New insights into the catalytic reduction of aliphatic nitro compounds with hypophosphites under ultrasonic irradiation

Article abstract of DOI:10.1039/c7gc01622k

This work describes an efficient process for the reduction of nitro compounds to the corresponding amines with a catalytic amount of Pd/C (0.6 mol%), and a mixture of sodium hypophosphite and hypophosphorous acid as a reducing agent in H₂O/2-MeTHF at 60 °C. The reaction was optimized under silent conditions. The conditions for the in situ production of H₂ using the mixture NaH₂PO₂/H₃PO₂ were studied. The influence of ultrasonic activation was investigated both in terms of efficiency and kinetics. The reaction was shown to be efficient in water, at 70 °C with a quantitative conversion and a maximal yield in only 15 min thanks to the ultrasonic activation. Finally, ultrasound was proved to act as a physical agent of phase transfer.

Full text of DOI:10.1039/c7gc01622k

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New insights into the catalytic reduction of aliphatic nitro
compounds with hypophosphites under an ultrasonic irradiation
a
a
a
b
c
b
a
Received 00th January 20xx,
Accepted 00th January 20xx
S. Letort , M. Lejeune , N. Kardos , E. Métay , F. Popowycz , M. Lemaire , M. Draye, *
This work describes an efficient process for the reduction of nitro compounds to the corresponding amines with a catalytic
DOI: 10.1039/x0xx00000x
amount of Pd/C (0.6%mol), a mixture of sodium hypophosphite and hypophosphorous acid as a reducing agent in H
MeTHF at 60°C. The reaction was optimized under silent conditions. The conditions for the in-situ production of H
the mixture NaH PO /H PO were studied. The influence of ultrasonic activation was investigated both in terms of
2
O/2-
www.rsc.org/
2
using
2
2
3
2
efficiency and kinetics. The reaction was shown to be efficient in water, at 70°C with a quantitative conversion and a
maximal yield in only 15 min. thanks to the ultrasonic activation. Finally, ultrasound was proved to act as a physical agent
of phase transfer.
hydride (LiAlH ), as a hydrogen source, in combination with
Introduction
4
5
transition metals leads to some boron or aluminium and lithium
The amine function is fundamental by its presence in natural
products, fine chemicals, dyes and drugs such as, benzodiazepines,
β-carbolines or phenethylamine derivatives. Its classical preparation
relies on the reduction of a wide variety of nitro precursors via
several synthetic methods, leading to the corresponding amines.
salts but is very efficient for the conversion of nitro to amines.
6
Other hydrogen donors such as formic acid and its derivatives, or
7
hydrosilanes and hydrosiloxanes have been used. Unfortunately,
most of them have a limited scope and can only reduce aromatic
7
b
nitro compounds into their corresponding amines. Thus, in the
context of Green Chemistry, the development of an efficient, eco-
friendly, economical and safe general method for the nitro-to-
amine conversion is still a major issue.
Among them, heterogeneous or homogeneous hydrogenation
1
catalyzed by metals such as Pd/C, Pt/C, Raney-Ni, PtO
2
,
RuCl
2
3
(PPh )
3
is still the most important method used in
petrochemical and pharmaceutical industries. However, these
protocols are often associated with a lack of chemoselectivity in the
presence of other reducible functions. In addition, the reaction is
very exothermic, and special equipment, pressurized hydrogen and
flammable solvents are required, involving particular precautions in
Although it has hitherto been less used, sodium hypophosphite
seems particularly interesting since its registration in 2010 by
REACH as a non-hazardous substance for human beings and for the
8
environment. Indeed, hypophosphorous acid and its salts are well-
2
known, mild, economical, and powerful reducing agents that are
terms of safety. Transfer hydrogenation processes do not require
9
widely used for the electroless deposition of metal. They have
pressurized hydrogen but present some drawbacks as well. The
demonstrated their ability to reduce a large number of functional
Bechamp reduction process is the oldest commercial process for
1
0
3
4
groups, with a good chemoselectivity depending on the nature of
the preparation of amines. It is performed under acidic conditions,
which are incompatible with certain functional groups, in the
presence of a large excess of metal, generating water-soluble metal
1
1
the associated metallic catalyst. These reductive systems have
been shown to be effective for the hydrogenolysis of certain
1
2
functional groups through in-situ H
2
production. Thus, they have
4
salts as waste. Sodium borohydride (NaBH ) or lithium aluminium
1
3
14,15
been used to reduce alkynes to alkenes, alkenes to alkanes,
1
5
15
16
azides to amines, epoxides to alcohols, nitriles to aldehydes,
17
ketones and aldehydes to alcohols,
carboxylic acids to
1
8
15,19
aldehydes,
aryl or alkyl halides to arenes or alkanes,
2
0
21
diazonium salts to arenes, nitroolefins to ketones, oximes to
17
22
carbonyls, aryl ethers to arenes. They have also shown abilities
1
4,23
14
to deprotect benzyl ethers,
benzyl carbonates and N-benzyl
2
4
25
derivatives and to achieve reductive desulfurization.
