 3aa
(
entries 17−19). Finally, o-nitrophenol 1j reacted successfully
with 2- and 4-methylquinolines 2b,d (entries 20−21).
While the mechanism of the transformation is not clear at this
moment, three important observations may be discussed. First,
the methyl group must be located at the 2- or 4-position of the
8
formation by ∼30%. Our objective was to find milder solvent-
free reaction conditions catalyzed by an Fe−S system.
13
Without a catalyst, no reaction occurred, and the starting
substrates remained intact after heating at 150 °C for 72 h (entry
pyridine ring or at the 2-position of the benzimidazole ring.
Second, the catalytic activity of iron sulfide depends strongly on
the preparation methods. Third, during the reaction process,
for example between 1a and 2a, only starting material 1a, 2a and
benzimidazole product 3aa were observed as the main
10
1
, Table 1). Gratifyingly, commercially available iron sulfide
powder (100 mesh, 99.9% trace metals basis, Sigma Aldrich) gave
the desired compound in 30% yield (entry 2, Table 1). Screening
other iron salts did not result in any significant conversion
1
components (by H NMR of the methanol soluble part of
(
entries 3−7, Table 1). When an iron sulfide catalyst generated in
reaction mixture). All the reaction intermediates were fixed on
the surface of the iron sulfide catalyst, and the entire sequence of
reactions including oxidation, reduction, and condensation was
carried out on the surface as well. We tentatively propose the
catalytic mode of the iron sulfide cluster. For clarity purposes,
situ from ion metathesis reaction between an equimolar mixture
of FeSO ·7H O and Na S was used (entry 8, Table 1), a similar
4
2
2
conversion was observed as for commercial FeS (entry 2, Table
). Remarkably, adding an equimolar mixture of metallic iron
1
powder and elemental sulfur (10 mol %) boosted the conversion
iron sulfide is presented as an uncharged Fe S cube A (Scheme
4 4
9
up to a nearly quantitative level (entry 9, Table 1). In order to
2). The first step could be the fixation of methylhetaryl 2 on A in
which a C−S bond is created with the removal of one hydride
from the methyl group. o-Nitroaniline is fixed at the vicinal iron
site by coordination to yield intermediate B. The next step could
be the redox reaction between the methylene group with the
nitro group with simultaneous removal of water to provide
thioacetimidate C. Nucleophilic attack of the vicinal amino group
on the thioacetimidate function would result in benzimidazole 2
and recycle the catalyst A.
In conclusion, we have developed a new, remarkably simple,
and straightforward method for the direct coupling of amino/
hydroxy nitrobenzenes and the methyl group bearing a 2-, 4-
picolyl or 2-benzimidazolyl substituent providing 2-hetaryl-
benzimidazoles/-benzoxazoles. The reaction employs a catalytic
amount of iron sulfide generated in situ from the elements under
solvent-free conditions. The utilization of inexpensive, readily
available starting materials and catalyst are significant advantages
confirm if iron sulfide generated in situ in this run or each separate
element is responsible for this reactivity enhancement, two other
experiments were carried out with elemental sulfur and iron
10
powder. Addition of sulfur in a 10 mol % amount resulted in 7%
conversion (entry 10, Table 1). This result is however
encouraging because it showed that sulfur displayed some
catalytic effect (oxidation of 1 mol of 4-picoline requires in
principle 3 mol of sulfur). However, metallic iron is not
catalytically active for this reaction. Although the equimolar
mixture Fe/S was highly active at a 10% amount, this system
displayed only negligible catalytic activity at 1% (entry 12, Table
1
). This result suggested that, at low concentration, the iron
sulfide formation decreases strongly. Moreover, in this case,
sulfur is consumed in promoting the reaction between 1a and 2a
as in entry 10, Table 1. Finally, a lower reaction temperature
resulted in lower conversion (entry 13, Table 1).
1
20
dx.doi.org/10.1021/ja311780a | J. Am. Chem. Soc. 2013, 135, 118−121

Journal of the American Chemical Society
Communication
that allow for the increased usefulness of the reaction. The
reaction shows high generality, excellent selectivity toward the 2-
and 4-methyl group of azine and 1,3-diazole systems, and good
functional group tolerance. Mechanistic, scope, and limitation
studies of the reaction as well as attempts to identify reaction
intermediates are in progress.
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ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, product characterization, and copies of
1
13
the H and C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
nguyen@icsn.cnrs-gif.fr
■
1
873. From amides: (x) Kornilov, M. Y.; Ruban, E. M. Zhur. Org. Khim.
Notes
1
973, 9, 2188. (y) Botta, A. U.S. Patent US3972890 A1, 1976.
The authors declare no competing financial interest.
(
8) Wu, M.; Hu, X.; Liu, J.; Liao, Y.; Deng, G. J. Org. Lett. 2012, 14,
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2
ACKNOWLEDGMENTS
We thank CNRS and ICSN for financial support.
■
4
(
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