Highly selective conversion of nitrobenzenes using a simple reducing system combined with a trivalent indium salt and a hydrosilane

Article abstract of DOI:10.1039/c000383b

Controlling the type of indium salt and hydrosilane enables a highly selective reduction of aromatic nitro compounds into three coupling compounds, azoxybenzenes, azobenzenes and diphenylhydrazines, and one reductive compound, anilines. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c000383b

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Highly selective conversion of nitrobenzenes using a simple reducing
system combined with a trivalent indium salt and a hydrosilanew
Norio Sakai,* Kohji Fujii, Shinya Nabeshima, Reiko Ikeda and Takeo Konakahara
Received (in Cambridge, UK) 7th January 2010, Accepted 13th February 2010
First published as an Advance Article on the web 10th March 2010
DOI: 10.1039/c000383b
Controlling the type of indium salt and hydrosilane enables a
highly selective reduction of aromatic nitro compounds into three
coupling compounds, azoxybenzenes, azobenzenes and diphenyl-
hydrazines, and one reductive compound, anilines.
several experiments were performed to evaluate the solvent
effect. THF produced azoxybenzene (3a) in a nearly quanti-
tative yield (run 2). Also, when the reduction was conducted
with DMF, the hydrazine 5a was obtained as the sole product
in an excellent yield (run 3). Interestingly, addition of a small
amount of H2O to the reaction system accelerated the desired
reduction, and the reaction was completed within 5 h (run 4).
Unfortunately, the InBr3–Et3SiH system was ineffective for
the preparation of azobenzene (4a). The use of In(OTf)3 in
place of InBr3 allowed for the preparation of azobenzene (4a),
but the product selectivity was rather low (run 5). Thus, in the
first step, we attempted to produce the diphenylhydrazine
derivative 5a using the In(OTf)3–Et3SiH reducing system,
followed by oxidative conversion of the hydrazine into the
corresponding azobenzene 4a under atmosphere. We also
found that In(OTf)3 promoted dehydrogenation of hydrazo
derivatives under atmosphere (run 6).14 Unfortunately, the
reducing system that used either InBr3 or In(OTf)3 did not
selectively convert nitrobenzene (1a) into aniline (2a).
Most nitrogen-containing compounds such as anilines,
azoxybenzene compounds or azobenzene derivatives, are
important and central building blocks in naturally occurring
compounds and functional materials.1 In general the reduction
of nitrobenzenes with an appropriate reducing reagent is a
straightforward method for the direct synthesis of these highly
valuable compounds.2–4 Currently, general conversion of
either a nitro group into an amino group or the corresponding
coupling product is most often achieved either by treatment
with a reducing reagent, such as H2 gas,2b,2c,5 CO gas,2a,6
NH2NH2,7 or NaBH4,8 in the presence of a transition metal or
by reduction with a zerovalent metal, such as Bi,3d Cr,3e Fe,9
In,2f Mg,4a Sm,2e or Zn3a under acidic/basic/neutral conditions.
However, these conventional procedures generally require
excess amounts of a reducing metal, flammable gas and
reagents, and the use of high-pressure equipment. Conventional
methods that require the use of a strong reducing reagent
often produce undesirable byproducts. Moreover, selective
conversion of one aromatic nitro compound into more than
one reductive product by use of a single reducing system has
not been studied extensively.10 During the last decade several
groups have reported that a reducing system comprised of an
indium salt and a hydrosilane, which is a mild reducing agent,
is highly effective for the reductive conversion of functional
groups.11 Our ongoing studies on the reductive conversion of
functional groups12 have yielded unprecedented results.13 The
use of our simple reducing system resulted in the highly
selective conversion of nitrobenzenes into four different
reductive compounds, azoxybenzenes, azobenzenes, hydrazo-
benzenes and anilines. Herein we report the preliminary results
of these studies.
Using the optimal conditions, the synthesis of azoxybenzene
derivatives from a variety of nitrobenzenes was examined
(Table 2). For instance, when o-nitrotoluene was used as the
starting material, the reductive conversion was completed
within 20 h, producing the corresponding azoxybenzene
compound 3b in 82% yield. The steric hindrance of the
ortho methyl group was not effective for this reduction. We
encountered problems in the solubility of the starting
nitrobenzenes. Thus, the following reactions were carried out
in DMF instead of THF. Nitrobenzenes with a halogen atom
Table 1 Examination of reaction conditions
We initially investigated the reductive conversion of
nitrobenzene (1a) with InBr3 and Et3SiH (Table 1). Based on
our previous work, when the reduction was carried out under
CHCl3 reflux, most of the nitrobenzene was recovered and
four derivatives were formed: aniline (2a), azoxybenzene (3a),
azobenzene (4a) and hydrazobenzene (5a) (run 1). Thus,
Yield/%a
2a
3a
4a
5a
Run
Solv.
