A convenient copper-catalyzed direct animation of nitroarenes with 9-alkylhydroxylamines

Article abstract of DOI:10.1039/a901537j

O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base and a copper catalyst to give aminonitroarenes in good yields, ortho- or para-Animation with respect to the nitro group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to give the sterically most congested 3c-f, 14 and 22g.

Full text of DOI:10.1039/a901537j

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A convenient copper-catalyzed direct amination of nitroarenes with
O-alkylhydroxylamines
Shinzo Seko,* Kunihito Miyake and Norio Kawamura
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., Tsukahara, Takatsuki,
Osaka 569-1093, Japan
Received (in Cambridge) 25th February 1999, Accepted 19th April 1999
O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base
and a copper catalyst to give aminonitroarenes in good yields. ortho- or para-Amination with respect to the nitro
group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted
nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to
give the sterically most congested 3c–f, 14 and 22g.
Table 1 Direct amination of nitrobenzene with O-alkylhydroxyl-
aminesa
Introduction
Aromatic amines represent an important class of compounds
for a wide variety of pharmaceuticals, pesticides, additives and
dyes. They have been synthesized in the chemical industry for
a long time by such classical methods as the sequence of
nitration–reduction, and substitution reactions of aromatic
halides or hydroxides with amines.1 Although direct amination
of aromatic compounds, which is the most simple synthetic
method for aromatic amines, is of great interest, there have been
no general and practical methods for it in spite of considerable
efforts in its exploitation.2 Vicarious nucleophilic substitution
(VNS),3 which has been intensely studied by Makosza and co-
workers, significantly serves as one of the nucleophilic substitu-
tions for aromatic hydrogen,4 although a nitro group in the
substrate is necessary. The VNS reaction consists of treatment
of nitroarenes with nucleophiles bearing a good leaving group
at the nucleophilic center to furnish the corresponding ortho-
or para-substituted nitroarenes (Scheme 1). VNS alkylations,5
NO2
NO2
ButOK
10 mol%CuCl
DMF
+ NHROR'
NHR
Entry
R
RЈ
Yield (%)b
o:pc
1
2
3
4
5
6
H
H
H
H
Me
H
Me
Ete
Bne
But e
Me
H
93 (60)d
68 (38)d
41
71:29 (65:35)d
68:32 (61:39)d
76:24
27:73
0:100
40
22f
0g
a Unless otherwise stated, reactions were performed with nitrobenezene
(1 equiv.), NHRORЈ (1.25 equiv.), ButOK (3 equiv.) and CuCl (0.1
equiv.) in DMF at room temperature for 1–24 h. b GC yields. c The o:p
ratios were determined by GC. d Results when CuCl was not used are in
parentheses. e Amine hydrochloride and an additional base (1.25 equiv.)
were used. f Isolated yield. g Starting material was recovered.
_
_
NO2
_
NO2
NO2
B
H
Nu
NuH
H3O+
Base
aminates 1,3-dinitrobenzene and bicyclic nitroarenes,8 it cannot
aminate mononitrobenzenes.
Nu
L
_
L
NO2
In our preliminary communication9 we briefly reported the
direct amination of nitrobenzenes with O-alkylhydroxylamines
in the presence of a copper catalyst to give nitroanilines in excel-
lent yields. ortho-Nitroanilines thus obtained are important as
precursors of o-phenylenediamines, which are readily converted
into benzimidazole or quinoxaline derivatives often found in
numerous pharmaceuticals.10 This paper gives a full account
of our studies on the amination of nitroarenes with O-alkyl-
hydroxylamines, in particular, O-methylhydroxylamine.
_
Nu
L
_
NO2
_
NO2
NO2
NuH
H3O+
Base
_
L
_
B
H
Nu
L
Nu
Scheme 1
Results and discussion
hydroxylation6 and aminations7 have been reported so far.
Among them, amination is of great importance as a direct
introduction of an amino group into an aromatic ring to give
aminonitroarenes. 4-Amino-1,2,4-triazoles,7a sulfenamides7b,c
and 1,1,1-trimethylhydrazinium iodide7d are known as aminat-
ing agents. However, since these agents have a complicated
leaving group of high molecular weight, additional treatment
and separation of the eliminated residue from the products
are necessary in the work-up procedures. On the other hand,
although it is known that unsubstituted hydroxylamine
We initially examined commercially available primary amines
with a N–N, N–O, N–S or N–halogen bond, as VNS aminating
agents for the amination of nitrobenzene in the presence of
ButOK in DMF. After screening many candidates we found
that O-methylhydroxylamine11 can efficiently aminate nitro-
benzene in the presence of ButOK (3 equiv.) in DMF at room
temperature to give ortho- and para-nitroanilines (o:p = 65:35)
in 60% yield (Table 1, Entry 1, values in parentheses). Some
metal catalysts such as zinc, copper, nickel and manganese salts
were next examined in order to improve the unsatisfactory
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444
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Table 3 Direct amination of nitrobenzenes with O-methylhydroxyl-
aminea
Table 2 The effect of experimental conditions on the yields of nitro-
anilines in the direct amination of nitrobenzene with O-methyl-
hydroxylaminea
NO2
NO2
ButOK
(equiv.)
CuCl
(equiv.)
Yield
(%)b
ButOK
+
NH2OMe
Entry
Solvent
o:pb
10 mol% CuCl
DMF
R
R
NH2
1
2
3
4
5
6
1
2
3
3
3
3
0.1
0.1
0.1
0.01
0.1
0.1
DMF
DMF
DMF
DMF
Toluene
Hexane
50
84
93
83
59
71
69:31
70:30
71:29
73:27
80:20
81:19
1
Ratio of
Yield
Entry
R
productsb
(%)c
a Reactions were performed with nitrobenzene (1 equiv.), NH2OMe
(1.25 equiv.), ButOK and CuCl in a solvent at room temperature for 3 h.
b Determined by GC.
NO2
NO2
NH2
+
NO2
NH2
H2N
+
R
R
R
2
3
4
1d
2
3
4
5
a
b
c
d
e
f
H
71 (65)e
50 (48)e
15 (15)e
18
:
:
:
:
:
:
na
:
:
:
:
:
:
29 (35)e
24 (21)e
24 (24)e
34
93 (60)e
93 (25)e
94 (57)e
85
yield. Consequently copper catalysts were found to play a
significant role in promoting the reaction. CuCl (10 mol%)
improved the yield up to 93% (o:p = 71:29) (Table 1, Entry 1).
