Aryl nitro reduction with iron powder or stannous chloride under ultrasonic irradiation

Article abstract of DOI:10.1080/00397910701481195

The selective reduction of aryl nitro compounds in the presence of sensitive functionalities, including halide, carbonyl, nitrile, and ester substituents, under ultrasonic irradiation at 35 kHz is reported in yields of 39-98%. Iron powder proved superior to stannous chloride with high tolerance of sensitive functional groups and high yields of the desired aryl amines in relatively short reaction times. Simple experimental procedure and purification also make the iron reduction of aryl nitro compounds advantageous over other methods of reduction. Copyright Taylor & Francis Group, LLC.

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Aryl Nitro Reduction with Iron Powder
or Stannous Chloride under Ultrasonic
Irradiation
Allan B. Gamble a , James Garner a , Christopher P. Gordon a , Sean M. J.
O'Conner a & Paul A. Keller a
a Department of Chemistry, University of Wollongong, Wollongong, Australia
Version of record first published: 14 Aug 2007.
To cite this article: Allan B. Gamble , James Garner , Christopher P. Gordon , Sean M. J. O'Conner & Paul
A. Keller (2007): Aryl Nitro Reduction with Iron Powder or Stannous Chloride under Ultrasonic Irradiation,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communicationsw, 37: 2777–2786, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701481195
Aryl Nitro Reduction with Iron Powder
or Stannous Chloride under
Ultrasonic Irradiation
Allan B. Gamble, James Garner, Christopher P. Gordon,
Sean M. J. O’Conner, and Paul A. Keller
Department of Chemistry, University of Wollongong, Wollongong,
Australia
Abstract: The selective reduction of aryl nitro compounds in the presence of sensitive
functionalities, including halide, carbonyl, nitrile, and ester substituents, under ultra-
sonic irradiation at 35 kHz is reported in yields of 39–98%. Iron powder proved
superior to stannous chloride with high tolerance of sensitive functional groups and
high yields of the desired aryl amines in relatively short reaction times. Simple exper-
imental procedure and purification also make the iron reduction of aryl nitro
compounds advantageous over other methods of reduction.
Keywords: iron powder, nitro reduction, ultrasound
Aryl amines are synthetically important compounds that act as precursors to
the synthesis of many interesting molecules and can be readily synthesized
from aryl nitro compounds via countless reduction methods. The most
general methods involve activated metal catalysis[1] and transition-metal-
catalyzed hydrogenation,[2] although the latter often employs harsh reaction
conditions affecting other reduction-sensitive functionalities such as halides,
ketones, aldehydes, esters, and nitriles in addition to the nitro substituent.[2]
The selective reduction of aryl nitro compounds using iron powder and
dilute acid[3] or stannous chloride[4] have been reported as efficient methods
for the synthesis of aryl amines in good yields. However, notable
Received in the USA January 10, 2007
Address correspondence to Paul A. Keller, Department of Chemistry, University of
Wollongong, Wollongong 2522, Australia. E-mail: keller@uow.edu.au
2777

2778
A. B. Gamble et al.
disadvantages to these methods include high reaction temperatures, relatively
long reaction times, potential halogenation reactions, and the incompatibility
of acid-sensitive functional groups associated with the use of a strong acid
such as HCl. The use of milder conditions, for example, acetic acid as
solvent, has been reported, but high temperatures and longer reaction times
are still evident.[5]
Ultrasound has been reported as an alternative energy source for the
initiation of organic reactions,[6] with the potential to accelerate chemical
transformations, affect product distributions, improve yields, and increase
the catalytic activity of metal particles by factors as high as 105.[7] Sonication
has been employed in many different types of organic reactions, in particular
transition-metal-catalyzed reduction. Generally reactions involving metal
reagents exhibit sluggish reaction times due to the presence of surface impu-
rities, but through continuous cleaning and chemical activation of the metal
surface and the high temperature and pressure produced by acoustic cavita-
tion, which potentially results in the formation of hot spots,[8a] an accelerated
reaction rate is often associated with ultrasound.[7]
There has been a limited number of aryl nitro reduction procedures via soni-
cation reported in the literature,[8] although a recent study utilizing stannous
chloride in the presence of ionic liquids provided aryl amines in good
yields.[8a] Other procedures investigated the reduction of nitrobenzene using
elemental iron[8b] and reduction of some simple aryl nitro compounds using
iron in the presence of multiple additional reagents,[8c] but the tolerance of
sensitive functional groups for iron-catalyzed nitro reduction promoted by ultra-
sound was not examined. The lack of iron and stannous-chloride-catalyzed nitro
reduction promoted by ultrasound in the literature prompted the search for more
efficient, selective, and relatively straightforward procedures.
The reduction of aryl nitro compounds is known to proceed via the
hydroxylamine, followed by azoxy and azo compounds, to its corresponding
aryl amine after a prolonged reaction time (Scheme 1).[9] Therefore, the ability
of ultrasonic irradiation to accelerate heterogeneous chemical reactions could
potentially reduce the reaction time and reduce the amount of intermediates
isolated, increasing the yield of aryl amine. To determine the optimal
reaction conditions for the reduction of aryl nitro compounds to their corre-
sponding aryl amines under ultrasound conditions without isolation of the
intermediates, a series of model reactions were performed (Table 1).
Scheme 1.