Si–H /Equiv.
1
2
3
CHCl3
THF
DMF
DMF
DMF
DMF
4
2.2
4
4
2.5
2.5
9
15
96
ND
ND
ND
—
2
10
ND
ND
ND
ND
—
Trace
ND
ND
64
Trace
94
95
29
—
4b
5c
6c,d
Department of Pure and Applied Chemistry, Faculty of Science and
Technology, Tokyo University of Science (RIKADAI), Noda, Chiba,
278-8510, Japan. E-mail: sakachem@rs.noda.tus.ac.jp;
Fax: +81-4 -7123-9890; Tel: +81-4-7122-1092
w Electronic supplementary information (ESI) available: Details of
experimental procedures and NMR spectra for prepared compounds.
See DOI: 10.1039/c000383b
(99)
a
b
NMR(Isolated) yield. Solvent: DMF–H2O = 95/5, Reaction time:
c
5 h. In(OTf)3 (5 mol%) was used. After the reduction, the resulting
d
mixture was stirred at 60 1C for 15 h under atmosphere.
ꢀc
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Table 2 Synthesis of azoxybenzene derivatives 3a
Table 4 Synthesis of diphenylhydrazine derivatives 5a
Entry
X
Time/h
Product
Yield/%
Entry
X
Time/h
Product
Yield/%
1
2
3
H
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
82
74
93
81
62
88
97
64
1
2
3
4
5
6
7
8
9
H
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
96
63b
41
82
72
81
78
81
64
2-Me
3-Me
4-Me
4-Cl
20
20
12
15
15
12
3
2-Me
3-Me
4-Me
4-Cl
15
15
15
8
4b
5b
6b
7b
8b
9b
4-Br
4-Br
8
4-CN
4-MeCO
4-MeCO2
4-CN
4-MeCO
4-MeCO2
20
20
20
12
a
b
a
b
InBr3 (5 mol%)/Et3SiH (2.2 equiv.) in THF at 60 1C. InBr3
(5 mol%)/Et3SiH (1.1 equiv.) in DMF at 60 1C.
InBr3 (5 mol%)/Et3SiH (4 equiv.) in DMF at 60 1C. 2-Methyl-
aniline was isolated in 22% yield.
instead of a cyano group were selectively and quantitatively
converted into the corresponding azoxybenzene derivatives
3d–i, if 1.1 equiv. of Et3SiH in DMF was used.15 In addition,
we found that this reducing reagent did not affect either an
acetyl group or an ester moiety.16
anions that form in situ, thus driving the reaction equilibrium
to completion.
The results shown above prompted us to examine the
selective preparation of aniline derivatives. After further
examination, we finally found a novel reducing system that
consisted of InI3 (5 mol%) and 2 equiv. (4 equiv. as Si-H) of
tetramethyldisiloxane (TMDS)18 in CHCl3 at room tempera-
ture, which successfully and selectively produced aniline (2a)
in quantitative yield.19 Moreover, when the reduction of
p-methylnitrobenzene (1d) was carried out under reductive
conditions, the desired p-toluidine (2d) was selectively
obtained in 82% yield (Scheme 1).
We next examined the synthesis of azobenzene derivatives
(Table 3). In the first step, we used the In(OTf)3–Et3SiH
reducing system to produce hydrazine 5. In the second step,
we successively and directly converted the hydrazine derivative
into the corresponding azobenzene 4 by oxidation under
atmosphere without isolation of the hydrazine. Most of the
nitrobenzene derivatives with a functional group, such as a
methyl group, halogen atom, cyano group, or ketone and ester
moiety, were successfully converted into the corresponding
azobenzene derivatives 4a–i in good yields.
