A mild one-pot procedure for the polynitration of activated arenes. Convenient preparation of dinitro- and trinitrodialkoxybenzenes

Article abstract of DOI:10.1055/s-2000-7597

When first treated with an excess of nitrogen dioxide alone and then in the presence of ozone at low temperature, dialkoxybenzenes are smoothly and stepwise polynitrated in a one-pot manner to afford the corresponding dinitro or trinitro derivatives in good yield.

Full text of DOI:10.1055/s-2000-7597

PAPER
1539
A Mild One-Pot Procedure for the Polynitration of Activated Arenes.
Convenient Preparation of Dinitro- and Trinitrodialkoxybenzenes
Masatoshi Nose, Hitomi Suzuki*
Department of Chemistry, School of Science, Kwansei Gakuin University, Uegahara 1-1-155, Nishinomiya 662-8501, Japan
Fax +81(798)510914; E-mail: hsuzuki@kwansei.ac.jp
Received 24 April 2000; revised 19 June 2000
the corresponding polynitro compounds in a high state of
purity and in satisfactory yield.
Abstract: When first treated with an excess of nitrogen dioxide
alone and then in the presence of ozone at low temperature, dialkox-
ybenzenes are smoothly and stepwise polynitrated in a one-pot
manner to afford the corresponding dinitro or trinitro derivatives in
good yield.
To a stirred solution of dialkoxybenzene 1a-c, 8 or 13 in
dichloromethane was added an excess of liquid nitrogen
dioxide at -10 °C and the resulting mixture was allowed
to stand for 0.5 hour. During the course of this time, the
substrate was mostly converted to mononitro derivative
2a-c, 9 or 14, respectively. Then a stream of ozonized ox-
ygen was passed slowly from a gas inlet tube to the solu-
tion under vigorous stirring. The Kyodai-nitration of 1,4-
dimethoxybenzene (1a) proceeded smoothly and stepwise
from mononitration to dinitration to trinitration in the ab-
sence of any catalyst, giving the corresponding nitration
product 2a, 3a/4a or 5a, all in good yield. With nitrogen
dioxide alone, initially formed 2a was quite reluctant to
react further under the conditions employed. In the pres-
ence of ozone, however, it readily underwent nitration to
give either dinitro isomers 3a/4a or trinitro derivative 5a,
depending on the amount of ozone employed (Scheme 1,
Table 1). Molecular orbital calculation carried out for
compound 2a has predicted that the relative reactivity of
unoccupied ring positions would decrease in the order 3-
> 5- >> 6-. In fact, two isomers 3a and 4a were formed ini-
tially in comparable amount at the dinitration stage, but
Key words: dialkoxybenzenes, nitration, polynitro compounds, ni-
trogen dioxide, ozone
Aromatic polynitro compounds are useful as starting ma-
terials for constructing multiply functionalized molecular
frameworks. They are usually prepared by the century-old
procedure involving treatment of arenes with an excess of
ordinary or fuming nitric acid, preferably in the presence
of concentrated sulfuric acid. Nonactivated and moderate-
ly activated aromatic substrates can be smoothly convert-
ed to polynitro derivatives simply by mixing with the
nitrating agent, often under mild heating conditions. With
highly activated arenes, however, the reaction usually oc-
curs vigorously, leading to a complex product mixture or
a resinous substance, from which the desired polynitro
compounds can be obtained laboriously in fair to low
yield. The use of sulfuric acid as a co-reagent or a reaction
medium facilitates the polynitration, but it leads to the loss
of substrate in part as a water-soluble by-product, particu-
larly arenesulfonic acid. It is often difficult to control the
whole reaction at the dinitration stage and the products are
more or less accompanied by trinitro derivatives. Con-
versely, in case we need a trinitro compound, the use of a
large excess of nitrating agent is in most cases necessary
to attain a high conversion. In this case, there arises a trou-
blesome problem of disposing of large amounts of spent
acid and waste-water.
We have recently reported that nitrogen dioxide is activat-
ed in the presence of ozone to react smoothly with a wide
variety of arenes, giving the corresponding nitro deriva-
tives in high yields (Kyodai-nitration).1 This methodology
has now been successfully applied to the facile one-pot
preparation of dinitro and trinitro derivatives from such
highly activated arenes as dialkoxybenzenes under mild
non-acid conditions. The reaction involves initial conver-
sion of a given substrate to a mononitro derivative using
nitrogen dioxide alone at -10 °C, followed by further ni-
tration with nitrogen dioxide in the presence of ozone. Un-
der these conditions, the dinitration and trinitration
proceed stepwise and simple crystallization of the respec-
tive reaction products from an appropriate solvent gives
Scheme 1
Synthesis 2000, No. 11, 1539–1542 ISSN 0039-7881 © Thieme Stuttgart · New York

1540
M. Nose, H. Suzuki
PAPER
Table 1 Nitration of Dialkoxybenzenes 1a−c, 8 and 13 with NO2–O3 and Mixed Acid Systems
Sub-
Reagent
Solventa
Reaction time (h) /Temp. (°C)
Major product
Yield /%b
stratea
c
1a
NO2
CH2Cl2
CH2Cl2
CH2Cl2
0.5 / -10
1.5 / -10
3.5 / -10
3.0 / r.t.