In 1910, Mailhe and Murat proposed the first procedure for the
2
6
reduction of nitro compounds to amines with hypophosphites.
2
7,28
Later, a few examples were published.
However, in many cases,
the reactions were specific to peculiar substrates and no general
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process was described. Moreover, some examples were confined to
Journal Name
2
8
nitroarenes that are easier to reduce.
Thus, we aimed to establish a general method to reduce both
aliphatic and nitroarenes compounds respectively to amine and
aniline derivatives with sodium hypophosphite under acceptable
risk conditions, with respect to the safety of man and environment
protection. Indeed, contrary to the procedures of reduction of nitro
aromatic derivatives into anilines reported by Parfenov and Smirnov
2
9
30
in 1992 and by Meshram in 2000, and requiring an over-
stoechiometric amount of metallic catalyst, a methodology using
catalytic quantity would be of great interest.
Scheme 1 Synthesis of the β-nitroethylbenzene, as a model, and subsequent
reduction
Power ultrasound assisted reactions proceed through the
formation, the growth and the quasi-adiabatic collapse of transient
cavitation bubbles. The consequences of this phenomenon are
extreme conditions of transient high temperature (up to 5000K) and
high pressure (up to 1000 atm) within the collapsing bubbles, the
formation of radicals (e.g. in water hydrogen and hydroxyle ones)
and shock wave generation, which lead to radical reactions but also
The influence of the solvent nature was evaluated by the
comparison of two solvent systems: water or a combination of two
2
non-miscible solvents, H O / 2-MeTHF, in order to prevent the
solubility problems of the nitro compound while facilitating the
isolation and purification processes (Table 1). Indeed, 2-
methyltetrahydrofuran is a non hydrosoluble solvent derived from
renewable sources, sugar cane.
3
1
generate some interesting physical effects.
Thus, the
enhancement of catalyst activity under low frequency ultrasonic
irradiation (e.g. f = 20 kHz) is assumed to be due to an improvement
of mass transfer between the liquid and the catalyst surface, the
reduction of particle size, an increase in specific surface and also to
an acceleration of suspended particle motion induced by shock
2 2 3 2
The model reaction was then carried out with NaH PO / H PO in
two different proportions: 2 eq /1 eq and 3 eq /1 eq respectively, in
the presence of 0.6 mol% of Pd/C (5%, 50% water) at 60°C for 16 h.
In both cases, the addition of the organic solvent had a slight
positive effect. Indeed, when the substrate was stirred in H
0°C, a complete conversion was observed but the yield (70-72%)
Table 1, entries 1-3) was lower than in H O/2-MeTHF (1/1, v/v) (78-
2
O at
3
2
waves and microstreaming.
6
3
3
In a previous paper a process was proposed for the reduction of
aliphatic and aromatic nitro groups to amines/anilines in a mixture
(
2
8
0%) (Table1, entries 2-4).
H
2
O
/
2-MeTHF under ultrasonic activation, using the
In water, with two different amounts and ratio of reducing
reductive system NaH PO / H PO (2 eq /1 eq and 3 eq /1 eq), no
hypophosphite reductive system catalyzed by Pd/C. Sonication was
shown to have a significant importance, however, its role was not
elucidated.
