Selective reduction of halogenated nitroarenes with hydrazine hydrate in the presence of Pd/C

Article abstract of DOI:10.1055/s-0033-1339025

A large variety of halogenated nitroarenes have been selectively reduced with hydrazine hydrate in the presence of Pd/C to give the corresponding (halogenated) anilines in good yield.

Full text of DOI:10.1055/s-0033-1339025

LETTER
▌1403
lSeteterlective Reduction of Halogenated Nitroarenes with Hydrazine Hydrate in
the Presence of Pd/C
Highly Selective and Efficient Reduction on Halogenated Nitroarenes
Fang Li,a,b Brendan Frett,a,b Hong-yu Li*a,b
a
College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA
Fax +1(520)6260794; E-mail: hongyuli@pharmacy.arizona.edu
b
BIO-5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd, Oro Valley, AZ 85737, USA
Received: 05.03.2014; Accepted after revision: 07.04.2014
versal strategy for the selective reduction of halogenated
Abstract: A large variety of halogenated nitroarenes have been se-
nitroarenes is highly desired to replace harsher (for exam-
lectively reduced with hydrazine hydrate in the presence of Pd/C to
ple Zn/H+) or non-selective conditions. Herein, we report
a simple, efficient, and highly selective reduction of halo-
genated nitroarenes.
give the corresponding (halogenated) anilines in good yield.
Key words: reduction, nitroarenes, hydrazine hydrate, palladium
on carbon, aromatic amines, transfer hydrogenation
Among the variety of catalytic metals, palladium catalysts
are most extensively used.6b,7 Hydrazine, as an indirect
hydrogen source, has been shown to be effective in nitro
reduction.8 Thus, our study started with evaluating the re-
duction of 1-bromo-4-(tert-butyl)-2-nitrobenzene (1a) by
Pd/C and hydrazine. At first, 1a was totally reduced to
3-(tert-butyl) aniline (2a) in a sealed tube with 10% Pd/C
and ten equivalents of hydrazine in one hour. Under the
same conditions, except utilizing open reflux heating,
2-bromo-5-(tert-butyl)aniline (3a) was obtained in five
minutes. These two reactions were exceptionally clean,
quick, and convenient for work-up (Scheme 1).
Aromatic amines are important precursors and key inter-
mediates for the synthesis of medicines, dyes, agricultural
chemicals, and polymers.1 Reduction of the correspond-
ing nitroarenes constitutes one of the most efficient meth-
ods for the synthesis of aniline-containing compounds.
Traditionally, nitroarenes were reduced by a metal and an
acid, a methodology developed by Bechamp in 18542
which has been replaced by catalytic hydrogenation with
less toxic and hazardous by-products.3
However, catalytic hydrogenation has two drawbacks: 1)
the danger and inconvenience of handling highly flamma-
ble hydrogen gas and 2) the low selectivity in the reduc-
tion of functionalized nitroarenes. Catalytic transfer
hydrogenation, using in situ hydrogen production, has
emerged as the best solution in the last century. Different
catalytic metals, such as iron, palladium, and platinum,
have been utilized to carry out nitro reductions. But for
highly functionalized substrates with liable halogen-based
functional groups reduction selectivity is a major prob-
lem.4
In our development of novel kinase inhibitor fragments,5
a highly selective and versatile reduction of a halogenated
nitroarene was required. Numerous selective reductions
on chlorinated nitroarenes have been reported with the
problem of enhanced reductive dehalogenation caused by
an in situ produced amino group.6 Therefore, a mild, uni-
Considering the only difference between the two reduc-
tions was an opened or sealed environment, we conclude
that hydrogen pressure plays a vital role in determining re-
action progression. For better observation and monitoring
of the direct pressure in the reaction vessel, microwave ir-
radiation was employed. Microwave irradiation has been
used as an efficient alternative to conventional heating in
the last two decades.9 Several microwave-assisted catalyt-
ic transfer hydrogenations have been reported recently.10
As expected, 2 was obtained exclusively through micro-
wave heating in about 30 minutes. The pressure rose to
about 6 psi, which progressed 1a to a full reduction.
