SCHEME 1. Syntheses of Modified Nitrophenols
A Convenient Method for Synthesizing
Modified 4-Nitrophenols
Yumi Nakaike, Yoshio Kamijo, Satoshi Mori,
Mina Tamura, Nagatoshi Nishiwaki,* and
Masahiro Ariga*
Department of Chemistry, Osaka Kyoiku University,
Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
the framework upon treatment with ketones.7,8 Nitro-
malonaldehyde (NMA-H) often appears as the synthon
in retrosyntheses for a variety of nitro compounds, but
it cannot actually be employed because of instability.
Thus, its sodium salt (NMA-Na) has been used as the
synthetic equivalent of NMA-H from old time.7 The salt
NMA-Na is prepared from furfural via mucobromic acid
with somewhat troublesome manipulations, and the
insolubility of NMA-Na in general organic solvents
obliges us to conduct reactions in aqueous medium or in
a highly polar solvent.9 Furthermore, crude NMA-Na is
impact-sensitive and thermally unstable and should be
handled as a potentially explosive material. Despite some
serious problems mentioned here, NMA-Na is widely
used even now in organic syntheses because of the
absence of any other efficient reagents.
From this viewpoint, we have shown two reagents that
behave as the synthetic equivalent of NMA-H. When 3,5-
dinitro-2-pyridone (2) was heated with ketones in the
presence of ammonia, the ring transformation proceeded
to give 5,6-disubstituted 3-nitropyridines accompanied by
elimination of anionic nitroacetamide.10 On the other
hand, our recent attention has been paid to 3-tert-
butylamino-2-nitro-2-propenal (formylnitroenamine 3,
see Scheme 1), which is readily prepared by aminolysis
of 1-methyl-5-nitro-2-pyrimidinone followed by half hy-
drolysis.11 Nitro-substituted pyrazoles, isoxazole, pyrrole,
pyrimidines, and diazepines could be easily synthesized
upon treatment of 3 with hetero dinucleophiles.12 Nitro-
enamine 3 is superior to NMA-Na and dinitropyridone
2 with regard to treatability, since 3 is soluble in almost
all general organic solvents and is not explosive. These
results prompted us to study the condensation of 3 with
carbon dinucleophiles for improvement of synthetic utility
Received August 11, 2005
â-Nitroenamine having a formyl group behaves as the
synthetic equivalent of unstable nitromalonaldehyde upon
treatment with ketones under basic conditions and leads to
2,6-disubstituted 4-nitrophenols. The present method is safer
than the conventional one using sodium nitromalonaldehyde
and enables the preparation of hitherto unknown nitrophe-
nols.
4-Nitrophenol derivatives 1 (see Scheme 1) reveal
versatile utilities for functional materials such as dyes,1
pharmaceutical agents,2 or their synthetic intermediates.
In the industrial process, substituted nitrophenols are
prepared by Friedel-Crafts alkylation followed by nitra-
tion.3 Friedel-Crafts reaction is a useful method for C-C
bond formation on the benzene ring;4 however, it suffers
from several disadvantages. Low regioselectivity of the
alkylation has not been overcome satisfactorily, although
energetic study has been performed on development of
catalysts for the alkylation.5 In addition, normal alkyl
groups longer than the ethyl group cannot be introduced
since the intermediate carbonium ion causes rearrange-
ment. The arylation6 and the monoalkylation of the
benzene ring also are not easily achieved.
(5) (a) Ota, H.; Aga, M. Jpn. Kokai Tokkyo Koho JP 271717; Chem.
Abstr. 2005, 142, 177305. (b) Yadav, G. D.; Salgaonkar, S. S. Ind. Eng.
Chem. Res. 2005, 44, 1706-1715. (c) Breslow, R.; Groves, K.; Mayer,
M. U. J. Am. Chem. Soc. 2002, 124, 3622-3635. (d) Inoue, Y.;
Nishizaki, T.; Beppu, M. Jpn. Kokai Tokkyo Koho JP 58146523. Chem.