2
2
3
2
significant improvement on the isolated yield was observed,
respectively 70 and 72% (Table 1, entries 1 and 2). A second run of
experiment was carried out with additional organic solvent 2-
methyltetrahydrofuran to enhance the solubility of the β-
nitroethylbenzene. The comparison showed that the addition of the
organic solvent had a slight positive effect with a significant
increase of the yield to 78-80% (Table1, entries 3 and 4).
The present study aims to elucidate the peculiar role of ultrasonic
irradiation and to give important information on the reducing
system in order to control and to judiciously exploit their
combination. Then, we report the screening of the influencing
parameters of the reduction of β-nitroethylbenzene, chosen as a
2 2 3 2
model substrate, with NaH PO /H PO and Pd/C as catalyst. After
2 2 3 2
After a brief study on the ratio of NaH PO / H PO in different
optimization, the best conditions were applied under ultrasonic
activation, in order to determine the predominant effects of
sonication on our benchmark reaction, which scope was then
extended to the reduction of other nitroalkanes.
solvents (Table1), the optimal conditions were conscientiously
evaluated (Table 2).
2 2 3 2
Table 1 Influence of solvent as a function of NaH PO /H PO ratio.
3 2
H PO
Results and discussion
a
Entry
NaH
2
PO
2
(eq)
Solvent
Yield (%)
(
eq)
2-Nitroethylbenzene, our model substrate, and was synthesized in
3
3
two steps. Based on a protocol published in the literature ,
1
2
2
3
1
H
2
O
O
70
72
nitrostyrene was first prepared by Henry reaction between
1
1
H
2
3
4
benzaldehyde and nitromethane with an excellent yield of 80%.
A
H
2
O/2-MeTHF (2/1
(v/v))
3
4
2
3
78
80
subsequent chemoselective reduction of the olefin was performed
in the presence of sodium borohydride providing isolated β-
nitroethylbenzene that was isolated in 52% yield (Scheme 1).
The reduction of β-nitroethylbenzene to phenylethylamine in the
H
2
O/2-MeTHF (2/1
1
(v/v))
The reaction mixture was stirred at 60°C with 0.6 mol% Pd/C (5%, 50% water) for
a
presence of sodium hypophosphite and/or hypophosphorous acid 16h. The yields were determined by GC/MS with benzylamine as internal
was then carried out as the model reaction (Scheme 1).
standard after derivatization with BSTFA.
2
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closely correlated with the number of phosphorous, n-P, present in
the reaction mixture (Table 2). For a same total number of P
(Table2, entries 3, 4, 5 and 8, 9, 10), the best yield was obtained
Table 2 Influence of the amount of reducing agents on the reduction.
a
Entry
NaH
2
PO
2
(eq)
H
3
PO
2
(eq)
n-P (eq)
Yield (%)
pHcal
1
2
3
4
5
6
7
8
9
0
1
0
1
2
2
3
4
5
0
1
0
2
1
0
1
1
1
0
5
1
1
2
2
2
3
4
5
5
5
1.15
27
27
71
80
73
78
80
90
84
82
when both NaH PO and H PO are present in the reaction mixture.
2 2 3 2
On one hand, introduction of the hypophosphite salts in the
biphasic system may help the transfer of the organics from one
7.83
1.00
1.98
7.98
2.28
2.46
2.58
8.18
0.80
3
6
phase to the other via salting in effect . On the other hand,
protonation of the amine leads to an increase of the E of the
0
3
7
corresponding oxido-reductive couple , making the nitro function
more easily reducible.
In the present situation, it is nevertheless difficult to give a rational
explanation for these results, and further experiments will be
needed to explain them.
