An efficient reduction of nitro and bromine naphthalene derivatives

Article abstract of DOI:10.1134/S1070363217040272

Reduction of 1,5-dimethoxy-4-nitronaphthalene by hydrazine hydrate was optimized in the course of current study. Influence of metals, temperature and solvents upon the process was tested. Yield of the reaction was the highest in the presence of Zn powder in DMF. Moderate heating made the process slightly more efficient than that at room temperature, whereas high temperature led to a decreased yield. The current approach made it possible to exclude high pressure and diminish experimental costs.

Full text of DOI:10.1134/S1070363217040272

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 4, pp. 837–841. © Pleiades Publishing, Ltd., 2017.
An Efficient Reduction of Nitro
and Bromine Naphthalene Derivatives1
J. Dong, Q. Zhang, G. Huang, Q. Meng*, and S. Li**
School of Pharmacy, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240 China
*e-mail: qqmeng@sjtu.edu.cn; **ssli@sjtu.edu.cn
Received January 11, 2017
Abstract—Reduction of 1,5-dimethoxy-4-nitronaphthalene by hydrazine hydrate was optimized in the course
of current study. Influence of metals, temperature and solvents upon the process was tested. Yield of the
reaction was the highest in the presence of Zn powder in DMF. Moderate heating made the process slightly
more efficient than that at room temperature, whereas high temperature led to a decreased yield. The current
approach made it possible to exclude high pressure and diminish experimental costs.
Keywords: nitro naphthalenes, reduction, naphthylamines, hydrazine hydrate, zinc powder
DOI: 10.1134/S1070363217040272
INTRODUCTION
that led to yields of 57% and 39% respectively [12].
Such low efficiency of the process stimulated our
search for a more efficient method. Hydrazine hydrate
is a conventional powerful reducing agent that can
react with nitro compounds in the presence of Pd or Ni
to give the corresponding amino compounds [11, 12].
The current study was carried out with various metal
reducing agents, solvents and temperatures pursuing
low cost and high efficiency. Reduction of compound
1 was carried out with a variety of activated powdered
metals, Mg, Al, Zn, Fe, and Sn, in MeOH at ambient
temperature. SnCl2 and CuCl were also tested in the
process (see the table). Zn powder demonstrated the
highest efficiency (yield 84%). No target compounds
were detected among the products formed in the
presence of Sn, Cu and CuCl powders or hydrazine
hydrate at room temperature. Al, Mg and Fe powders
exhibited the activity similar to that of Pd/C–H2
leading to 4,8-dimethoxy-1-naphthylamine with the
yields of 52, 61, and 63%, respectively. Interestingly,
all of the studied metals, except SnCl2, demonstrated
no significant difference in affecting the reaction time
at room temperature. The process was monitored by
TLC that indicated no by-products formation upon
prolonged the reaction time. Though SnCl2 could
shorten reaction time with the yield of 71%, the
following work-up was complicated because of poor
solubility of SnCl2 in water and generation of by-
products. The reaction with NH2–NH2/Zn at ambient
temperature (entries 11–14) proceeded smoothly in
MeOH, DCM, THF, or DMF with substantial yields.
The highest yield (94%) was achieved in DMF. Upon
Naphthylamines are valuable building blocks and
act as intermediates in synthesis of various pharma-
ceuticals. For example, N-aryl-naphthylamines inter-
fere the interaction between HIV integrase and the
cofactor LEDGF/p75 [1]. As potent antiaggregating
βA agents, N-arylnaphthylamines were used in treating
the Alzheimer disease and other neurological diseases
caused by deposits of amyloid aggregates [2]. Naph-
thylamines are widely used in preparation of fluore-
scent probes [3, 4]. Reduction of nitro compounds was
considered to be one of the prevailing approaches
to amines. In most cases reduction of nitro compounds
involves high pressure catalytic hydrogenation in the
presence of a metal in acidic aqueous or organic media
[5]. Palladium, platinum,and rhodium complexes [6–9]
are used as catalysts. Naphthylamines are usually
obtained by reduction of the corresponding nitro-
naphthalenes in the presence of H2 and Pd or Pb and
hydrochloric acid. Such approaches are characterized
by some limitations including high pressure, application
of extensive palladium catalysts, health risks [3], com-
plicated work up, and some more. In the current study
we present an efficient method of preparing naphthyl-
amines by using hydrazine hydrate in the presence of
metals under optimized temperature and media.
RESULTS AND DISCUSSION
Reduction of 1,5-dimethoxy-4-nitronaphthalene 1
by H2 with Pd or Sn was used as the model processes
1 The text was submitted by the authors in English.
837

