Indium powder as the reducing agent in the synthesis of 2-amino-1,1′-biphenyls

Article abstract of DOI:10.1016/j.tetlet.2016.02.007

An improved and simplified In-based protocol for the reduction of 2-nitro-1,1′-biphenyls to the corresponding 2-amino-1,1′-biphenyls is disclosed. The method utilizes only a stoichiometric quantity of indium powder as the reducing reagent along with a stoichiometric quantity of ammonium chloride. The work-up is very simple, it requires only a simple filtration of the post-reaction mixture whereupon the reaction medium is removed under reduced pressure. The method was also proven to operate with a variety of functional groups to provide high to excellent yields of the target 2-amino-1,1′-biphenyls. A proposal for a reaction mechanism is also provided.

Full text of DOI:10.1016/j.tetlet.2016.02.007

Tetrahedron Letters 57 (2016) 1224–1226
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium powder as the reducing agent in the synthesis
of 2-amino-1,10-biphenyls
⇑
Vijayaragavan Elumalai, Hans-René Bjørsvik
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
a r t i c l e i n f o
a b s t r a c t
An improved and simplified In-based protocol for the reduction of 2-nitro-1,10-biphenyls to the corre-
sponding 2-amino-1,10-biphenyls is disclosed. The method utilizes only a stoichiometric quantity of
indium powder as the reducing reagent along with a stoichiometric quantity of ammonium chloride.
The work-up is very simple, it requires only a simple filtration of the post-reaction mixture whereupon
the reaction medium is removed under reduced pressure. The method was also proven to operate with a
variety of functional groups to provide high to excellent yields of the target 2-amino-1,10-biphenyls. A
proposal for a reaction mechanism is also provided.
Article history:
Received 27 November 2015
Revised 28 January 2016
Accepted 2 February 2016
Available online 3 February 2016
Keywords:
Indium
2-Nitro-1,10-biphenyl
2-Amino-1,10-biphenyl
Reduction
Ó 2016 Elsevier Ltd. All rights reserved.
Sealed tube
HO
2
OH
Introduction
I
B
R1
R2
NO2
NO2
Suzuki
Reduction
R2
R1
+
R
For a project dedicated to the synthesis of the 1H-carbazole
scaffold, we have previously disclosed a highly efficient method
for the synthesis of 2-nitro-1,10-biphenyls by means of the Suzuki
cross coupling reaction (Scheme 1).1 For the subsequent step,
which encompasses reduction of the 2-nitro-1,10-biphenyl inter-
mediate to the corresponding 2-amino-1,10-biphenyl, we were
searching for a reliable, simple, and efficient reduction method.
To approach the target 1H-carbazole frameworks, we planned to
use the combined C–H functionalization and C–N bond formation
as disclosed by Buchwald and collaborators,2 or the newly reported
iridium(III) catalyzed intramolecular C–H amination method by
Miura and collaborator.3
Numerous methods exist for the Ph—NO2 ? Ph—NH2 transfor-
mation, including catalytic hydrogenation with Pd/C4 or Raney
nickel,5 Pd catalyzed reduction using silicon hydride as the reduc-
ing agent,6 and the Bechamp reduction that involves treatment of
the nitroaromatic with iron and hydrochloric acid.7
H
R1
R2
NH2
N
R1
C-H / C-N bond
functionalization
Scheme 1. Outline for the synthesis of 2-amino-1,10-biphenyls,8 a key intermediate
for the synthesis of 1H-carbazoles.
Results and discussion
In order to utilize the Moody method,14 a highly diluted sub-
strate mixture in ethanol should be treated with a large excess of
indium powder and a saturated solution of aqueous ammonium
chloride for a long reaction time, up to 72 h. We began to investi-
gate this method with our substrate 2-nitro-1,10-biphenyl, trials
that proved to function perfectly well. Chromatographic analysis
of the post-reaction mixture revealed full conversion of the sub-
strate to the desired 2-amino-1,10-biphenyl (Scheme 2, entry 1).
However, the subsequent workup procedure required several steps
including filtration, pH adjustment, extraction, solvent removal,
and finally column chromatography, which only provided a low
isolated yield (41%) of our target 2-amino-1,10-biphenyl.
It turned out that the work-up procedure resulted in decompo-
sition or other loss of the target reduction product and in some
occasions we also observed ring closure to give the 1H-carbazole
frameworks, but only in small quantities. Although, with consider-
able challenges to implement this reduction method, we found
Additionally, protocols encompassing either SnCl2,9 TiCl3,10 Zn,11
Sm,12 or sodium dithionite (Na2S2O4)13 as reducing agents consti-
tute functioning methods developed for the nitroarene to aniline
transformation. A method disclosed by Moody and collaborators14
attracted our attention due to its simplicity involving the treatment
of nitroarene with elemental In in an ammonium chloride solution.
⇑
Corresponding author. Tel.: +47 55 58 34 52; fax: +47 55 58 94 90.
E-mail address: hans.bjorsvik@kj.uib.no (H.-R. Bjørsvik).
http://dx.doi.org/10.1016/j.tetlet.2016.02.007
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