A variety of copper compounds such as CuBr, CuI, CuCl2,
Cu(acac)2, Cu(OAc)2 and Cu(NO3)2 as well as CuCl showed
the same effect, but CuCN and CuSO4 were less effective. It is
worth noting that both univalent and bivalent copper catalysts
could be used equally well. Various O-alkylhydroxylamines
could be found to aminate nitrobenzene to give ortho- and para-
nitroanilines, as shown in Table 1. Among them, O-methyl-
hydroxylamine was the best aminating agent in terms of yield
of nitroanilines, which was higher than those in the previously
reported VNS aminations of nitrobenzene.7 O-Methylhydroxyl-
amine could be used both as the free amine as well as its hydro-
chloride salt together with additional base to provide similar
results. The use of O-ethylhydroxylamine, O-benzylhydroxyl-
amine and O-tert-butylhydroxylamine gave somewhat lower
yields (Entries 2–4). The reaction with O-tert-butylhydroxyl-
amine gave para-rich nitroanilines because of its steric bulk
(Entry 4). Methylamination using N,O-dimethylhydroxylamine
also occurred with para-selectivity, although in low yield (Entry
5). Amination with an unsubstituted hydroxylamine, known to
aminate 1,3-dinitrobenzene and bicyclic nitroarenes,8 did not
take place under these conditions, and the starting material was
recovered quantitatively (Entry 6).
3-CF3
3-OMe
3-Cl
26 (31)e
61 (61)e
48
3-F
15
55
30
88
6
3-NMe2 10 (10)e
75 (73)e
15 (17)e
99 (65)e
NO2
H2N
5
R
7
8
9
g
h
i
j
k
l
m
n
o
4-OMe
4-OPh
4-SMe
4-But
4-CF3
4-Cl
69 (41)e
70 (42)e
92 (65)e
91
10
11
12
13
14
15
76 (28)e
86 (39)e
71
4-Br
4-F
17
70
4-(1H-imidazol-1-yl)
NO2
NO2
Ph
H2N
Ph
+
6
7
NH2
16
p
2-Ph
70 (99)e
:
30 (1)e
86 (31)e
The theoretical amount of the base in the VNS reaction
(Scheme 1) is 2 equivalents to the substrate. The present amin-
ation also required 2 equivalents of the base according to the
VNS reaction (Table 2, Entries 1 and 2). Excess base (3 equiv.)
further improved the yield of nitroanilines (Entry 3). Use of
only 1 mol% of CuCl gave a somewhat lower yield than that of
10 mol% (Entry 4). The reaction proceeded even in low-polar
hydrocarbon solvents such as toluene and hexane in spite of
poor solubility of the base and catalyst (Entries 5 and 6). Such
solvents influenced the o:p ratio of the products, which were
slightly changed to 80:20 from 70:30.
Amination of a variety of mono-substituted nitrobenzenes
with O-methylhydroxylamine in the presence of ButOK and
CuCl catalyst in DMF at room temperature afforded the corre-
sponding substituted nitroanilines in excellent yields. The results
are summarized in Table 3. A remarkable regioselectivity was
observed in the amination of meta-substituted nitrobenzenes
in which the substituent has a lone pair of electrons such as
OMe, Cl, F and NMe2. The most sterically congested 1,2,3-
trisubstituted nitroanilines 3c–f were predominantly produced
(Entries 3–6).12 In particular the reaction of N,N-dimethyl-3-
nitroaniline afforded 3f in 75% yield and selectivity (Entry 6).
These compounds cannot easily be synthesized by conventional
methods due to the steric hindrance. Addition of CuCl has no
effect on the orientation of the aminations. Simple electron
charge or orbital control, according to molecular calculations
on the substrates, could not explain this regioselectivity. The
reaction of para-substituted nitrobenzenes gave 5-substituted
a Reactions were performed with NH2OMe (1.25 equiv.), ButOK (3
equiv.) and CuCl (0.1 equiv.) in DMF at room temperature for 10–60
min. b Unless otherwise noted, all isomers were isolated. c Total yield of
all isomers. d Yield and ratio of the products were determined by GC.
e Results when CuCl was not used are in parentheses.
2-nitroanilines as sole products in good yields (Entries 7–13 and
15). It is noteworthy that p-chloro- or p-bromonitrobenzene
can be aminated smoothly to provide 5-chloro- or 5-bromo-2-
nitroaniline in good yields without formation of 4-(N-methoxy-
amino)nitrobenzene 8, which is a conventional nucleophilic
aromatic substitution (SNAr) product, despite the fact that the
chlorine or bromine atom was activated by the p-nitro group in
the substrate (Entries 12 and 13). On the other hand, in the case
of p-fluoronitrobenzene, the desired aminated product 5n was
obtained in only 17% yield along with 9 (37%), 10 (14%), 11
(25%) and 12 (7%), but without 8 (Entry 14). The para-
fluorine atom, being more reactive than either the chlorine or
bromine atom, was substituted by a tert-butoxy anion derived
from the base or a methoxy anion generated in situ after the
amination to give 9, 10, 11 and 12. However, even though
p-fluoronitrobenzene has such a high reactivity towards SNAr,
the compound 8, which should be produced through SNAr
with NH2OMe, was not detected. This fact suggests that the
direct amination with NH2OMe is much faster than SNAr with
NH2OMe. The byproduct 9 is particularly intriguing as it
arises from stepwise and regioselective introduction of both
1438
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444

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Table 4 Direct amination of p-nitrobenzoic acid with O-methyl-
NH2 and MeO in NH2OMe, although in low yield. In the reac-
tion of 2-nitrobiphenyl 1p preferential ortho-orientation was
observed (Entry 16, Table 3).
hydroxylaminea
NO2
NO2
NH2
ButOK
NO2
NO2
NO2
NO2
NO2
+ NH2OMe
10 mol% Copper cat.
Solv.
NH2
NH2
19
20
COOH
COOH
ButOK
(equiv.)
Copper
cat.
Yield
(%)b
NHOMe
OMe
OBut
OMe
OBut
NH2OMe
(equiv.)
Entry
Solvent
8
9
10
11
12
1
2
3
4
5
6
7
1.25
3
4
4
4
4
7
7
CuCl
CuCl
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
DMF
DMF
DEMc
DMEd
DMF
DMEd
14
28
35
27
36
40
51
As an example of the amination of a disubstituted nitro-
benzene, the amination of 3,4-dichloronitrobenzene 13 with
O-methylhydroxylamine in the presence of ButOK (3 equiv.)
and Cu(OAc)2 (0.1 equiv.) in diethoxymethane at room tem-
perature for 2 h furnished the 2,3-dichloro-6-nitroaniline 14
(75%) and 4,5-dichloro-2-nitroaniline 15 (14%) (Scheme 2). The
1.25
1.25
1.25
1.25
2.00
2.00
a Reactions were performed with p-nitrobenzoic acid, NH2OMe,
ButOK and a copper catalyst in a solvent at room temperature for 3 h.
b Isolated yield. c Diethoxymethane. d Dimethoxyethane.
