Highly efficient rhodium-catalyzed transfer hydrogenation of nitroarenes into amines and formanilides

Article abstract of DOI:10.1055/s-0033-1341250

An efficient and selective rhodium-catalyzed transfer hydrogenation of nitroarenes with formic acid as the hydrogen source to give amines or formanilides has been developed. The addition of iodide ion accelerates the reaction, which can take place at room temperature. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341250

LETTER
▌1295
letter
Highly Efficient Rhodium-Catalyzed Transfer Hydrogenation of Nitroarenes
into Amines and Formanilides
Rhodium-Catalyzed Transfer Hydrogenation of Nitroarenes
Yawen Wei,a Jianjun Wu,b Dong Xue,a Chao Wang,*a Zhaotie Liu,a Zhuozhuo Zhang,a Guangfu Chen,a
Jianliang Xiao*a,b
a
Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education and School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an 710062, P. R. of China
Fax +86(29)81530727; E-mail: c.wang@snnu.edu.cn
b
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
E-mail: j.xiao@liv.ac.uk
Received: 02.02.2014; Accepted after revision: 25.03.2014
amines or formanilides in a one-pot highly efficient reac-
Abstract: An efficient and selective rhodium-catalyzed transfer
tion with substrate–catalyst (S/C) ratios of up to 1000.
hydrogenation of nitroarenes with formic acid as the hydrogen
source to give amines or formanilides has been developed. The ad-
dition of iodide ion accelerates the reaction, which can take place at
room temperature.
We recently discovered that combining the simple dimer-
ic precatalyst tetrachlorobis(η5-pentamethylcyclopentadi-
enyl)dirhodium ([Cp*RhCl2]2) with iodide ion permits a
highly efficient reduction of various heterocycles with an
azeotropic formic acid–triethylamine mixture (2.5:1) as
the hydrogen source.6 To further test the power of this cat-
alytic system, we attempted to use the system in the reduc-
tion of nitroarenes. We chose 4-nitroanisole as a model
substrate. Treatment of this compound with 1 mol% of
[Cp*RhCl2]2 and a formic acid–triethylamine (2.5:1) mix-
ture as both the solvent and hydrogen source at 40 °C for
four hours did indeed give 4-methoxyaniline (2a), but
only when potassium iodide was present. No reduction
was observed in the absence of potassium iodide (Table 1,
entries 1 and 2). Under the conditions used, the maximum
activity was achieved by addition of one equivalent of po-
tassium iodide (entries 2–5). By increasing the tempera-
ture to 100 °C and the extending the reaction time to 12
hours, full conversion was achieved. However, the major
product that was isolated was the formanilide 3a rather
than 4-methoxyaniline (2a) (entry 6). The formanilide 3a
was probably formed by the reaction of formic acid with
the amine 2a generated in situ.7 As formanilides are also
important intermediates for various applications,8 we fur-
ther optimized the conditions for the formation of forma-
nilide 3a. When the catalyst loading was lowered to 0.1
mol%, substantial activity was still maintained, and for-
manilide 3a was isolated in 35% yield after four hours
(entry 7). Isoelectronic iridium and ruthenium complexes
showed no activity or much lower activities under these
conditions (entries 8 and 9). Studies on the effects of the
solvent and the formic acid–triethylamine ratio revealed
that a slightly higher yield of 48% could be obtained in di-
methyl sulfoxide with 0.1 mol% of the catalyst (entry 10
and Supporting Information, Tables S1 and S2). Further
optimization of the reaction conditions in dimethyl sulf-
oxide by varying the amount of formic acid and prolong-
ing the reaction time (Supporting Information; Table S3)
led to a satisfactory isolated yield of 89% of formanilide
3a (Table 1, entry 12). To probe the role of potassium io-
dide, we synthesized tetraiodobis(η5-pentamethylcyclo-
pentadienyl)dirhodium ([Cp*RhI2]2) and tested it under
Key words: reduction, hydrogenation, nitroarenes, amines, am-
ides, catalysis, rhodium
Aromatic amines are important intermediates for the syn-
thesis of pharmaceuticals, dyes, and agrochemicals.1
Among the various methods available for the preparation
of aromatic amines, the reduction of nitroarenes is the
most widely adopted method in laboratories and on an in-
dustrial scale. In industrial-scale production, heteroge-
neous catalytic hydrogenation of nitroarenes is the
preferred route.2 However, because the handling of haz-
ardous hydrogen gas is not favored in laboratory opera-
tions, stoichiometric reduction systems, such as the
Béchamp reduction or sulfide reduction, or stoichiometric
reducing agents with metal catalysts3 are commonly used
in laboratory reduction of nitro groups. Although conve-
nient, these stoichiometric systems are not environmental-
ly benign, as the reducing agents used are often hazardous
and expensive, and they frequently generate large
amounts of waste. Transfer hydrogenation,4 which em-
ploys cheap, safe, and easily accessible reducing agents
such as isopropanol or formic acid as hydrogen sources,
avoids the use of hydrogen gas and is more environmen-
tally friendly than stoichiometric reductions. However,
there are only a few examples of homogeneous transfer
hydrogenation of nitroarenes.5 Recently, Beller and co-
workers reported that iron5f and molybdenum5g catalysts
can be used as catalysts for the transfer hydrogenation of
nitroarenes with formic acid as the hydrogen source. De-
spite this progress, the efficiency of homogeneous transfer
hydrogenation of nitro groups needs to be improved, as
most of the systems employ catalyst loadings of more than
1 mol%. Here, we describe a rhodium-catalyzed transfer
hydrogenation of nitroarenes with formic acid to form
SYNLETT 2014, 25, 1295–1298
Advanced online publication: 29.04.2014
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DOI: 10.1055/s-0033-1341250; Art ID: st-2014-w0090-l
© Georg Thieme Verlag Stuttgart · New York