Iron Reduction under Ultrasound Irradiation
2779
Table 1. Investigation of ultrasound-promoted reduction of 3-nitroanisole 1
Entry
1
Reducing agent
Fe(s) (1 equiv.)
Solvent
Time (h) Yield (%)a
Ethanol/glacial
acetic acid/water
Ethanol/glacial
acetic acid/water
Ethanol/glacial
acetic acid/water
Ethanol/water
Glacial acetic
acid/water
2
2
1
36
59
89
2
3
Fe(s) (2 equiv.)
Fe(s) (5 equiv.)
4
5
Fe(s) (5 equiv.)
Fe(s) (5 equiv.)
2
1.5
0
75
.
6
7
8
SnCl2 2H2O (1 equiv.)
Ethanol
Ethanol
2
2
2
26
45
76
.
SnCl2 2H2O (5 equiv.)
.
SnCl2 2H2O (10 equiv.) Ethanol
aIsolated yield.
From these reactions, the optimal conditions were 5 equivalents of iron
powder in a mixture of ethanol, glacial acetic acid, and water (2:2:1)
exposed to ultrasound for 1 h (entry 3). The reaction was repeated under
thermal conditions (2.5 h at 608C) with the yield of aryl amine 2 determined
to be 85%, similar to the optimal conditions in entry 3, but the temperature and
time of reaction required for the complete conversion of 1 and its intermedi-
ates to 2 were notably higher and longer. This demonstrates that the
high-energy effects of acoustic cavitation in addition to the continuous
cleaning of the iron surface due to ultrasound are responsible for the
enhanced reaction rate. The latter probably accounts for the greatest enhance-
ment in reaction rate because under thermal heating, surface impurities such as
oxides, hydroxides, and carbonates inhibit contact between the aryl nitro and
the iron surface.[7] In addition, cleansing of the iron sweeps reactive inter-
mediates or products from the surface, making, way for subsequent
reactions.[8b]
Entries 1 and 2 demonstrate that the yield of aryl amine 2 decreases sig-
nificantly as the molar equivalents of iron powder are reduced, probably
because of the presence of the intermediates not converted to the aryl amine
(Scheme 1), and the yield of 2 was slightly reduced in the absence of
ethanol (entry 5). When glacial acetic acid, which presumably helps to