2a
98
81
82
22
63
88
83
38
31
45
52
56
41
64
97
91
87
37
73
NO2d – O3
NO2d – O3
3a + 4af
e
5a
g
g
h
fum-HNO3-98%H2SO4
fum-HNO3-98%H2SO4
NO2d – O3
CH2Cl2
5a
CH3CNh
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
8.0 / r.t. –50i
3.5 / -10
3.5 / -10
0.5 / -10
2.5 / -10
4.0 / -10
6.0 / -10
1.5 / -10
3.0 / r.t.
5a
1b
1c
8
5b
NO2d – O3
5c
c
NO2
9
NO2d – O3
10
NO2d – O3, MeSO3Hj
NO2d – O3, MeSO3Hj
NO2d – O3, MeSO3Hj
fum-HNO3-98%H2SO4
fum-HNO3-98%H2SO4
12
12
10 + 11k + 12l
g
g
h
CH2Cl2
12
CH3CNh
CH2Cl2
CH2Cl2
CH2Cl2
8.0 / r.t. –50i
0.5 / -10
1.0 / -10
3.0 / -10
3.0 / r.t.
10 + 12m
c
13
NO2
14
15
17
17
17
NO2d – O3
NO2d – O3
g
g
h
fum-HNO3-98%H2SO4
CH2Cl2
fum-HNO3-98%H2SO4
CH3CNh
8.0 / r.t. –50i
a All reactions were carried out using a substrate (5 mmol) in a given solvent (30 mL), unless otherwise indicated.
b Isolated yield.
c Liquid NO2 (1.5 mL; d = 1.49) was used.
d Liquid NO2 (3.0 mL) was used.
e Substrate used was 10 mmol.
f Isomer ratio 3a : 4a was 7 : 6.
g A mixture of fum-HNO3 (6 mL; d = 1.50) and 98%-H2SO4 (9 mL; d = 2.0) was used.
h Solvent used was 40 mL. In the reaction of compound 8, an appreciable amount of tarry materials was formed.
i The mixture was gradually warmed up to 50°C.
j Methanesulfonic acid (0.35 mL, 5 mmol; d = 1.48) was added as catalyst.
k Product 11 was not isolated.
l Product ratio 10 : 11 : 12 was 97 : trace : 3.
m Product ratio 10 : 12 was ca. 1 : 1.
the former was nitrated more easily, thus the isomeric reaction took place vigorously to produce a complex mix-
mixture gradually became richer in 4a. Under similar con- ture of products as a tarry oil or a resinous solid. When ac-
ditions, compounds 1b and 1c were readily converted to etonitrile was used as the solvent, the reaction proceeded
the expected trinitro derivatives 5b and 5c, respectively, smoothly up to the dinitration stage, but the third nitration
in comparable yield. Compound 3a melted at 192- required prolonged heating at 50 °C with a large excess of
193 °C, considerably higher than the reported value of the nitrating agent to realize a satisfactory conversion.
183 °C.2 However, the vicinal location of two nitro groups Both in the classical and the Kyodai-nitrations, the forma-
in 3a was unambiguously established by converting it to tion of tetranitro derivatives could not be observed.
the known benzimidazole derivative 7 via 1,2-diamine 6.
The Kyodai-nitration of 1,3-dimethoxybenzene (8)
When the direct polynitration of substrates 1a-c was at- stopped at the dinitration stage under similar conditions,
tempted in dichloromethane using a mixture of fuming ni- but in the additional presence of methanesulfonic acid as
tric acid and 98% sulfuric acid as the nitrating agent, the catalyst, it proceeded further to give the trinitration
Synthesis 2000, No. 11, 1539–1542 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Mild One-Pot Procedure for the Polynitration of Activated Arenes
1541
product 12 in moderate yield. In this case, however, the
reaction was always accompanied by partial decomposi-
tion of the substrate. In view of the susceptible nature of
compound 8 toward electrophiles or oxidants, this was not
unexpected. Supposedly, part of substrate 8 was lost as
polymeric or oxidative degradation products during the
reaction. In the classical nitration in acetonitrile, the major
polynitration product was dinitro derivative 10 accompa-
nied by small amounts of an isomer 11. The formation of
trinitro derivative 12 was quite sluggish at room tempera-
ture (Scheme 2, Table 1).