To optimize reduction conditions, extensive studies were
conducted on catalyst loading, heating, and solvent. After
confirming methanol as the best solvent for nitro reduc-
tions (Table 1, entries 1 and 2), 5% Pd/C was found ade-
Br
Br
Pd/C, NH2NH2⋅H2O
MeOH
Pd/C, NH2NH2⋅H2O
NH2
NH2
NO2
MeOH
sealed tube, 80 °C
reflux, 80 °C
95%
97%
2
3
1
Scheme 1 Selective reduction on bromo-4-(tert-butyl)-2-nitrobenzene 1 under different heating conditions
SYNLETT 2014, 25, 1403–1408
Advanced online publication: 12.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339025; Art ID: st-2014-r0200-l
© Georg Thieme Verlag Stuttgart · New York

1404
F. Li et al.
LETTER
duction conditions are found under method B (Table 1,
entry 8).
Table 1 Optimization of Reduction Conditions
Pd/C
NH2NH2⋅H2O
solvent
heating
Pd/C
NH2NH2⋅H2O
solvent
With optimal conditions in hand, we investigated the sub-
strate scope and generality of the reduction on a variety of
bromo-, chloro-, and iodonitroarenes, as demonstrated in
Table 2. Simple nitroarenes were tested first under meth-
ods A and B, and the corresponding anilines and haloge-
nated anilines were obtained in high yield (Table 2, entries
1 and 2). Bromonitroarenes, unlike chloronitroarenes,
have been sparsely investigated for chemoselective reduc-
tions utilizing palladium, because C–Br bonds are more
catalytically active than C–Cl bonds.6 We were pleased to
identify, through the utilization of our system in Table 1,
that nitro groups with various halogenated substituents
could be selectively reduced under open reflux conditions
while total reductions were achieved with microwave ir-
radiation (Table 2, entries 3–5).
Br
Br
NH2
NH2
NO2
sealed tube
heating
method B
method A
2a
1a
3a
Entry
Temp
Catalyst Solvent
loading
Time Product Yield
(min)
(°C)
(%)a
1
2
80b
80b
10%
10%
5%
MeOH
EtOH
5
5
3
3
3
2
2
2
2
2
2
2
2
95
86
95
95
96
95
96
95
94
79
85
3
80b
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
5
4
80c
10%
10%
10%
10%
10%
20%
5%
60
30
30
30
15
15
15
15
Electron-donating groups, such as amino groups, have
been found to impair chemoselectivity. When substrates
containing amino groups were utilized (Table 2, entries 6–
10), dehalogenation cleavage was observed under reflux.
This was easily remedied by completing the reaction at
room temperature. Similarly, dinitro substrates could be
selectively reduced at room temperature with higher cata-
lyst loading (entry 11). We then investigated substrates
with two halogen substituents. Monodehalogenation oc-
curred under reflux, while a selective nitro reduction oc-
curred at room temperature (Table 2, entries 12–14).
Notably, the highly palladium active C–I bond is not af-
fected by the mild conditions (Table 2, entry 14).
5
80d
6
100d
120d
120d
120d
120d
120d
7
8
9
10
11
10%
a Isolated yield.
b Heating was performed under reflux condition.
c Heating was performed in sealed tube.
We decided to extend our research on heteroaromatics to
investigate the full scope of the nitroarene reduction. Pyr-
idines, as electron-deficient heterocycles, showed a good
yield and selectivity (Table 2, entries 15 and 16). Nitro
groups on fused bicyclic ring systems such as indole can
also be selectively reduced (Table 2, entry 17), which ren-
ders this methodology very attractive for indole ring con-
taining pharmaceuticals.11
d Heating was performed in a microwave reactor.
quate without lowering yield (Table 1, entry 3). The
optimized selective reduction conditions are listed under
method A (entry 3).