Cl
Cl
NO2
ButOK
+
NH2OMe
10 mol% Cu(OAc)2
DEM
3-amino-4-nitrobenzoic acid 20 in only 14% yield, and 80% of
the starting material was recovered (Table 4, Entry 1). How-
ever, by the use of 2 equivalents of O-methylhydroxylamine, 7
equivalents of ButOK and 0.1 equivalent of Cu(OAc)2 in DME,
the yield of the product was improved to 51% (Entry 7). The
use of Cu(OAc)2 provided a slightly better yield than that of
CuCl (Entries 2 and 3). DME was the best choice of solvent,
and a large excess of the base and O-methylhydroxylamine was
effective for the amination of 19. The results of the amination
of o- and m-nitrobenzoic acid and nitrobenzoic acids bearing
a chlorine or a methoxy group are summarized in Table 5.
With o- or m-nitrobenzoic acid, no trends in regioselectivity
could be observed (Entries 1 and 2). In the previous papers,7
1,2,3-trisubstituted isomer 22d could not be detected by the
aminations of m-nitrobenzoic acid. However, in our case, it
was obtained in 21% yield accompanied with 22c (30%) and
22e (31%) (Entry 2). The amination of 2-chloro-4-nitrobenzoic
acid 21d gave 3-amino-2-chloro-4-nitrobenzoic acid 22g with
high regioselectivity (Entry 4), which is consistent with those
observed in the amination of 3-chloronitrobenzene or 3,4-
dichloronitrobenzene. Fairly good yields were indicated in the
reactions of 21e and 21f, and a sole product was obtained in
each case (Entries 5 and 6).
DEM = diethoxymethane
13
NH2
Cl
Cl
NO2
Cl
NO2
75%
+
NH2
14%
Cl
14
15
Scheme 2
reaction in the presence of CuCl (0.1 equiv.) in DMF gave the
products in only 34% yield. Also in this case the unusual
regioselectivity was observed and 1,2,3,4-tetrasubstituted
product 14, which is a versatile intermediate for a herbicide,13
was predominantly produced. The direct aminations of nitro-
naphthalenes have been extensively studied.7a–c,8a,b In the
present case, the reaction of 1-nitronaphthalene 16 with O-
methylhydroxylamine gave 2-amino-1-nitronaphthalene 17 and
1-amino-4-nitronaphthalene 18 in 41% and 7% yields, respect-
ively (Scheme 3). On the other hand, unfortunately, the
NO2
A proposed reaction mechanism, in principle, follows the
general VNS reaction with a modification of the copper
catalyzed system (Scheme 4). The copper salt should catalyze
the addition of O-methylhydroxylamine to the nitroarene. The
copper amide ate complex 24 might be generated and undergo
oxidative addition to ortho- and para-positions of the nitro-
arene 25 to give 26 and 27.16 Examination of the NMR
spectrum of O-methylhydroxylamine in the presence of a
copper salt and a base suggests the generation of 24. The
1H-NMR spectrum (DMSO-d6) of O-methylhydroxylamine in
the presence of ButOK and CuCl showed two singlets at δ 3.35
and 3.22 ppm assignable as the methoxy groups of O-methyl-
hydroxylamine itself and copper complexed O-methylhydroxyl-
amine, while in the absence of CuCl only one singlet at δ 3.34
ppm was observed. This indicates the existence of some inter-
action between O-methylhydroxylamine and CuCl. Nilsson
reported a copper salt mediated VNS alkylation of 1,3-dinitro-
benzene, where the addition of a stoichiometric amount of
copper salt changed the regioselectivity by chelation of the
σ-adduct to the copper ion.17 However, we assume that the
copper catalyst does not activate the substrate or the σ-adduct
in our amination because a catalytic amount of the copper salt
is sufficient to promote the reaction and the addition of the
copper catalyst does not affect the regioselectivity of the amin-
ButOK
+
NH2OMe
10 mol% CuCl
DMF
16
NO2
NO2
NH2
+
NH2
17
41%
7%
18
Scheme 3
amination of 1,3-dinitrobenzene, nitrothiophenes or nitropyri-
dines14 was unsuccessful under the present copper-catalyzed
conditions, although these compounds could be aminated by
the aminating agents previously reported.7
Our attention then turned to an amination of nitrobenzoic
acids due to their significance as intermediates for pharm-
aceuticals.15 An attempted amination of p-nitrobenzoic acid 19
with O-methylhydroxylamine under the same conditions as
those in the amination of nitrobenzene [NH2OMe (1.25 equiv.),
ButOK (3 equiv.), CuCl (0.1 equiv.) in DMF] gave the expected
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444
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Table 5 Direct amination of nitrobenzoic acids with O-methyl-
to a contribution of a neighboring effect of the nitro group on
hydroxylaminea
the σ-adduct 28. The neighboring nitro group may assist in
elimination of the methoxy anion to form five-membered
intermediate 32 (Scheme 5).
NO2
NO2
ButOK
In conclusion, we have demonstrated that the novel copper-
catalyzed direct amination of nitroarenes with O-alkylhydroxyl-
amines, particularly O-methylhydroxylamine, provides the
shortest synthesis of ortho- and para-nitroanilines. Com-
mercially available O-methylhydroxylamine is a useful and
effective aminating agent since it has only a methoxy group as
the leaving group, and thus treatment after completion of the
reaction is easier than for the other known VNS aminations,7 in
which the aminating agents have complicated and heavy leaving
groups. The unusual regioselectivity observed in this amination
allowed the synthesis of a new class of nitroanilines which
are quite difficult to synthesize by conventional methods. In
particular, ortho-nitroanilines obtained here are of extreme
importance as intermediates of numerous pharmaceuticals
containing benzimidazole or quinoxaline heterocycles.