1296
Y. Wei et al.
LETTER
the optimal conditions without the addition of potassium formic acid were used, the amine was completely convert-
iodide. A slightly lower yield of 30% was obtained, indi- ed into the corresponding formanilide (entries 3–14). Ni-
cating that [Cp*RhI2]2 might be the real catalyst in the re- troarenes with electron-donating substituents in the
action (entry 11). The addition of nitrogen or phosphine position para to the nitro group generally showed better
ligands decreased the rate of the reaction without affecting activity than those with electron-withdrawing substituents
the selectivity (entries 13–16). These results suggest that (entries 1–7). Isolated yields of over 80% were obtained
the selectivity between the amine and formanilide prod- with 4-methoxy- and 4-methyl-substituted substrates (en-
ucts was unaffected by the catalyst, but was affected by tries 1 and 3, respectively). Halo groups were tolerated,
the temperature. At 100 °C, formanilide was the major except for iodide (entries 5–8, 10, and 12). 1-Iodo-4-nitro-
product (entries 6–16), whereas at lower temperatures, the benzene underwent dehalogenation to give the formani-
amine product was obtained exclusively (entries 2–5).
lide 3b in moderate yield (entry 8). 1-Methylsulfanyl-4-
nitrobenzene required 2 mol% of catalyst to obtain an ac-
ceptable yield, possibly because of the strongly coordinat-
ing nature of the sulfur atom (entry 9). Nitroarenes with
meta-substituents reacted equally as well as their para-
substituted analogues (entries 11 and 12). When a reduc-
ible carbonyl group was presented, the nitro group was se-
lectively reduced and the carbonyl remained intact
(entries 11, 17, and 18). However, substrates bearing
The substrate scope for the N-formylation of various ni-
troarenes was examined with [Cp*RhCl2]2 as catalyst
(S/C = 1000) and formic acid–triethylamine (3:1) as the
hydrogen source in dimethyl sulfoxide.9 Substantial
amounts of amines 2 were obtained from various sub-
strates under the optimized conditions (Table 2); however,
their formation could be suppressed simply by increasing
the concentration of formic acid. When 20 equivalents of
Table 1 Effects of Additives and Temperature on the N-Formylation of 4-Nitroanisole (1a)a
H
O
N
NH2
NO2
metal, additive
HCO2H, Et3N
+
MeO
MeO
MeO
1a
2a
3a
Entry
Metalb
(mol%)
Additive (equiv)Ligandc
(mol%)
HCO2H
(equiv)
Et3N
(equiv) (mL)
DMSO Temp
Time
(h)
Yieldd
(%) of 2a (%) of 3a
Yieldd
(°C)
1
2
[Rh] (1)
–
–
25
25
25
25
25
25
25
25
25
15
15
15
15
15
15
15
10
10
10
10
10
10
10
10
10
5
–
–
–
–
–
–
–
–
–
2
2
2
2
2
2
2
40
40
4
4
n.r.
[Rh] (1)
KI (0.1)
KI (0.5)
KI (1)
KI (3)
KI (1)
KI (1)
KI (1)
KI (1)
KI (1)
–
–
5e
20e
28e
29e
n.d.
3
n.d.
n.d.
n.d.
n.d.
80
35
n.r.
5
3
[Rh] (1)
–
40
4
4
[Rh] (1)
–
40
4
5
[Rh] (1)
–
40
4
6
[Rh] (1)
–
100
100
100
100
100
100
100
100
100
100
100
12
4
7
[Rh] (0.1)
[Ir] (0.1)
[Ru] (0.1)
[Rh] (0.1)
[RhI] (0.1)
[Rh] (0.1)
[Rh] (0.1)
[Rh] (0.1)
[Rh] (0.1)
[Rh] (0.1)
–
8
–
4
<1
<1
4
9
–
4
10
11
12
13
14
15
16
–
4
48
30
89
9
–
5
4
2
KI (1)
KI (1)
KI (1)
KI (1)
KI (1)
–
5
20
4
<5
0
bpy (0.2)
Cy3P (0.4)
dppp (0.2)
5
5
4
0
9
5
4
0
10
8
BINAP (0.2)
5
4
0
a Reaction conditions: 4-nitroanisole (1a; 1.6 mmol), metal catalyst, KI (if added), HCO2H (40 mmol, 25 equiv), Et3N (16 mmol, 10 equiv),
ligand (if added), DMSO (if added), 4 h, under argon.
b [Rh] = [Cp*RhCl2]2; [Ir] = [Cp*IrCl2]2; [Ru] = [Ru(p-cymene)Cl2]2; [RhI] = [Cp*RhI2]2.
c dppp = Ph2P(CH2)3PPh2.
d Isolated yield; n.r. = no reaction; n.d. = not determined.
e Determined by HPLC.
Synlett 2014, 25, 1295–1298
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rhodium-Catalyzed Transfer Hydrogenation of Nitroarenes