V. Elumalai, H.-R. Bjørsvik / Tetrahedron Letters 57 (2016) 1224–1226
1225
In, t, reflux (78 oC)
Table 1
aq. sat. NH4Cl (3 mL)
Introductory exploration of an improved procedure for the reduction of 2-nitro-1,10-
biphenyl to 2-amino-1,10-biphenyl
EtOH (10 mL)
NO2
Entry
1
2
3
4
NH2
Yield (%)a
In [equiv.] t [min.]
R1
R2
R1
R2
quant.
7
90
3.5
2
90
quant.
87
In (2 equiv.), 3 h, Reflux (78 oC)
aq. sat NH4Cl, EtOH
90
quant.
2
150
a Yield based on GC
NH2
NO2
Scheme 2. Indium reduction of 2-nitro-1,10-biphenyls to 2-amino-1,10-biphenyls.
Entry
1
2-Nitrobiphenyl
2-Aminobiphenyl
Yielda (%)
100 (51)
H3C
H3C
O
O
that it looked attractive due to its simplicity, which spurred us to
explore, adapt, and simplify the Moody method for our amino-
biphenyl application.
NO2
NH2
To the best of our knowledge, the In reduction method has not
been thoroughly investigated from a mechanistic point of view.
Nevertheless, for us it was reasonable to draw a parallel to the
Zn powder reduction method, which would require two or three
equivalents of In for each nitro group depending on the final oxida-
tion state of the oxidized indium.
H3CO
O
H3CO
O
2
3
4
100 (61)
100 (42)
100 (35)
NO2
NH2
Cl
Cl
NO2
NH2
Therefore, we reduced the amount of indium, 7 ? 3.5 equiv, an
alteration that still provided quantitative yields (measured with
GC) of the 2-amino-biphenyl. Further lowering the quantity of In
to only 2 equiv afforded a yield of 87% (GC). This experiment was
repeated with prolonged reaction time, 150 min (Scheme 2, entry
4), which successfully provided the target molecule in quantitative
yields (GC). The achieved results suggested a mechanism where In
ends up at an oxidation state of +3, see our proposal for a mecha-
nism in Scheme 3. During this experimentation we also observed
that the particle size of the indium powder was important in rela-
tion to the reaction rate and overall performance of the reaction.
For the reduction experiments, we utilized a freshly opened con-
tainer of indium powder (100 mesh, 99.99%) to achieve a quantita-
tive conversion in almost all trials. However, the reactivity of the
indium as a reductant was observed to be impaired even at few
days of storage when stored under a normal atmosphere at room
temperature, which we believe is due to surface oxidation.
A scope and limitation of the reduction method was evaluated
by means of a small library of various substituted 2-nitro-1,10-
biphenyls (Table 1). Unfortunately, the hitherto developed method
was revealed to operate in low to medium yields only.
These results (Table 1) encouraged us to further explore the
experimental variables with the goal to improve the outcome.
The reaction temperature was raised (78?120 °C) and for this pur-
pose the reaction was conducted in a sealed tube reactor. The sol-
vent (EtOH) volume was lowered (10?4 mL) and a lowered
quantity of ammonium chloride was utilized [16 mmol
(0.85 g)15 ? 1.03 mmol (0.055 g)]. These conditions were explored
with a library composed of fifteen 2-nitro-1,10-biphenyls (Table 2).
The results show that the method provides high to excellent yields
in all cases and displays a good functional group tolerance. The
achieved results also suggest that the developed method is consis-
tent with the proposed mechanism resulting in an oxidation of In
to In+2 and thus requiring 3 equiv of elemental In.
H3CO
H3CO
NH2
H3C
H3C
O
NO2
O
5
6
100 (45)b
100 (48)b
NO2
NH2
NH2
O
O
Cl
Cl
NO2
a
Yield based on GC (isolated yield after column chromatography).
Additional In powder (2 equiv) and aq satd NH4CI (3 mL) was added after 3 h in
an attempt to attain higher conversion and yield.
b
Table 2
Exploration of the scope and limitation of the In promoted reduction of 2-nitro-1,10-
biphenyl to 2-amino-1,10-biphenyl8
R1
R2
R1
R2
In (3 equiv.), 3 h, 120 o
C
aq. NH4Cl (1.03 mmol mL-1
EtOH, sealed tube
)
NO2
NH2
Entry 2-Nitro-biphenyl
2-Amino-biphenyl
Yielda (%)
91
1
NO2
NH2
HOOC
HOOC
2
75
95
NO2
NH2
3
NO2
NH2
NH2
SET
In
SET
O
O
O
O
O
OH
O
OH
O
OH
H
In
N
R
N
R
N
R
N
R
4
69b
92
In2
In
H
NO2
H2O
SET
In
SET
H
O
H
O
OH
OH
H
O
O
In
H
N
R
N
R
N
R
N
R
5
In2
In
NO2
NH2
O
H
O
H
SET
In
SET
In
In2
H
94b
H
H
OH
H
OH
H
H
6
H
H
N
R
N
R
N
R
N
R
NO2
NH2
In + H2O
(continued on next page)
Scheme 3. Mechanism proposal for the In promoted reduction of the Ar-NO2 group.