+
NH2OMe
NH2
10 mol% Cu(OAc)2
DME
COOH
R
R
COOH
21
22
Entry Substrate
Products, Yields (%)b
NH2
NO2
NO2
NO2
1
H2N
COOH
COOH
COOH
21a
22a (35)
22b (34)
NH2
NO2
NO2
NO2
NH2
NO2
2
H2N
COOH
21b
COOH
22c (30)c
COOH
22d (21)
COOH
22e (31)c
Experimental
NH2
Melting points were determined on a Yanagimoto micro melt-
ing point apparatus and Electrothermal IA9300 (Mitamura
NO2
NO2
3
4
1
Riken), and are uncorrected. H- and 13C-NMR spectra were
HOOC
OMe
22f (40 (78)d)
HOOC
OMe
recorded in CDCl3 or DMSO-d6 as solvent on a JEOL JNM-
EX270 spectrometer (at 270 and 67.8 MHz, respectively) and
Varian UNITY-400P spectrometer (at 400 and 100 MHz,
respectively), with tetramethylsilane for 1H and CDCl3 or
DMSO-d6 for 13C as internal standards. Chemical shifts are
quoted in parts per million (ppm). The following abbreviations
are used for multiplicities: s, singlet; br s, broad singlet; d, doub-
let; t, triplet; q, quartet; m, mutiplet. Coupling constants (J) are
given in hertz (Hz). Mass spectra were recorded on a GC/MS
HP 5971A and 5972A mass spectrometer. High resolution mass
spectra were recorded on a JEOL JMS-SX-102A mass spec-
trometer. Elemental analyses were performed on a Elementar
Vario EL analyzer. Analytical thin layer chromatography
(TLC) was conducted on glass-backed 0.25 mm thick silica gel
60 F254 plates (Merck, No. 5719) and the chromatograms were
visualized under a 254 nm UV lamp. Preparative thin layer
chromatography (PLC) was carried out on 20 × 20 cm glass
plates coated with silica gel 60 F254 (Merck, No. 13895) and
eluted with the solvent system indicated. Flash column chrom-
atography was carried out on silica gel 60 (Merck, No. 9385)
and eluted with the solvent system indicated. Gas chrom-
atography was carried out on a DB-1701 Megabore capillary
column (J & W Scientific) in a Shimadzu GC-9A gas chromato-
graph, with dimethyl phthalate as an internal standard.
Diethoxymethane (DEM) was obtained from Eastman
Chemicals Co., Ltd.
21c
NH2
e
NO2
NO2
NH2
NO2
HOOC
HOOC
HOOC
Cl
Cl
22g (62)
Cl
22h (trace)
21d
NH2
NO2
NO2
5
6
7
COOH
MeO
COOH
MeO
22i (85)
21e
21f
NH2
NO2
NO2
COOH
COOH
22j (78)
Cl
Cl
NH2
NO2
NO2
NO2
MeO
MeO
NH2
COOH
22k (21)
MeO
COOH
21g
COOH
22l (44)
a Reactions were performed with NH2OMe (2 equiv.), ButOK (7 equiv.)
and Cu(OAc)2 (0.1 equiv.) in DME at room temperature for 2–4 h. b All
isomers were isolated, unless otherwise noted. c 22c and 22e could not
be separated. d Calculated on consumed substrate. e The structure could
not be fully determined.
Typical procedure for the amination of nitrobenzene with O-alkyl-
hydroxylamine
ation. The intermediates 26 and 27 should subsequently under-
go reductive elimination to give the σ-adducts, Meisenheimer
complexes 28 and 29, respectively. Finally the reaction of 28
and 29 with a base provides the deep red intermediates 30 and
31 according to the usual VNS reaction mechanism3 and a sub-
sequent acidic work-up gives the corresponding ortho- and
para-nitroanilines. In the competitive non-catalytic system, 23
directly adds to nitroarene 25 to give 28 and 29, which are
reversible reactions. However the non-catalytic system gave
insufficient conversion of 25 and yields of nitroanilines. The
regioselectivity would be governed by the irreversible steps
(28→30, 29→31), base-induced β-eliminations. This would be a
reasonable explanation for the fact that the copper catalyst did
not influence the orientation of the amination. The preferential
ortho-orientation observed in some cases might be attributable
A solution of O-ethylhydroxylamine hydrochloride (244 mg, 2.5
mmol) and a nitrobenzene (246 mg, 2 mmol) in DMF (3 ml)
was added dropwise to a stirred suspension of ButOK (954 mg,
8.5 mmol) and CuCl (20 mg, 0.2 mmol) in DMF (7 ml) over 5
min at room temperature. After stirring for 60 min at room
temperature, it was quenched with saturated aq. NH4Cl and the
products were extracted with CH2Cl2. The organic extract was
dried over anhydrous MgSO4 and concentrated in vacuo. The
crude product included 2-nitroaniline (127 mg, 46%), 4-nitro-
aniline (61 mg, 22%) and nitrobenzene (34 mg, 14%), which
were determined by the GC-IS method.
N-Methyl-4-nitroaniline was isolated and purified by silica
gel thin layer chromatography (AcOEt–hexane = 1:1). Prod-
ucts, 2-nitroaniline, 4-nitroaniline and N-methyl-4-nitroaniline
were identical with commercially available authentic samples.
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J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444

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+
+
+
K
K
K
_
_
_
_
B
NO2
NO2
NO2
NO2
H
H
NH
NH2
+
H3O
Base
R
R
NH OMe
Cu
X
R
R
NHOMe
_
MeOH
26
28
30
25
25
NO2
+
_
Cu
K
NH2OMe + ButOK
CuX + KNHOMe
NHOMe
24
23
R
25
X
25
25
ButOH
+
+
+
K
K
_
K
_
_
NO2
NO2
NO2
NH2
NO2
+
Base
H3O
R
R
R
R
_
B
_
MeOH
H
NH OMe
Cu
X
H
NHOMe
NH
29
31
27
Scheme 4
_
O
_
_
O
+
5-chloro-2-nitroaniline 5l and 4-nitroanisole 11 were identical
with commercially available authentic samples.
+
K
K
O
+
+
O
N
N
_
B
NH OMe
H
NH
N4,N4-Dimethyl-2-nitro-1,4-phenylenediamine 2f.20 Rf 0.10
(EtOAc–hexane = 1:5); δH (270 MHz; CDCl3) 2.87 (6H, s), 5.78
(2H, br s), 6.77 (1H, d, J 9.23), 7.06 (1H, dd, J 2.97 and 9.23),
7.36 (1H, d, J 2.97).
R
H
30
28
32
Scheme 5
2-Nitro-6-(trifluoromethyl)aniline 3b.21 Rf 0.61 (EtOAc–
hexane = 1:5); δH (270 MHz; CDCl3) 6.67 (2H, br s), 6.75–6.81
(1H, m), 7.74 (1H, d, J 7.59), 8.35 (1H, d, J 8.58).
4-tert-Butylnitrobenzene 1j. To a mixture of 96% sulfuric acid
(12.6 g, 123 mmol) and 60% nitric acid (12.6 g, 120 mmol) was
added tert-butylbenzene (5.37 g, 40 mmol) at 5–10 ЊC. After
stirring for 60 min at room temperature, it was quenched with
ice-water and the product was extracted with CH2Cl2. The
organic extract was dried over anhydrous MgSO4 and concen-
trated in vacuo. Purification by flash column chromatography
(EtOAc–hexane = 1:10) afforded 4-tert-butylnitrobenzene 1j18
(2.30 g, 32%) as a pale yellow oil; Rf 0.62; δH (270 MHz; CDCl3)
1.36 (9H, s), 7.54 (2H, dm, J 8.57), 8.15 (2H, dm, J 8.57).