Scheme 3
All mps were measured on a YANACO MP-S3 apparatus and are
1
uncorrected. H NMR spectra were obtained with a JEOL JNM-
A400 spectrometer at 400 MHz for CDCl3 solutions with TMS as
an internal standard. J values are given in Hz. IR measurements
were made on a JEOL FTIR-5300 spectrophotometer for KBr pel-
lets and only prominent peaks below 2000 cm-1 were recorded.
Chemical ionization (CI) mass spectra were obtained on a Shimad-
zu GCMS QP-5000 instrument using isobutane as an ionizing gas at
ionization potential of 70 eV. Merck precoated silica gel sheets 60F-
254 were used for TLC monitoring. Chromatographic separation
and purification were performed with Wakogel 200 (100-200
mesh) using hexane/EtOAc (1-10:1) as the eluent. Products were
identified by NMR, IR and MS analyses or by direct comparison
with the authentic samples.
Scheme 2
All reagents and solvents were reagent-grade commercial samples,
except for 1,4-diethoxybenzene (1b) and 1,4-dipropoxybenzene
(1c), which were prepared according to the reported procedure3 and
purified by recrystallization from MeOH. CH2Cl2 was distilled from
CaH2 prior to use. NO2 (99% purity; impurities involve NO and
small amounts of N2) was purchased from Sumitomo Seika Co. Ltd.
and used after transfer distillation. An apparatus (Nippon Ozone Co.
Ltd., type ON-1-2) was used for the generation of O3. The machine
produced O3 at a rate of 10 mmol h-1 under the following condi-
tions: O2 flow rate 10 dm3 h-1, applied voltage 80 V.
Under similar conditions, the Kyodai-nitration of 1,2-
dimethoxybenzene (13) proceeded stepwise up to the tri-
nitration stage with comparable ease to those of com-
pounds 1a-c. The orientation of the entering nitro group
was of particular interest. At the mononitration stage, the
product was solely 14. However, compound 15 was
the only product at the dinitration stage and isomeric
1,2-dimethoxy-3,5-dinitrobenzene (16) was not formed in
any detectable amount. Consequently, in the final product
17, all three nitro groups were located together on one side
of the aromatic ring (Scheme 3).
Kyodai-Nitration of Dialkoxybenzenes 1a-c, 8 and 13 to Trini-
trodialkoxybenzenes 5a-c, 12 and 17; General Procedure
1,4-Dialkoxybenzene 1, 8 or 13 (0.69 g, 5 mmol) was dissolved in
Except for dinitration products 3a/4a, all polynitration freshly distilled CH2Cl2 (30 mL) and placed in a two-necked 30 mL
flask fitted with a gas inlet tube and a vent which permitted waste
products were easily obtained in a high state of purity by
gas to escape. The solution was cooled to -10 °C under magnetic
simple recrystallization from ethanol. A mixture of 3a/4a
stirring with a cooling bath (EYELA COOL ECS-1 with two ther-
could be separated by chromatography on silica gel (hex-
mometers THS-40 and THD-50) and liquid NO2 (1.5 mL, 45 mmol)
ane/EtOAc). The latter isomer eluted earlier. Rather sur-
was introduced in one portion. After stirring for 0.5 h, an additional
prisingly, the literature lacks the spectral data of most
polynitration products obtained in the present work, so we
amount of liquid NO2 (1.0 mL, 30 mmol) was added and a stream
of ozonized oxygen was introduced slowly under vigorous stirring
have tabulated the melting points, mass, infrared, and 1H through the inlet tube, which dipped just below the surface of
the liquid in the flask. Ozonized oxygen was continuously fed for
NMR data of four dinitro and five trinitro compounds de-
3-4 h at the same temperature. Under these conditions, the loss of
rived from dialkoxybenzenes 1a-c, 8 and 13 in Table 2.
NO2 was not significant. The progress of the reaction was intermit-
Unfortunately, 1,3-dimethoxy-2,4-dinitrobenzene (11)
tently monitored by TLC. When the reaction was almost complete,
could not be included in the Table, since we were unable
to isolate this minor product in a high state of purity
enough for spectral measurement.
the cooling bath was removed and excess NO2 was expelled by
blowing air into the solution and recovered in a cold trap for reuse.
