Rapid and convenient conversion of nitroarenes to anilines under microwave conditions using nonprecious metals in mildly acidic medium

Article abstract of DOI:10.1080/00397911.2017.1310897

Nitroarenes are reduced to the corresponding aniline derivatives using iron or zinc under mild conditions under microwave heating conditions. Mild acidity is provided by ammonium chloride in an aqueous methanol medium. The conditions are tolerant to other functional groups, with the exception of bromoalkyl derivatives, which yield complex reaction mixtures; otherwise, yields are generally quite high (80–99%).

Full text of DOI:10.1080/00397911.2017.1310897

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Rapid and Convenient Conversion of Nitroarenes
to Anilines under Microwave Conditions Using
Non-precious Metals in Mildly Acidic Medium
Corey S. Keenan & S. Shaun Murphree
To cite this article: Corey S. Keenan & S. Shaun Murphree (2017): Rapid and Convenient
Conversion of Nitroarenes to Anilines under Microwave Conditions Using Non-precious Metals in
Mildly Acidic Medium, Synthetic Communications, DOI: 10.1080/00397911.2017.1310897
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1310897
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Date: 03 April 2017, At: 22:11

Rapid and Convenient Conversion of Nitroarenes to Anilines under Microwave
Conditions Using Non-precious Metals in Mildly Acidic Medium
Corey S. Keenan1, S. Shaun Murphree1
1Department of Chemistry, Allegheny College, Meadville, PA
Corresponding author: S. Shaun Murphree. E-mail: smurphre@allegheny.edu
Abstract
Nitroarenes are reduced to the corresponding aniline derivatives using iron or zinc under
mild conditions under microwave heating conditions. Mild acidity is provided by
ammonium chloride in an aqueous methanol medium. The conditions are tolerant to
other functional groups, with the exception of bromoalkyl derivatives, which yield
complex reaction mixtures; otherwise, yields are generally quite high (80-99%).
GRAPHICAL ABSTRACT
KEYWORDS: nitroarenes; anilines; reduction; iron; zinc; microwave chemistry
INTRODUCTION
Anilines are among the oldest and most indispensible organic intermediates for both
laboratory-scale and commercial synthesis.[1] Moreover, the aniline and anilide
substructures are widely distributed among natural products of biological interest.[2,3]
1

Consequently, access to this privileged moiety remains a high priority for the synthetic
chemist.[4]
Owing to the ease and versatility of aromatic nitration,[5,6] the reduction of nitroarenes is
among the most convenient methods for the preparation of anilines. Although well
established, this approach continues to provide a platform for useful innovation.[7,8] Next
to catalytic hydrogenation,[9] Béchamp-inspired[10] conditions find the greatest
application, thanks to practical simplicity and broad functional group tolerance. A
particularly mild variation features ammonium chloride as an acidifying agent, which has
been used in combination with zinc in aqueous[11,12] and methanolic[13] medium, iron in
aqueous ethanol[14,15] and aqueous acetone,[16] and indium in aqueous ethanol.[17–19] In
connection with our ongoing work in adapting workhorse synthetic transformations for
rapid microwave protocols,[20,21] we were interested in studying how well these modified
Béchamp conditions would behave in a dedicated microwave reactor.
RESULTS & DISCUSSION
A comparison of some of the literature conditions (Table 1) reveals modest variation in
reaction parameters, as well as significant differences in cost. Whereas reductions with
iron and zinc are relatively inexpensive, using indium as the reductant costs almost $1000
per mole of nitroarene converted (entry 3). Another factor impacting the utility of the
method is the speed with which the metals effect reduction in mildly acidic medium at
elevated temperatures. Thus, a few commonly available metals were surveyed by
reaction with nitrobenzene in aqueous ammonium chloride for 5 min at 120°C (Table 2).
2

Interestingly, zinc, iron, and indium led to the highest conversions (entries 1-3). It is
noteworthy that the results do not cleanly correlate to parameters such as standard
reduction potentials, but rather depend upon physicochemical characteristics, such as the
robustness of the passive oxide layers.[22] These results demonstrate that iron and zinc
are the most attractive reductants from both economic and kinetic standpoints.
Since this process is a six-electron reduction, and zinc is a two-electron reductant,
theoretically only three equivalents of zinc are necessary. However, in practice an excess
is needed to achieve rapid and full conversion (Table 3). Carrying out the reaction with
nitrobenzene and a deficiency (2 equiv) of zinc leads to an almost equimolar mixture of
nitrobenzene, aniline, and phenylhydroxylamine (entry 1). With a slight excess of zinc (4
equiv), some residual phenylhydroxylamine is still present after 5 min (entry 2). Best
results are achieved with a twofold excess of reductant (entry 3). This does not appear to
be a surface area phenomenon, as granular zinc gives essentially the same results as zinc
dust (entry 5). The method can also be conveniently run on a 5-mmol scale with equal
efficiency (entry 6). It is worth noting that a control experiment using open reflux
provided predominantly phenylhydroxylamine and no aniline (entry 7).
A variety of nitroarenes were then examined to explore the scope of this procedure (Table
4). Thus, the substrate was taken up in methanol, diluted with an equal volume of
saturated ammonium chloride, treated with 6 equiv of iron or zinc, and heated in a sealed
tube under microwave irradiation for 5 min at 120 °C. A variety of functional groups
were tolerated, including esters, ketones, aldehydes, amides, and halogens; and many
3