It is noteworthy that this reducing method could be applied
to the direct preparation of unsymmetrical azobenzene
derivatives.1,20 After tuning the reaction conditions, we found
that when the DMF solution containing 3 equiv. of nitro-
benzene (1a) and 1 equiv. of p-chloronitrobenzene (1e) was
treated with 10 mol% of In(OTf)3 and an excess (10 equiv.) of
Et3SiH, the desired unsymmetrical azobenzene derivative 8
was directly obtained in a practical yield (Scheme 2). Although
the homo-coupling azobenzenes formed as by-products, silica
gel column purification enabled us to isolate the desired
unsymmetrical product from the mixture.
Then, when InBr3 and 4 equiv. of Et3SiH in DMF were
used, nitrobenzenes were successfully converted into the
corresponding diphenylhydrazine derivatives 5a–i (Table 4).
Unlike the preparation of azoxybenzenes and azobenzenes,
substitution at the ortho position had an effect on the product
ratio. When 2-nitrotoluene was used, 2-methylaniline was
isolated in 22% yield as a by-product. When 2-(phenylethynyl)-
nitrobenzene 6 was subjected to the standard conditions, no
hydrazine derivative was produced, but 2-(phenylethynyl)-
aniline 7 was obtained in 83% yield. As described in run
4 of Table 1, it is noteworthy that when 5 wt% of H2O was
added to the reaction system, the time required to complete the
reduction and produce a hydrazine derivative was markedly
reduced.17 This acceleration of the reaction rate might occur
because protic solvents are proton sources that trap the amide
To understand the reaction path, we performed several
control experiments. When nitrosobenzene was subjected to
our standard reaction conditions, which consisted of 5 mol%
of InBr3 and 3 equiv. of Et3SiH in DMF, the corresponding
diphenylhydrazine (5a) was isolated in 94% yield. Also, when
a Mills-type reaction of nitrosobenzene with p-chloroaniline
was examined in the absence of an indium salt and/or a
hydrosilane, no coupling products were obtained. Moreover,
the reaction of nitrobenzene with p-chloroaniline gave
diphenylhydrazine (5a) in 93% yield, and did not produce
the crossed hydrazine derivative. Thus, these results showed
that the combination of an indium salt and a hydrosilane was
essential, and that generation of a nitrosobenzene derivative,
Table 3 Synthesis of azobenzene derivatives 4a,b
Entry
X
Time/h
Product
Yield/%
1
2
3
4
5
6
7
8
9
H
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
99
62
78
72
70
80
74
92
95
2-Me
3-Me
4-Me
4-Cl
20
20
12
6
6
5
4-Br
4-CN
4-MeCO
4-MeCO2
12
5
a
b
In(OTf)3 (5 mol%)/Et3SiH (2.2 equiv.) in DMF at 60 1C. After the
first reduction, the resulting mixture was stirred at 60 1C for 15 h under
atmosphere.
Scheme 1 Reductive conversion to anilines.
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Scheme 2 Direct synthesis of an unsymmetrical azobenzene.
but not aniline, was required for the reductive coupling of
nitrobenzene derivatives. Also, formation of an aniline
derivative may proceed via direct reduction of nitrosobenzene,
and not by further reductive cleavage of a hydrazine.
In summary, we demonstrated that a reducing system
consisting of a trivalent indium salt and a hydrosilane
allowed the highly selective conversion of aromatic nitro
compounds into four derivatives. Azoxybenzenes [InBr3–Et3SiH
(1.1–2.2 equiv.) in THF or DMF], azobenzenes [In(OTf)3–Et3SiH
(2.5 equiv.) in DMF–oxidation step], diphenylhydrazines
[InBr3–Et3SiH (4 equiv.) in DMF] and anilines [InI3–(Me2SiH)2O
(2 equiv.) in CHCl3] were produced by controlling the type of
trivalent indium salt, hydrosilane and solvent, and the number
of hydrosilane equivalents used in the reaction. We also found
that this reducing system allowed for the direct preparation of
an unsymmetrical azobenzene.
9 M. E. Krolski, A. F. Renaldo, D. E. Rudisill and J. K. Stille,
J. Org. Chem., 1988, 53, 1170.
The authors are very grateful to Shin-Etsu Chemical Co.,
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program supported by MEXT for a financial support.
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decrease in the amount of a hydrosilane.
16 In this system, the nitro compounds containing a OH or SH group
did not produce a complex mixture.
17 Addition of 5 wt% of MeOH also showed a similar effect.
However, addition of MS4A was ineffective for the reaction.
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Chem. Commun., 2010, 46, 3173–3175 | 3175