Novel application of the palladium-catalyzed N-arylation of hydrazones to a versatile new synthesis of pyrazoles

Article abstract of DOI:10.1016/S0040-4039(02)00245-9

A versatile synthesis of pyrazoles from aryl benzophenone hydrazones was demonstrated with a variety of 1,3-bifunctional substrates under acidic conditions. The obtained regioselectivity is consistent with transhydrazonation followed by subsequent cycliza

Full text of DOI:10.1016/S0040-4039(02)00245-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2171–2173
Novel application of the palladium-catalyzed N-arylation of
hydrazones to a versatile new synthesis of pyrazoles
Nizar Haddad* and James Baron
Boehringer Ingelheim Pharmaceuticals, Inc., Department of Chemical Development, 900 Ridgebury Rd., PO Box 368, Ridgefield,
CT 06877-0368, USA
Received 17 December 2001; revised 31 January 2002; accepted 1 February 2002
Abstract—A versatile synthesis of pyrazoles from aryl benzophenone hydrazones was demonstrated with a variety of 1,3-bifunc-
tional substrates under acidic conditions. The obtained regioselectivity is consistent with transhydrazonation followed by
subsequent cyclization. © 2002 Elsevier Science Ltd. All rights reserved.
Aryl pyrazoles posses a widespread occurrence as sub-
structures in a large variety of compounds with impor-
tant biological activities and pharmacological prop-
erties.1,2 The synthesis of this important family of com-
pounds is well reviewed.2 The conventional approach
for pyrazole formation based on condensation of substi-
tuted hydrazines with 1,3-diketones or their equivalents,
such as b-ketoesters and b-cyanoketones. With the limi-
tation associated with availability of differently substi-
tuted aryl- and hetero-aryl hydrazines,3 it became
attractive to develop a one-pot synthesis of pyrazoles
from N-arylated benzophenone hydrazones, which could
easily be prepared following Buchwald4a and Hartwig4b
procedures. We postulated that upon treatment of aryl-
hydrazones with dicarbonyl compounds, a transhydra-
zonation reaction4a followed by subsequent cyclization
would take place, leading eventually to pyrazoles.
Hydrazones 3, 4 and 11, were prepared in high yields,
following Hartwig’s procedure4b for the preparation of
4. The synthesis of aryl pyrazoles was first examined by
refluxing 3, 4 and 11 with symmetrical 1,3-diketones 5
or 6 in ethanol under different acidic conditions (HCl,
AcOH, TFA, NH4Cl, p-TsOH) (Scheme 1). The best
yields were obtained by using p-TsOH or HCl in etha-
nol under reflux conditions for ca. 5–8 h. Pyrazoles 8, 9
and 12 were obtained in 75–94% isolated yields5 under
p-TsOH/EtOH conditions. Similar yields were obtained
in preparing pyrazoles 7 and 12 under HCl/EtOH
conditions.6
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00245-9

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N. Haddad, J. Baron / Tetrahedron Letters 43 (2002) 2171–2173
The results obtained with symmetrical diketones
prompted us to examine the regioselective synthesis of
unsymmetrical pyrazoles or pyrazole-related structures.
Treatment of 3 and 4 with ethyl acetoacetate, under
p-TsOH/EtOH conditions, has provided pyrazoles 14 and
15, respectively in 52 and 43% isolated yield (Scheme 2).7
The products are consistent with the transhydrazonation
intermediate13. Attemptsforthesynthesisofpyrazolones
upon treatment of hydrazone 4 with diethyl malonate
under the p-TsOH reaction conditions were not success-
ful. No pyrazolone formation was obtained and most of
hydrazone 4 was recovered after 52 h. However, the poor
reactivity of 1,3-diesters was overcome by treatment of
3 with ethyl malonyl chloride in refluxing dioxane,
affording after 10 min the corresponding compound 16
in 80–83% isolated yield. Subsequent cyclization of 16 in
p-TsOH/EtOHafforded, after1.5h, pyrazolone17in70%
confirmed by its preparation from phenylhydrazine (21)
with 18 under similar reaction conditions.
The utility of the cross-coupling/pyrazole formation
sequence was further demonstrated in the synthesis of
heteroaryl pyrazole 22 in 81% isolated yield.
In order to examine the regioselectivity of pyrazole
formation with unsymmetrical diketones, hydrazone 3
was treated with 1-benzoylacetone under the typical
conditions.6 A mixture of 3-methyl-1,5-diphenylpyrazole
(23) and 5-methyl-1,3-diphenylpyrazole (24) was
obtained in 5:1 ratio, respectively in 82% total yield
(Scheme 4). However, 22:1 ratio of 23 versus 24 was
obtained on their preparation from hydrazine 21 and
1-benzoylacetone.5 Higher regioselectivity was expected
in the pyrazole formation from 2,2-dimethyl-3,5-hexane-
dione. Indeed, single products 25 and 26 were obtained
upon its reaction under the p-TsOH/EtOH conditions
with hydrazones 4 and 11 in 84 and 88% yields, respec-
tively.9
1
yield. The H NMR of compound 17 was found in full
agreement with previously reported data.8
Preparation of pyrazole amines was expected to be
possible by treating hydrazones with cyanoketone 18
under acidic conditions. Regioselective transhydrazo-
nation could be expected to be similar to that obtained
with b-ketoesters which then will provide pyrazole amines
of type 19 (Scheme 3). Indeed, treatment of aryl hydra-
zones 3 with pivaloylacetonitrile (18) afforded single
products 19 in 80% isolated yield. The structure of 19 was
Preparation of tetra-substituted pyrazoles from hydra-
zone 11 with a-acetylphenylacetonitrile and 3-methyl-
2,4-pentanedione was examined under the developed
conditions and provided pyrazoles 27 and 28 in 40 and
64% isolated yields, respectively.
Scheme 2.
Scheme 3.