products were isolated without the need for column chromatography. Notable exceptions
included nitrophenyl acetate (entry 5), which underwent concomitant hydrolysis under
the reaction conditions, and bromoalkyl derivatives (entries 10 and 11), which suffered
decomposition and provided complex reaction mixtures that proved recalcitrant to
purification.
The two metals gave comparable results, each having its own practical advantage. Iron is
more readily available, but it tends to complicate the subsequent cleaning of glassware
and equipment. Zinc is much tidier to work with, but it is more pyrophoric than iron and
it conforms less to green chemical principles, as it is listed among the endangered
elements because of increasing global demand.[23] While a purely aqueous system could
be used in some cases, an alcohol co-solvent led to more consistent results in our hands,
presumably due to the limited water solubility of some starting materials.
In summary, the Béchamp reduction of nitroarenes using ammonium chloride as an
acidifier is well behaved under sealed-tube microwave heating conditions, rapidly
providing the corresponding aniline derivatives in high purity in most cases. The speed
and operational simplicity of this method makes it a particularly attractive protocol for
laboratory-scale synthesis.
EXPERIMENTAL
General Procedure For The Reduction Of Nitroarenes 1
4

To a 10 mL microwave vial was added the nitroarene (0.50 mmol), zinc dust (3.00
mmol), MeOH (1.0 mL), and sat. aq NH4Cl. The vial was sealed and heated at 120 °C
for 5 min. The reaction mixture was transferred to a separatory funnel containing sat aq
Na2CO3 (10 mL) and extracted with CH2Cl2 (3 x 8 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to provide anilines 2.
Spectral Data For Selected Compounds
Aniline (2a).[24] The general procedure provided 2a (46.1 mg, 99%) as a light amber oil
1
with physical properties identical to those found in the literature: H NMR (400 MHz,
CDCl3) δ 7.18 (t, J = 7.8 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 2H), 3.58
(br s, 2H); 13C NMR (100 MHz, CDCl3) δ 146.41, 129.43, 118.73, 115.29.
p-Methoxyaniline (2c).[25] The general procedure, followed by column chromatography
(30% EtOAc/hexane), provided 2c (45.6 mg, 74%) as a brown solid with physical
1
properties identical to those found in the literature: mp 53-55 °C (lit. 56-59 °C); H
NMR (400 MHz, CDCl3) δ 6.74 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.9 Hz, 2H), 3.74 (s,
3H), 3.30 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.93, 139.91, 116.55, 114.88,
55.83.
Ethyl p-aminobenzoate (2d).[19] The general procedure provided 2d (76.8 mg, 93%) as
a buff solid with physical properties identical to those found in the literature: mp 87-89
1
°C (lit. 88-90 °C); H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.7 Hz, 2H), 6.61 (d, J =
5

8.7 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.93 (br s, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.95, 151.05, 131.63, 119.89, 113.85, 60.45, 14.51.
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support from the National Science
Foundation (TUES 1323024).
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
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8

Table 1. Typical conditions for metal-mediated reduction in NH4Cl solution.
Entry metal
(eq)
eq
solvent system
T°C t
cost
ref
NH4Cl
3.0
(h) ($)a
2-5 2.59
1
Fe (n.r.)
water/acetone
(1:2.5)
57
80
16
2
3
Zn (7.25) 2.0
In (4.0) 10
water
0.5 5.87
2.5 933
12
19
water/ethanol (1:2) 78
acost of metal to convert 1 mol of nitroarene; prices taken from the Sigma-Aldrich web
catalog (www.sigmaaldrich.com); for cost calculation, 7.25 eq of iron were assumed.
9

Table 2. Efficacy of various metals in reducing nitrobenzene.a
entry metal E0
(V)
equivb conv
(%)c
1
2
3
4
5
6
7
Zn
Fe
In
-0.76 3.5
-0.41 3.5
-0.34 7.0
-2.83 3.5
-0.23 3.5
-1.66 2.3
-1.63 3.5
93
88
81
51
24
7
Mg
Ni
Al
Ti
3
aconditions: 0.5 mmol PhNO2, 2.5 mL H2O, 2.0 equiv NH4Cl; 5 min @ 120°C
bstoichiometry standardized to give 7.0 equiv of electrons
cconversion determined by HPLC
10

Table 3. Impact of metal stoichiometry.a
entry Zn
(equiv)
2.0
reaction mixtureb
1a
2a
3
1
37%
0%
0%
0%
0%
0%
9%
34%
89%
29%
11%
2
4.0
6.0
8.0
6.0
6.0
6.0
3
> 99% < 1%
> 99% < 1%
> 99% < 1%
> 99% < 1%
4
5c
6d
7e
0%
91%
aconditions: 0.5 mmol PhNO2, 1.0 mL MeOH, 1.0 mL sat'd NH4Cl; 5 min @ 120°C
bmolar ratio determined by NMR
cgranular zinc used instead of zinc dust
drun on a 5.0 mmol scale
eheated under reflux for 5 min
11

Table 4. Anilines prepared by the reduction of nitroarenes.a
entry
R
product
isolated yield
Zn
99
Fe
90
94
91
95
32
95
97
91
90
<10b
17
64
65
1
-H
2a
2b
2c
2d
2e
2f
2
-Me
95
3
-OMe
-CO2Et
-OAc
74
4
93
5
18
6
-CHO
-C(O)Me
-Br
34
7
95
2g
2h
2i
8
94
9
-Cl
95
10
11
12
13
-CH2Br
-CH2CH2Br
-NH2
<38b
<33b
82
2j
2k
2l
-NHAc
86
2m
aconditions: 0.5 mmol ArNO2, 3.0 mmol metal, 1.0 mL MeOH, 1.0 mL sat'd NH4Cl; 5
min @ 120°C; conversion cost (including work-up) per mole of substrate: Fe, $3.04; Zn,
$5.76
bcomplex reaction mixture
12