tures of unsymmetrical pyrazoles in these reactions.3,4Sev-
eral elegant methods for the regioselective synthesis of
unsymmetrically substituted 1-arylpyrazoles have been
developed in recent years;1c,d,2 however despite their
promising potential, these methods have limited applica-
tions in terms of generality and offer only little improve-
ment over classical phenylhydrazine-â-diketone route to
this class of compounds. Our own interest in addressing
this regiochemistry issue stems from our ongoing re-
search program utilizing R-oxoketene dithioacetals as
versatile 1,3-electrophilic building blocks for regiospecific
synthesis of substituted and condensed five- and six-
membered heterocycles and aromatic compounds.5-7 Dur-
ing the course of these studies, we became interested in
probing the reaction of R-oxoketene N,S-acetals with an
unsymmetrical binucleophile such as phenylhydrazine
with a view to achieve synthesis of both 5- and 3-amino-
1-arylpyrazoles in highly regiocontrolled fashion by varia-
tion of reaction conditions (Chart 1). Although several
Highly Regioselective Synthesis of 1-Aryl-3
(or 5)-alkyl/aryl-5 (or
3)-(N-cycloamino)pyrazoles
S. Peruncheralathan,† A. K. Yadav,† H. Ila,*,† and
H. Junjappa*,‡
Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India, and BioOrganics and Applied
Materials Pvt. Ltd., Peenya, Bangalore 560058, India
Received July 16, 2005
CHART 1
An efficient highly regioselective protocol for the synthesis
of isomeric 1,3-diaryl (or 1-aryl-3-alkyl) and 1,5-diaryl (or
1-aryl-5-alkyl)-5 (or 3)-(N-cycloamino)pyrazoles has been
reported by cyclocondensation of common R-oxoketene N,S-
acetal precursors with arylhydrazines by variation of reac-
tion conditions.
5-alkyl/arylamino-1-arylpyrazoles have found applica-
tions as pharmaceuticals and agrochemical agents ex-
2,8-10
hibiting a range of biological activities,
only a few
The 1-N-arylpyrazole ring system represents an im-
portant heterocyclic template that has attracted consid-
erable interest because of its long history of application
in pharmaceutical and agrochemical industry.1 Numer-
ous compounds containing 1-N-arylpyrazole moiety have
been shown to exhibit antihyperglycemic, analgesic, anti-
inflammatory, sedative, and hypnotic activities.1-3 Some
of these compounds have emerged as potent and selective
γ-aminobutyric acid (GABA)-gated chloride channel an-
tagonists,2 novel ligands for estrogen receptors,3 and
agrochemicals of economic importance. One of the most
important methods for the synthesis of substituted 1-N-
arylpyrazoles involves cyclocondensation of 1,3-dicarbo-
nyl compounds and their equivalent 1,3-dienophilic syn-
thons such as propargylic ketone, â-dialkylamino/alkoxy/
chloroketones with arylhydrazines.2b,c,3 However the
appealing generality of this method is somewhat vitiated
as a result of the frequent formation of regioisomeric mix-
scattered reports are available on the synthesis of 1-aryl-
3-(or 5)-N,N-disubstituted aminopyrazoles, which are not
well represented in the literature.10 The reported meth-
ods for the synthesis of 5-alkyl/arylaminoyrazoles require
either harsh reaction conditions9d,e or are limited only to
a defined set of precursors.2,9 In a recent report,10 a few
of the substituted 1-aryl-5-(N,N-disubstituted)aminopy-
(4) (a) Murray, W.; Wachter, M.; Barton, D.; Forero-Kelly, Y.
Synthesis 1991, 18. (b) Kashima, C.; Harada, H.; Kita, I.; Fukuchi, I.;
Hosomi, A. Synthesis 1994, 61. (c) Spivey, A. C.; Diaper, C. M.; Adams,
H.; Rudge, A. J. J. Org. Chem. 2000, 65, 5253.
(5) Reviews: (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (b) Ila, H.; Junjappa, H.; Mohanta, P. K. Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Perga-
mon: New York, 2001; Vol. 13, Chapter 1, p 1. (c) Ila, H.; Junjappa,
H.; Barun, O. J. Organomet. Chem. 2001, 624, 34.
(6) Purkayastha, M. L.; Ila, H.; Junjappa, H. Synthesis 1989, 21.
(7) (a) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3498. (b) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa,
H. Tetrahedron 2004, 60, 3457. (c) Nandi, S.; Panda, K.; Suresh, J. R.;
Ila, H.; Junjappa, H. Tetrahedron 2004, 60, 3663.
(8) (a) Tang, J.; Shewchuk, L. M.; Sato, H.; Hasegawa, M.; Washio,
Y.; Nishigaki, N. Bioorg. Med. Chem. Lett. 2003, 13, 2985. (b)
Braibante, M. E. F.; Braibante, H. T. S.; da Roza, J. K.; Henriques, D.
M. Synthesis 2003, 1160. (c) Schenone, S.; Bruno, O.; Ranise, A.;
Bondavalli, F.; D’Amico, M.; Filippelli, W.; Falcone, G.; De Novellis,
V. Il Farmaco 1995, 50, 179. (d) Cooper, C. B.; Helal, C. J.; Sanner,
M. A.; Wagner, T. T. PCT WO 18346 A1, 2002.
† Indian Institute of Technology.
‡ BioOrganics and Applied Materials Pvt. Ltd.
(1) Reviews: (a) Elguero, J. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon
Press: Oxford, 1984; Vol. 5, p 167. (b) Elguero, J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon Press: Oxford, 1996; Vol. 3, p 1. (c) Kost, A. N.;
Grandberg, I. I. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Boulton, A. J. Eds.; Academic Press: New York, 1966; Vol. 6, p
347. (d) Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44,
6737 and references therein.
(9) (a) Ansel, J. E.; El Kaim, L.; Gadras, A.; Grimaud, L.; Jana, N.
K. Tetrahedron Lett. 2002, 43, 8319. (b) Atlan, V.; Buron, C.; El
Ka×c0m, L. Synlett 2000, 489. (c) Palacios, F.; Aparicio, D.; de los
Santos, J. M. Tetrahedron 1996, 52, 4123. (d) Moreno-Mana˜s, M.;
Sebastia´n, R. M.; Vallribera, A.; Carini, F. Synthesis 1999, 157. (e)
Abdel-Rahman, R. M.; Seada, M.; Fawzy, M.; El-Baz, I. Pharmazie
1994, 49, 729.
(2) Sakya, S. M.; Rast, B. Tetrahedron Lett. 2003, 44, 7629 and
references therein.
(3) Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833
and references therein.
(10) Dodd, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45, 4265.
10.1021/jo051478u CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/19/2005
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J. Org. Chem. 2005, 70, 9644-9647