Iron-Catalyzed Sulfur-Promoted Decyanative Redox Condensation of o-Nitrophenols and Arylacetonitriles: An Unprecedented Route to 2-Arylbenzoxazoles

Article abstract of DOI:10.1002/ejoc.201701607

Elemental sulfur in the presence of a catalytic amount of FeCl₂·4H₂O was found to be highly efficient for the promotion of decyanative redox condensation reactions of o-nitrophenols with arylacetonitriles, to give a wide range of 2-arylbenzoxazoles. The utility of elemental sulfur was highlighted by its role as cyanide scavenger and external reducing agent.

Full text of DOI:10.1002/ejoc.201701607

A Journal of
Accepted Article
Title: Iron-Catalyzed Sulfur-Promoted Decyanative Redox
Condensation of o-Nitrophenols and Arylacetonitriles: an
Unprecedented Route to 2-Arylbenzoxazoles
Authors: Binh Thanh Nguyen and Jerome Cheung Lung
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10.1002/ejoc.201701607
European Journal of Organic Chemistry
COMMUNICATION
Iron-Catalyzed Sulfur-Promoted Decyanative Redox
Condensation of o-Nitrophenols and Arylacetonitriles: an
Unprecedented Route to 2-Arylbenzoxazoles
Thanh Binh Nguyen,*[a] and Jerome Cheung Lung [a]
Abstract: Elemental sulfur in the presence of catalytic amount
FeCl2•4H2O was found to be highly efficient to promote decyanative
among these derivatives), a direct combination of 1 with 2
would avoid unnecessary intermediate transformations, limit
waste formation and maximize atom efficiency. In the
present case, an external reductant is needed to avoid
redox condensation reactions of o-nitrophenols
1
with
arylacetonitriles 2 to a wide range of 2-arylbenzoxazoles 3. The
utility of elemental sulfur was highlighted by its role as cyanide
scavenger and external reducing agent.
excess use of the reducing partner
providing only 4 e- while the oxidizing partner
2
since
2
is capable of
requires 6
1
e-. Elemental sulfur is particularly suitable for acting as
external reductant. Moreover, as elemental sulfur has long
been known to react with cyanide to yield relatively non-
Introduction
5
toxic thiocyanate, we reasoned that sulfur could act
perfectly as cyanide ion scavenger. Finally, the combination
Fe/S, which is ubiquitous in biological world, even in the
simplest forms, would be potentially useful for catalyzing
redox transformation.6
Nitrile groups are widely present in natural products, bioactive
molecules (pharmaceuticals, agrochemicals) and functional
materials. They constitute an important functional group in
organic chemistry as they involve in a wide range of reaction
and can readily be transformed into other functionalities such as
amines, amidines, amides, aldehydes, carboxylic acids and
heterocyclic moieties. 1 Additionally, due to their pseudohalogen
nature, nitrile groups can act as leaving group, being removed
as cyanide ion. 2 Although this chemical behavior has been
largely explored and resulted in powerful synthetic methods,3 an
evident drawback is the high toxicity of the cyanide byproduct.
Consequently, care should be taken during the reaction workup,
especially in large-scale synthesis. Herein, we suggest an eco-
responsible solution for this issue using iron-sulfur system
applied to the decyanative redox condensation reaction between
Results and Discussion
To validate our hypothesis, we selected o-nitrophenol 1a and
phenylacetonitrile 2a as model substrates in the redox
condensation reaction leading to 2-phenylbenzoxazole 3aa
(Table 1).7 The reactions were carried out under solvent-free
conditions in the presence of elemental sulfur (2 equiv) and
simple iron salt FeCl2•4H2O (5 mol %) as iron/sulfur catalyst
precursors. The optimization of reaction conditions was
performed based on the screening of base additives. In the
absence of additive or when DMF or DMSO was used, no trace
of the desired benzoxazole 3aa was observed (entries 1-3). The
starting materials 1a and 2a remained unchanged. Gratifyingly,
nitrogen heterocycles which have been previously demonstrated
to be efficient activator of elemental sulfur4 were shown to
promote the expected decyanative redox condensation, leading
to benzoxazole 3aa. While the activation of heteroaromatic
additives such as pyridine and 3-picoline remained weak (entries
4-5), N-methylated six-membered ring bases such as N-
o-nitrophenols
with
arylacetonitriles
to
provide
2-
arylbenzoxazoles.
methylmorpholine,
N-methylpiperidine
and
1,4-
dimethylpiperazine exhibited good promoting capacities (entries
6-8) with highest yield achieved with N-methylpiperidine (entry 7).
