A novel approach towards chemoselective reduction of nitro to amine

Article abstract of DOI:10.1016/j.tetlet.2019.151028

Chemo selective reduction of a wide range of aromatic nitro compound has been performed by using inexpensive Zn powder and CuSO₄ system in water medium at room temperature. This system has high tolerance to other highly reducible groups present in nitro substance along with high conversation and selectivity. This chemo-selective reduction also provides a facile root for the synthesis of other industrially important fine chemicals or biologically important compounds where other highly reducible groups are present in close proximity to the targeted nitro groups.

Full text of DOI:10.1016/j.tetlet.2019.151028

Journal Pre-Proof
A novel approch towards chemoselective reduction of nitro to amine
Hridoydip Ranjan Dasgupta, Suvodip Mukherjee, Pranab Ghosh
PII:
S0040-4039(19)30785-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151028
TETL 151028
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 June 2019
3 August 2019
7 August 2019
Please cite this article as: Ranjan Dasgupta, H., Mukherjee, S., Ghosh, P., A novel approch towards chemoselective
reduction of nitro to amine, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151028
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A NOVEL APPROCH TOWARDS CHEMOSELECTIVE REDUCTION OF
NITRO TO AMINE
Hridoydip Ranjan Dasgupta, Suvodip Mukherjee and Pranab Ghosh*
Department of Chemistry, University of North Bengal, Dist. Darjeeling, West Bengal, India.
Tel.: +91 (0353) 2776381; fax: +91 (0353) 2699001.
E-mail address: pizy12@yahoo.com (P. Ghosh).
Abstract: Chemo selective reduction of a wide range of aromatic nitro compound has been
performed by using inexpensive Zn powder and CuSO4 system in water medium at room
temperature. This system has high tolerance to other highly reducible groups present in nitro
substance along with high conversation and selectivity. This chemo-selective reduction also
provides a facile root for the synthesis of other industrially important fine chemicals or
biologically important compounds where other highly reducible groups are present in close
proximity to the targeted nitro groups.
Key words: Chemo selective, non-hazardous reducing agents, aromatic nitro compound, metal
salt.
Introduction:
Substituted aromatic amines are very important feedstock for synthesis of many significant fine
chemicals like agrochemicals, dyes, biological active compounds, polymers and various other
industrially important compounds.[1] Aromatic amines also form substructures of many
pharmaceutical compounds . An acetyl derivative of p-aminophenol known as Paracetamol[2] 1a,
a widely used analgesic and antipyretic. Bicalutamide[3] 1b has a p-cyano-m-trifluoroaniline
component in its structure, is a non-steroidal antiandrogen administered orally for the treatment
of prostate cancer and hirsutism.
OH
O
S
O
H
O
F3C
NC
N
NH
O
F
HO
Paracetamol 1a
Bicalutamide 1b
Anticancer (Prostate)
(Analgesic,Antipyratic)
Vastly employed method for the preparation of substituted aromatic amines is reduction of
corresponding nitro substrates. But selective reduction of a functional group in presence of other

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functional group which is also reducible is often a very difficult task.[4] In general employing
transition metal catalyst results in reduction of olefinic and halogeno functions than that of N-O
bond. Moreover, traditional non-catalytic processes often produce large amount of waste and
hence environmentally non-sustainable.[5] Catalytic hydrogenation is often a convenient and
clean method but lacks selectivity.[6] Another alternative to catalytic hydrogenation, catalytic
transfer of hydrogen is also introduced for reduction purpose in which hydrocarbons, alcohols,
organic acids and their salts, hydrazine etc. were used as source of hydrogen with variety of
metal based catalysts.[7-11] However, it’s worth a note the main disadvantages to these procedures
include the catalysts being incompatible to the acid-sensitive functional groups and requires
higher reaction temperature, longer reaction time and suffers from low or mixed yield of
products. [12]Recent successful attempt of reducing nitroarenes selectively by employing CO2 gas
at very high pressure resulting in-situ generation of carbonic acid, which further gets associated
[13]
with reducing metals and performs the selective reduction process.
Nonetheless, the
requirement of high CO2 pressure in order to activate the reducing metal and generate carbonic
acid, and high reaction temperature are the main drawbacks of the scheme. Another recent report
worth mentioning is reduction of nitro compounds to corresponding amines selectively in
presence of photo catalyst and Pd/CeO2, CdS. [14] Despite the scheme shows high selectivity and
considerable activity in presence of noble metals, costly noble metals are the major hurdles in
this article. Recent communications on catalytic systems based on Co-Co2B, Fe2O3, Co2O3 etc.
[15-17]
show high activity and directs toward the development of more economical efforts.
But
most of the contrivance uses harsh condition which is undesirable. Pure water has been
[18]
employed as solvent by Poliakoff and Boix
using metallic reducing agents for selective
reduction of nitroarenes at 250oC. With iron powder the yield reported is only 10% of substituted
aniline under mentioned reaction condition. Modification has been done by Wang at. al. [19] and
iron powder has been replaced by nano-sized activated iron for direct and selective reduction of
nitroarenes in water [20]. Though good yield has been achieved, the temperature requirement was
still 210oC. In addition to that preparation of nano-sized particle and maintaining the size
requires extra effort and expense.
There exist very few reports on eco-friendly, inexpensive metal catalysts or reducing
agents that can promote reduction of nitro groups selectively at room temperature. And needless
to mention water based conversions are of critical importance in organic chemistry. Therefore,
development of a cost effective, greener, easily achievable, less time consuming reaction scheme
with non-hazardous reducing agents is highly desirable. Regarding this context our interest was