N. Haddad, J. Baron / Tetrahedron Letters 43 (2002) 2171–2173
2173
Scheme 4.
In summary, variety of pyrazoles and pyrazolones
could be prepared, under the developed conditions,
from easily accessible aryl and heteroaryl benzophe-
none hydrazones with different 1,3-bifunctional groups.
4. (a) Wagaw, S.; Yang, H. B.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 6621; (b) Hartwig, J. F. Angew. Chem., Int.
Ed. 1998, 37, 2090.
5. All new compounds were characterized by full spectro-
scopic data, yields refer to chromatographed materials
with purity of >95%. Structure of 7 found in agreement
with previously reported data: Texier-Boullet, F.; Klein,
B.; Hamelin, J. Synthesis 1986, 409.
Acknowledgements
We gratefully acknowledge Dr. Vittorio Farina and Dr.
Kevin Webb for valuable discussions. We also thank
Dr. Paul-James Jones for assistance with the 2D-NMR
spectroscopic measurements.
6. Typical procedure:
Solution of the benzophenone hydrazone (1.75 mmol),
p-TsOH (or conc. HCl) (8.75 mmol) and the bi-functional
substrate (2.63 mmol) in EtOH (10 mL) was refluxed for a
period of 8–16 h. The reaction mixture was cooled to rt,
then NaHCO3 saturated solution (10 mL) and EtOAc (10
mL) were added. The layers were separated, and the
aqueous layer washed with EtOAc. The combined organics
dried (Na2SO4), concentrated then purified by column
chromatography.
References
1. (a) Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P.;
Gilmore, G.; Graham, A. G.; Grob, P. A.; Hickey, E. R.;
Moss, N.; Pav, S.; Regan, J. Nature Struct. Biol., in press;
(b) Dumas, J.; Hatoum-Mokdad, H.; Sibley, R.; Riedl, B.;
Scott, W. J.; Monahan, M. K.; Lowinger, T. B.; Brennan,
C.; Natero, R.; Turner, T.; Johnson, J.; Schoenleber, R.;
Bhargava, A.; Wilhelm, S. W.; Housley, T. J.; Gerald, E.
R.; Shrikhande, A. Bioorg. Med. Chem. Lett. 2000, 10,
2051; (c) Menozzi, G.; Mosti, L.; Schenone, P.; Donnoli,
D.; Schiariti, F.; Marmo, E. Farmaco 1990, 45, 167.
2. On the synthesis of pyrazoles and pyrazole related struc-
tures see: (a) Makino, K.; Kim, H. S.; Kurasawa, Y. J.
Heterocyclic Chem. 1998, 35, 489; (b) Elguero, J. Compr.
Heterocyclic Chem. II 1996, 3, 1; (c) Takagi, K.; Huber-
Habart, M. J. Heterocyclic Chem. 1996, 33, 1003; (d)
El-Rayyes, N. R.; Al-Awadi, N. A. Synthesis 1985, 1028;
(e) Sammes, M. P.; Katritzky, A. R. Advances in Hetero-
cyclic Chemistry, Vol. 34, Academic Press, 1983; (g) Behr,
L. C.; Fusco, R.; Jarboe, C. H. The Chemistry of Hetero-
cyclic Compounds; Weissberger, A., Ed., Interscience Pub-
lishers: John Wiley and Sons, 1967.
1
7. Selected H NMR data from 14: l 5.47 (1H, s), 4.12 (2H,
q), 2.28 (3H, s), 1.43 (3H, t) (in full agreement with
reported data: Katritzky, A. R.; Main, F. W. Tetrahedron
1964, 20, 299). Compound 15: l 5.44 (1H, s), 4.07 (2H, q),
2.26 (3H, s), 1.33 (3H, t).
1
8. Selected H NMR data from 17: l 4.35 (2H, q), 3.48 (1H,
s) (in full agreement with literature; Molinari, A.; Oliva, A.
J. Heterocyclic Chem. 1996, 33, 479.)
9. NOESY experiments indicate NOE between the aryl-rings
and the t-butyl substituents and absence of NOE with the
methyl substituent on the pyrazole rings in structures 25
and 26. These results are consistent with the expected
regioselectivity.
3. For palladium-catalyzed coupling of t-butylcarbazate with
activated aryl bromides, see: Wang, Z.; Skerlj, R. T.;
Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543.