Conversion of nitroalkanes into carboxylic acids via iodide catalysis in water

Article abstract of DOI:10.1039/c5cc08681g

We report a new method for the conversion of nitroalkanes into carboxylic acids that achieves this transformation under very mild conditions. Catalytic amounts of iodide in combination with a simple zinc catalyst are needed to give good conversions into the corresponding carboxylic acids.

Full text of DOI:10.1039/c5cc08681g

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Conversion of Nitroalkanes into Carboxylic Acids via
Iodide Catalysis in Water
a
a
b
*a
Patricia Marcé, James Lynch, A. John Blacker, Jonathan M. J. Williams
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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1
2
We report a new method for the conversion of nitroalkanes presence of copper and zinc salts. Moreover, it is well known that
into carboxylic acids that achieves this transformation under nitroalkanes under acidic conditions are in equilibrium with the
3
f
very mild conditions. Catalytic amounts of iodide in corresponding nitronic acids.
combination with a simple zinc catalyst are needed to give
good conversions into the corresponding carboxylic acids.
Table 1 Optimization of reaction conditions for the conversion
of nitropropane into propionic acid
Organic molecules containing nitro group are synthetically important due
to the fact the nitro group can be converted into several other functional
O
Catalyst (20 mol%)
Additive
NO
2
OH
Toluene, 110 oC, 24 h
1
2
3
4
5
1
2
groups such as ketones, aldehydes, carboxylic acids, amines, alkenes
b
a
6
Entry
Catalyst
CuO
Cu(OAc)
Additive
Conversion (%)
and alkanes.
1
2
3
4
5
6
7
8
9
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
--
0
4
0
0
4
100
60
50
44
The use of nitroalkanes in organic synthesis often relies on their easy
2
conversion into the corresponding nitronate anions facilitated by the nitro
CuCl
ZnCl
Zn(OAc)
ZnI
ZnI
ZnI
2
7
group lowering the pKa of the hydrogen at the
α
-position. Nitronate salts
2
2
can act as carbon nucleophiles with a range of electrophiles such as
8
9
2
haloalkanes and aldehydes, or they can be used as well as Michael
2
10
c
acceptors. In particular, the reduction of the nitro group along with the
Nef reaction have become the most important transformations.
2
AcOH
HCl
d
ZnI
--
2
1
1
0
1
AcOH
0 f
The Nef reaction has been applied not only to the synthesis of aldehydes
and ketones but also to carboxylic acids under oxidative conditions.
e
b
d
--
TBAI - AcOH
100
g
h
12
Zn(OAc)2
TBAI - AcOH
100
3
a,3b
Current methodologies use a large excess of oxidant such as KMnO
4
,
a
1
Conversions were determined by analysis of the H-NMR
spectra. 2 equivalents of additive were used. 4 equivalents of
additive were used. 1 equivalent of additive was used.
equivalent of TBAI was used. 10% of propionamide and 10% of
3
f-3i
3c,3d
b
c
NaNO
McMurry’s method employs TiCl
compounds to aldehydes and ketones by means of oxime formation.
2
-AcOH or oxone.
d
e
to reduce nitronate salts or nitro
1
3
f
1
f,11
g
N-ethylformamide were also observed along with the acid. 10
At the same time, oximes can be efficiently converted into amides in the
h
mol% of Zn(OAc)
2
was used. 2 mol% of TBAI was used.
Herein we describe a new method for the conversion of nitroalkanes
and nitromethylbenzenes into carboxylic acids under very mild
conditions using catalytic amounts of an iodide source. The new
reaction conditions allow both aromatic and aliphatic carboxylic acids
to be obtained without the need to pre-form the nitronate species
usually required in the Nef reaction.
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DOI: 10.1039/C 868
Jou5CrnC0al Na1Gme
Furthermore, the reactions can be performed in water. Alternatively, for
more complex substrates that are non-compatible or insoluble in water a
combination of toluene and urea can also be employed (further details are
given in the supporting information).
a
Table 3 Conversion of nitrobenzyl compounds into carboxylic acids
We decided to explore the possibility of converting nitroalkanes into
carboxylic acids in the presence of a simple Lewis acid. Acetic acid
was employed as an additive to enhance the reactivity of the nitro group
(
Table 1).