2-Methoxy-6-nitroaniline
3c.7c
Rf
0.37
(EtOAc–
hexane = 1:5); δH (270 MHz; CDCl3) 3.91 (3H, s), 6.42 (2H, br
s), 6.60 (1H, dd, J 7.92 and 8.91), 6.88 (1H, dd, J 1.32 and 7.92),
7.72 (1H, dd, J 1.32 and 8.91).
2-Chloro-6-nitroaniline 3d.7c Rf 0.50 (EtOAc–hexane = 1:5);
δH (270 MHz; CDCl3) 6.56 (2H, br s), 6.66 (1H, dd, J 7.91 and
8.91), 7.52 (1H, dd, J 1.65 and 7.91), 8.09 (1H, dd, J 1.65 and
8.91).
1-(4-Nitrophenyl)-1H-imidazole 1o. A mixture of p-fluoro-
nitrobenzene (1.41 g, 10 mmol), imidazole (748 mg, 11 mmol),
K2CO3 (690 mg, 5 mmol) and DMF (5 ml) was stirred for 3 h at
100–120 ЊC. The reaction mixture was quenched with water and
the product was extracted with CH2Cl2. The organic extract was
washed twice with water and dried over anhydrous MgSO4 and
concentrated in vacuo. Purification by recrystallization (EtOAc,
hexane, MeOH) afforded 1-(4-nitrophenyl)-1H-imidazole 1o19
(1.03 g, 54%) as a brown crystalline solid; δH (270 MHz; CDCl3)
7.28 (1H, s), 7.40 (1H, s), 7.61 (2H, d, J 9.90), 8.00 (1H, s), 8.38
(2H, d, J 9.90).
2-Fluoro-6-nitroaniline 3e.7d Rf 0.49 (EtOAc–hexane = 1:5);
δH (270 MHz; CDCl3) 6.41 (2H, br s), 6.63 (1H, ddd, J 5.28,
7.91 and 8.58), 7.23 (1H, ddd, J 1.32, 7.91 and 10.56), 7.92 (1H,
td, J 1.32 and 8.58).
N1,N1-Dimethyl-3-nitro-1,2-phenylenediamine 3f. Rf 0.49
(EtOAc–hexane = 1:5); δH (270 MHz; CDCl3) 2.66 (6H, s), 6.61
(1H, dd, J 7.59 and 8.91), 6.69 (2H, br s), 7.21 (1H, dd, J 1.32
and 7.59), 7.88 (1H, dd, J 1.32 and 8.91); δC (67.8 MHz; CDCl3)
43.92, 115.08, 121.17, 125.41, 132.15, 141.40, 143.13; m/z (EI)
181(Mϩ), 162, 147, 145, 133, 119, 105, 92, 78, 65, 52, 42;
HRMS(FAB) Found: (M ϩ H)ϩ, 182.0948. C8H12N3O2 requires
M, 182.0930.
General procedure for the amination of nitroarenes 1
A solution of O-methylhydroxylamine (118 mg, 2.5 mmol) and
a nitroarene 1 (2 mmol) in DMF (3 ml) was added dropwise to a
stirred suspension of ButOK (672 mg, 6 mmol) and CuCl (20
mg, 0.2 mmol) in DMF (7 ml) over 5 min at room temperature.
After stirring for 10–60 min at room temperature, it was
quenched with saturated aq. NH4Cl and the products were
extracted with CH2Cl2. The organic extract was dried over
anhydrous MgSO4 and concentrated in vacuo. Purification by
silica gel thin layer chromatography (EtOAc–hexane) afforded
the nitroanilines 2–7. Products, 2-nitro-4-(trifluoromethyl)-
aniline 2b, 4-methoxy-2-nitroaniline 2c, 4-chloro-2-nitroaniline
2d, 4-fluoro-2-nitroaniline 2e, 4-nitro-2-(trifluoromethyl)aniline
4b, 2-methoxy-4-nitroaniline 4c, 2-chloro-4-nitroaniline 4d,
2-Fluoro-4-nitroaniline 4e.7 Rf 0.15 (EtOAc–hexane = 1:5);
δH (270 MHz; CDCl3) 5.20 (2H, br s), 6.81 (1H, t, J 8.58), 7.85–
7.92 (2H, m).
N2,N2-Dimethyl-4-nitro-1,2-phenylenediamine 4f.22 Rf 0.15
(EtOAc–hexane = 1:5); δH (270 MHz; CDCl3) 2.68 (6H, s), 4.74
(2H, br s), 6.66 (1H, d, J 8.58), 7.87 (1H, dd, J 2.64 and 8.58),
7.91 (1H, d, J 2.64).
5-Methoxy-2-nitroaniline 5g, 9.7c Rf 0.14 (EtOAc–hexane =
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444
1441

View Article Online
1:5); δH (270 MHz; CDCl3) 3.83 (3H, s), 6.17 (1H, d, J 2.64),
6.28 (1H, dd, J 2.64 and 9.57), 6.25 (2H, br s), 8.07 (1H, d,
J 9.57).
methane (2 ml) was added dropwise to a stirred suspension of
ButOK (337 mg, 3 mmol) and Cu(OAc)2 (18 mg, 0.1 mmol) in
diethoxymethane (3 ml) over 5 min at room temperature. After
stirring for 2 h at room temperature, it was quenched with
saturated aq. NH4Cl and the products were extracted with
EtOAc. The organic extract was dried over anhydrous MgSO4
and concentrated in vacuo. Purification by silica gel thin layer
chromatography (EtOAc–hexane = 1:5) afforded 2,3-dichloro-
6-nitroaniline 1428 (156 mg, 75%) Rf 0.62; δH (270 MHz; CDCl3)
6.83 (1H, d, J 9.24), 8.06 (1H, d, J 9.24) and 4,5-dichloro-2-
nitroaniline 1529 (29 mg, 14%) Rf 0.52; δH (270 MHz; CDCl3)
6.03 (2H, br s), 6.91 (1H, s), 8.17 (1H, s).
2-Nitro-5-phenoxyaniline 5h.23 Rf 0.29 (EtOAc–hexane =
1:5); δH (270 MHz; CDCl3) 6.14 (2H, br s), 6.16 (1H, d, J 2.63),
6.33 (1H, dd, J 2.63 and 9.57), 7.07–7.45 (5H, m), 8.10 (1H, d,
J 9.57).
5-Methylthio-2-nitroaniline 5i.24 Rf 0.17 (EtOAc–hexane =
1:5); δH (270 MHz; CDCl3) 2.48 (3H, s), 6.20 (2H, br s), 6.51
(1H, d, J 1.98), 6.51 (1H, dd, J 1.98 and 9.56), 7.99 (1H, d,
J 9.56).
Amination of 1-nitronaphthalene 16
5-tert-Butyl-2-nitroaniline 5j.7c Rf 0.26 (EtOAc–hexane =
1:5); δH (270 MHz; CDCl3) 1.29 (9H, s), 6.12 (2H, br s), 6.72–
6.76 (2H, m), 8.00 (1H, d, J 8.91).