1226
V. Elumalai, H.-R. Bjørsvik / Tetrahedron Letters 57 (2016) 1224–1226
the reaction medium was revealed to be necessary. The lowered
Table 2 (continued)
reduction reagent loading gives rise to a simple work-up, namely
only filtration of the post reaction mixture followed by evaporation
of the solvent. This is in contrast to previous methods, which
required column chromatography for purification of the reaction
product. Furthermore, the method displays a high functional group
tolerance to provide high to excellent yields, demonstrated with a
series of 2-nitro-1,10-biphenyls. A proposal for a reaction mecha-
nism is described based on analogy with the Zn reduction and
experimental observations, namely the required quantities of the
elemental In as reduction reagent.
Entry
2-Nitro-biphenyl
2-Amino-biphenyl
Yielda (%)
92
N
N
7
NO2
NH2
8
9
92
91
NO2
NH2
H3CO
H3CO
NO2
NH2
H3CO
Acknowledgment
H3CO
Cl
Cl
10
11
96
95
V.E. gratefully acknowledges the Department of Chemistry at
the University of Bergen – Norway for funding his research fellow-
ships. Dr. Bjarte Holmelid is acknowledged for excellent technical
support with the HRMS analyses.
NO2
NO2
NH2
H3CO
H3CO
NH2
Cl
Cl
Supplementary data
12
13
95
90
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
007.
NO2
NH2
H3C
H3C
O
O
O
References and notes
NH2
NO2
Cl
Cl
1. González, R. R.; Liguori, L.; Carrillo, A. M.; Bjørsvik, H.-R. J. Org. Chem. 2005, 70,
9591–9594.
2. Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560–
14561.
3. Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2015, 17, 1597–1600.
4. Bavin, P. M. G. Org. Synth. 1973, Coll. Vol. 5, 30.
14
15
88
94
NO2
NH2
O
Cl
Cl
5. Allen, C. F. H.; VanAllan, J. Org. Synth 1955, Coll. Vol. 3, 63.
6. Rahaim, R. J.; Maleczka, R. E. Org. Lett. 2005, 7, 5087–5090.
7. Fox, B. A.; Threlfall, T. L. Org. Synth. 1973, Coll. Vol. 5, 346.
8. General procedure: 2-Nitrobiphenyl (1 mmol, 0.2 g) was dissolved in EtOH
(4 mL) and transferred to a tube reactor. Then, a mixture of NH4Cl (2 mmol,
0.107 g) in H2O (1.2 mL) and indium powder (3 mmol, 0.344 g, 99.99%
100 mesh, use preferably a freshly opened bottle or stored under Ar) were
added whereupon a magnetic stirrer bar was transferred to the tube. The tube
was then sealed and the reaction mixture was stirred and heated at 120 °C for
3 h. The reaction mixture was cooled to room temperature and diluted with
ethyl acetate (30 mL). The resulting mixture was filtered through a pad of celite
to remove the catalyst. Another portion (20 mL) of ethyl acetate was used to
wash through the filter pad. The resulting transparent organic phase was dried
over Na2SO4, filtered and the solvent was removed under reduced pressure
using a rotary evaporator to obtain the target compound.
9. (a) Albert, A.; Linnel, W. H. J. Chem. Soc. 1936, 1614; (b) Bellamy, F. D.; Ou, K.
Tetrahedron Lett. 1984, 25, 839–842.
10. Somei, M.; Kato, K.; Inoue, S. Chem. Pharm. Bull. 1980, 28, 2515–2518.
11. Raju, B.; Ragul, R.; Sivasankar, B. N. Indian J. Chem. 2009, 48, 1315–1318.
12. Basu, M. K. Tetrahedron Lett. 2000, 41, 5603–5606.
13. Redemann, C. T.; Redemann, C. E. Org. Synth. 1955, Coll. Vol. 3, 69.
14. (a) Moody, C. J.; Pitts, M. Synlett 1988, 1028; (b) Pitts, M. R.; Harrison, J. R.;
Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2001, 955–977.
15. The Merck Index, 12th ed.; Merck & Co.: Whitehouse Station, NJ, USA, 1996.
Monograph number 537, p 89. Ammonium chloride solubility in water: 28.3
w/w-% (0.283 g mL3) at 25 °C.
NO2
NH2
a
Isolated yield.
b
Product was not isolated, measured by GC.
Advantages of the improved indium reduction method com-
prise a considerably simplified work-up and high purity of target
product. When the reduction was completed at 3 h, ethyl acetate
was added to the post reaction mixture and the solid inorganics
could be filtered off. The resulting filtrate was dried over Na2SO4
and the solvent was removed under reduced pressure using a
rotary evaporator. The target 2-amino-1,1-biphenyls were isolated
in yields in the range of 69–96%.
Conclusions
In conclusion, we have explored and improved a method suit-
able for the preparation of 2-amino-1,10-biphenyls by reduction
of the corresponding 2-nitro-1,10-biphenyls.
A
stoichiometric
quantity of indium powder (3 In: 1 substrate) with ethanol as