Regioselective synthesis of 1,3,5-triaryl-4-alkylpyrazoles: novel ligands for the estrogen receptor.

Article abstract of DOI:10.1021/ol0062650

[reaction: see structure] A regioselective synthesis of 4-alkyl-1,3,5-triarylpyrazoles has been developed for the preparation of unsymmetrically substituted systems of interest as ligands for the estrogen receptor.

Full text of DOI:10.1021/ol0062650

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2833-2836
Regioselective Synthesis of
1,3,5-Triaryl-4-alkylpyrazoles: Novel
Ligands for the Estrogen Receptor
Ying R. Huang and John A. Katzenellenbogen*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
jkatzene@uiuc.edu
Received June 27, 2000
ABSTRACT
A regioselective synthesis of 4-alkyl-1,3,5-triarylpyrazoles has been developed for the preparation of unsymmetrically substituted systems of
interest as ligands for the estrogen receptor.
In our efforts to discover novel ligands for the estrogen
receptor (ER) that might act as selective estrogen receptor
modifiers (SERMs),1 we found that 1,3,5-triaryl-4-alkylpyra-
zoles such as 1 and 2 (Scheme 1) were good ligands for
ER, demonstrating high binding affinities and transcriptional
efficacy that in some cases were very selective for the ER R
subtype (ERR).2,3 Initially, we synthesized these pyrazoles
by condensation of 2-alkyl-1,3-diketones with arylhydra-
zines.4-6 Of course, when the 1,3-diketones were unsym-
metrical, this approach did not afford any significant regio-
selectivity. This lack of regioselectivity became of concern
when we needed the corresponding monophenols 3 and 4
for structure-activity studies to determine which phenol in
pyrazole 2 mimics the A-ring of estradiol. According to a
classical approach, the monophenol with the higher affinity
can be presumed to be the one that corresponds to the A-ring
of estradiol.7,8 However, when the original 1,3-dione-
hydrazine condensation pyrazole synthesis was used to
prepare these monophenols, only an inseparable mixture of
the two regioisomers 3 and 4 was afforded (Scheme 1). Thus,
a regioselective approach to these and related compounds
was needed.
In a related effort, we wanted to develop these novel 1,3,5-
triaryl-4-alkylpyrazole ligands into the sort of mixed agonist/
antagonists that typically have SERM activity.9,10 This
generally involves incorporating a basic or polar side chain
(such as a piperidinylethoxy group) onto either the C(3) or
C(5) phenyl groups. However, when pyrazoles 6 and 7 were
prepared by condensation of 4-methoxyphenylhydrazine with
unsymmetrical 1,3-diketone 5, we obtained the regiosiomeric
pyrazoles 6 and 7 in pure form only after exhaustive
chromatography, and we had to obtain an X-ray structure of
the more crystalline isomer 6 to establish the identity of these
regioisomers (Scheme 1).
(1) Grese, T. A.; Dodge, J. A. Curr. Pharm. Des. 1998, 4, 71-92.
(2) Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205-219.
(3) Stauffer, S. R.; Katzenellenbogen J Comb. Chem. 2000, 2, 318-
329.
(4) Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205-219.
(5) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. Submitted.
(6) Stauffer, S. R.; Huang, Y.; Coletta, C. J.; Tedesco, R.; Kazenellen-
bogen, J. A. Bioorg. Med. Chem. In press.
(7) Anstead, G. M.; Carlson, K. E.; Katzenellenbogen, J. A. Steroids
1997, 62, 268-303.
The results from cell-based transcriptional assays showed
that pyrazole 7 has the desired antagonistic character typical
for a SERM. However, to examine this series further we
(8) Anstead, G. M.; Peterson, C. S.; Katzenellenbogen, J. A. J. Steroid
Biochem. 1989, 33, 877-887.
(9) Grese, T. A.; Dodge, J. A. Curr. Pharm. Des. 1998, 4, 71-92.
(10) Magarian, R. A.; Overacre, L. B.; Singh, S.; Meyer, K. L. Curr.
Med. Chem. 1994, 1, 61-104.
10.1021/ol0062650 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/16/2000

