SCHEME 1
Facile Scalable Reduction of N-Acylated
Dihydropyrazoles
Michael D. Curtis,* Nancy C. Hayes, and Patricia A. Matson
Chemical DeVelopment, Procter & Gamble Pharmaceuticals,
P.O. Box 191, Norwich, New York 13815
pyrazolone-based compounds (6) which have been shown to
be potent inhibitors of cytokines, namely tumor necrosis factor-R
(TNF-R).7
ReceiVed March 14, 2006
Several methods have been reported for constructing this key
pyrazolidine pharmacophore including dipolar cycloaddition
techniques as well as the linear protocol employing the
orthogonal protecting group strategy depicted in Scheme 2 (7-
9).7-11 While this latter route was certainly capable of producing
gram quantities to supply early studies in the development of
the pyrazolone-based drug candidates (6), a method capable of
quickly producing multiple-kilogram quantities of this key
intermediate was required to supply additional studies.
The reduction of a variety of highly functionalized N-acylated
dihydropyrazoles (1) with BH3‚pyridine is described. The
process through which this unexpectedly difficult reduction
was discovered and developed is reported. A facile atom-
efficient route to the N-acylated dihydropyrazole reduction
precursors (1) is also illustrated. The resulting acylpyrazo-
lidine products (2) that arise upon reduction were isolated
in good to high yields following exposure to reaction
conditions which have been shown to tolerate a variety of
different functional groups. Finally, this route has been dem-
onstrated on a kilogram scale and provides direct access to
potential proline surrogates for peptidomimetic applications.
SCHEME 2
The significance of the pyrazolidine heterocycle is evidenced
by its presence as a structural subunit in a variety of compounds
frequently utilized in both the photography and pharmaceutical
industries.1-7 The photography industry has employed pyrazo-
lidinediones (3) as the main component in both pigments as
well as thermal-based printing materials (Scheme 1).1 Further-
more, pyrazolidine compounds have been converted into aza-
proline amino acids (4), which have been studied upon
incorporation into traditional peptides as well as small molecule
peptidomimetics (5).2-6 Our interest in this heterocycle stems
from its presence as a key pharmacophore in a series of
One potential shorter alternative route to this key intermediate
9 was recognized which originates with the condensation of
hydrazine and acrolein to provide the dihydropyrazole (11)
(Scheme 2).12,13 Acylation of 11 with the requisite acid chloride
followed by reduction of cyclic hydrazone (12) would quickly
open up access to the acylpyrazolidine (9) in an atom-efficient
fashion.
The synthesis of 11 from hydrazine and acrolein has been
previously described in the literature.12,13 However, these
methods are complicated by both the instability and water
solubility of 11, which hinder its isolation or require specialized
equipment to effect this transformation neat in the vapor phase.
A viable short synthetic process to 9 was developed which
circumvented the stability and water solubility problems inherent
(1) Wiley, R. H.; Wiley, P. In The Chemistry of Heterocyclic Compounds;
Weissburger, A., Ed.; Wiley-Interscience: New York, 1964; pp 123-125.
(2) Lecoq, A.; Boussard, G.; Marraud, M. Tetrahedron Lett. 1992, 33,
5209-5212.
(3) Zhang, W.-J.; Berglund, A.; Kao, J. L-F.; Couty, J.-P.; Gershengorm,
M. C.; Marshall, G. R. J. Am. Chem. Soc. 2003, 125, 1221-1235.
(4) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789-12854.
(8) Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen,
G. Org. Lett. 2004, 6, 2193-2196.
(9) Barluenga, J.; Fernandez-Mari, F.; Viado, A. L.; Aguilar, E.; Olano,
B.; Garcia-Granda, S.; Moya-Rubiera, C. Chem. Eur. J. 1999, 5, 883-
896.
(5) Liu, B.; Brandt, J. D. Moeller, K. D. Tetrahedron 2003, 59, 8515-
8523.
(6) Kim, H.-O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997, 38, 4935-
4938.
(10) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2,
4265-4267.
(7) Clark, M. P.; Laughlin, S. K.; Laufersweiler, M. J.; Bookland, R.
G.; Brugel, T. A.; Golebiowski, A.; Sabat, M. P.; 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) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc.
1997, 119, 8379-8380.
(12) Heinemann, U.; Thomas, R.; Lantzsch, L.; Ditgens, K.; Weber, E.
U.S. Patent 4 434 292, 1984.
(13) Engel, P. S.; Bodager, G. A. J. Org. Chem. 1988, 53, 4748-4758.
10.1021/jo060567j CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/24/2006
J. Org. Chem. 2006, 71, 5035-5038
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