838
DONG et al.
Reduction of 1,5-dimethoxy-4-nitronaphthalene under various reaction conditions
O
NO2
O
NH2
NH2−NH2/metal
solvent
O
O
1
2
Entry no.
Reducing agent
Pd/C–H2
Solvent
T, °C
Time, h
12
3
Yield, %a
1
MeOH
HCl–MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
Room temperature
Reflux
57
39
0
2
Sn
3
NH2–NH2
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
50
24
30
30
24
24
1
4
NH2–NH2/Al
NH2–NH2/Mg
NH2–NH2/Fe
NH2–NH2/Sn
NH2–NH2/SnCl2
NH2–NH2/Cu
NH2–NH2/CuCl
NH2–NH2/Zn
NH2–NH2/Zn
NH2–NH2/Zn
NH2–NH2/Zn
NH2–NH2/Zn
NH2–NH2/Zn
52
61
63
0
5
6
7
8
71
0
9
24
24
36
16
36
36
12
8
10
11
12
13
14
15
16
0
84
72
54
90
91
76
THF
DMF
DMF
DMF
100
a Isolated yields.
completion of the process Zn powder was filtered off
and a pale white crude product 2 could be used as a
reactant directly without further purification. Heating
of the reaction mixture at 50°C made the process
slightly more efficient than that at room temperature
(yields of 91% and 90%, respectively), and high
temperature (100°C) led to decreased yield (76%).
compounds 5 and 8 were synthesized by addition of
the corresponding amounts of NBS. Aldehyde 10 was
prepared on the basis of our earlier study [13]. Dinitro
compound 3 could be efficiently reduced under the
optimized conditions into 4,8-dimethoxynaphthalene-
1,5-diamine 4 with high yield (87%) without any 4,8-
dimethoxy-5-nitronaphthalen-1-amine formed. Under
similar conditions the compound 6 gave the product of
its debromination 2 (83%) instead of the expected
compound 7. Tendency to debromination was tested
also with intermediates 5 and 8. The product 12 was
obtained in high yield via reducing both compounds.
Such result suggested a promising method of
dehalogenation in organic synthesis. Reduction of
compound 10 induced by NH2–NH2/Zn proceeded
over longer period of time and led to the corresponding
product 11 (yield 71%). In general, the reducing
system under study could be used with various
compounds, though with some limitations. The
probable mechanisms of reduction of nitro and
Based on the preliminary data, NH2–NH2/Zn
induced reduction of 1,5-dimethoxy-4,8-dinitronaph-
thalene 3, 1-bromo-4,8-dimethoxy-5-nitronaphthalene 6
and 1,4,5,8-tetramethoxy-2-naphthaldehyde 10 in DMF
at 50°C was subsequently carried out for determining
the scope and limitations of the reducing system. 1,5-
Dimethoxynaphthalene 12 served as the key inter-
mediate in the synthesis (Scheme 1) which was easily
prepared from 1,5-dihydroxynaphthalene 13 by the
process of methylation. Formation of mononitro or
dinitro derivatives 1 and 3 could be controlled by the
amount of nitric acid. Similarly, bromine containing
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017