Then, the minimal load of the metallic catalyst necessary to
preserve a quantitative conversion and a maximal yield was
1
0
evaluated from the defined conditions (16h, 60°C) (Table
3). Only
The reaction mixture was performed at 60°C for 16h with 0.6 mol% Pd/C (5%,
a
the palladium catalyst was investigated: as previously reported no
5
2
0% water), H O / 2-MeTHF (2/1, v/v) The yields were determined by GC/MS
26
with benzylamine as internal standard after derivatization with BSTFA.
conversion occurred with Ir/C 1%, Pt/C 5%, Rh/C 5% and Ru/C 5%.
As expected, the presence of the metallic catalyst was essential
because no reaction was observed without palladium: the substrate
The reduction mechanism by hypophosphite possibly involves two
reactions, i.e., hypophosphite ions are catalytically oxidized and
water is reduced. A part of the released hydrogen is adsorbed onto
the catalytic surface, which reduces the nitro-compound.
was fully recovered at the end of the reaction (Table 3, entry 1).
When the load of the catalyst was ranged from 0.6 mol% to 2.5
mol%, the conversion was complete and yields were good to
With only one equivalent of hypophosphorous acid (Table 2, entry
excellent (Table 3, entries 2-13). Moreover, the influence of the
1) or one equivalent of sodium hypophosphite (Table 2, entry 2),
load of the catalyst was determined with different amounts of
reducing agents. This study showed that after 16 h of reaction at
the reduction started but the conversion was not complete and the
yields were low, estimated at around 27% by GC/MS analysis,
detecting the starting nitro substrate as the major compound. The
6
0°C the increase in the amount of catalyst did not improve the
conversion and the yield in a substantial way (Table , entries 2 to 4,
entries 5 to 7, entries 8 to 10 and entries 11 to 13). These results
3
conversion was complete by the use of
2 equivalents of
hypophosphites (acid or salt) but the yield was maximal with the
reducing system sodium hypophosphite / hypophosphorous acid
are in accordance with those already obtained in Table
fixed load of the catalyst.
2, with a
(4eq/1eq) (Table 2, entry 8).
The conversions and the yields were also evaluated at different
temperatures between 5°C and 60°C. The reaction was performed
3
5
On Eh-pH diagram of phosphorous , the position of predominance
domain of hypophosphorous acid and hypophosphites, indicates
that these compounds are strong reducing agents,
thermodynamically instable in the presence of aqueous solutions
whatever their pH. Theoretically, they should decompose water
with hydrogen gas production, whereas they are transformed in
with NaH
2 2 3 2
PO / H PO (4 eq / 1 eq), 0.6 mol% Pd/C (5%, 50% water)
for 16h. The results showed that the conversion was complete after
1
2
6 h at 20°C, 30°C or 60°C leading to similar yields (Table 3, entries
to 3). However, at 5°C, the conversion was incomplete and the
yield only reached 33% after 16 h (Table 3, entry 4).
-
2-
phosphorous acid, H
3
PO
3
, or phosphites, H
2
PO
3
2 3
and H PO ,
depending on pH. In fact, this reductive action on water is infinitely
slow. In aqueous solution, hypophosphorous acid and
hypophosphites are almost stable in the absence of oxidant and
their reductive character is usually little marked. However, in the
presence of catalysts such as Pd, their reductive character fully
reveals itself ((Eq. 1) and (Eq. 1)
ꢅꢆ/ꢇ
ꢄ
ꢀꢁ
ꢀꢁ
ꢂꢃ ꢁꢄ + ꢀ ꢃ ꢈꢉꢉꢊ ꢀ ꢂꢃ + ꢀ (Eq. 1)
ꢁ ꢁ ꢁ
ꢋ
ꢅꢆ/ꢇ
ꢂꢃ + ꢀ ꢃ ꢈꢉꢉꢊ ꢀ ꢂꢃ + ꢀ (Eq. 2)
ꢁ
ꢁ
ꢁ
ꢋ
ꢁ
ꢄ
ꢄ
ꢀꢁ
ꢂꢃ /ꢀ ꢂꢃ ꢌ ꢌꢍ = −0,504 − 0,0591ꢏꢀ (Eq. 3)
ꢁ
ꢁ
ꢋ
ꢎ
ꢀꢋꢂꢃ /ꢀ ꢂꢃ
ꢌꢍ = −0,499 − 0,0591ꢏꢀ (Eq. 4)
ꢎ
ꢁ
ꢋ
ꢋ
From the equations of the Eh-pH diagram ( (Eq. 3 and (Eq. 4)) and
its calculation, the pH has a low influence both on the E of the two
0
couples and on the yields in amines. Only the latter seems however
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Table 3 Influence of the amount of catalyst.
