3198
T. A. Brugel et al. / Tetrahedron Letters 47 (2006) 3195–3198
9. (a) Cirillo, P. F.; Pargellis, C.; Regan, J. Curr. Top. Med.
Conclusions
Chem. 2002, 2, 1021–1035; (b) Adams, J. L.; Badger, A. M.;
Kumar, S.; Lee, J. C. In Progress in Medicinal Chemistry;
King, F. D., Oxford, A. W., Eds.; Elsevier: Amsterdam,
2001; Vol. 39, pp 1–60.
A methodology for the convergent synthesis of 2,3-bis-
aryl pyrazolones has been developed highlighted by
the cyclization of a bisacylated hydrazine intermediate
using either NaH or DBU as base. The route allows
for the synthesis of both simple and substituted bicyclic
and tricyclic pyrazolone scaffolds as well as differentially
substituted monocyclic pyrazolones in moderate to
excellent yield. This new route allows for more rapid
development of SAR about the pyrazolone ring, as well
as entry into more complex and differentially substituted
systems not available by this previous method. Further
development of this methodology towards the synthesis
of other heterocycles is being investigated.
10. Clark, M. P.; Laughlin, S. K.; Laufersweiler, M. J.;
Bookland, R. G.; Brugel, T. A.; Golebiowski, A.; Sabat,
M.; Townes, J. A.; VanRens, J. C.; Djung, J. F.; Natchus,
M. G.; De, B.; Hsieh, L. C.; Xu, S. C.; Walter, R. L.;
Mekel, M. J.; Heitmeyer, S. A.; Brown, K. K.; Juergens,
K.; Taiwo, Y. O.; Janusz, M. J. J. Med. Chem. 2004, 47,
2724–2727.
11. Dutta, A. S.; Morley, J. S. J. Chem. Soc., Perkin Trans. 1
1975, 1712.
12. Representative procedure for the synthesis of pyrazolone 6
from pyrazolidine 11: A solution of 2-(4-fluoro-phenyl)-1-
[2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-
1-yl]-ethanone 11 (78.0 g, 0.217 mol) in DMF (400 mL)
was added over 30 min to a 0 ꢂC slurry of NaH (21.6 g of
60% dispersion in mineral oil, 0.540 mol) in DMF
(150 mL). The mixture was stirred at 0 ꢂC for 30 min,
then quenched slowly with saturated aqueous ammonium
chloride solution (6 L). The mixture was extracted with
EtOAc (2 · 2L) and the combined organic layers dried
over Na2SO4, filtered and concentrated in vacuo to give a
viscous oil. The crude product was purified by flash
chromatography on silica gel (600 g SiO2, EtOAc to 10%
MeOH/EtOAc to 20% MeOH/EtOAc) to give product 6
(36.0 g, 49%) as a yellow foam: 1H NMR (300 MHz,
CDCl3) d 8.42 (dd, J = 5.4, 1.5 Hz, 1H), 7.41 (dd, J = 8.4,
5.4 Hz, 2H), 7.07 (dd, J = 8.4, 8.4 Hz, 2H), 6.83 (dd,
J = 5.4, 1.5 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 4.09 (t,
J = 6.9 Hz, 2H), 2.76 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H),
2.60 (s, 3H); ESI/MS: 343 (M+H).
Acknowledgements
We thank John VanRens and Steven K. Laughlin for
helpful discussions. We also thank Mark Webster for
chemistry support.
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