A. Bose et al. / Tetrahedron Letters 48 (2007) 3945–3947
3947
nitroestrones (entry 17). The mixture of estrone with
CAN in the presence of refluxing benzene produced 2
in low yield. Unreacted estrone (approximately 30%)
was recovered from the reaction mixture.
122, 119, 50, 48, 42, 37, 36, 31, 29, 26, 21, 14; MS:
m/e 315 (M+).
Compound 3: mp 185–188 °C;12 IR (CH2Cl2): 3622,
2255, 1917, 1817, 1793, 1635, 1558 cmꢀ1 1H NMR
;
These results indicate that the nitration strongly depends
on the nature of the solid support. Based on a publica-
tion,11 we believe that the binding of metal nitrates to
the free hydroxyl group of the multi-metallic montmoril-
lonite is important and that this complex produces the
nitronium ion. Clearly, the success of bismuth nitrate,
calcium nitrate and zinc nitrate to produce mostly a sin-
gle product with alumina and molecular sieves strength-
ens the importance of the composition of the solid
support. It is noteworthy to observe a successful nitra-
tion of estrone with calcium nitrate and zinc nitrate
using montmorillonite and other solids. These experi-
ments have suggested that excess nitrate salts in the pres-
ence of acidic surface (at room temperature to reflux
temperature) are the choices to produce 2- and 2,4-dini-
troestrones. Nonacidic surfaces are necessary to direct
the reaction to the mononitration side. This also sug-
gests that the temperature of the reaction is not an
important factor in this method. Concentrated nitric
acid is not an effective reagent for the nitration of
estrone. Because of the presence of a phenolic hydroxyl
group, estrone may undergo a variety of oxidations with
nitric acid. These experiments have indicated that the
amount of solid supports is not crucial. For example,
nitration of estrone proceeds equally well with 1 g or
5 g of montmorillonite. But, the presence of solid sur-
faces is important (either in dry or wet form). Nitration
of estrone is not possible with these salts without a solid
adsorbent. The presence of water retards nitration dra-
matically. A reaction without Dean Stark under an iden-
tical condition proceeds much slowly than a reaction
that has been performed under azetropic distillation. It
has also been found that the reaction proceeds much
better if the mixture is dry enough. Keeping the solid
reaction mixture in the presence of clay gives the prod-
uct, but it takes 24 h to complete the reaction. Drying
the same reaction mixture under a vacuum pump accel-
erates the speed of the reaction (30 min).
(CDCl3) d: 10.65 (s, 1H), 8.20 (s, 1H), 2.98–1.45 (m,
15H), 0.97 (s, 3H) 13C NMR (CDCl3) d: 220, 145, 140,
134, 132, 122, 50, 47, 42, 36, 35, 32, 27, 26, 25, 22, 13;
MS: m/e 360 (M+).13
Acknowledgements
We are grateful to the Welch Foundation departmental
grant (BG0017). We also thank NIH-SCORE
(2S06GM008038-36) for the support to B.K.B.
References and notes
1. (a) Cornelis, A.; Delaude, L.; Gertmans, A.; Laszlo, P.
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A. Aldrichim. Acta 1988, 21, 97; (c) Laszlo, P.; Vandor-
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A.; Gerstmans, A.; Laszlo, P. Chem. Lett. 1988, 1839.
2. (a) Banik, B. K.; Samajdar, S.; Banik, I. Tetrahedron Lett.
2003, 44, 1699; (b) Srivastava, N.; Banik, B. K. J. Org.
Chem. 2003, 68, 2109.
3. (a) Kraychy, S. J. Am. Chem. Soc. 1959, 81, 1702; (b)
Patton, T. L. J. Org. Chem. 1959, 24, 1795; (c) Rozhin, J.;
Ludwig, E. H.; Corombos, J.; Odden, D.; Horwitz, J. P.;
Hughes, R.; Hughes, D. E.; Wilson, E.; Brooks, S. C. Can.
Res. 1983, 43, 2611; (d) Jordan, V. C.; Koch, R.
Endocrinology 1989, 124, 1717; (e) Palomino, E.; Heeg,
M. J.; Pilat, M. J.; Hafner, M.; Polin, L.; Brooks, S. C.
Steroids 1996, 61, 670.
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5. Banik, B. K.; Becker, F. F. Bioorg. Med. Chem. 2001, 9,
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8. Cornelis, A.; Laszlo, P. Synthesis 1985, 909.
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In summary, we have demonstrated a simple, rapid and
convenient method for the aromatic nitration of estrone
with bismuth nitrate, calcium nitrate and zinc nitrate in
the presence of different solid surfaces. The superiority
of this method over others includes a very rapid reaction
with readily available non-corrosive reagents. Further,
our method requires no strong acid for the preparation
of the surface, no acetic anhydride for the reaction and it
can be applied to the most important sex hormone and
results in a high overall yield. Nitro estrones are excel-
lent substrates for the preparation of advanced inter-
mediates that can be used as steroids.
10. Sathunuru, R.; Biehl, E. Arkivoc 2004, 89.
11. Kropp, J. P.; Breton, G. W.; Fields, J. D.; Tung, J. C.;
Loomis, B. R. J. Am. Chem. Soc. 2000, 122, 4280.
12. Werbin, H.; Holoway, C. J. Bio. Chem. 1956, 651, The
melting point of 2-nitroestrone as reported in this paper is
184 °C. The melting point of 2,4-dinitroestrone as
reported in this paper is 185–187 °C.
13. A representative experimental procedure is as follows:
Estrone (1 mmol) and montmorillonite KSF (500 mg,
Aldrich) were added to a suspension of bismuth nitrate
pentahydrate (1 mmol) in THF (10 mL). The solvent was
then evaporated under reduced pressure and dried in a
vacuum pump for 5 min. The mixture was then repeatedly
washed with dichloromethane (25 mL) and concentrated
to afford the crude product. The pure product was isolated
Compound 2: mp 178–180 °C;12 IR (CH2Cl2): 3320,
1
1740, 1525, 1310 cmꢀ1; H NMR (CDCl3) d: 10.40 (s,
by crystallization (ethyl acetate/hexanes = 20:80).
A
1H), 7.95 (s, 1H), 6.82 (s, 1H), 3.0–1.4 (m, 15H), 0.95
number of conditions were examined as can be seen in
Table 1.
(s, 3H) 13C NMR (CDCl3) d: 220, 153, 149, 133, 131,