100
a
b
80
Entry
Pd/C
NaH
2
PO
2
(eq)
Yield (%)
1
2
3
4
5
6
7
8
9
0
3
1
1
1
2
2
2
3
3
3
4
4
4
0
6
4
0
0
0.6
80
82
78
78
85
86
80
85
88
90
90
92
1.25
2.5
20
0
0.6
1.25
2.5
0
5
10
15
Reaction time (h)
0.6
Fig. 1 Kinetics monitoring of the reaction at 20°C (ꢀ ), 30°C (ꢀ) and 60°C (ꢁ). The
reaction mixture was performed with NaH
0% water) in H O/2-MeTHF (2/1).
2 2
PO
(4 eq), H
PO
3 2
(1 eq), 0.6 mol% Pd/C (5%,
1.25
2.5
5
2
1
0
1
1
0.6
1
1
2
3
1.25
2.5
1
00
80
60
40
20
0
a
The reaction mixture was stirred at 60°C for 16h. Pd/C (5%, 50% H
2
O) (mol%),
b
H
2
O / 2-MeTHF (2/1, v/v) The yields were determined by GC/MS with
benzylamine as internal standard after derivatization with BSTFA.
No significant difference in terms of yield was observed when the
reaction was run at temperatures above 20°C for 16 h. A kinetics
monitoring of the reaction was then achieved as a function of the
temperature (Fig. 1). Although the temperature was not a pivotal
parameter for 16 hours of reaction, this parameter should be
studied when the reaction time was shortened. Indeed, when the
reaction was carried out at 60°C, the total conversion and a
20
40
60
80
Temperature (°C)
Fig. 2 Influence of the ultrasounds on the reduction. The reaction was performed under
O (ꢀ) or in H O/2-MeTHF (2/1) (ꢁ).The yields
maximal yield of 90% were reached after 1.5 h in comparison to the ultrasonic activation for 15 min in H
2
2
were determined by GC/MS with benzylamine as internal standard after derivatization
3
3
2
6% observed at 30°C and 33% at 20°C during the same time. At
0°C, the reaction was completed in 5h. Moreover, the effect of the
-methyltetrahydrofuran was more significant when the reaction
with BSTFA.
In an attempt to increase the rate of the reaction while increasing
the yields in amines, the reduction was performed under ultrasonic
activation. In order to differentiate the effects of sonication from
those of temperature, the reactions were thermostatically
controlled. The results obtained were then compared with those
under silent conditions. The reaction was carried out for 15 minutes
was performed at 60°C for only 1.5 h. Indeed, when the reaction
was carried out in water, the conversion was incomplete and the
yield only reached 35%. These differences could be due to a better
solubility of the nitro substrate in the additional organic solvent 2-
MeTHF, enhancing the kinetics of the reduction.
2 2
in the two solvent systems (H O and H O / 2-MeTHF (2/1, v/v) (Fig.
Table 4 Influence of the temperature on the reduction.
2
).
a
Entry
Temp (°C)
Yield (%)
The study showed that the biphasic solvent system is once again
more efficient than water. Indeed, in a temperature range from
1
2
3
4
5
33
88
89
90
3
5°C to 65°C, the yield was higher in the mixture H O/2-MeTHF
2
20
30
60
(
2/1, v/v) rather than in water. The differences between the two
solvent systems started being significant from 35°C (Fig. 2).