2780
A. B. Gamble et al.
activate the iron powder, is not used in the reaction, no reduction of the aryl
nitro was observed (entry 4).
The ability of stannous chloride to selectively reduce an aryl nitro substi-
tuent to an aryl amine was also investigated using ethanol as the solvent. Entry
8 demonstrates that for good conversion to the aryl amine, 10 molar equiva-
lents of stannous chloride are required. In the presence of only 1 equivalent
(entry 6) and 5 equivalents (entry 7) of stannous chloride, the yields of aryl
amine were significantly lower.
The optimal reduction conditions (entry 3) were applied to further nitro
aromatic derivatives, examining the selectivity of the reduction for nitro sub-
stituents in the presence of other sensitive functionalities (Table 2). Entries 1
to 3 allow comparison between iron- and stannous-chloride-catalyzed
reduction, but because of the superiority of iron reduction, entries 4–8 were
only performed via this method.
Entries 1 and 2 demonstrate the tolerance of iron reduction for ketone
functionalities, which under catalytic hydrogenation conditions could poten-
tially be reduced to their corresponding alcohols and methylene groups.[10]
The tolerence of ketone functionalities to iron-catalyzed nitro reduction is
well precedented in the literature,[1a,11] and with yields of 77% and 85% for
p-aminoacetophenone and m-aminoacetophenone under ultrasonic irradiation
respectively, our conditions also allow complete selectivity for the nitro sub-
stituent over the ketone moiety. Both of these compounds have been reported
in the literature with yields of 92%[1a] and 80%[12] for the para- and meta-
substituted compounds respectively, and although the former yield is higher
than our reported yield, the reaction was done under high pressure at a temp-
erature of 2108C for 2 h with water as solvent. Therefore the iron-catalyzed
reduction conditions promoted by ultrasound at 308C for 1 h are advantageous
as they are significantly milder, safer, and easier to perform.
Aryl halides are known to be susceptible to dehalogenation under harsh
reduction conditions, in particular catalytic hydrogenation.[2] Entries 3–7
examine the selective reduction of the aryl nitro substituent over the aryl
halide, with good to excellent yields obtained in all reactions. Entries 3–6
demonstrate the tolerance of bromine to the optimized iron reduction con-
ditions and, with the exception of entry 3, the yields of desired aryl amine
are excellent (86%, 98%, and 85% for entries 4–6 respectively). Although
thin-layer chromatography (TLC) showed 100% conversion of 2-bromo-4-
methoxy-6-nitrophenol to its corresponding aryl amine (entry 3) with no
other intermediates identified, it could only be isolated in 65% yield.
During workup, difficulties in isolation of the desired aryl amine were encoun-
tered with the product partitioning between both the organic and aqueous
phase, therefore contributing to the lower than expected yield. Entry 5
demonstrates the ability of iron-catalyzed reduction under ultrasound to selec-
tively reduce two nitro substituents of a symmetrical dimer with an almost
quantitative yield of 98%. The same compound in entry 5 has reportedly
been synthesized via iron-catalyzed reduction, in the presence of ferric

Iron Reduction under Ultrasound Irradiation
2781
Table 2. Reduction of aryl nitro compounds with reduction-sensitive functional groups
Yield
Fe(s) using
Yield using
. .
Fe(s) SnCl2 2H2O SnCl2 2H2O
rxn.
Entry
1
Reagent
Productb
time
(%)a
rxn. time
(%)a
1 h
77
2 h
58
2
3
1 h
2 h
85
65
2 h
2 h
54
35
4
5
1 h
1 h
86
—
—
—
—
98c
6
7
1 h
1 h
85
82
—
—
—
—
8
15 min
78
—
—
aIsolated yield, 100% conversion, monitored by TLC analysis for completion of the
reaction.
1
bProducts characterized by H NMR, 13C NMR, and MS and known compounds
compared to the literature.
c12 Equivalents of iron used.

2782
A. B. Gamble et al.
chloride and concentrated HCl at reflux in ethanol, although it could only be
isolated in 69% yield,[13] indicating the superiority of iron-catalyzed reduction
promoted by ultrasound. Entry 7 demonstrates the tolerance of chlorine sub-
stituents on a pyrimidine ring with a yield of 82% obtained, with previously
reported iron-catalyzed reduction reporting a yield of 64%.[14]
Finally, entry 8 was used to examine the tolerance of both an ester and
nitrile functionality on an aliphatic chain. The reaction was complete in just
15 min as indicated by TLC analysis and provided the desired aryl amine in
78% yield, demonstrating the ability of ultrasound to drastically accelerate
the iron-catalyzed reduction of an aryl nitro functionality in the presence of
these reduction-sensitive groups.
In conclusion, an effective and efficient method for the reduction of aryl
nitro compounds to their corresponding aryl amine under ultrasonic irradiation
has been reported. Although in some instances, marginally higher yields are
reported, the reaction of aryl nitro compounds with iron powder in a solvent
mixture of ethanol, acetic acid, and water promoted by ultrasonic irradiation
provides a much more accessible and simple procedure. Additionally, the
short reaction times at relatively low temperature and the use of environmen-
tally benign solvents and cheap reagents make this an attractive and
advantageous method for reduction of aryl nitro compounds in organic
synthesis.
EXPERIMENTAL
Reagents and solvents used in the experiments were purchased as reagent
grade and used without further purification. Sonication was performed in an
Elma Transsonic T460 ultrasonic cleaning bath (at a frequency of 35 kHz
and a nominal power of 85 W) with all reactions exposed to air in standard
glassware or glass sample vials with the temperature of the bath maintained
at 308C. Melting points were determined in a Gallenkamp (Griffin) melting-
1
point apparatus. H NMR spectra were acquired on a Varian Unity-300 or
Unity-500 spectrometer at 300 MHz and 500 MHz respectively. Spectra
were recorded in deuterated chloroform (CDCl3), using chloroform (d
7.26 ppm) as internal standard. 13C NMR spectra were acquired with a
Varian Unity-300 or Unity-500 spectrometer at 76 MHz and 126 MHz
respectively using CDCl3 as solvent and chloroform (d 77.16 ppm) as the
internal standard. Electron impact (EI) mass spectra were obtained on a
Shimadzu QP-5000 MAT-44 quadrupole spectrometer performed via a
direct insertion technique, with an electron beam of 70 eV and a source temp-
erature of less than 2008C, and electrospray ionization (ES) mass spectra were
obtained on a VG Quattro-triple quadropole. All data reported for known
compounds were spectroscopically identical to those reported in the literature
(see compound references).