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solely on developing a new scheme using low cost, greener, metal-metal salt based reducing
agent and to carry out the reaction on most easily available solvents like water and ethanol.
Herein, we report selective reduction of nitroarenes at room temperature in presence of
non-hazardous, inexpensive and easily available metal salt like CuSO4 and Zn metal in water
solvent system within 30 minutes – 60 minutes. (Scheme 1)
Scheme 1.Reduction of aryl nitro to corresponding amine
RESULTS AND DISCUSSIONS:
Aromatic nitro and substituted nitro compounds were reduced in good yield to the corresponding
amino compounds under mild conditions in the presence of low cost and easily available metal
and metal salt Zn and CuSO4 respectively in water, with single product. The compound obtained
were monitored by TLC and separated by column chromatography. The general scheme and
reaction are shown in scheme I.
Table1:aOptimizationof the reaction condition for reduction of Nitroarenes to the corresponding
Anilines.
Entry Metal/Metal salt
Solvent
Nil
Time (min) Temperature (0C) bYield (%)
1
2
Fe/CuSO4
Zn
180
180
180
180
180
180
180
180
180
180
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
Nil
Nil
Nil
Nil
68
H2O
3
Fe
H2O
4
CuSO4
H2O
5
Fe/CuSO4
Fe/CuSO4
Fe/ CuSO4
Cu/CuSO4
Zn/CuSO4
Zn/FeSO4
H2O
6
H2O+EtOH
EtOH
H2O
60
7
56
8
65
9
H2O
95
10
H2O
80

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11
12
13
14
15
16
17
18
19
20
Zn/ZnSO4
Zn/NiSO4
Zn/CuSO4
Zn/CuSO4
Zn/CuSO4
Zn/CuCl2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
180
180
120
60
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
60
76
72
95
94
70
84
72
66
89
87
30
60
Zn/Cu(OAc)2
Zn/CuBr2
60
60
Zn/CuSO4
Zn/CuSO4
60
aReacti
60
80
on of o-
nitrobenzaldehyde (1 mmol), Zn (3 mmol), CuSO4 (3 mmol) in water on magnetic stirrer
bIsolated yield
Table 2: aOptimization of amount of Zn and CuSO4
Entry
Zn (mmol)
CuSO4 (mmol)
Time (min)
bYield (%)
1
2
3
4
1
2
3
4
1
2
3
4
60
60
60
60
54
67
94
95
aReaction of o-nitrobenzaldehyde (1 mmol) in water on magnetic stirrer
bIsolated yield
At first, we investigated the influences of solvents, additives, metals, time and temperature on
the reduction of aromatic nitro to its corresponding amine (Scheme 1, Table 1). The reduction of
selected model nitro substrate, o-nitrobenzaldehyde revealed that high conversion and selectivity
could be achieved within 60 min in the presence of water. Entry 1 demonstrates that the reaction
could not proceed in absence of solvent. From entry 1-7 (Table 1) we conclude that water is the
superior solvent for the process, as in this process hydrogen ion is efficiently supplied by water.
Further water is the most easily available and green solvent which enhances the cost
effectiveness of our scheme.
We found that both metal and additive were necessary for this reduction process (Table 1, entries
3, 4, 5). Compared with that CuSO4, other additives were inferior in terms of yield of product
and reaction time. Entry 5, 8, 9 (Table 1) implies that here Zn metal play a vital role for nitro
reduction. Electro chemical series also support our result. The reduction potential of applied
metal and additive is as follows,E0Zn2+/Zn=- 0.76, E0Fe2+/Fe=-0.44 and E0Cu2+/Cu=+0.34, which
clearly indicates the reduction potential difference between Zn and Cu is higher, which facilitate

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the transfer of electrons in the process than the other couples. This concept is in accordance with
our observed results (Table 1). But entry 11 also suggest that acidic nature of metal salts is
indebted for reduction and reduction potential difference between metals amplify the potency of
the process. Entries 9 to 14 implies that if we lower the time from 180 minutes to 60 minutes the
yield of the product more or less same, but when we were tried to decrease the time from 60
minutes to 30 minutes then product’s yield decreases remarkably. Now we were tried to
optimize temperature. With the help of entries 14, 19, 20 we observed that if we increase the
temperature yield of the product decreases. So with respect to time, temperature, metal/metal salt
entry 14 is the optimized condition. Further we optimized the amount of Zn and CuSO4
required (Table 2). We started our optimization with 1 mmol each. The yield was considerable
but low. As the amount of reagents has been increased and we reached our maximum yield at 3
mmol Zn and 3 mmol CuSO4. No further increase in yield has been observed with increasing
reagents. Considering the above mentioned points, under atmospheric pressure, 60 minutes of
reaction time and room temperature is finalized as the optimum condition for this reaction(Table
1).
This procedure is followed for all of the reactions listed in Table(3)
Table 3: aZn and CuSO4 mediated reduction to amines
Entry
1
Reactant
Product
Time (min)
50
bYield (%)
90
NO2
NH2
NO2
NH2
NH2
NH2
2
3
4
30
30
30
85
85
95
NO2
Cl
NH2
Cl
NO2
CH3
NH2
CH3
NO2
NH2
5
30
92
CH3
CH3

