Zinc-promoted direct amination of nitropyridines with methoxyamine via vicarious nucleophilic substitution

Article abstract of DOI:10.1039/a803497d

Direct animation of nitropyridines with methoxyamine in the presence of a stoichiometric amount of zinc(II) chloride under basic conditions proceeds to give aminonitropyridines.

Full text of DOI:10.1039/a803497d

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Zinc-promoted direct amination of nitropyridines with methoxyamine via
vicarious nucleophilic substitution
Shinzo Seko*† and Kunihito Miyake
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd, Tsukahara, Takatsuki, Osaka 569-1093, Japan
Direct amination of nitropyridines with methoxyamine in
the presence of a stoichiometric amount of zinc(II) chloride
under basic conditions proceeds to give aminonitropyr-
idines.
chloride. Thus zinc(ii) chloride was found to be the best
promoter of this amination. In the absence of zinc catalyst, the
reaction did not proceed and starting material was recovered.
The zinc(ii) salt may act as an acceptor of an unshared electron
pair from the nitrogen in pyridine ring or the oxygen of the
N-oxide, and thus activates the substrate. A catalytic amount of
zinc salt is insufficient to promote the amination since zinc also
forms a coordination complex with the product as well as the
substrate. This differs from the previously reported copper-
catalyzed amination of nitrobenzenes with methoxyamine, in
which interaction between the copper catalyst and methoxy-
amine was observed.10
Direct amination of nitropyridine is a simple synthetic approach
to aminonitropyridines, which are of great importance as
intermediates of various biologically active compounds con-
taining imidazopyridine, triazolopyridine etc.1 The well-known
Chichibabin amination,2 in which the a-position of the pyridine
ring is aminated by an alkali metal amide, fails to aminate
nitropyridines.3 Although oxidative direct amination of 3-
nitropyridines using liquid ammonia/potassium permanganate
has been reported,4 2- and 4-nitropyridines do not react in this
system. On the other hand, alkylation of nitropyridines5 and
amination of nitrobenzenes6 via vicarious nucleophilic substitu-
tion (VNS),7 which has been extensively studied by Makosza,
has been reported. However, little attention has been given to
the VNS amination of nitropyridines.8 Recently, we have found
that alkoxyamines, in particular methoxyamine,9 efficiently
aminate nitrobenzenes in the presence of a copper catalyst via
VNS.10 As part of our investigations to develop new amination,
we report here the direct amination of nitropyridines with
methoxyamine in the presence of a stoichiometric amount of a
zinc salt.
An ortho selectivity with respect to the nitro group was
observed in the case of 2-chloro-3-nitropyridine (entries 10 and
11). This selectivity is in good agreement with those observed in
the amination of nitrobenzenes with methoxyamine.10 We
presume that in both cases (Scheme 1, X = C,N), ortho
selectivity was observed because the neighboring nitro group in
the s-adduct 3, derived from the ortho attack of methoxyamine
on the nitroarene, assists in the elimination of the methoxy