Iron Reduction under Ultrasound Irradiation
2783
General Procedure for Nitro Reduction with Iron
To a suspension of 1 (0.147 g, 0.961 mmol) in a mixture of glacial acetic acid
(2 mL), ethanol (2 mL), and water (1 mL), was added reduced iron powder
(0.279 g, 5.00 mmol). The resulting suspension was exposed to ultrasonic
irradiation for 1 h at 308C with TLC analysis monitoring for the completion
of the reaction. The reaction mixture was filtered to remove the iron
residue, which was washed with ethyl acetate (30 mL). The filtrate was parti-
tioned with 2M KOH, and the basic layer was further extracted with ethyl
acetate (3 ꢀ 25 mL). The combined organic extracts were washed with
brine (2 ꢀ 25 mL) and water (3 ꢀ 50 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude residue was then subjected to flash silica-
gel column chromatography (20% ethyl acetate in hexanes), yielding 3-meth-
oxyaniline 2 (89%).
General Procedure for Nitro Reduction with Stannous Chloride
To a solution of 1 (0.148 g, 0.967 mmol) in ethanol (5 mL), was added
.
SnCl2 2H2O (2.26 g, 10.0 mmol). The reaction mixture was exposed to ultra-
sonic irradiation for 2 h at 308C until the reaction was complete as indicated
by TLC analysis. The solvent was removed under reduced pressure, and the
crude residue was partitioned between ethyl acetate and 2M KOH. The
aqueous layer was extracted with further portions of ethyl acetate
(3 ꢀ 25 mL), and the combined organic extracts were washed with brine
(2 ꢀ 25 mL) and water (3 ꢀ 50 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude residue was subjected to flash silica-gel
column chromatography (20% ethyl acetate in hexanes) yielding 3-methoxy-
aniline 2 (76%).
Data
3-Methoxyaniline (Table 1)[15]
Dark yellow oil. 1H NMR (CDCl3): d 7.07 (dd, J ¼ 8.1 Hz, 7.8 Hz, 1H); 6.33
(dd, J ¼ 8.1 Hz, 2.4 Hz, 1H); 6.30 (dd, J ¼ 7.8 Hz, 1.8 Hz, 1H); 6.25 (dd,
J ¼ 2.4 Hz, 2.4 Hz, 1H); 3.77 (s, 3H); 3.66 (bs, 2H). 13C NMR (CDCl3): d
160.8, 147.9, 130.2, 108.0, 104.0, 101.1, 55.1. MS (EI) m/z 123 (M, 100%).
p-Aminoacetophenone (Table 2, Entry 1)[16]
1
Opaque crystalline solid. Mp: 102–1038C (lit.[16] 106–1078C). H NMR
(CDCl3): d 7.79 (d, J ¼ 8.7 Hz, 2H); 6.63 (d, J ¼ 9.3 Hz, 2H); 4.20 (bs,