This activating is negligible in the absence of iron (entry 9) or
significantly reduced when only one equivalent of sulfur was
used (entry 10). Good results could also be obtained with lower
iron catalyst loading (entries 11-12). Finally, the conversion
dropped appreciably when the reaction temperature was
lowered to 80 °C (entry 13 vs 7).
The optimized conditions were next applied to the reaction of
o-nitrophenol 1a with a range of arylacetonitriles 2b-h (Scheme
2). In each case, arylacetonitriles substituted with electron-
donating or electron-withdrawing groups condensed with
heterocyclic o-nitrophenol to generate diversely substituted
benzoxazole products with moderate to good yields. These
substituents include chlorine, fluorine, methyl, methoxy,
trifluoromethyl. The most challenging substrates for this system
were that o-substituted arylacetonitriles by a methyl or a benzo
Scheme 1. Decyanative redox condensation vs classical non-redox
condensation leading to benzoxazole 3aa
Our group has been interested in the redox
4
condensation of aromatic nitro compounds,
which
constitutes an attractive alternative approach to classical
non-redox condensation. Scheme 1 depicts an example
leading to benzoxazole
condensation, the starting materials
provide
Because aniline
via a 6e- reduction while acid ii can be obtained by the
oxidation of its derivatives of lower oxidation states (2 is
3
.
In
a
classical non-redox
i
and ii condense to
3
with the formation of water as the only by-product.
is generally prepared from the parent nitro
i
1
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10.1002/ejoc.201701607
European Journal of Organic Chemistry
COMMUNICATION
group such as 2g-h. They displayed lower reactivities, their
reactions with o-nitrophenol 1a even with higher catalyst loading
(5 mol %) and at higher temperature (110 °C) resulted in low
yields.
transformation were merely a one-pot of three elementary
reactions including: (1) reduction of o-nitrophenol 1a into o-
aminophenol i; (2) oxidation of benzyl cyanide 2a into benzoic
derivative ii’; and (3) condensation of i and ii’ leading to 3aa.
The nearly quantitative recovery of 1a or 2a when each of them
was subjected to the standard conditions excluded this
hypothesis (eq. 1 and 2).
Table 1. Optimization of the reaction conditions
Entry[a]
T (ºC)
100
100
100
100
100
100
100
100
100
100
100
100
80
additive
x
y
yield (%)[b]
0[c]
1
-
5
5
5
5
5
5
5
5
0
5
2
1
5
2
2
2
2
2
2
2
2
2
1
2
2
2
2
DMF
0[c]
3
DMSO
0[c]
4
pyridine
<5[c]
<5c
55
5
3-picoline
6
N-methylmorpholine
N-methylpiperidine
1,4-dimethylpiperazine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
7
71
8
67
9
<5[c]
35
10
11
12
13
72
Scheme 2. Reaction scope with arylacetonitriles 2
69
42
The formation of o-aminophenol as a reaction intermediate
under the standard conditions was further invalidated by the
experiment resumed in eq. 3. Indeed, when o-aminophenol i
was used in place of o-nitrophenol 1a, 2-benzylbenzoxazole 4
was formed in excellent yield as a result of a non-redox
[a]
Reaction conditions unless otherwise noted: 1a (1 mmol), 2a (n mmol),
FeCl2•4H2O (x mol %), S (y mmol, 32 mg.mmol-1), base (z equiv), at T °C for
16 h. [b] Isolated yield. [c] Determined by 1H NMR of the crude reaction mixture.
condensation of both starting materials
concomitant elimination of ammonia (eq. 3).
i and 2a with
Based on the successful decyanative redox condensation of
o-nitrophenol 1a with arylacetonitriles 2, we briefly explored the
scope of substituted o-nitrophenols 1b-g under conditions B
(FeCl2•4H2O 5 mol % at 110 °C) (Scheme 3). In all cases tested,
o-nitrophenols substituted with neutral (1b,c), electron-
withdrawing (1d) electron-donating (1e-f) groups coupled with
benzyl cyanide 2a in good yields. It should be noted that 5-
amidobenzoxazoles based on 3fa scaffold was previously found
potentially useful for the treatment of Duchenne muscular
dystrophy.8 Azabenzoxazole 3ga was also efficiently prepared
from 3-nitro-4-hydroxypyridine 1g.