anion via a five-membered intermediate 4.6b In contrast,
Wozniak has reported that the same substrate was aminated by
liquid ammonia/potassium permanganate with para selectivity
to give mainly 6-amino-2-chloro-3-nitropyridine in 40% yield.
Treatment of 6-methoxy-3-nitropyridine with methoxyamine
in the presence of a stoichiometric amount of zinc(ii) chloride
under strongly basic conditions in DMSO at room temperature
gave 2-amino-6-methoxy-3-nitropyridine in 87% yield (Table
1, entry 1). The yield of the amination was strongly influenced
by the combination of substrates and solvents used. In
diethoxymethane (DEM), THF, DME, toluene and DMF, yields
of 2-amino-6-methoxy-3-nitropyridine were 62, 59, 43, 19 and
0%, respectively (entries 2, 3, 4, 5 and 6). In DMF, the reaction
with 2-chloro-3-nitropyridine also did not give the aminated
products (entry 12). However, with 4-nitropyridine or 2-amino-
3-nitropyridine, DMF was a good solvent (entries 7, 8 and 15).
In general, DMSO was relatively favored in this reaction.
DMSO may play a significant role in the activation of a
Meisenheimer intermediate,11 which result from nucleophilic
attack of methoxyamine ortho or para to the nitro group.
4-Nitropyridine and 4-nitropyridine N-oxide were aminated
with methoxyamine to afford 3-amino-4-nitropyridine and
3-amino-4-nitropyridine N-oxide, respectively (entries 7 and 8).
The N-oxide provided the better result. The product is a
precursor of 3,4-diaminopyridine, an important intermediate of
many pharmaceuticals, which is presently synthesized from
pyridin-4-ol via a tedious reaction sequence.1c Our method-
ology provides a new efficient route to 3,4-diaminopyridine
from 4-nitropyridine N-oxide, which is cheaper than pyridin-
4-ol. The use of other metallic halides as a promoter of the
reaction with 4-nitropyridine N-oxide was examined. In the
presence of titanium(iv) chloride, manganese(ii) chloride,
cobalt(ii) chloride, nickel(ii) chloride, copper(i) chloride or
aluminum(iii) chloride instead of zinc(ii) chloride, the reaction
gave 3-amino-4-nitropyridine N-oxide in 2, 8, 17, 0, 35 and 0%
yields, respectively. The result with copper(i) chloride lacked
reproducibility although it was similar to that with zinc(ii)
Table 1 Direct amination of nitropyridines 1 with methoxyaminea
H2N
ZnCl2
R
NO2
+ NH2OMe
R
NO2
ButOK, room temp.
N
N
(O)n
1
(O)n
2
Yieldsb
(%)
Position
Position of
Entry
R
n
of NO2
Solvent amination
of 2
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
15d
16d
17d
6-MeO
6-MeO
6-MeO
6-MeO
6-MeO
6-MeO
H
H
3-EtO
2-Cl
2-Cl
2-Cl
6-Cl
2-NH2
2-NH2
2-NH2
2-OH
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
3
3
3
3
3
3
4
4
2
3
3
3
3
3
3
5
5
DMSO
DEM
THF
DME
Toluene
DMF
2
2
2
2
2
—
3
3
5
87
62 (70)c
59 (63)c
43 (50)c
19 (24)c
0
DMF
DMF
25
38
7 (10)c
34
28/8
0
DMSO
DME
DMSO
DMF
DEM
DMSO
DMF
4
4/6
—
2/4
6
6
6
9/13
58 (85)c
53
DEM
DEM
17 (26)c
9 (17)c
6
a
Unless otherwise noted, the amination of 1 was carried out with
methoxyamine (1.5 equiv.), zinc(ii) chloride (1 equiv.) and potassium tert-
b
butoxide (3 equiv.) in solvent at room temperature for 1–10 h. Isolated
yields. c Yields in parentheses are based on the conversion of 1. d 4 equiv.
of potassium tert-butoxide was used.
Chem. Commun., 1998
1519