Ultrasonic irradiation speeded up the reduction reaction in both
The reaction mixture was performed for 16h with NaH
2 2 3 2
PO / H PO
2
(4 eq /1 eq), solvent systems. In the mixture H O/2-MeTHF (2/1) a complete
a
0
.6 mol% Pd/C (5%, 50% water), H
2
O / 2-MeTHF (2/1, v/v) The yields were conversion with a maximal yield of 92% was obtained in only 15 min
determined by GC/MS with benzylamine as internal standard after derivatization
with BSTFA.
under sonication whereas 1.5 h were required at 60°C under silent
conditions. Furthermore, when the reaction was not thermostated,
the temperature reached 73°C and the yield achieved 92% in 15
min, confirming that the reaction is temperature dependent.
4
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ARTICLE
2
O, the effects of the ultrasounds are more significant. Under Finally, these two last graphs clearly showed that sonication and
silent conditions, the yield achieved 35% only after 1.5 h at 60°C but vibromixing led to the fairly same yields. Thus the predominant
under ultrasonic activation it reached around 60% at 60°C in only 15 effects of the ultrasonic activation on the reduction reaction are of
min. Moreover, in H
2
O, complete conversion and maximal yield of physical nature: the reaction mechanism is not affected by
9
0% are obtained after 15 min of irradiation when the reaction cavitation, and its chemical intermediates are not coming from
temperature was increased to 70°C. This result showed that it is cavitation. Indeed, in this case of two-phase liquid / liquid system,
possible to get the desired amine without an organic solvent with a sonication causes a phenomenon of intense micro-emulsion. Micro-
3
8
quantitative conversion and a maximal yield in only 15 min thanks droplets with high interfacial surface area are propelled from one
to the ultrasonic activation. phase to the other, providing significant contact between the
The effects of ultrasounds can be chemical, physical or both. Thus, reactants present in each of the non-miscible phases. By acting as
to understand how sonication influences the reduction, the physical agent of phase transfer, ultrasound allows a highly efficient
reaction mixture was stirred with a vibroacoustic mixer, also called mass transfer thereby facilitating the reaction, without a chemical
vibromixer, which gives rise to hydrodynamic cavitation leading phase transfer catalyst. Moreover, it improves the hydrogen
3
9
only to physical effects.
production by improving degassing of the medium. Finally, it
probably decreases the size of the metallic catalyst particles,
4
0
100
increasing and activating then the specific surface . This reaction
4
1
can be classified as type II reaction, termed "false sonochemistry" .
The methodology scope was extended to other aliphatic nitro
compounds to prove the versatility of the reduction method; results
were compared to those obtained with 2-Nitroethylbenzene, our
model substrate (Table 5). The (1-methyl-2-nitroethyl)benzene was
reduced with NaH PO / H PO (4 eq / 1 eq), 0.6 mol% Pd/C (5%,
80
60
40
20
0
2
2
3
2
5
0% water) in H
stirring (Table 5, Entry 3) and for 15 min under ultrasonic activation
Table 5, Entry 4). The results were similar, with a complete
2
O / 2-MeTHF (2/1) at 60°C for 1.5 h under magnetic
2
5
35
45
55
65
75
(
Temperature (°C)
conversion and a yield of 84%. The reduction was then tested on
Fig. 3 Comparison between ultrasonic activation and the vibromixer Ultra Turrax in
water. The reaction was performed under ultrasonic activation (ꢁ) or with the
the 3-(2-nitroethyl)-1H-indole (Table 5, Entries 5-9), that is less
1
reactive, and the crude product was analysed by H NMR. Under
vibromixer UltraTurrax (ꢀ) for 15 min with NaH
Pd/C (5%, 50% water) in H
as internal standard after derivatization with BSTFA.