The reaction mixture was washed with sat. NaHCO3, and the organ-
ic phase was extracted with CH2Cl2 (2 ¥ 50 mL). The extract was
Synthesis 2000, No. 11, 1539–1542 ISSN 0039-7881 © Thieme Stuttgart · New York

1542
M. Nose, H. Suzuki
PAPER
Table 2 Physical Data of Polynitration Products 3a,4a, 5a–c, 10, 12, 15 and 17
Product
mp (°C)
192–193
Lit.
mp (°C)
MS (CI) m/z (%)
IR (KBr) n (cm−1)
1H NMR (CDCl3 /
TMS), d, J (Hz)
3a
1832
229 (M++1, 85), 199 (100),
184 (22), 169 (25), 154 (3)
1543 (NO2), 1495, 1356 (NO2),
1277, 1194, 1057
3.93 (s, 6 H, CH3), 7.21 (s,
2 H)
4a
5a
209–210
98–100
201–2025
98–995
229 (M++1, 82), 199 (100),
183 (3.1), 169 (15)
1543 (NO2), 1442, 1356 (NO2),
1285, 1231, 1019
1566 (NO2), 1487, 1454, 1435,
1404, 1343 (NO2), 1312, 1273,
1159, 1080
1545 (NO2), 1491, 1464, 1426,
1389, 1362 (NO2), 1263, 1113,
1073
3.98 (s, 6 H, CH3), 7.57 (s,
2 H)
4.05 (s, 6 H, CH3), 7.73 (s,
1 H)
274 (M++1, 24), 257 (3),
244 (100), 229 (43), 214
(14), 199 (44)
5b
135–137
302 (M++1, 26), 272 (100),
257 (54), 242(19), 227 (50)
1.36–1.57 (m, 6 H), 4.18-
4.29 (m, 4 H), 7.67 (s, 1 H)
5c
10
112–114
157–158
330 (M++1, 18), 300 (100),
285 (54), 271 (14), 255 (35),
243 (11), 229 (5)
1552 (NO2), 1491, 1462, 1426,
1356 (NO2), 1265, 1076, 999
0.94–1.09 (m, 6 H), 1.75–
1.91 (m, 4 H), 4.05–4.18
(m, 4 H), 7.66 (s, 1 H)
4.10 (s, 6 H, CH3), 6.63 (s,
1 H), 8.77 (s, 1 H)
1546
229 (M++1, 100), 199 (26)
1616, 1589, 1526 (NO2), 1431,
1360, 1302 (NO2), 1225, 1065,
1003
1588, 1543 (NO2), 1383, 1343
(NO2), 1296, 1109, 972
154–1577
12
123–125
124–1252
274 (M++1, 29), 258 (5),
244 (100), 229 (91), 214 (9),
199 (16)
4.11 (s, 6 H, CH3), 8.77 (s,
1 H)
15
17
130–132
150–151
130–1322
229 (M++1, 81), 199 (100),
184 (11), 168 (8)
1593, 1530 (NO2), 1373, 1333,
1285 (NO2), 1235
1547 (NO2), 1499, 1458, 1356
(NO2), 1302, 1242, 1192, 1076,
1024
4.02 (s, 6 H, CH3), 7.34 (s,
2 H)
4.10–4.12 (d, J = 5.6, 6 H,
CH3), 7.65 (s, 1 H)
1452
274 (M++1, 28), 257 (6),
244 (100), 229 (44), 214
(21), 199 (13)
washed with brine, dried (MgSO4), and evaporated under reduced
pressure to leave a solid residue, which was recrystallized from
EtOH to give the expected trinitro derivatives 5a-c, 12 or 17 as pale
yellow crystals.
1H NMR (CDCl3): d = 6.54 (s, 2H), 3.93 (s, 6H), 2.60 (s, 3H).
GC-MS (CI): m/z (%) = 193 (M++1, 100).
References
When a stream of ozonized oxygen was slowly bubbled through a
solution of 1a (0.69 g, 5 mmol) and NO2 (1.5 mL, 45 mmol) in
CH2Cl2 (30 mL) at -10 °C for 1.5 h and the reaction mixture was
worked up as usual, there resulted a 7:6-mixture of dinitro deriva-
tives 3a and 4a as a yellow solid (0.93 g), which was chromato-
graphed on silica gel using hexane/EtOAc as the solvent to elute 4a
and 3a in this order.
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at 100 °C with stirring. After 3 h, the mixture was made alkaline by
adding aqueous NaOH until a temporary white precipitate dissolved
completely. The organic phase was extracted with Et2O (2 ¥ 25 mL)
and the combined extracts were washed with brine, dried (MgSO4),
and evaporated under reduced pressure to leave crude diamine 6 as
a syrupy residue. The residue was dissolved in HOAc (10 mL) and
heated under gentle reflux overnight. The reaction mixture was di-
luted with H2O and the product was extracted with CH2Cl2 (2 ¥ 25
mL). The extract was washed with brine, dried (MgSO4), and evap-
orated to leave compound 7 as a solid residue, which was recrystal-
lized from a mixture of hexane and EtOAc to give the pure product
(31 mg; 56%) as yellow crystals; mp: 235-237 °C (Lit.4 mp: 224-
226 °C).
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Article Identifier:
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Synthesis 2000, No. 11, 1539–1542 ISSN 0039-7881 © Thieme Stuttgart · New York