With conventional heating, one hour was needed for full
reduction (Table 1, entry 4), while microwave irradiation
could reduce the reaction time to 30 minutes (Table 1, en-
try 5). After carefully optimizing the temperature, 120 °C
was found to be ideal for the shortest reaction time (15
min) and highest yield (Table 1, entries 6–8). Higher tem-
peratures cause higher pressure in the reaction vessel,
which permits facile dual nitro and halogen reductions. A
higher catalyst loading (20%) did not improve the reaction
yield (Table 1, entry 9), while a lower catalyst loading
(5%) caused a substantial decrease in yield (Table 1, entry
10). Correspondingly, methanol is the best solvent for to-
tal reduction (Table 1, entry 11). The optimized full re-
Unfortunately, cyano groups were also reduced under the
reduction conditions (Table 2, entry 18). And it is note-
worthy that the yield substantially decreased with the
presence of a fluorine group (Table 2, entries 19 and 20).
Because of the convenient workup, Pd/C could be recy-
cled with filtration after the reaction. The chemoselective
reaction recyclability was measured on substrate 1a and
conversion to 2a was determined by LC–MS (Table 3).
There is no major catalytic activity loss for up to four
cycles.
Synlett 2014, 25, 1403–1408
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly Selective and Efficient Reduction on Halogenated Nitroarenes
1405
Table 2 Substrate Scope
NH2
NO2
NH2
method B
method A
X
X
3
substrate
2
Entry 1
Substrate
Product yield and ratioa (method A)b
Product yielda (method B)c
NH2
NO2
NH2
1
Cl
Cl
2b (93%)
14:1
3b (90%)
1b
Cl
Cl
NH2
NH2
NO2
2
3b (90%)
2c (94%)
15:1
1c
NH2
NO2
NH2
Br
3
4
Br
2d (92%)
14:1
3b (92%)
1d
NH2
NO2
NH2
Br
Br
2e (93%)
16:1
3e (92%)
1e
Br
Br
NH2
NH2
NO2
5
6
3b (91%)
2f (95%)
14:1
1f
NH2
NH2
NH2
NH2
NO2
NH2
Br
Br
2g (95%)d
18:1
3g (96%)
1g
NH2
NH2
NH2
NH2
NO2
NH2
7
8
Cl
Cl
2h (93%)d
only product
3g (97%)
1h
H2N
NH2
H2N
NO2
H2N
NH2
Cl
Cl
2i (95%)d
only product
3i (96%)
1i
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1403–1408

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F. Li et al.
LETTER
Table 2 Substrate Scope (continued)
NH2
NO2
NH2
method B
X
method A
X
3
substrate
2
Entry 1
Substrate
Product yield and ratioa (method A)b
Product yielda (method B)c
Cl
Cl
NH2
NH2
NO2
Me
9
Me
Me
NH2
NH2
NH2
2j (94%)d
14:1
3j (91%)
1j
Br
Br
NH2
NH2
NO2
Me
Me
10
Me
NH2
NH2
NH2
2k (92%)d
15:1
3j (97%)
1k
Cl
NH2
NH2
NH2
NH2
Cl
NO2
NO2
11
12
2l (90%)d
11:1
1l
3g (89%)
Cl
Cl
NH2
NH2
NO2
Cl
Cl
2m (90%)d
12:1
3b (88%)
1m
Br
Br
NH2
NO2
NH2
13
14
Cl
Cl
Cl
3b (91%)
2n (89%)d
10:1
1n
Cl
NH2
NH2
NO2
I
I
2o (88%)d
9:1
3b (92%)
1o
NH2
NO2
N
NH2
N
N
Cl
15
16
Cl
2p (87%)
10:1
3p (89%)
1p
Cl
Cl
NH2
NH2
N
NO2
N
N
3p (84%)
2q (85%)
9:1
1q
Synlett 2014, 25, 1403–1408
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly Selective and Efficient Reduction on Halogenated Nitroarenes
1407
Table 2 Substrate Scope (continued)
NH2
NO2
NH2
method B
X
method A
X
3
substrate
2
Entry 1
Substrate
Product yield and ratioa (method A)b
Product yielda (method B)c
Br
Br
N
H2N
17
18
N
N
H
H2N
O2N
1r
H
H
2r (91%)
12:1
3r (87%)
CONH2
NH2
CN
CONH2
NO2
NH2
Cl
Cl
F
3e (86%)
2s (84%)
9:1
1s
F
NH2
F
NO2
NH2
19
20
Br
Br
F
3t (29%)
2t (37%)
3:1
1t
F
NH2
F
NO2
NH2
Cl
Cl
3u (27%)
2u (25%)
2.5:1
1u
a Separated yield, the ratio between 2 and 3 is based on LC–MS.