A solution of O-methylhydroxylamine (118 mg, 2.5 mmol) and
1-nitronaphthalene 16 (346 mg, 2 mmol) in DMF (3 ml) was
added dropwise to a stirred suspension of ButOK (673 mg, 6
mmol) and CuCl (20 mg, 0.2 mmol) in DMF (7 ml) over 5 min
at room temperature. After stirring for 20 min at room temper-
ature, it was quenched with saturated aq. NH4Cl and the prod-
ucts were extracted with CH2Cl2. The organic extract was dried
over anhydrous MgSO4 and concentrated in vacuo. Purification
by silica gel thin layer chromatography (EtOAc–hexane = 1:5)
afforded 2-amino-1-nitronaphthalene 177c (154 mg, 41%) Rf
0.32; δH (270 MHz; CDCl3) 6.42 (2H, br s), 6.88 (1H, d, J 8.91),
7.32–7.38 (1H, m), 7.57–7.74 (3H, m), 8.68 (1H, d, J 9.57) and
1-amino-4-nitronaphthalene 187c (28 mg, 7%) Rf 0.14; δH (270
MHz; DMSO-d6) 6.75 (1H, d, J 8.91), 7.55–7.81 (2H, m), 7.64
(2H, br s), 8.36 (1H, d, J 8.58), 8.45 (1H, d, J 8.91), 8.97 (1H, d,
J 8.58).
5-(Trifluoromethyl)-2-nitroaniline 5k.7c Rf 0.49 (EtOAc–
hexane = 1:5); δH (270 MHz; CDCl3) 6.31 (2H, br s), 6.90 (1H,
dd, J 1.65 and 8.91), 7.13 (1H, d, J 1.65), 8.22 (1H, d, J 8.91).
5-Bromo-2-nitroaniline 5m.25 Rf 0.52 (EtOAc–hexane = 1:5);
δH (270 MHz; CDCl3) 6.12 (2H, br s), 6.82 (1H, dd, J 1.98 and
9.24), 7.02 (1H, d, J 1.98), 7.98 (1H, d, J 9.24).
5-Fluoro-2-nitroaniline 5n.7c Rf 0.35 (EtOAc–hexane = 1:5);
δH (270 MHz; CDCl3) 6.23 (2H, br s), 6.40–6.51 (2H, m), 8.16
(1H, dd, J 5.94 and 9.57).
5-(1H-Imidazol-1-yl)-2-nitroaniline 5o.26 Rf 0.26 (EtOAc);
δH (270 MHz; CDCl3) 6.30 (2H, br s), 6.76 (1H, dd, J 2.31
and 9.24), 6.82 (1H, d, J 2.31), 7.24 (1H, s), 7.26 (1H, s), 7.92
(1H, s), 8.27 (1H, d, J 9.24).
Typical procedure for amination of p-nitrobenzoic acid 19
A solution of O-methylhydroxylamine (188 mg, 4 mmol) and
p-nitrobenzoic acid 19 (334 mg, 2 mmol) in DME (12 ml) was
added dropwise to a stirred suspension of ButOK (1.57 g, 14
mmol) and Cu(OAc)2 (36 mg, 0.2 mmol) in DME (8 ml) over 5
min at room temperature. After stirring for 3 h at room tem-
perature, it was quenched with water and acidified by 2 M HCl.
The products were extracted with EtOAc. The organic extract
was dried over anhydrous MgSO4 and concentrated in vacuo.
Purification by silica gel thin layer chromatography (CHCl3–
MeOH–AcOH = 10:1:0.1) afforded 3-amino-4-nitrobenzoic
acid 2030 (186 mg, 51%) Rf 0.38; δH (270 MHz; DMSO-d6) 7.07
(1H, dd, J 1.65 and 8.90), 7.56 (2H, br s), 7.68 (1H, d, J 1.65),
8.04 (1H, d, J 8.90), 13.47 (1H, br s) and 40% of the starting
material was recovered.
3-Amino-2-nitrobiphenyl 6. Rf 0.11 (EtOAc–hexane = 1:5);
mp 77–78 ЊC; δH (270 MHz; CDCl3) 5.03 (2H, br s), 6.65 (1H,
dd, J 1.32 and 7.59), 6.76 (1H, dd, J 1.32 and 8.24), 7.21–7.41
(6H, m); δC (67.8 MHz; CDCl3) 117.07, 120.45, 127.35, 127.71,
128.52, 132.36, 135.54, 138.33, 138.71, 141.80; m/z (EI)
214(Mϩ), 197, 185, 167, 157, 139, 130, 115, 91, 77, 63, 51, 39;
Found: C, 67.01; H, 4.81; N, 12.99. C12H10N2O2 requires C,
67.28; H, 4.71; N, 13.08%.
5-Amino-2-nitrobiphenyl 7. Rf 0.06 (EtOAc–hexane = 1:5);
mp 115–116 ЊC; δH (270 MHz; CDCl3) 4.64 (2H, br s), 6.49 (1H,
d, J 2.64), 6.60 (1H, dd, J 2.64 and 8.91), 7.23–7.39 (5H, m),
7.91 (1H, d, J 8.91); δC (67.8 MHz; CDCl3) 112.90, 117.07,
127.82, 127.98, 128.05, 128.39, 128.61, 139.37, 140.45, 151.09;
m/z (EI) 214(Mϩ), 197, 185, 167, 158, 139, 130, 63; Found: C,
66.89; H, 4.86; N, 12.94. C12H10N2O2 requires C, 67.28; H, 4.71;
N, 13.08%.
2-Methoxy-5-nitrobenzoic acid 21g. To a mixture of 96%
sulfuric acid (18.4 g, 180 mmol) and 60% nitric acid (13.8 g, 131
mmol) was added o-methoxybenzoic acid (7.61 g, 50 mmol) at
5–10 ЊC. After stirring for 2 h at the same temperature, it was
quenched with ice-water and the product was extracted with
EtOAc. The organic extract was dried over anhydrous MgSO4
and concentrated in vacuo. Purification by recrystallization
(EtOH) afforded 2-methoxy-5-nitrobenzoic acid 21g31 (3.67 g,
59%) as a pale yellow crystalline solid; δH (270 MHz; CDCl3)
4.04 (3H, s), 7.18 (1H, d, J 9.24), 8.36 (1H, dd, J 2.97 and 9.24),
8.66 (1H, d, J 2.97).
5-tert-Butoxy-2-nitroaniline 10. Rf 0.31 (EtOAc–hexane =
1:5); mp 90–92 ЊC; δH (270 MHz; CDCl3) 1.45 (9H, s), 6.11
(2H, br s), 6.31 (1H, s), 6.33 (1H, d, J 8.25), 8.03 (1H, d, J 8.25);
δC (67.8 MHz; CDCl3) 28.81, 80.25, 107.91, 112.11, 127.40,
127.53, 146.52, 162.70; m/z (EI) 210(Mϩ), 195, 154, 138, 124,
108, 96, 81, 68, 57; Found: C, 57.05; H, 6.60; N, 13.37.