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NO2
NH2
6
7
40
30
80
93
COOH
Cl
COOH
Cl
NH2
NO2
OH
NO2
OH
OH
8
9
30
30
40
50
93
94
93
87
NH2
OH
NO2
NH2
I
I
10
11
NH2
NO2
N
NO2
N
NH2
NH2
NO2
12
13
60
50
89
92
CHO
CHO
NH2
NO2
CN
CN
aReaction of nitro compound (1mmol), Zn (3 mmol), CuSO4 (3 mmol) in water at room temperature for different
time intervals on magnetic stirrer.
bIsolated yields
On the basis of the table 1, reduction of other nitroarenes were carried out by using Zn/CuSO4 in
water without any organic solvent at room temperature under atmospheric pressure(Table 2).
Aldehyde, halogens, nitrile, acid functionality present in aromatic ring remained unaffected
during reduction of the corresponding nitro benzene by this process (entries). These results
demonstrate that we can employ this technique to nitroarenes containing reduction-sensitive
substituent. The reaction took place smoothly and chemoselectively to produce corresponding
anilines in moderate to high yields (entries).

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Plausible mechanism:
Zn2+
2e-
Zn
+
Cu(OH)2
+
H2SO4
CuSO4
+
2 H2O
Weak base
Strong acid
2H+ (aq)
+
SO42- (aq)
(aq)
H2SO4
H
OH
N
O
N
O
N
O
O
O
Zn
Zn
R
R
R
Zn
OH
N
H
H
H
N
-H2O
O
O
N
OH
Zn
R
R
Zn
R
Substituted Nitrosobenzene
H
N
H
H
H
N
OH2
Zn
N
OH
OH
Zn
R
R
R
Substituted Hydroxylamine
-H2O
H
N
H
H
H
N
H
N
H
Zn2+
+
Zn
Zn
R
R
R
Substituted aromatic amine
Fig 2. Plausible mechanism for synthesis of amine from nitro derivative

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A plausible mechanism has been shown in fig 2. For the nitro reduction we need source of
electron and hydrogen ion. From the mechanism we can see that in our reaction electrons are
supplied by Zn metal and hydrogen ions are supplied by H2O and here CuSO4 increase the
acidity of the medium which facilitate the reaction leading to the corresponding amine
For reduction of nitroarenes leading to aromatic amines with Zn metal, methods employing
Zn/HCl[21], Zn/aq. NaOH/EtOH[22], Zn/NH3[23], Zn/CaCl2/EtOH[24], Zn/near-critical water[25],
Zn/Ru-complex/H2O/KOH[26], Zn/ether/H2O[27], Zn/CO2/H2O[28], Zn/SiO2-PEG[29] have been
reported. However, since the conventional methods required organic solvents and/or drastic
conditions using an irritant reagents such as NH3, corrosive reagents HCl, NaOH, it is difficult to
contend that these methods are environmentally harmonious. On the other hand, the reaction
time is prolonged for Zn/NH3 (24h), Zn/Ru-complex/H2O/KOH (16h), Zn/ether/H2O (5-11h).In
addition, some special apparatus and high temperature is required for some processes. To
overcome these hurdles, we have introduced our scheme using Zn metal, CuSO4 and water at
room temperature. The greatest advantage of our method compared with other methods is easy
handling, cost effective, environmentally benign.
All of this products are known compounds and were easily characterized by comparison of their
spectra with those reported.
Experimental section:
Representative Experimental Procedure for Reduction of Aromatic Nitro Compounds.
A mixture of nitro compound (1 mmol), Zn powder (3 mmol), CuSO4 (3 mmol) in 5 mL water at
room temperature was stirred on a magnetic stirrer. The progress of the reaction was monitored
by TLC. After completion of the reaction,the metallic part was filtered off. The filtrate was
poured into 100 mL water and extracted with ethyl acetate, washed several times with water.
Evaporation of solvent followed by column chromatography over basic alumina using petroleum
ether/ethyl acetate (3:1) as eluent toafford the pure aryl amines ().The spectroscopic data
(IR,1HNMR,) of this compound are in good agreement with those reported.
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A Novel Approach Towards Chemoselective Reduction of Nitro to Amine
Hridoydip Ranjan Dasgupta, Suvodip Mukherjee, Prof. Pranab Ghosh*

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HIGHLIGHTS
1. Chemo selective reduction
2. high tolerance to other highly reducible groups
3. clean method
4. selective reduction of nitro arenes at room temperature