2 2 3 2
PO / H PO (4 eq /1 eq), 0.6 mol%
2
O.The yields were determined by GC/MS with benzylamine silent conditions, the desired amine was synthesized with a yield of
8%. However, the reduction was a little more difficult under
9
ultrasonic activation. Indeed, with the same load of the catalyst, the
yield in amine only reached 61% in 10 min (Table 5, Entry 6), 78% in
1
00
2
0 min (Table 5, Entry 7) and 84% in 30 min (Table 5, Entry 8). Thus,
under these conditions, the conversion was total, but although the
amine was the main product, it was obtained with another
compound that was not identified. Finally, the reaction required 30
min and a higher load of the catalyst (1.25 mol% Pd/C) to afford the
expected compound in an almost quantitative 98% yield (Table 5,
Entry 9). The 3-(1-methyl-2-nitroethyl)-1H-indole was then reduced
but under the previous conditions (silent or ultrasonic), a mixture of
the desired product with another minor side product was observed
8
6
4
2
0
0
0
0
0
(
Table 5, Entries 10-13). It was necessary to increase the amount of
20
40
60
80
catalyst up to 1.25 mol% and to run the reaction for 30 min under
ultrasonic activation; under these conditions, the conversion was
complete and the yield achieved 90% (Table 5, Entries 14).
Temperature (°C)
Fig. 4 Comparison between ultrasonic activation and the vibromixer Ultra Turrax in
water / 2-MeTHF. The reaction was performed under ultrasonic activation (ꢁ) or with
the vibromixer UltraTurrax (ꢀ) for 15 min with NaH
2 2 3 2
PO / H PO (4 eq /1 eq), 0.6 mol% Finally, the reduction was tested on the β-nitrostyrene (Table 5,
Pd/C (5%, 50% water) in H O/2-MeTHF (2/1). The yields were determined by GC/MS
2
Entry 15). However, we did not obtain the corresponding
with benzylamine as internal standard after derivatization with BSTFA.
unsaturated amine nor the saturated one but a mixture of the (E)-
and (Z)-2-phenylacetaldehyde oxime. The yields were respectively
The reaction was carried out for 15 min. In the two solvent systems
1
3
8% and 44% for the E and Z stereoisomers, after treatment for H
(
H O and H O / 2-MeTHF (2/1, v/v) the results were compared to
2 2
NMR analysis. These results are consistent with the previous
those obtained under ultrasonic activation. The yields in amines
observed under ultrasonic activation and under vibromixing are
4
2
research work published by Kabalka et al. in 1986, describing the
reduction of α,β-unsaturated nitroalkenes to oximes in the
presence of palladium on charcoal with sodium hypophosphite.
similar in water (Fig. 3) and in the biphasic solvent system H O / 2-
2
MeTHF (2/1) (Fig. 4).
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4
2
Table 5 Extension of the methodology scope to other aliphatic nitro compounds.
the reaction described by Kabalka and al. was carried out in THF
for 2 hours with 30% (w/w of nitroalkene) of Pd/C. Indeed, the
authors underlined that the reactions were incomplete with
catalytic amounts of Pd/C even after 24 hours.
Reaction Yield
Entry
Substrate
Product
conditions (%)
1
h30,
a
a
a
a
1
2
3
4
5
6
7
8
9
90%
90%
84%
84%
98%
61%
78%
84%
98%
80%
78%
80%
85%
90%
silent*
Experimental section
The commercially available reagents and solvents were used
1
5 min,
)))**
)
without
further
purification.
(BSTFA)
N,O-
Bis(trimethylsilyl)trifluoroacetamide
with
1%
1
h30,
trimethylchlorosilane used for the derivatization procedure was
purchased from Aldrich. Because of its low boiling point (78°C),
reactions with 2-methyltetrahydrofuran were performed in a closed
tube. The reactions under ultrasonic activation were carried out
with a sonotrode at 20 kHz frequency, Pacoustic= 3.94 W. The
reactions with the vibromixer were performed with an Ultra-turrax
silent
1
5 min,
)))
)
1
h30,
a
-1
silent
T25 Janke & Kunkel IKA apparatus at 24’000 tr.min . The reactions
were monitored by thin-layer chromatography (TLC) on a plate of
silica gel 60 F254. Developed plates were visualized using ultraviolet
light and/or by dipping the plates into a solution of ninhydrin in
1
0 min,
)))
a
a
a
b
a
)
1
2
3
3
0 min,
)))
ethanol followed by heating with a heat gun. H NMR spectra were
)
recorded on a BRUKER, Avance III HD at 400 MHz. Chemical shifts
were assigned relatively to the reference solvent in ppm.