C10H14N2O3 requires C, 57.13; H, 6.71; N, 13.32%.
General procedure for amination of nitrobenzoic acids 21
A solution of O-methylhydroxylamine (188 mg, 4 mmol) and a
nitrobenzoic acid 21 (2 mmol) in DME (12 ml) was added
dropwise to a stirred suspension of ButOK (1.57 g, 14 mmol)
and Cu(OAc)2 (36 mg, 0.2 mmol) in DME (8 ml) over 10 min at
room temperature. After stirring for 2–4 h at room temperature,
it was quenched with water and acidified by 2 M HCl. The
products were extracted with EtOAc. The organic extract was
dried over anhydrous MgSO4 and concentrated in vacuo.
4-(tert-Butoxy)nitrobenzene 12.27 Rf 0.65 (EtOAc–
hexane = 1:5); δH (270 MHz; CDCl3) 1.46 (9H, s), 7.05 (2H, d,
J 9.23), 8.16 (2H, d, J 9.23).
Amination of 3,4-dichloro-1-nitrobenzene 13
A solution of O-methylhydroxylamine (59 mg, 1.25 mmol) and
3,4-dichloro-1-nitrobenzene 13 (192 mg, 1 mmol) in diethoxy-
1442
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444

View Article Online
Purification by silica gel thin layer chromatography (CHCl3–
MeOH–AcOH) afforded the aminonitrobenzoic acids 22.
124.21, 131.63, 150.08, 163.61, 164.92; HRMS(FAB) Found:
(M ϩ H)ϩ, 213.0559. C8H9N2O5 requires M, 213.0512.
3-Amino-2-nitrobenzoic acid 22a.30 Rf 0.54 (CHCl3–MeOH–
AcOH = 10:10:0.1); δH (400 MHz; DMSO-d6) 6.37 (2H, br s),
6.72 (1H, d, J 6.88), 6.92 (1H, d, J 8.39), 7.22 (1H, dd, J 6.88
and 8.39).
Acknowledgements
We wish to thank Professor Z. Yoshida and Professor
M. Tokuda for helpful discussions.
5-Amino-2-nitrobenzoic acid 22b.32 Rf 0.25 (CHCl3–MeOH–
AcOH = 10:10:0.1); δH (400 MHz; DMSO-d6) 6.35 (2H, br s),
6.40 (1H, d, J 9.23), 6.41 (1H, s), 7.67 (1H, d, J 9.23).
References
1 M. J. Astle, Industrial Organic Nitrogen Compounds, Reinhold
Publishing Corp., New York, 1961, p. 83.
2 L. Schmerling, US 2 948 755/1960 (Chem. Abstr., 1961, 55, 1 527g);
E. N. Squire, DE 2 114 254/1971 (Chem. Abstr., 1972, 76, 24 892n);
P. Kovacic, in Friedel Crafts and Related Reactions, ed. G. A. Olah,
John Wiley & Sons, Inc., New York, 1964, Vol. III, part 2, p. 1493;
F. Minisci, R. Galli and M. Cecere, Tetrahedron Lett., 1965, 4663;
G. G. Arzoumanidis and F. C. Rauch, J. Chem. Soc., Chem.
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T. D. Ernst, J. Org. Chem., 1989, 54, 1203; R. A. Abramovitch,
J. M. Beckert, P. Chinnasamy, H. Xiaohua, W. Pennington and
A. R. V. Sanjivamurthy, Heterocycles, 1989, 28, 623; N. R.
Ayyangar, S. N. Naik and K. V. Srinivasan, Tetrahedron Lett., 1990,
31, 3217; H. Takeuchi, T. Adachi and H. Nishiguchi, J. Chem. Soc.,
Chem. Commun., 1991, 1524; H. Mitchell and Y. Leblanc, J. Org.
Chem., 1994, 59, 682; M. Wozniak, M. Grzegozek, W. Roszkiewicz
and B. Szpakiewicz, Recl. Trav. Chim. Pays-Bas, 1995, 114, 13;
M. K. Stern, B. K. Cheng and J. Clark, New J. Chem., 1996, 20, 259
and references cited therein.
3 J. Golinski and M. Makosza, Tetrahedron Lett., 1978, 3495;
M. Makosza and T. Glinka, J. Org. Chem., 1983, 48, 3860;
M. Makosza and K. Wojciechowski, Liebigs Ann./Recl., 1997, 1805.
4 F. Terrier, Nucleophilic Aromatic Displacement: the Influence of
the Nitro Group, VCH Publishers, Inc., New York, 1991, p. 257;
O. N. Chupakhin, V. N. Charushin and H. C. van der Plas,
Nucleophilic Aromatic Substitution of Hydrogen, Academic Press,
San Diego, 1994, p. 1.
5 M. Makosza and J. Winiarski, Acc. Chem. Res., 1987, 20, 282.
6 M. Makosza and K. Sienkiewicz, J. Org. Chem., 1990, 55, 4979;
1998, 63, 4199.
7 (a) A. R. Katritzky and K. S. Laurenzo, J. Org. Chem., 1986, 51,
5039; 1988, 53, 3978; (b) M. Makosza and M. Bialecki, J. Org.
Chem., 1992, 57, 4784; (c) M. Makosza and M. Bialecki, J. Org.
Chem., 1998, 63, 4878; (d) P. F. Pagoria, A. R. Mitchell and
R. D. Schmidt, J. Org. Chem., 1996, 61, 2934.
8 (a) J. Meisenheimer and E. Patzig, Chem. Ber., 1906, 39, 2533;
(b) C. C. Price and S.-T. Voong, Org. Synth., 1955, Coll. Vol. III,
664; (c) H. E. Baumgarten, J. Am. Chem. Soc., 1955, 77, 5109;
(d) M. Hasegawa and T. Okamoto, Yakugaku Zasshi, 1973, 93,
1024 (Chem. Abstr., 1973, 79, 104 485j); (e) R. Nasielski-Hinkens,
J. Kotel, T. Lecloux and J. Nasielski, Synth. Commun., 1989, 19, 511.
9 S. Seko and N. Kawamura, J. Org. Chem., 1996, 61, 442.
10 For example, see J. Senn-Bilfinger, H. Schaefer, V. Figala, K.
Klemm, G. Rainer, R. Riedel, C. Schudt and W. Simon, DE 3 240
248/1983 (Chem. Abstr., 1983, 99, 70 734k).