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(3 ml) was added dropwise a solution of the nitropyridine (1
mmol) and NH2OMe (1.5 mmol) in DMSO (2 ml), and the
mixture was stirred at room temperature. After 1–10 h, the
reaction was quenched in saturated aq. NH4Cl and the products
were extracted with EtOAc. The combined organic layers were
washed with water, dried, filtered and concentrated. The crude
products were purified by silica gel thin layer chromatography
to afford the pure aminonitropyridine.
–
MeO
NH
O
O
NH
HN
+
+
H
–
–
–
N
–
N
NO2
O
O
B
+
H
product
X
X
X
3
X = C,N
4
5
Scheme 1
In conclusion, we have developed a new direct amination of
nitropyridines with methoxyamine in the presence of a
stoichiometric amount of zinc salt. An ortho selectivity to the
nitro group was observed, which is useful for the synthesis of
many pharmaceuticals containing imidazopyridine, triazolopyr-
idine and so on. The general, industrially practical method for
direct amination of aromatic compounds has yet to be achieved,
especially from the viewpoint of environmental protection.
Further studies in this field are in progress in our laboratory.
We thank Professor Z. Yoshida and Professor M. Tokuda for
helpful discussions.
He explained that the orientation of this reaction was controlled
by the charge distribution.4 However, neither charge control nor
orbital control obtained by molecular calculations could explain
our results.
It is noteworthy that the amination of 2-amino-3-nitropyr-
idine, 2-amino-5-nitropyridine and 5-nitropyridin-2-ol in the
presence of excess base (4 equiv.) proceeded (entries 14, 15, 16
and 17), despite no previous reports of VNS reactions of o- or
p-nitroaniline and o- or p-nitrophenol. Under strongly basic
conditions, o- or p-nitroaniline, o- or p-nitrophenol, 2-amino-
3-nitropyridine, 2-amino-5-nitropyridine, 3-nitropyridin-2-ol
and 5-nitropyridin-2-ol are easily deprotonated to form 6 or 7. A
Notes and References
–
–
NO2
NO2
† E-mail: seko@sc.sumitomo-chem.co.jp
X
Y
Y
X
1 (a) J. A. May, Jr. and L. B. Townsend, J. Org. Chem., 1976, 41, 1449;
(b) K. B. de Roos and C. A. Salemink, Recueil, 1969, 88, 1263; (c) J. B.
Campbell, J. M. Greene, E. R. Lavagnino, D. N. Gardner, A. J. Pike and
J. Snoddy, J. Heterocycl. Chem., 1986, 23, 669 and references cited
therein.
6
7
a X = C, Y = NH, O
b X = N, Y = NH, O
nucleophile cannot attack 6a and 7a because of the lack of an
electrophilic carbon center. However nitropyridine derivatives
6b and 7b are susceptible to addition of a nucleophile at the
a-position of the pyridine ring as well as to the Chichibabin
reaction. Therefore, the amination of 2-amino-3-nitropyridine
did not proceed with ortho selectivity but proceeded with para
selectivity to give 2,6-diamino-3-nitropyridine (entries 14 and
15).
Similarly 4-nitroquinoline N-oxide was aminated, although
in low yield (Scheme 2). This is important because, in spite of
many reports of direct amination of bicyclic nitroarenes12 with
hydroxylamine or liquid ammonia/potassium permanganate,
direct amination of 4-nitroquinoline derivatives has not been
previously reported.
2 R. A. Abramovitch and J. G. Saha, Adv. Heterocycl. Chem., 1966, 6,
229.
3 D. A. de Bie, B. Geurtsen and H. C. van der Plas, J. Org. Chem., 1985,
50, 484.
4 M. Wozniak, A. Baranski and B. Szpakiewicz, Liebigs Ann. Chem.,
1991, 875.
5 M. Makosza and K. Wojciechowski, Liebigs Ann./Recueil, 1997,
1805.
6 (a) A. R. Katritzky and K. S. Laurenzo, J. Org. Chem., 1986, 51, 5039;
(b) A. R. Katritzky and K. S. Laurenzo, J. Org. Chem., 1988, 53, 3978;
(c) M. Makosza and M. Bialecki, J. Org. Chem., 1992, 57, 4784; (d)
P. F. Pagoria, A. R. Mitchell and R. D. Schmidt, J. Org. Chem., 1996,
61, 2934.
7 M. Makosza and J. Winiarski, Acc. Chem. Res., 1987, 20, 282.
8 J. H. Boyer and W. Schoen, J. Am. Chem. Soc., 1956, 78, 423.
9 T. C. Bissot, R. W. Parry and D. H. Campbell, J. Am. Chem. Soc., 1957,
79, 796.
A typical experimental procedure is as follows. To a
suspension of ZnCl2 (1 mmol) and ButOK (3 mmol) in DMSO
10 S. Seko and N. Kawamura, J. Org, Chem., 1996, 61, 442.
11 N. R. Ayyangar, S. N. Naik and K. V. Srinivasan, Tetrahedron Lett.,
1990, 31, 3217
NO2
NO2
12 J. Meisenheimer and E. Patzig, Chem. Ber., 1906, 39, 2533; H. E.
Baumgarten, J. Am. Chem. Soc., 1955, 77, 5109; O. N. Chupakhin, V.
N. Charushin and H. C. van der Plas, Tetrahedron, 1988, 44, 1; H. C.
van der Plas, M. Wozniak and H. J. W. van der Haak, Adv. Heterocycl.
Chem., 1983, 33, 95; R. Nasielski-Hinkens, J. Kotel, T. Lecloux and J.
Nasielski, Synth. Commun., 1989, 19, 511.
NH2
i
+ NH2OMe
+
+
N
N
O–
O–
Scheme 2 Reagents and conditions: i, ZnCl2, ButOK, DMF, room temp.,
21%.
Received in Cambridge, UK, 11th May 1998; 8/03497D
1520
Chem. Commun., 1998