Electrospray ionization (ESI) mass spectrometry (MS) experiments
were performed on a Thermo Finnigan LCQ Advantage mass
spectrometer. Purifications were carried out by flash
chromatography on silica gel (230–400 mesh; 40–63 μm).
0 min,
)))
)
0 min,
)))
)
1
h30,
General reduction procedure
In a closed tube, 1-(2-nitroethyl)benzene (151 mg, 1 mmol) was
1
1
1
1
0
1
2
3
silent
solubilized in solvent (water or 2-methyltetrahydrofurane) (1 mL)
and Pd/C (5% wt, 50% in water) (27 mg, 0.6 mol %) was added.
1
5 min,
)))
a
)
After the addition of
a mixture of sodium hypophosphite
2
3
3
0 min,
)))
monohydrate (4 mmol) and hypophosphorous acid (50% in water)
(1 mmol) solubilized in water (2 mL), the reaction mixture was
stirred for 16 hours at 60°C. After cooling down to room
temperature, the reaction mixture was diluted with ethyl acetate
a
a
b
)
0 min,
)))
)
(
20 mL), basified with a 2.5 M sodium hydroxide solution (10 mL)
®
0 min,
)))
and filtered on celite . The aqueous phase was extracted with ethyl
acetate (3 × 20 mL). The combined organic layers were washed with
brine (10 mL), and dried over magnesium sulfate.
1
1
4
5
)
b
38% (E)
3
0 min,
)))
For an analysis by GC/MS, the dried organic phase was filtered on a
volumetric flask. The volume was adjusted to the graduation mark
with ethyl acetate to prepare the standard solution.
)
b
4
4% (Z)
1
*
without the use of ultrasound: silent, ** under ultrasound irradiation: ))))
For an analysis by H NMR, the dried organic phase was filtered and
concentrated under reduced pressure to get the crude product.
Before each experiment, the tube was washed twice with
The reaction mixture was performed at 60°C with NaH
2 2 3 2
PO /H PO (4 eq / 1 eq) in
H
2
O/2-MeTHF (2/1). The yields were determined by GC/MS (Entries 1-4) or by
NMR (Entries 5-15) with benzylamine as internal standard. The conversion is hydrochloric acid.
a
b
1
00%. 0.6%mol Pd/C. 1.25%mol Pd/C
General analysis procedure by GC/MS
However, the authors did not specify the ratio of the E and Z
Trimethylsilyl derivatization
stereoisomers and the global yield was lower and only reached
The yields of some reduction reactions were determined by GC/MS
after derivatization of the product. As the silylation is one of the
widely used derivatization procedure, BSTFA was chosen to replace
5
6%. In addition, in our work, the reduction was performed in a
biphasic mixture of H O / 2-MeTHF (2/1, v/v) with a catalytic
amount of Pd/C for only 15 min under ultrasonic activation whereas
2
4
3
hydrogen of the amine function by the trimethylsilyl group .
6
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Pleas Ge rdeo e nn o Ct ah de j mu si ts mt r ya rgins
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DOI: 10.1039/C7GC01622K
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ARTICLE
Derivatized benzylamine was chosen as an internal standard to with some nitro indole derivatives, the conditions described in this
eliminate instrumental and sample preparation errors. Several work are nevertheless very competitive, especially for aliphatic
solutions containing increasing concentrations of derivatized nitro compounds that are usually difficult to reduce. For all these
analyte and fixed concentration of derivatized benzylamine were reasons, this protocol could be of great interest for further
prepared to establish a calibration curve. First, stock solutions of industrial applications.
benzylamine (the internal standard) and phenethylamine (the
analyte) in ethyl acetate were prepared. Then, the standard
Acknowledgements
solutions were prepared by mixing an identical volume of the stock
benzylamine solution with crescent volumes of the stock
The authors gratefully thank Jean-Charles Francony for good
phenethylamine solution and the volume is completed to 200µL
technical assistance and advices.
with a BSTFA-1% TMCS solution. The standard solutions were
derivatized by stirring for 2h at 50°C. After cooling to room
Notes and references
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