An efficient and fast procedure for the preparation of 2-nitrophenylamines under microwave conditions

Article abstract of DOI:10.1055/s-2003-37530

2-Nitrophenylamines were prepared in good yields from 2-chloronitrobenzen (or 2-fluoronitrobenzene) and amines in the presence of anhydrous potassium fluoride under microwave irradiation and solvent free conditions.

Full text of DOI:10.1055/s-2003-37530

5
64
LETTER
An Efficient and Fast Procedure for the Preparation of 2-Nitrophenylamines
under Microwave Conditions
P
Z
reparation of
2
h
-Nitropheny
i
lamine
-
s under
M
B
icrowave
C
ond
i
itions n Xu, Ying Lu, Zong-Ru Guo*
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China
Fax +86(10)83155752; E-mail: zrguo@imm.ac.cn
Received 21 January 2003
O
N+
O
N+
Abstract: 2-Nitrophenylamines were prepared in good yields from
-chloronitrobenzen (or 2-fluoronitrobenzene) and amines in the
presence of anhydrous potassium fluoride under microwave irradi-
ation and solvent free conditions.
2
KF/K CO
O-
2
3
O-
+ NH2R
MW
R
X
N
H
Key words: aminations, amines, microwave irradiation, nucleo-
philic aromatic substitution
1
a
b
X=F
X=Cl
3
2
1
Scheme 1
Benzimidazoles as pharmacophore or scaffold exhibit
1
many pharmacological activities. In general, 2-nitrophe- In the search for optimal reaction conditions, different
nylamines are important intermediates in the synthesis of equivalents of anhydrous potassium fluoride and potassi-
this kind of benzo-fused heterocycles. The traditional um carbonate were examined. The reaction times were
methods for synthesizing 2-nitrophenylamines often re- also varied (Table 1). It showed that the best results were
quire vigorous conditions and the yields are not satisfac- obtained when the anhydrous potassium fluoride and po-
2
3
tory. The improved procedures often use palladium tassium carbonate were used in equivalent amount. Due to
acetate complexes supported by 2,2′-bis(diphenylphos- short reaction times and high yields, the easy work-up
phino)-1,1′-binaphthyl (BINAP) or 2-(di-tert-butylphos- procedure by crystallization was possible.
phino)biphenyl as catalysts. However these phosphine
4
5
Table 1 Optimization of Reaction Condition for the Synthesis of N-
ligands are expensive. Kulagowski et al. and Lin et al.
(
4′-Methoxy-phenyl)-2-nitro-phenylamine
had reported that 2-fluoronitrobenzene or 2-chloro-
nitrobenzene can react with substituted anilines in the
presence of anhydrous potassium fluoride. These reac-
tions were carried out at 160–180 °C for 12–48 hours.
O
O-
N+
NH2
O
H
N
N+
O-
MW
+
To shorten the reaction time, considerable attention has
been focused on microwave assisted organic synthesis.
Although it is not very clear why many reactions work ex-
tremely well under microwave irradiation, these methods
F
OMe
OMe
Domestica Yield
En- 2-Fluoroni- p-Methox- Anhydrous K CO
try trobenzene ypheny-
2
3
6
7
has gained popularity in recent years. Loupy et al. have
published a number of reviews on solvent-free reactions
under microwave irradiation. This technique has been
claimed to be particularly environmentally friendly and
decreasing the risk of explosions, since it avoids the use of
solvents and offers simple methods of workup. Recent
publications also reported that the nucleophilic aromatic
b
KF
(equiv)
(equiv) Micro-
wave,
(%)
(equiv)
lamine
(equiv)
Time (min)
1
2
3
4
5
1
1
1
1
1
2
1
1
1
1
1
1
0
1
1
0
20
33
60
30
93
90
0.5
1
20
20
8
8
substitution reactions could be accelerated in solvent and
9
solvent-free conditions under microwave irradiation.
1
Amination reactions were completed with the unsatisfied
yield (17–68%) in the presence of potassium carbonate
and cuprous bromide under microwave in the absence of
2
8
a
NationalTM domestic microwave oven (90 W).
Yield of isolated product, based on 2-fluoronitrobenzene.
1
0
b
solvent. It encouraged us to investigate if the yield of
compound 3 could be increased and the reaction time de-
creased under microwave irradiation and solvent-free
conditions (Scheme 1).
It is accepted that thermal effects and specific microwave
effects can induce the acceleration of reactions under mi-
crowave irradiation. In order to interpret the microwave
effect, this reaction was carried out in oil bath under sim-
ilar conditions (Table 2). It suggested that specific micro-
wave effects play an important role in these reactions.
1
1
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0564,0566,ftx,en;U14402ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Preparation of 2-Nitrophenylamines under Microwave Conditions
565
Table 2 Comparison between Heating in Oil Bath (∆) and Micro-
wave Irradiation (MW)
Table 3 Synthesis of N-Substituted 2-Nitrophenylamines (3a–h)
O
N+
O
O–
NH2
N
O–
R
O
N
H
N
OH
N
H
+
X
OMe
Prod- R
uct
Domestic
Yield mpc
Ref.
OMe
1
1
a
b
X=F
X=Cl
Microwave,a (%)
Time (min)
b
(°C)
Substrate Reaction conditions Yield (%, ∆)b Yield (%, MW)b,c
5d
5d
3a
8
8
93
90
83–86
OMe
CH3
1
1
a
8 min, 90 °Ca
10 min, 90 °Ca
23
–d
93
90
3
b
67–70
b
a
4d
The temperature measured by immediately introducing a thermo-
3c
20
20
75
80
135–137
148–50
Cl
meter at the end of irradiation
b
Yield of isolated product, based on 2-fluoronitrobenzene or
3
3
3
3
d
e
f
5d
2
-chloronitrobenzene;
Br
c
TM
National domestic microwave oven (90 W).
d
Not detected by TLC.
20
20
20
70
60
75
82–83
84–86
63–64
5d
F
In order to extend the reaction scope, seven substituted
anilines and one aliphatic amine were used in the reac-
–d
COOEt
1
2
tion. All products were purified by the crystallization
from petroleum ether and formed in moderate to good
yield (60–93%), which are summarized in Table 3. The
data indicated that under microwave irradiation and sol-
vent-free condition, aliphatic amines and substituted
anilines with electron donating groups react smoothly
with compound 1 in the presence of anhydrous potassium
fluoride and potassium carbonate. But the substituted
anilines with electron withdrawing groups had low yields
due to their deactivating effect. It should also be noted that
there was no by-product separated under the reaction con-
ditions.
–d
g
F
–d
3
h
2
88
64–66
a
b
c
d
NationalTM domestic microwave oven (90 W).
All yield listed refer to pure isolated products based on compound 1.
Uncorrected.
1
All compounds are characterized by H NMR (300 MHz) in CDCl
and MS. Elemental Analysis were satisfactory for the products 3f, 3g,
h.
3
3
In conclusion a microwave-enhanced method for synthe-
sizing 2-nitrophenylamines has been developed which in-
volves the use of a solvent-free mixture of anhydrous
potassium fluoride and cheap potassium carbonate. The
process is highly efficient with easy workup.
(
3) (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (b) Emoto,
T.; Kubosaki, N.; Yamagiwa, T.; Kamilawa, T. Tetrahedron
Lett. 2000, 41, 355.
(
4) Kulagowski, J. J.; Rees, C. W. Synthesis 1980, 215.
Acknowledgement
(5) Zhu, Y. F.; Lin, G. Q.; Chen, Y. Q. Synthesis 1990, 430.
(
6) (a) Abramovich, R. A. Org. Prep. Proced. Int. 1991, 23,
We are grateful for Prof. Xiaotian Liang and Guangzhong Yang for
their advice on this work. We also wish to thank the Department of
Analytical Chemistry for support.
683. (b) Bose, D. S.; Jayalakshmi, B. J. Org. Chem. 1999,
64, 1713.
(
(
7) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213.
8) (a) Salmoria, G. V.; Dall’Ogllo, E.; Zucco, C. Tetrahedron
Lett. 1998, 39, 2471. (b) Cherng, Y. J. Tetrahedron 2002,
58, 887. (c) Cherng, Y. J. Tetrahedron 2002, 58, 1125.
(d) Cherng, Y. J. Tetrahedron 2002, 58, 4931.
References
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1) (a) Anon, U. K. Expert Opinion on Therapeutic Patents
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(
3
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Synlett 2003, No. 4, 564–566 ISSN 0936-5214 © Thieme Stuttgart · New York