b Reaction condition: nitroarenes (1 mmol), Pd/C [13 mg, 10 wt% loading (dry basis)], NH2NH2·H2O (10 mmol), MeOH (5 mL), 80 °C, 5 min.12
c Reaction condition: nitroarenes (1 mmol), Pd/C [26 mg, 10 wt% loading (dry basis)], NH2NH2·H2O (10 mmol), MeOH (5 mL), microwave
(120 °C, 15 min).12
d The reaction was carried out at room temperature.
Table 3 Recyclability
Time
1st
2nd
98
3rd
95
4th
90
5th
80
Conversion
100
a Reaction conditions: 1a (1 mmol), Pd/C (13 mg), NH2NH2·H2O (10 mmol), MeOH (5 mL), 80 °C, 5 min.
In summary, we have developed a highly efficient, selec-
tive reduction of halogenated nitroarenes. Several advan-
tages compared to other methods exist: (1) The
chemoselectivity can be conveniently controlled by ap-
plying different heating methods with the same catalyst
system. (2) The methodology works on bromo, chloro,
iodo and multihalogenated substrates. (3) The methodolo-
gy works on normal arenes and hetereoarenes. (4) As a
heterogeneous catalyst, Pd/C can be recycled up to four
times with minimal loss of catalytic activity.
Acknowledgment
This work was supported by a training grant from The National In-
stitutes of Health (T32 GM008804), University of Arizona startup
funding, and The Caldwell Health Sciences Research Fellowship.
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
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F. Li et al.
LETTER
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(12) General Procedures; Method A: To a mixture of
halogenated nitroarene (1 mmol), Pd/C(5%), and MeOH (5
mL) was added NH2NH2·H2O (10 mmol), and the resulting
solution was heated at 80 °C reflux condition for 5 min. Then
the mixture was filtered and concentrated in vacuo. The
crude material was purified by flash column
chromatography using hexanes and EtOAc. Method B: To a
mixture of halogenated nitroarene (1 mmol), Pd/C(10%),
and MeOH (5 mL) was added NH2NH2·H2O (10 mmol), and
the resulting solution was heated at 120 °C by Biotage
Initiator Classic microwave synthesizer for 15 min. The
mixture was filtered and condensed in vacuo. The crude
material was purified by flash column chromatography
using hexanes and EtOAc.
2-Bromo-5-(tert-butyl)aniline (3a): compound 3a was
prepared in 95% yield according to the general procedure
(Method A). 1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J =
8.4 Hz, 1 H), 6.79 (d, J = 2.3 Hz, 1 H), 6.66 (dd, J = 8.3, 2.4
Hz, 1 H), 4.02 (br s, 2 H), 1.27 (s, 9 H). 13C NMR (100 MHz,
CDCl3): δ = 151.8, 143.5, 132.0, 117.0, 113.1, 106.3, 34.5,
31.2 (3 × C).
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Synlett 2014, 25, 1403–1408
© Georg Thieme Verlag Stuttgart · New York