Scheme 1. Pyrazole Ligands for the Estrogen Receptor R
Scheme 2. Regiospecific Preparation of
1,3,5-Triaryl-4-halopyrazoles and Their Reactions
be formed through oxidation of the initially formed dihy-
dropyrazole (pyrazoline 11), although it was not certain
whether air (the reaction was run in air) or dimethyl sulfoxide
served as the oxidant for this transformation. On the basis
of these observations, we investigated methods to introduce
the 4-alkyl substituent after the formation of the pyrazole
system 12.
When deprotonation at the 4-position of 12 with s-BuLi
followed by trapping with ethyl iodide failed to give the
desired product, we turned our attention to routes through
the corresponding bromide 13 and iodide 14, which were
readily prepared from pyrazole 12 by treatment with the
corresponding halo succinimide in CH2Cl2 at room temper-
ature. When bromide 13 was treated with n-BuLi followed
by ethyl iodide, pyrazole 12 was the only isolated product.
In our attempts to effect ethyl or vinyl group substitution at
C(4) of iodide 14 using various transition metal-mediated
reactions (Pd, Ni), we isolated only the reduction product
12 and starting iodide 14, suggesting that â-hydride transfer
competes with reductive elimination in this hindered system.
Consistent with this is the fact that we were only able to
introduce an acetylene group (producing 15) or aryl group
(not shown) by this approach.13
Because of the difficulties we encountered in introducing
the C(4)-alkyl substituent in these heterocycles after the
pyrazoles had been formed, we wondered whether we might
be able to intercept the pyrazoline intermediate and introduce
the alkyl substituent before its oxidation to the pyrazole.
Indeed, by carrying out the enone-arylhydrazine condensa-
tion reaction under an inert atmosphere and eventually using
required a regioselective method for the synthesis of the basic
side chain derivatives of these 1,3,5-triaryl-4-alkylpyrazole
systems.
Regioselective Synthesis of the Monophenolic Tetra-
substituted Pyrazoles (3 and 4). To develop a regioselective
synthesis of these tetrasubstituted pyrazoles, we investigated
the reaction of R,â-unsaturated ketones with arylhydrazines,
having as our initial goal the synthesis of the two monophe-
nolic pyrazoles 3 and 4 (Scheme 2). Although R,â-unsatur-
ated ketone 10 condensed smoothly with phenylhydrazine
to afford a single pyrazole product, 12, its R-substituted
counterpart 8 failed to react under these conditions. The
regioisomeric structure of 12 was assigned on the basis of a
similar type of reaction reported in the literature,11,12 although
the mechanism that accounts for the regioselectivity was not
clear at this point (vide infra). Pyrazole 12 was presumed to
(11) Elguero, J. In ComprehensiVe Heterocyclic Chemistry, Vol. 5;
Katrizky, Rees, Eds.; Pergamon: Oxford, 1985; Vol. 5, p 167.
(12) Elguero, J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
Rees, Scriven, Eds.; Pergamon: Oxford, 1996; p 1.
(13) Routes involving palladium-mediated coupling of aryl groups to
other pyrazole systems have been described: ref 5 and Wang, X.; Tan, J.;
Grozinger, K. Tetrahedron Lett. 2000, 41, 4713-4716.
2834
Org. Lett., Vol. 2, No. 18, 2000

DMF as solvent in place of DMSO, we were able to isolate
the air-sensitive pyrazoline intermediate 11 in 61% yield
(Scheme 3). Deprotonation of the acidic C(4) methylene
Scheme 4. Regioselective Synthesis of Pyrazole 7 and Its
Derivatives (36-41)
Scheme 3. Regioselective Synthesis of
1,3,5-Triaryl-4-alkylpyrazoles 3 and 4
group of 11 with LDA at -78 °C in THF, followed by
trapping of the resulting anion with ethyl iodide, afforded
ethyl-substituted pyrazoline 16 (as a racemate) in 63% yield,
with only small amounts of pyrazole 12 as the side product.
Pyrazoline 16 was formed as a single diasteomer, and the
4,5-substituents are presumed to be trans to each other, based
on the 3.7 Hz vicinal coupling constant between the two
methine protons.14 In contrast to the air-sensitivity of its
unsubstituted counterpart 11, the C(4)-alkylated pyrazoline
16 is reasonably stable. It can be stored for a prolonged
period of time without apparent oxidation or decomposition,
and subsequent oxidation to the corresponding pyrazole
actually requires rather harsh conditions. Initially, we used
MnO2, either at high temperature (reflux benzene) or with
ultrasonic agitation, and we obtained the desired 1,3,5-triaryl-
4-alkylpyrazoles 9 in 66% yield, but the reaction took 48 h.
Later, DDQ was found to be a more efficient oxidant. After
demethylation of the protected pyrazole 9 with BBr3, we
obtained the first desired monophenolic pyrazole 3. The other
desired monophenolic pyrazole (4) was obtained by the same
reaction sequence, starting from enone 17. Although it is
apparent that the two regioisomers 3 and 4 are different and
we were quite confident in our structural assignments based
on literature precedent,15-18 the regioselectivity of this route
was firmly established only later, by X-ray crystallography
(vide infra).
With both pyrazole isomers 3 and 4 in hand, we deter-
mined their relative binding affinities for ER and, as
described elsewhere,5 we were able to conclude that the C(3)
phenol of these pyrazoles is the ring that mimics the A-ring
of estradiol.
(14) Vicinal coupling constants were calculated using the Karplus
relationship within Macromodel v7.0. Monte Carlo conformational searches
were conducted using the Amber force field with CHC13 as a solvent model.
All generated conformers from Monte Carlo searches underwent full matrix
assisted minimization using the FMR function with a convergence criteria
of 0.001 kcal/mol, and the Boltzman-averaged constants for the cis and
trans compounds are estimated to be 9.3 and 4.8 Hz, respectively. Thus,
pyrazolines 16 and 19 are presumed to be the trans isomers. NOE
experiments on these pyrazolines gave ambiguous results regarding stereo-
chemistry. See also: Hassner, A.; Michelson, M. J. J. Org. Chem. 1962,
27, 3974. Elguero, J.; Marzin, C. Bull. Soc. Chim. Fr. 1970, 3466.
Regioselective Synthesis of Tetrasubstituted Pyrazoles
with Basic Side Chains (7, 33-41). For the synthesis of
(15) Sangwan, N.; Rastogi, S. N. Indian J. Chem. 1979, 18B, 65.
(16) Gupta, S.; Rastogi, S. N. Indian J. Chem.. 1995, 34B, 245.
(17) Kaufman, F. B.; Engler, E. M. J. Am. Chem. Soc. 1979, 101, 547.
(18) Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63, 723.
Org. Lett., Vol. 2, No. 18, 2000
2835