5
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Z.-B. Xu et al.
LETTER
(
(
11) (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
a glass vial. After irradiation under microwave (90 W), the
mixture was treated with water and CH Cl . The organic
(
2
2
Tetrahedron 2001, 57, 9225.
layer was washed with 10% HCl and brine. The CH Cl
2
2
12) General Procedure: The preparation of N-(4′-methoxy-
phenyl)-2-nitrophenylamine (3a) is representative for all
synthesis.
solution was dried over anhyd Na SO , evaporated and
2
4
crystallized from petroleum ether (bp 60–90 °C) to give
4
1
orange crystals [mp 83–86 °C (lit. ref. : mp 89 °C)]. H
p-Methoxy phenylamine (1.1 mmol), anhyd KF (1.1 mmol)
and K CO (1.1 mmol) were well powdered with a mortar
NMR (CDCl , 300MHz): δ = 3.85 (s, 3 H, OCH , 6.72–8.19
3
3)
(8 H, aromatic H), 9.41 (s, br, 1 H, NH). MS (EI) m/z = 244
2
3
+
+
and pestle. 2-Chloronitrobenzene (or 2-fluoronitrobenzene)
1.1 mmol) was then added to the mixture and mixed well in
[M ], 229 [M – 15].
(
Synlett 2003, No. 4, 564–566 ISSN 0936-5214 © Thieme Stuttgart · New York