A. Pezzella et al. / Tetrahedron Letters 46 (2005) 3541–3544
3543
O
I
antitumor propertiesÕ (PRIN 2003) and Regione Camp-
ania (L.R. 5, 2002) projects. We thank Mrs. Silvana
Corsani for technical assistance and the ÔCentro Interdi-
partimentale di Metodologie Chimico-FisicheÕ (CIMCF,
University of Naples Federico II) for NMR and mass
facilities. We thank Professor S. Quideau, University
of Bordeaux, for very helpful discussions on IBX chem-
istry and critical reading of the manuscript.
OH
O
H
O
O
I
O
I
HO
O
O
O
IBX
O
-25°C
O
O
O
O
O
I
HO
HO
HO
O
NaBH4/MeOH
-25°C
O
I
References and notes
OH
O
1. Martucci, C. P.; Fishman, J. Pharmacol. Ther. 1993, 57,
237–257.
Scheme 1.
2. Bolton, J. L.; Chang, M. Adv. Exp. Med. Biol. 2001, 500,
497–507.
3. (a) Kraychy, S. J. Am. Chem. Soc. 1959, 81, 1702–1704;
(b) Gelbke, H. P.; Haupt, O.; Knuppen, R. Steroids 1973,
21, 205–218; (c) Stubenrauch, G.; Knuppen, R. Steroids
1976, 28, 733–741; (d) Kiuru, P. S.; Wahala, K. Steroids
2003, 68(4), 373–375.
the reaction allows for the regioselective conversion of
monophenols to o-diphenols (catechols), and that in
few cases, that is, 1, 2, and 8, two ortho regioisomers
are produced in comparable yields. This is a reflection
of the comparable steric hindrance and reactivity on
the two positions ortho to the OH group.
4. Pezzella, A.; Lista, L.; Napolitano, A.; dÕIschia, M. J. Org.
Chem. 2004, 69, 5652–5659.
5. For a friendly synthesis of IBX see: Frigerio, M.;
Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537–4538, CAUTION! IBX is explosive under impact or
heating to >200 °C.
The IBX-induced conversion of phenol to catechol with
a brief mechanistic description6,8 is illustrated in Scheme
1.
´
6. Ozanne, A.; Pouysegu, L.; Depernet, D.; Francois, B.;
Quideau, S. Org. Lett. 2003, 5, 2903–2906.
´
7. Quideau, S.; Pouysegu, L.; Deffieux, D.; Ozanne, A.;
Gagnepain, J.; Fabre, I.; Oxoby, M. Arkivoc 2003, 6, 106–
119.
Use of cold methanolic NaBH4 after oxidation of phen-
ols 7–13 proved to be critical for efficient quinone reduc-
tion since, with CHCl3 or a CHCl3/MeOH mixture as
the solvent, a simple reductive work-up with sodium
dithionite at room temperature6 was not entirely satis-
factory leading in some cases to a poor recovery of the
catechol products. In a previous paper7 Quideau et al.
reported oxidation of 2,5-dimethylphenol (9) with Stabi-
lized IBX (SIBX), a non-explosive alternative to IBX, in
THF to give as main product a dimeric species arising
from hydroxylation at the carbon bearing the methyl
group. We did not notice the presence of that dimer in
our mixture, so it is likely that the different regioselectiv-
ity observed in the present study reflects the change of
solvent and/or temperature favoring attack of the oxy-
gen to the unsubstituted position of the aromatic ring.
8. Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.;
Pettus, T. R. R. Org. Lett. 2002, 4, 285–288.
9. Dwivedy, I.; Devanesan, P.; Cremonesi, P.; Rogan, E.;
Cavalieri, E. Chem. Res. Toxicol. 1992, 5, 828–833.
10. 2-Hydroxy-estra-1,3,5(10)-trien-3,17b-diol (3). Pale yellow
powder. UV (MeOH): kmax 281 nm. ESI/MS m/z: 287
[MÀH+]; ESI-HRMS calculated for C18H23O3 (MÀH+)
287.1647, found 287.1649. 1H NMR (CDCl3), d (ppm)
selected signals: 0.78 (s, 3H, CH3), 3.73 (t, J = 8.8 Hz, 1H,
CHOH), 6.58 (s, 1H), 6.81 (s, 1H).
4-Hydroxy-estra-1,3,5(10)-trien-3,17b-diol. (4) Pale yellow
powder. UV (MeOH): kmax 280 nm. ESI/MS m/z: 287
[MÀH+]; ESI-HRMS calculated for C18H23O3 (MÀH+)
287.1647, found 287.1648. 1H NMR (CDCl3), d (ppm)
selected signals: 0.77 (s, 3H, CH3), 3.73 (t, J = 8.8 Hz, 1H,
CHOH), 6.69 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H).
2-Hydroxyestrone (5). Pale yellow powder. UV (MeOH):
kmax 282 nm. ESI/MS m/z: 285[M ÀH+]; ESI-HRMS
calculated for C18H21O3 (MÀH+) 285.1491, found
285.1491. 1H NMR (CDCl3), d (ppm) selected signals:
0.78 (s, 3H, CH3), 6.61 (s, 1H,), 6.82 (s, 1H).
4-Hydroxyestrone (6). Pale yellow powder. UV (MeOH):
kmax 282 nm. ESI/MS m/z: 285[M ÀH+]; ESI-HRMS
calculated for C18H21O3 (MÀH+) 285.1491, found
285.1490, found 288.1725. 1H NMR (CDCl3), d (ppm)
selected signals: 0.77 (s, 3H, CH3), 6.67 (d, J = 8.4 Hz,
1H), 6.74 (d, J = 8.4 Hz, 1H).
The potential of IBX for the conversion of phenols to o-
quinones and catechols was also underscored in a recent
paper,8 in which a number of phenols substituted with
electron-donating groups were shown to undergo regio-
selective oxidation. The procedure described herein not
only stands comparison with the previous one, as judged
from the reported oxidation of 11 in CDCl3,8 but
expands its scope to include the estrogens and several
other phenolic compounds.11 Particularly worthy of
note is the conversion in good yield of phenol itself,
for which the IBX-mediated hydroxylation was reported
to be unsuccessful.8
Catechol. Brownish powder. UV (MeOH): kmax 280 nm.
ESI/MS m/z: 109 [MÀH+]; ESI-HRMS calculated for
C6H5O2 (MÀH+) 109.0289, found 109.0291.
4,5-Dimethylcatechol. Pale brown powder. UV (MeOH):
kmax 280 nm. ESI/MS m/z: 137 [MÀH+]; ESI-HRMS
calculated for C8H9O2 (MÀH+) 137.0603, found 137.0604.
1H NMR (CDCl3), d (ppm) selected signals: 2.20 (s, 6H,
CH3), 5.51 (s, 2H).
Acknowledgements
This work was carried out in the frame of the MIUR
ÔNatural products and their synthetic analogues with