A series of control experiments was conducted to gain
insight into the possible mechanism for this process under the
standard reaction conditions (entry 10, Table 1) and the results
were presented in Scheme 4.
Scheme 3. Reaction scope with o-nitrophenols 1
The formation of benzoxazole 4 was however not observed
in the redox condensation reaction (entry 10, Table 1, eq. 4). On
the other hand, along with the formation of 2-phenylbenzoxazole
Since elemental sulfur was known to act as either oxidant or
reductant, at first glance, one could think that the present
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10.1002/ejoc.201701607
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3aa, the presence of 2-benzoylbenzoxazole 5 was noticeable in
the crude mixture in trace amounts (eq. 4). It is noteworthy that
for each successful decyanative redox condensation reaction
presented in Schemes 2 and 3, the aqueous extracts were
shown to contain thiocyanate (colored red with Fe3+), suggesting
the cyanide by-product reacted with sulfur and transformed into
thiocyanate. Finally, non-benzylic cyanides such as butyronitrile,
3-phenylpropionitrile or benzonitrile were inactive under the
standard conditions, suggesting a benzylic methylene is a
prerequisite for the reaction success.
phenolate oxygen atom on the nitrile group followed by water-
assisted cascade of transacylation and deamination.
Scheme 5. Proposed mechanism
Conclusions
FeCl2•4H2O and elemental sulfur was found to be highly efficient
in catalyzing
a decyanative redox condensation reaction
between o-nitrophenols and arylacetonitriles. While the yields
remained moderate in some cases, the scope of this
transformation seems to be rather broad and the method is
environmentally friendly. Elemental sulfur was found to be
particularly suitable for this transformation due to its multiple
roles as (i) cyanide ion scavenger; (ii) external reductant; and
(iii) constitutional component for Fe/S catalyst. Compared to
known methods of redox condensation using o-nitrophenols with
other reducing partners to provide 2-arylbenzoxazoles and
required and complex/expensive catalysts,7 the present
approach is highlighted by its simplicity, its inexpensiveness and
its environmental friendliness. It is hoped that the catalytic
activities of Fe/S system in decyanative reactions may be
applied to other redox condensation reactions, and such
investigations are in progress in our laboratory.
Scheme 4. Survey of reaction pathways
On the basis of these observations and the experimental
results involving related Fe/S catalyst in our earlier work,4i we
proposed the reaction mechanism for the decyanative redox
condensation of o-nitrophenol 1a with benzylcyanide 2a
depicted in Scheme 5. The first step would be the formation of
iron-sulfur cluster A from iron salt elemental sulfur and in the
presence of N-methylpiperidine. The cubane structure was
arbitrarily selected although other forms were also possible. For
the sake of simplicity, the charges/oxidation states of iron and
sulfur as well as external ligands were not indicated. The next
step would involve the fixation of both starting materials on the
cluster to yield B by coordination. Subsequent sulfur promoted
monodeoxygenation of the nitro group would provide chelate
nitroso complex C. Condensation between the nitroso group with
the methylene moiety of benzyl cyanide fragment would next
proceed with simultaneous removal of a water molecule to yield
D. Fragmentation of D would yield the expected benzoxazole
3aa, cyanide anion and recycle cluster A. In the presence of
excess elemental sulfur, the resulting cyanide anion would be
trapped as thiocyanate, making the step D  A irreversible. The
formation in trace quantities of 2-benzoylbenzoxazole 3aa could
be explained by a cyclization of D via nucleophilic attack of the
Acknowledgements
We thank Dr. A. Marinetti (ICSN) for her support.
Keywords: iron-sulfur catalyst • redox condensation •
benzoxazole • benzyl cyanide • o-nitrophenol
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10.1002/ejoc.201701607
European Journal of Organic Chemistry
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10.1002/ejoc.201701607
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Key Topic*
Thanh Binh Nguyen,* and Jerome
Cheung Lung
Page No. – Page No.
Iron-Catalyzed Sulfur-Promoted
Decyanative Redox Con-densation of
o-Nitrophenols and Arylacetonitriles:
an Unprecedented Route to 2-
Arylbenzoxazoles
Elemental sulfur in the presence of catalytic amount FeCl2•4H2O was found to be
highly efficient to promote decyanative redox condensation reactions of o-
nitrophenols 1 with arylacetonitriles 2 to a wide range of 2-arylbenzoxazoles 3. The
utility of elemental sulfur was highlighted by its role as cyanide scavenger and
external reducing agent.
This article is protected by copyright. All rights reserved.