4
a, 81%
d, 88%
4b, 92%
4e, 76%
4c, 89%
4f, 81%
We initiated our investigations using nitropropane as a model substrate in
the presence of copper salts using two equivalents of AcOH in toluene at
o
1
10 C for 24 h. Under these conditions only traces of product or no
conversion to the desired propionic acid were obtained (Table 1, entries
-3). When the Lewis acid was changed to ZnCl and Zn(OAc) no
improvement was observed (Table 1, entries 4 and 5). However, the use
ZnI gave the desired final product in 100% conversion (Table 1, entry 6).
1
2
2
4
2
The amount of additive was also studied. It was observed that decreasing
or increasing the amount of acetic acid, or the use of HCl, resulted in
lower reaction conversion (Table 1, entries 7-9). Control experiments in
the absence of additive or catalyst showed that while the presence of
acetic acid is key for an optimum reaction outcome (Table 1, entry 7), the
4
g, 93%
4h, 50%
4k, 90%
4n, 94%
4i, 77%
4l, 91%
4o, 90%
2
use of ZnI is also essential for the reaction to take place (Table 1, entry
1
0).
4
j, 84%
In light of these results, we became intrigued about the role of iodide in
this transformation and decided to test several iodide sources. The
treatment of 1-nitropropane with several iodide sources showed that
TBAI (tetrabutylamonium iodide) and KI in the presence of acetic acid
also promoted the formation of propionic acid. While the use of Lewis
acid improved conversions and avoided the formation of byproducts, it is
not absolutely essential for obtaining the carboxylic acid, showing that
the iodide is the key factor in this transformation (Table 1, entry 11). The
best conditions found involved the use of 2 mol% of TBAI, 10 mol% of
4
m, 88%
F
O
OH
F
b
4
p, 89%
4q, 88%
2b, 0%
2
Zn(OAc) and 1 equivalent of AcOH (Table 1, entry 12).
c
Table 2 Optimization of reaction conditions for the conversion of
nitromethylbenzene into benzoic acid
2
a, 0% (95%)
a
b
Isolated yields. The reaction was also performed using 1 equiv
c
TBAI and 2 equiv of AcOH and the starting material was recovered.
Isolated yield using 1 equiv of AcOH as additive.
in the reaction conversion (Table 2, entry 1). In light of the results, the
reaction was re-optimized for the transformation of nitromethylbenzene.
Water was the best solvent to obtain benzoic acid in the presence of 5
mol% of TBAI and 2 equivalent of AcOH (Table 2, entry 2). In contrast
to nitroalkanes, nitromethylbenzene can react in the absence of AcOH
with no decrease of the reaction conversion (Table 2, entries 2 and 3).
Several Lewis acids were also tested in this transformation. The addition
-
Lewis
acid
--
--
--
Conversion
Entry
[I ] source
Solvent
toluene
a
(%)
62
80
77
100
b
1
2
3
TBAIb
TBAIc
H
H
2
O
O
TBAI
2
d
4
5
6
7
TBAI
H
2
H
2
H
2
H
2
O
O
O
O
Cu(OAc)
2
4
a:5 80:20
88
d
TBAI
ZnCl
2
of 10 mol% of Cu(OAc)
conversions allowing to decrease the amount of TBAI to 2 mol% (Table
2, entry 4 and 5). The use of Zn(OAc) turned out to be the best Lewis
2 2
or ZnCl provided the benzoic acid in high
d
100
TBAI
Zn(OAc)
--
2
4
a:5 95:5
--
0
2
a
1
b
acid leading to the formation of benzoic acid in 95% conversion along
with traces of benzaldehyde (Table 2, entry 6).
Conversions were determined by analysis of the H-NMR spectra. 2
c
equiv of AcOH and 5 mol% of TBAI were used. 5 mol% of TBAI
without AcOH. 2 mol% of TBAI and 10 mol% of Lewis acid were
used.
d
With the optimized reaction conditions in hand, the substrate scope was
explored (Table 3). This transformation is compatible with a wide range
of substituents at the phenyl ring. The presence of electron-withdrawing
and electron-donating groups were well-tolerated at the ortho-, meta- and
para-positions affording the corresponding benzoic acid in excellent
In order to study the scope of the reaction, nitromethylbenzene 3a was
treated with TBAI in the presence of AcOH giving a significant reduction
2
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yields. Only when the reaction was performed on 4-tert
-
a
b
1
0 mol%. 2 mol%
butyl(nitromethyl)benzene, was the acid obtained in moderate yield.