4-Amino-3-nitrobenzoic acid 22c.7d Rf 0.50 (CHCl3–MeOH–
AcOH = 10:1:0.1); δH (270 MHz; DMSO-d6) 7.06 (1H, d,
J 8.91), 7.86 (1H, dd, J 1.98 and 8.91), 7.95 (2H, br s), 8.56 (1H,
d, J 1.98), 12.99 (1H, br s).
2-Amino-3-nitrobenzoic acid 22d.33 Rf 0.63 (CHCl3–MeOH–
AcOH = 10:1:0.1); δH (270 MHz; DMSO-d6) 6.72 (1H, dd,
J 7.59 and 8.58), 8.23 (1H, dd, J 1.65 and 7.59), 8.32 (1H, dd,
J 1.65 and 8.58), 8.51 (2H, br s), 13.45 (1H, br s).
2-Amino-5-nitrobenzoic acid 22e.7c Rf 0.50 (CHCl3–MeOH–
AcOH = 10:1:0.1); δH (270 MHz; DMSO-d6) 6.88 (1H, d,
J 9.24), 7.95 (2H, br s), 8.08 (1H, dd, J 2.64 and 9.24), 8.61 (1H,
d, J 2.64), 12.99 (1H, br s).
3-Amino-5-methoxy-4-nitrobenzoic acid 22f. Rf 0.48 (CHCl3–
MeOH–AcOH = 10:1:0.1); mp 200–205 ЊC (dec.); δH (270
MHz; DMSO-d6) 3.86 (3H, s), 6.78 (1H, s), 7.15 (1H, s); δC (67.8
MHz; DMSO-d6) 56.37, 98.73, 111.02, 129.26, 133.75, 142.63,
152.62, 166.42; HRMS(FAB) Found: (M ϩ H)ϩ, 213.0506.
C8H9N2O5 requires M, 213.0512.
3-Amino-2-chloro-4-nitrobenzoic acid 22g. Rf 0.38 (CHCl3–
MeOH–AcOH = 10:5:0.1); mp 151–153 ЊC; δH (270 MHz;
DMSO-d6) 6.91 (1H, d, J 8.91), 7.47 (2H, br s), 8.08 (1H, d,
J 8.91); δC (67.8 MHz; DMSO-d6) 114.07, 118.46, 124.89,
132.31, 139.07, 142.32, 166.65; HRMS(FAB) Found: Mϩ,
215.9987. C7H5ClN2O4 requires M, 215.9938.
5-Amino-2-chloro-4-nitrobenzoic acid 22h. Rf 0.28 (CHCl3–
MeOH–AcOH = 10:5:0.1); δH (270 MHz; DMSO-d6) 7.43
(1H, s), 7.45 (2H, br s), 8.03 (1H, s).
3-Amino-5-methoxy-2-nitrobenzoic acid 22i. Rf 0.46 (CHCl3–
MeOH–AcOH = 10:5:0.1); mp 188–190 ЊC (dec.); δH (270
MHz; DMSO-d6) 3.81 (3H, s), 6.30 (1H, d, J 2.64), 6.53 (1H, d,
J 2.64), 7.36 (2H, br s); δC (67.8 MHz; DMSO-d6) 55.91, 100.11,
106.15, 123.29, 135.10, 148.05, 163.04, 167.91; HRMS(FAB)
Found: (M ϩ H)ϩ, 213.0528. C8H9N2O5 requires M, 213.0512.
11 CAUTION: Dried O-methylhydroxylamine has deflagration
potential. T. C. Bissot, R. W. Parry and D. H. Campbell, J. Am.
Chem. Soc., 1957, 79, 796.
12 Similar regioselectivity was observed in VNS alkylation. See M.
Makosza, T. Glinka and A. Kinowski, Tetrahedron, 1984, 40, 1863.
13 W. Buck, R. Sehring, G. Linden and S. Lust, DE 2 831 262/1980
(Chem. Abstr., 1980, 93, 26 083z).
3-Amino-5-chloro-2-nitrobenzoic acid 22j. Rf 0.50 (CHCl3–
MeOH–AcOH = 7:3:0.1); mp 178–180 ЊC; δH (270 MHz;
DMSO-d6) 6.79 (1H, d, J 1.98), 7.14 (2H, br s), 7.15 (1H, d,
J 1.98); δC (67.8 MHz; DMSO-d6) 115.38, 119.00, 129.22,
133.19, 137.92, 145.30, 166.33; HRMS(FAB) Found:
(M ϩ H)ϩ, 217.0056. C7H6ClN2O4 requires M, 217.0017.
14 For zinc promoted direct amination of nitropyridines, see S. Seko
and K. Miyake, Chem. Commun., 1998, 1519.
15 T. Naka, K. Nishikawa and T. Kato, EP 459 136/1991 (Chem.
Abstr., 1992, 116, 128 924k).
16 B. H. Lipshutz and S. Sengupta, in Organic Reactions, ed.-in-chief
L. A. Paquette, John Wiley & Sons, Inc., New York, 1992, Vol. 41,
ch. 2, p. 135.
17 O. Haglund, A. A. K. M. Hai and M. Nilsson, Synthesis, 1990, 942;
O. Haglund and M. Nilsson, Synthesis, 1994, 242.
18 J. B. Shoesmith and A. Mackie, J. Chem. Soc., 1928, 2334.
19 M. L. Cerrada, J. Elguero, J. de la Fuente, C. Pardo and M. Ramos,
Synth. Commun., 1993, 23, 1947.
20 K.-Y. Chu and J. Griffiths, J. Chem. Soc., Perkin Trans. 1, 1978,
1194.
21 M. Lemaire, A. Guy, P. Boutin and J. P. Guette, Synthesis, 1989,
761.
2-Amino-6-methoxy-3-nitrobenzoic acid 22k. Rf 0.48 (CHCl3–
MeOH–AcOH = 10:1:0.1); mp 173–175 ЊC; δH (270 MHz;
DMSO-d6) 3.90 (3H, s), 6.56 (1H, d, J 9.57), 7.51 (2H, br s),
8.21 (1H, d, J 9.57); δC (67.8 MHz; DMSO-d6) 56.66, 101.26,
107.42, 126.63, 130.53, 145.39, 163.65, 167.19; HRMS(FAB)
Found: (M ϩ H)ϩ, 213.0511. C8H9N2O5 requires M, 213.0512.
4-Amino-2-methoxy-5-nitrobenzoic acid 22l. Rf 0.33 (CHCl3–
MeOH–AcOH = 10:1:0.1); mp 207–209 ЊC (dec.); δH (270
MHz; DMSO-d6) 3.82 (3H, s), 6.53 (1H, s), 7.83 (2H, br s),
8.51 (1H, s); δC (67.8 MHz; DMSO-d6) 56.07, 98.67, 109.65,
J. Chem. Soc., Perkin Trans. 1, 1999, 1437–1444
1443

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