2784
A. B. Gamble et al.
2H); 2.49 (s, 3H). 13C NMR (CDCl3): d 196.7, 151.3, 130.9, 127.9, 113.8,
26.2. MS (EI) m/z 135 (M, 60%), 120 (M-15, 100%).
m-Aminoacetophenone (Table 2, Entry 2)[12]
Light bronze solid. Mp: 88–898C (lit.[12] 98–998C). 1H NMR (CDCl3): d 7.31
(ddd, J ¼ 7.5 Hz, 1.8 Hz, 1.2 Hz, 1H); 7.25 (dd, J ¼ 1.8 Hz, 1.2 Hz, 1H); 7.21
(dd, J ¼8.1 Hz, 7.5 Hz, 1H); 6.85 (ddd, J ¼ 8.1 Hz, 2.1 Hz, 1.2 Hz, 1H); 3.85
(bs, 2H); 2.54 (s, 3H). 13C NMR (CDCl3): d 198.6, 146.9, 138.3, 129.5, 119.7,
118.9, 114.1, 26.8. MS (EI) m/z 135 (M, 85%), 120 (M-15, 100%).
2-Amino-6-bromo-4-methoxyphenol (Table 2, Entry 3)[17]
1
Dark brown semisolid. H NMR (CDCl3): d 6.41 (d, J ¼ 2.7 Hz, 1H); 6.26
(d, J ¼ 2.7 Hz, 1H); 3.70 (s, 3H). 13C NMR (CDCl3): d 154.3, 136.2, 134.8,
109.8, 105.3, 102.1, 55.9. MS (EI) m/z 217 (M79Br, 100%), 219 (M81Br,
90%).
3-Bromo-2,5-dimethoxyaniline (Table 2, Entry 4)
Brown viscous oil. 1H NMR (CDCl3, 500 MHz): d 6.45 (d, J ¼ 3.0 Hz, 1H);
6.23 (d, J ¼ 2.5 Hz, 1H); 3.93 (bs, 2H); 3.78 (s, 3H); 3.71 (s, 3H). 13C NMR
(CDCl3, 126 MHz): d 156.9, 141.7, 138.7, 117.1, 107.1, 101.3, 59.9, 55.7. MS
(EI) m/z 231 (M79Br, 100%), m/z 233 (M81Br, 90%). HRMS (EI) calculated
for C8H10NO2Br: 230.9895, found 230.9888.
3,30-Diamino-5,50-dibromo-2,20-dimethoxy-1,10-biphenyl (Table 2,
Entry 5)[13]
1
Light brown/red crystalline solid. Mp: 172–1758C (lit.[13] 185–1868C). H
NMR (CDCl3, 300 MHz): d 6.89 (d, J ¼ 2.4 Hz, 2H); 6.80 (d, J ¼ 2.1 Hz,
2H); 3.96 (bs, 4H); 3.44 (s, 6H). 13C NMR (CDCl3, 75 MHz): d 144.0,
141.5, 132.3, 122.8, 118.1, 116.8, 60.1. MS (EI) m/z 400 (M79Br79Br,
50%), 402 (M81Br79Br, 100%) 404 (M81Br81Br, 50%). HRMS (EI) calculated
for C14H14N2O729Br79Br: 399.9422, found 399.9419.
2-Bromo-3-methylaniline (Table 2, Entry 6)[18]
1
Yellow oil. H NMR (CDCl3): d 7.00 (dd, J ¼ 7.8 Hz, 7.5 Hz, 1H); 6.64
(m, 2H); 3.95 (bs, 2H); 2.39 (s, 3H). 13C NMR (CDCl3): d 144.4, 138.8,
127.5, 120.38, 113.2, 112.3, 23.7. MS (EI) m/z 238 (M79Br, 100%), 240
(M81Br, 90%).

Iron Reduction under Ultrasound Irradiation
2785
5-Amino-4,6-dichloropyrimidine (Table 2, Entry 7)[14]
1
White solid. H NMR (CDCl3): d 8.21 (s, 1H); 4.50 (bs, 2H). 13C NMR
(CDCl3) d 146.0, 144.3, 136.0. MS (ES þ ) m/z 164 ([MH35C135Cl]þ,
100%) 166 ([MH37C135Cl]þ, 60%), 168 ([MH37Cl37Cl]þ, 10%).
4-Amino-N-(10-cyanoethyl)-N-(acetoethyl)aniline (Table 2, Entry 8)
1
Light brown oil. H NMR (CDCl3, 500 MHz): d 6.66 (d, J ¼ 8.9 Hz, 2H);
6.61 (d, J ¼ 8.9 Hz, 2H); 4.12, (t, J ¼ 5.6 Hz, 2H); 3.66 (s, 2H); 3.49
(t, J ¼ 6.1 Hz, 2H); 3.42 (t, J ¼ 6.1 Hz, 2H); 2.46 (t, J ¼ 6.8 Hz, 2H); 2.00
(s, 3H). 13C NMR (CDCl3, 126 MHz): d 171.2, 140.2, 139.5, 118.9, 118.2,
116.9, 62.2, 51.9, 49.2, 21.1, 16.5. MS (ES þ ) m/z 248 ([MH]þ, 100%).
HRMS (ES þ ) calculated for C13H18N3O2: 248.1399, found 248.1405.
ACKNOWLEDGMENTS
A. B. G. thanks the Australian government for an Australian Postgraduate
Award, AVEXA Limited for financial support, and the Centre for Medicinal
Chemistry and Pharmacology, UOW, for financial support.
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