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M. L. Di Gioia et al. / Tetrahedron Letters 56 (2015) 5341–5344
Table 1
Results of reduction of substituted nitrobenzenes with the reducing system LiAlH4/
TiCl4 in molar ratio 5:1
NO2
N
OH
2
2
Entry R1
R2
R3
Yielda
(%)
2
Yielda
(%)
3
Reaction
time
a
b
c
d
e
f
g
h
i
SO2NEt2
H
H
F
Cl
Br
H
CH3
OCH3
H
H
H
92
89
—
—
—
—
—
—
25
28
20
15 min
25 min
25 min
45 min
45 min
45 min
15 h
SO2NEt2
H
H
H
H
H
H
H
SO2NEt2 90
H
H
H
H
H
H
98
91
94
48
45
43
HO
N
N
N
N
OH
26 h
29 h
Scheme 1. Probable formation mechanism of azo compounds.
a
Isolated yield.
tetrahydrofuran (THF). The reaction mixture was kept stirring at
room temperature for 48 h. After this time the starting
N,N-diethyl-4-nitrobenzensulfonamide was recovered unchanged.
The formation of reduction products was not even observed with
the substrates 1-chloro-4-nitrobenzene (1e), nitrobenzene (1g),
and 1-methoxy-4-nitrobenzene (1i) when they were treated under
the same reaction conditions of 1a. Even the reducing system,
prepared by using LiAlH4 and TiCl4 in the molar ratio 2:1, was
not effective in reducing the same substrates (1a, 1e, 1g, and 1i).
After several attempts, a reducing system able to reduce effi-
ciently nitro aromatic derivatives to amines has been found. It
was prepared by adding LiAlH4 (5 mmol) to a stirred suspension
of TiCl4 (1 mmol) in diethyl ether. The reaction mixture was stirred
at room temperature for 15 min. As a result of filtration the
obtained black suspension was recovered as a black solid which,
when it is dry, burns mildly in air and reacts with water with
moderate and constant evolution of hydrogen.
The so prepared reagent system was tested to reduce
N,N-diethyl-4-nitrobenzensulfonamide (1a) chosen as a model
substrate. In a typical experiment 1a (1 mmol), was added slowly
to the obtained black reducing suspension in diethyl ether.14 The
reaction was completed in 15 min and, after work up of the reac-
tion mixture, 4-amino-N,N-diethylbenzenesulfonamide (2a) was
recovered in 92% yield (Scheme 2, Table 1). Also 3-amino-N,N-
diethylbenzenesulfonamide (1b) and 2-amino-N,N-diethylben-
zenesulfonamide (1c), treated under the same reaction conditions
of 1a, afforded the corresponding amines 2b and 2c in high yields
(Scheme 2, Table 1). In all cases the reduction reaction provided, at
room temperature and within very short reaction times, the
corresponding amines as unique reaction products.
provided the corresponding aniline derivatives 2d–f in excellent
yields (Scheme 2, Table 1). All the recovered products did not
require further purification and their structures were assigned
based on 1H and 13C NMR spectra.
On the contrary the reaction of nitrobenzene (1g) with the same
reducing system went to completion in 15 h at room temperature
as detected by TLC. After this time, aniline (2g, 48% yield), 1,2-
diphenyldiazene (3g, 25% yield), and benzidine (6, 5% yield) were
recovered after short column chromatography (diethyl ether/pet-
roleum ether 60:40 v/v). Long reaction times were also required
for the reduction of 1-methyl-4-nitrobenzene (1h), that, after
26 h, afforded p-toluidine (2h, 45% yield), 4,40-dimethylazoben-
zene (3h, 28% yield).
The treatment of 1-methoxy-4-nitrobenzene (1i) provided, after
29 h and separation of the reaction mixture by short column chro-
matography (diethyl ether/petroleum ether, 60:40 v/v),
4-methoxyaniline (2i, 43% yield) and 1,2-bis(4-methoxyphenyl)
diazene (3i, 20% yield).
The reduction of nitrobenzenes 1h–i, bearing electron-donor
substituents in the 4-position, gave a mixture of azobenzene and
aniline derivatives and reaction times became significantly longer
(Scheme 2, Table 1).
Additional experiments were performed in order to explore the
reaction progress for the synthesis of aromatic amino compounds
under modified reaction conditions. Nitrobenzene (1g, 1 mmol),
1-methyl-4-nitrobenzene (1h, 1 mmol) and 1-methoxy-4-
nitrobenzene (1i, 1 mmol) were treated with a different reducing
system prepared by adding LiAlH4 (10 mmol) to a suspension of
TiCl4 (1 mmol) in diethyl ether at room temperature.
The reaction went to completion after about 30 min of stirring,
then a NaOH aqueous solution was added and the phases were sep-
arated. The resulting organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated to dryness under reduced pres-
sure to give the corresponding substituted anilines 2g–i in very
high yields (86–90%) (Scheme 3, Table 2), reaction by-products
were not observed.
1,4-Dinitrobenzene (4) was also particularly reactive in fact, in
just 15 min was reduced into the corresponding diamine, 1,4-
phenylenediamine (5), in quantitative yield (98%). Subsequently
we investigated the reaction of nitrobenzenes substituted
with electron-withdrawing groups using the above optimized
conditions. The reduction of halogen substituted nitrobenzenes
proceeded without dehalogenation. The reduction of 1-fluoro-4-
nitrobenzene (1d), 1-chloro-4-nitrobenzene (1e), and 1-bromo-4-
nitrobenzene (1f), was, in all cases, completed in 45 min and
The results of reduction reactions of substrates 1g–i suggested
that azobenzenes could be key intermediates of the reduction
process. In order to gain a better understanding of the reduction
R1
R1
R2
R3
R2
R3
LiAlH4
TiCl4
NH2
2 g-i
NO2
1 g-i
Scheme 2. Reduction of substituted nitrobenzenes with the reducing system
Scheme 3. Reduction of nitrobenzene and nitrobenzenes bearing electron donor
LiAlH4/TiCl4 in molar ratio 5:1.
substituents with the reducing system LiAlH4/TiCl4 in molar ratio 10:1.