pyrazole 7 and its analogues, we prepared R,â-unsaturated
ketone 21 by an aldol condensation of 4-methoxyacetophe-
none and p-hydroxybenzaldehyde, according to a literature
procedure19 with modifications (Scheme 4). Despite numer-
ous attempts, we were unable to obtain good yields in this
simple reaction. However, we were able to isolate the highly
crystalline enone 21 easily.
Scheme 5. Possible Mechanistic Pathways for the
Regiospecific Formation of Pyrazolines
Enone 21, protected as its silyl ether (22), reacted with
4-methoxylphenylhydrazine to give pyrazoline 23. This
material was alkylated, as before, with various iodides to
give pyrazolines 24-26, which were oxidized with either
MnO2 or DDQ to afford the desired pyrazoles 27-29.
Fluoride ion cleavage of the silyl group the gave the C(5)
phenolic pyrazoles 30-32. An X-ray structure of one of these
pyrazoles (31, Scheme 4) secured the structure of this
compound, in the process confirming the regioselectivity of
this route to pyrazoles. Installation of the piperidinylethoxy
side chain was accomplished by a Mitsunobu reaction.
Although BBr3 cleaved all three ether groups, AlCl3-EtSH
selectively cleaved only the methyl ethers, leaving the basic
side chain unaffected and giving pyrazoles 33-35 in very
high yield. A number of other side chain derivatives (36-
41) were prepared in the C(4) ethyl series. Pyrazole 41 was
prepared by a closely related route (not shown). We are
currently investigating the biological activities of all of the
new pyrazole compounds bearing the various polar/basic side
chains.
of a pentadienyl anion to a 1-azaallyl anion. No intermediates
are observed in this transformation. Thus, at this point, there
is no definitive basis for favoring one mechanism over the
other. However, the fact that R-substituted unsaturated
ketones (e.g., 8) fail to react under conditions where the
unsubstituted congeners (e.g., 10) react well (see Scheme
2) would be more consistent with mechanism a.
Acknowledgment. We are grateful for support of this
research through grants from the U.S. Army Breast Cancer
Research Program (DAMD17-97-1-7076) and the National
Institutes of Health (HHS 5R37 DK15556). Y.R.H. is grateful
for an NIH training grant (HHS T32 CA09067-24). We thank
Rosanna Tedesco for helpful discussions. NMR spectra were
obtained in the Varian Oxford Instrument Center for Excel-
lence in NMR Laboratory. Funding for this instrumentation
was provided in part from the W.M. Keck Foundation and
the National Science Foundation (NSF CHE 96-10502). Mass
spectra were obtained on instruments supported by grants
from the National Institute of General Medical Sciences (GM
27029), the National Institute of Health (RR 01575), and
the National Science Foundation (PCM 8121494).
Basis of Regioselectivity. The regioselectivity of this
pyrazole synthesis derives from the initial enone-aryl-
hydrazine condensation, which results in the attachment of
the aryl-substituted hydrazine nitrogen to the enone â-carbon
and the unsubstituted hydrazine nitrogen to the enone
carbonyl carbon. Two mechanisms seem plausible for this
transformation (Scheme 5), and they differ in the timing of
bond formation. In path a, the aryl-substituted nitrogen reacts
first, undergoing a Michael-type addition to the â-carbon of
the enone which is followed by an intramolecular imine
formation between the carbonyl group and the free amine.
In path b, imine formation between the unsubstituted nitrogen
and the carbonyl group occurs first, this being followed by
a cyclization process to a zwitterionic species that undergoes
proton tautomerization to furnish the pyrazoline. Whereas
pathway b might first appear to be an ionic 5-endo-trig
process, it can more reasonably be considered to be a
concerted, symmetry-allowed closure of a 1,2-diaza analogue
Supporting Information Available: Procedures for the
preparation of all of the compounds mentioned in this paper
and their spectroscopic characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Kaufman, F. B.; Engler, E. M. J. Am. Chem. Soc. 1979, 101, 54.
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