1297
NO2
ortho-substituents gave less than 50% conversions, even
with 2 mol% of catalyst, possibly as a result of steric hin-
drance (entries 12 and 13). More notably, amines were ob-
tained as products from several electron-deficient
substrates, presumably as a result of the reluctance of the
amine products to add to formic acid (entries 16–18). The
strongly electron-withdrawing nitrile group also inhibited
the reduction of the nitro group, but was not itself reduced
(entry 16).
NH2
[Cp*RhCl2]2, KI
R
R
HCO2H, Et3N
25 °C, 36 h
2a, R = 4-MeO, 84%
2e, R = 4-Me, 86%
2f, R = 4-Cl, 66%
2g, R = 3-Cl, 31%
2h, R = 3,4-Cl2, 61%
Scheme 1 Transfer hydrogenation of 4-nitroanisole at room temper-
ature. Reagents and conditions: 4-nitroanisole (0.5 mmol),
[Cp*RhCl2]2 (0.01mmol), KI (0.5 mmol), HCO2H (12.5 mmol), Et3N
(12.5 mmol), 25 °C, 36 h.
Table 2 N-Formylation of Nitroarenesa
H
O
N
NO2
NH2
A proposed mechanism is shown in Scheme 2. The potas-
sium iodide additive might assist the formation of the an-
ionic diiodo rhodium hydride, which is presumed to be the
active catalyst for reduction. The stronger reducing ability
of the diiodo rhodium hydride might stem from its anionic
charge and the trans-effect of the iodide ligand.6 The
mechanism for the nitro reduction step requires further
study. One possibility is direct transfer of the hydride to
the nitro nitrogen atom by an ionic or outer-sphere mech-
anism, as in the reduction of ketones.10
[Cp*RhCl2]2, KI
R
R
or
R
HCO2H, Et3N
DMSO, 100 °C, 20 h
2
3
1
Entry
R
Product Catalyst (mol%) Yieldb (%)
1c
2c
3
4-MeO
H
3a
3b
3c
3d
3e
3f
0.1
0.1
0.1
0.2
0.2
0.1
0.1
0.1
2
89
69
82
77
76
73
78
68
63
86
68
38
35
89
68
46
68
97
4-Me
4-t-Bu
4-F
4
CO2
5
I
O
H
Rh
S
[Cp*RhCl2]2
Rh
S
I
I
H
H
6
4-Cl
I
O
HCO2
7
4-Br
3g
3b
3h
3i
I
8
4-I
I
Rh
I
H
9
4-MeS
3-Cl
NO2
O
N
CO2
R
R
10
11
12
13
14
15
16
17
18
0.1
0.2
2
3-Ac
2-Cl
3j
HCO2H
3k
3l
OH
[Rh-H], H+
– H2O
NH2
N
O
2-MeO
3,4-Cl2
3,4-(MeO)2
4-NC
4-Ac
2-Ac
2
HCO2
R
R
I
Rh
I
3m
3n
2b
2c
2d
0.1
0.1
0.1
0.2
0.2
I
Scheme 2 Proposed mechanism for N-formylation of nitro com-
pounds by formic acid in the presence of the [Cp*RhCl2]2–iodide sys-
tem [S = solvent (DMSO)].
In conclusion, we have developed a simple and efficient
protocol for chemoselective transfer hydrogenation of ni-
troarenes to amines or formanilides by using commercial-
ly available [Cp*RhCl2]2 as the catalyst and formic acid as
the hydrogen source. The addition of potassium iodide ac-
celerated the transfer hydrogenation reaction, and the
presence of a keto or halo group on the substrate was tol-
erated. At room temperature, the reduction gave the corre-
sponding amines, providing a practical alternative method
for the reduction of nitroarenes.
a Reaction conditions: substrate (1.6 mmol), [Cp*RhCl2]2, KI (1.6
mmol), DMSO (2 mL), HCO2H (32 mmol), Et3N (10.7 mmol),
100 °C, 20 h, under argon.
b Isolated yield.
c HCO2H (24 mmol) and Et3N (9.6 mmol).
The reduction could be carried out at room temperature
with a higher catalyst loading and a longer reaction time
to give the corresponding amines 2 (Scheme 1). For exam-
ple, reduction of 4-nitroanisole with 2 mol% of
[Cp*RhCl2]2 at 25 °C for 36 hours gave p-anisidine (2a)
in 84% yield (Scheme 1).
Acknowledgment
We are grateful for the financial support of the National Science
Foundation of China (21103102), the Program for Changjiang
Scholars and Innovative Research Teams in Universities (IRT
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1295–1298

1298
Y. Wei et al.
LETTER
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m
iotSrat
maotrin
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