Abstr. 1984, 100, 34255. (e) Kudoh, A.; Kawamata, M.; Ohshima, K.;
Kotani, M.; Mutoh, M.; Tsuda, T. Jpn. Kokai Tokkyo Koho JP
56063932; Chem. Abstr. 1981, 95, 203536. (f) Inoue, M.; Enomoto, S.
Chem. Pharm. Bull. 1976, 24, 2199-2203.
As another methodology for construction of nitrophe-
nols 1, a building block having a nitro group is built in
* To whom correspondence should be addressed. Tel: 81-729-78-
3399. Fax: 81-729-78-3399.
(1) (a) Osterby, B. R.; McKelvey, R. D. J. Chem. Educ. 1996, 73,
260-261. (b) Reichardt, C.; Eschner, M. Liebigs Ann. Chem. 1991,
1003-1012. (c) Kessler, M. A.; Wolfbeis, O. S. Synthesis 1988, 635-
636.
(2) (a) Fujimoto, K.; Asai, F. Jpn. Kokai Tokkyo Koho JP 2003002832;
Chem. Abstr. 2003, 138, 66685. (b) Selassie, C. D.; Verma, R. P.; Kapur,
S.; Shusterman, A. J.; Hanasch, C. J. Chem. Soc., Perkin Trans. 2 2002,
1112-1117. (c) Butera, J. A.; Caufield, C. E.; Graceffa, R. F.; Greenfield,
A.; Gunderson, E. G.; Havran, L. M.; Katz, A. H.; Lennox, J. R.; Mayer,
S. C.; McDevitt, R. E. U.S. Patent US 01/018525; Chem. Abstr. 2001,
134, 280608.
(3) (a) Shi, M.; Cui, S.-C.; Yin, W.-P. Eur. J. Org. Chem. 2005, 2379-
2384. (b) Muathen, H. A. Molecules 2003, 8, 593-598. (c) Rigterink,
R. H.; Bisabri-Ershadi, B. U.S. Patent US 86/923237; Chem. Abstr.
1990, 112, 98225.
(6) (a) Panda, G.; Mishra, J. K.; Sinha, S.; Gaikwad, A. K.; Srivas-
tava, A. K.; Srivastava, R.; Srivastava, B. S. Arkivoc 2005, ii, 29-45.
(b) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett., 2004, 6, 1159-1162. (c) Pal, M.; Batchu, V. R.; Para-
suraman, K.; Yeleswarapu, K. R. J. Org. Chem. 2003, 68, 6806-6809.
(7) Fanta, P. E.; Stein, R. A. Chem. Rev. 1960, 60, 261-266.
(8) Vaughan, W, R.; Finch, G. K. J. Org. Chem. 1956, 21, 1201-
1210.
(9) Fanta, P. E. Organic Syntheses; Wiley: New York, 1963; Collect.
Vol. IV, p 844-845.
(10) Matsumura, E.; Ariga, M.; Tohda, Y. Tetrahedron Lett. 1979,
20, 1393-1396.
(4) (a) Redde, V. P.; Prakash, G. K. S. In Chemistry of Phenols;
Rappoport, Z., Ed.: John Wiley & Sons, Ltd.: Chichester, 2003; Vol.
1, pp 605-660. (b) Chen, Y.-J.; Li, F. L.; Wang, D. Tetrahedron 2003,
59, 7609-7614.
(11) Nishiwaki, N.; Tohda, Y.; Ariga, M. Bull. Chem. Soc. Jpn. 1996,
69, 1997-2002.
(12) Nishiwaki, N.; Ogihara, T.; Takami, T.; Tamura, M.; Ariga, M.
J. Org. Chem. 2004, 69, 8382-8386.
10.1021/jo0516990 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/14/2005
J. Org. Chem. 2005, 70, 10169-10171
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