Surprisingly, the treatment of 1-nitro-2-phenylethane with 1 equivalent of
TBAI and 2 equivalent of AcOH did not lead to the formation of the
carboxylic acid with only starting material returned. In contrast, propionic
acid could be achieved in excellent yield when 1 equivalent of AcOH was
employed as additive.
The roles of water and oxygen in the overall transformation were also
explored. The conversion of nitromethylbenzene to benzoic acid under
anaerobic conditions provided the final product in 60% yield,
suggesting that oxygen is involved in this process (see ESI). The same
reaction was carried out under anhydrous conditions using toluene as
1
Intrigued by the mechanism of this reaction we decided to explore which
could be the most likely intermediates for the conversion of nitro
compounds to the corresponding acids. For this purpose, benzaldoxime,
benzamide and benzaldehyde were subjected to the reaction conditions
solvent. The analysis of the reaction crude by H-NMR showed a very
complex reaction mixture in which the final products could not be
identified (see ESI). Finally, we decided to perform this transformation
1
8
18
using H
2
O (10 atom % O) to determine if water was in fact taking
(
Scheme 1). Interestingly, benzaldoxime and benzamide were recovered
part in this process. Analysis of the reaction crude by ESI-HRMS
18
after the reaction. In contrast, benzaldehyde was transformed into benzoic
acid in excellent conversions. We assume that oxygen is the terminal
oxidant present in this process.
showed the incorporation of O into the final product. This fact
suggested that the oxygen from the carbonyl could come from the
incorporation of water during the reaction course (see ESI).
Considering these results, and taking into account that the main by-
product detected in the optimization of the reaction conditions was
benzaldehyde, a possible mechanism starts by the formation of the
aldehyde which is then oxidised under the reaction conditions.
The fact that this transformation takes place via the formation of the
nitronate species would also explain why the transformation of nitro
compounds is more favoured for benzylic substrates. The lower pKa of
the benzylic position leads to the production of the nitronate species
just in the presence of a Lewis acid. In contrast, nitroalkanes required
stronger acid conditions such as 2 equivalents of AcOH to form the
same intermediate species.
Scheme 1
Thus, the coordination of Zn(OAc)
the formation of the nitronate species (Scheme 2). Then the attack of
water to the -position would lead to the
dihydroxyamino)(phenyl)methanol intermediate which can evolve to
2
to the nitro group would facilitate
†
In order to study the role of each reagent in the oxidation step
α
2
benzaldehyde was treated with Zn(OAc) , TBAI and water obtaining the
(
benzoic acid in high conversions in all the cases (Table 4). This
experiment pointed out that if the reaction goes through the formation of
an aldehyde as intermediate, no further oxidants are required to convert
them into the corresponding benzoic acids.
the aldehyde by a Nef reaction mechanism. Once the aldehyde is
formed, oxidising conditions are needed to convert the aldehyde into a
carboxylic acid. In that sense, we initially assumed that this step was
-
being catalysed by the addition of IO (which would be formed by
-
13,14,15,16
Table 4 Oxidation of benzaldehyde
oxidation of I by either liberated HNO or by nitroalkane),
but
the results in Table 4 indicate that at least for benzylic oxidation, this is
not required, with simple aerobic oxidation providing the more likely
pathway. The role of iodide is therefore not entirely clear, but may
17
assist with the hydrolysis of the nitronate by nucleophilic addition.
In summary, this is the first example of the conversion of nitroalkanes
and nitromethylbenzenes into carboxylic acids catalysed by the presence
Entry
Catalyst
Conversion (%)
of Zn(OAc)
2
and TBAI. It has been shown that this transformation
a
1
2
3
Zn(OAc)
2
80
90
96
tolerates a variety of substituents on the phenyl ring.
b
TBAI
--
Scheme 2 A plausible mechanism for the conversion of nitroalkanes into carboxylic acids
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-
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