AN EFFICIENT REDUCTION OF NITRO AND BROMINE NAPHTHALENE DERIVATIVES
839
Scheme 1.
O
NO2
O
NO2
O
NH2
O
NH2
b
e
OR
OR
O
NO2
O
O
NH2
O
e
4
1
3
2
O
O
NO2
O
OH
O
NH2
No reaction
occured
e
c
d
a
Br
O
Br
O
O
OH
Br
O
6
5
12
13
7
e
O
O
O
O
O
O
O
O
O
Br
OHC
CH2OH
e
c
g
f
O
O
O
O
Br
O
10
11
8
9
a: (CH3)2SO4, NaOH, THF–H2O, 0°C; b: HNO3, HOAc, room temperature; c: NBS, CH3CN, room temperature; d: HNO3,
HOAc, 0°C; e: NH2-NH2/Zn, DMF, 50°C; f: CH3ONa, DMF–CH3OH, reflux; g: POCl3, DMF, DCM, reflux.
bromine compounds as well as aldehydes is presented
in Scheme 2.
naphthalene (3.76 g, 20 mmol) in acetic acid (50 mL)
at room temperature. Upon stirring overnight at
ambient temperature, the precipitate was filtered off
and washed with water. The crude product was
recrystallized from methanol and dried. Light yellow
EXPERIMENTAL
Chemicals and solvents were purchased from
commercial suppliers. All anhydrous solvents were
purified and dried according to standard methods.
NMR spectra were measured on a Varian Mercury-300
(400 MHz) spectrometer in DMSO-d6 using TMS as
the standard. Reactions progress was monitored by
TLC (silica gel GF254) and visualized with UV light
(254 nm). Some products were purified by flash
chromatography (silica gel 100-200 mesh). Metal
powders were activated by pretreating with HCl (1M)
and washing with water and ether thoroughly.
1
solid, yield 85%. H NMR spectrum, δ, ppm: 3.92 s
(3H), 4.03 s (3H), 6.74 d (J = 8.3 Hz, 1H), 7.01 d (J =
7.8 Hz, 1H), 7.44–7.53 m (2H), 7.90 d (J = 8.5 Hz,
1H). 13C NMR spectrum, δ, ppm: 56.03, 56.06, 102.24,
108.31, 114.68, 117.16, 121.65, 127.15, 127.21,
141.18, 153.64, 157.04.
4,8-Dimethoxy-1-naphthylamine (2). To a stirred
suspension of 1,5-dimethoxy-4-nitronaphthalene (1.2 g,
5 mmol) and activated Zn powder (1.3 g, 20 mmol) in
DMF (20 mL) was added 85% hydrazine hydrate
(1.2 g, 20 mmol) at 50°C under the atmosphere of N2.
Upon completion of the reaction (TLC), Zn powder
was filtered off and the filtrate was poured into ice
1,5-Dimethoxy-4-nitronaphthalene (1). 70%
Nitric acid (1.5 mL) in acetic acid (1.5 mL) was added
slowly to a stirred suspension of 1,5-dimethoxy-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017

840
DONG et al.
Scheme 2. Plausible mechanisms for reduction of nitro, bromine and formyl derivatives by NH2–NH2/Zn.
Zn NH
O
N
H
O
N
O
N
H
+ H Zn
NHNH2
+
Zn
N H
HN NH
+
R
OH
R
O
R
O
R
H
−H2O
Zn NH
N
O
H
Zn
+
HN NH
NHNH2
+ R N OH
H Zn
R N O +
N
H
H
H
NHNH2
H Zn
−H2O
R N
H
Zn NH
N
R NH + Zn +
HN NH
2
H
H
H
R
R
Zn
H
Zn NHNH2
+
+
+ BrH
+ Zn
H
HN NH
R
Br
H
Br
NH
N
H
Zn NH
N
O
O
R
CH OH
+
+ Zn
HN NH
H
2
+
H
Zn
NHNH2
R
H
R
H
H
H
R = alkyl or aryl.
water (500 mL). The crude product was precipitated,
filtered off and purified by column chromatography on
silica gel. White solid, yield 91%. H NMR spectrum,
δ, ppm: 3.81 s (3H), 3.90 s (3H), 5.68 s (2H), 6.48 d
(J = 8.3 Hz, 1H), 6.76 d (J = 8.3 Hz, 1H), 6.82 d (J =
7.7 Hz, 1H), 7.27 t (J = 8.1 Hz, 1H), 7.59 d (J =
8.5 Hz, 1H). 13C NMR spectrum, δ, ppm: 56.03, 56.16,
104.81, 107.60, 107.89, 114.46, 115.20, 125.56, 127.92,
139.83, 145.44, 157.85.
8.01 d (J = 8.5 Hz, 2H). 13C NMR spectrum, δ, ppm:
57.45, 107.87, 116.85, 124.51, 140.69, 155.01.
1
4,8-Dimethoxynaphthalene-1,5-diamine (4). To a
stirred suspension of 1,5-dimethoxy-4,8-dinitronaph-
thalene (1.4 g, 5 mmol) and activated Zn powder
(1.3 g, 20 mmol) in DMF (20 mL) was added 85%
hydrazine hydrate (1.2 g, 20 mmol) at 50°C under the
atmosphere of N2. The following procedure was
carried out the same way as presented above for the
product 2. Yield 87%. 1H NMR spectrum, δ, ppm: 3.71
s (6H), 5.61 s (4H), 6.36 d (J = 8.4 Hz, 2H), 6.60 d
(J = 8.4 Hz, 2H). 13C NMR spectrum, δ, ppm: 57.21,
108.33, 108.41, 117.15, 140.21, 148.33.
1,5-Dimethoxy-4,8-dinitronaphthalene (3). 70%
Nitric acid (4.5 mL) in acetic acid (4.5 mL) was added
slowly to a stirred suspension of 1,5-dimethoxy-
naphthalene (3.76 g, 20 mmol) in acetic acid (50 mL)
at room temperature. Upon stirring overnight at am-
bient temperature, the precipitate was filtered off,
washed with water, recrystallized from methanol, and
dried. Light yellow solid, yield 82%. 1H NMR
spectrum, δ, ppm: 3.91 s (6H), 7.31 d (J = 8.5 Hz, 2H),
1-Bromo-4,8-dimethoxynaphthalene (5). To a sus-
pension of 1,5-dimethoxy-naphthalene (3.76 g, 20 mmol)
in acetonitrile (50 mL) was added NBS (3.9 g,
22 mmol) at room temperature. Upon stirring for 2 h,
the precipitate was filtered off and washed with
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AN EFFICIENT REDUCTION OF NITRO AND BROMINE NAPHTHALENE DERIVATIVES
841
acetonitrile thus giving the crude product which was
recrystallized from methanol and dried. Cyan-blue
solid, yield 88%. H NMR spectrum, δ, ppm: 3.85 s
(3H), 3.90 s (3H), 6.74–7.13 m (2H), 7.29-7.48 m
(1H), 7.54–7.87 m (2H). 13C NMR spectrum, δ, ppm:
55.51, 55.72, 105.05, 107.99, 108.26, 114.92, 125.94,
128.76, 132.23, 133.67, 154.69, 155.48.
ACKNOWLEDGMENTS
The study was supported by Shanghai Science and
Technology Innovation Program (no. 15431900700),
Shanghai Natural Science Fund (no. 16ZR1418100)
and China Postdoctoral Science Foundation (no.
2014M561479).
1
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1-Bromo-4,8-dimethoxy-5-nitronaphthalene (6).
70% Nitric acid (1.5 mL) in acetic acid (1.5 mL) was
added slowly to a stirred suspension of 1-bromo-4,8-
dimethoxynaphthalene (5.3 g, 20 mmol) in acetic acid
(50 mL) and the mixture was stirred for at 0°C. Upon
completion of the process (TLC) the precipitate was
filtered off, washed with water and purified by column
chromatography to give an off-white solid, yield 48%.
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(1,4,5,8-Tetramethoxy-2-naphthyl)methanol
(11). To a stirred suspension of 1,4,5,8-tetramethoxy-2-
naphthaldehyde (1.4 g, 5 mmol) and activated Zn
powder (1.3 g, 20 mmol) in DMF (20 mL) was added
85% hydrazine hydrate (1.2 g, 20 mmol) at 50°C under
the atmosphere of N2. Upon completion of the reaction
(TLC), Zn powder was filtered off. The filtrate was
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CONCLUSIONS
An efficient synthetic method for reduction of
nitronaphthalene derivatives by using commercial
hydrazine hydrate and Zn powder is reported. Besides
the nitro group, it can be suitable for bromo and formyl
groups. DMF was determined to be the most
appropriate solvent. Mild heating could accelerate the
reaction. Contrary to the earlier methods, the current
approach is characterized by decreased experimental
cost and no pressure equipment involved. Probably the
method can be extended to reducing some polycyclic
nitro and bromine compounds.
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