Indazole estrogens: Highly selective ligands for the estrogen receptor β

Article abstract of DOI:10.1021/jm049223g

The estrogen receptors, ERα and ERβ, are important pharmaceutical targets. To develop ERβ-selective ligands, we synthesized a series of nonsteroidal compounds having a phenyl-2H-indazole core with different groups at C-3. Several of these show high affinity and good ERβ selectivity, especially those with polar and/or polarizable substituents at this site (halogen, CF₃, nitrile); the best compounds have affinities for ERβ comparable to estradiol, with ERβ affinity selectivity >100. This potency and ERβ selectivity is also seen in cell-based transcriptional assays, where several compounds showed ERβ efficacies equivalent to that of estradiol with ERβ potency selectivities of 100. These compounds might prove useful as selective pharmacological probes to study the biological actions of estrogens mediated through ERβ, and they might lead to the development of useful pharmaceuticals. These findings also contribute to an evolving pharmacophore that characterizes certain nonsteroidal ligands having high ERβ subtype affinity and potency selectivity.

Full text of DOI:10.1021/jm049223g

1132
J. Med. Chem. 2005, 48, 1132-1144
Indazole Estrogens: Highly Selective Ligands for the Estrogen Receptor â
Meri De Angelis,† Fabio Stossi,‡ Kathryn A. Carlson,† Benita S. Katzenellenbogen,‡ and
John A. Katzenellenbogen*,†
Department of Chemistry and Department of Molecular and Integrative Physiology, University of Illinois,
600 South Matthews Avenue, Urbana, Illinois 61801
Received September 23, 2004
The estrogen receptors, ERR and ERâ, are important pharmaceutical targets. To develop ERâ-
selective ligands, we synthesized a series of nonsteroidal compounds having a phenyl-2H-
indazole core with different groups at C-3. Several of these show high affinity and good ERâ
selectivity, especially those with polar and/or polarizable substituents at this site (halogen,
CF3, nitrile); the best compounds have affinities for ERâ comparable to estradiol, with ERâ
affinity selectivity >100. This potency and ERâ selectivity is also seen in cell-based
transcriptional assays, where several compounds showed ERâ efficacies equivalent to that of
estradiol with ERâ potency selectivities of 100. These compounds might prove useful as selective
pharmacological probes to study the biological actions of estrogens mediated through ERâ,
and they might lead to the development of useful pharmaceuticals. These findings also
contribute to an evolving pharmacophore that characterizes certain nonsteroidal ligands having
high ERâ subtype affinity and potency selectivity.
Introduction
Estrogens are hormones that have many important
physiological and pharmacological activities that include
critical roles in the development and function of the
female reproductive system, in the maintenance of bone
mineral density,1,2 and in control of blood lipid levels.3,4
Moreover, recent data show that estrogens can also
exert neuroprotective effects.5,6 The mediators of the
actions of estrogenic hormones are the estrogen recep-
tors (ERs), of which there are two subtypes encoded by
different genes: ERR, the first discovered, and ERâ,
which was only discovered in 1996.7,8 The overall amino
acid sequence identity of the two ER subtypes is 44%;
the DNA-binding domain is very well conserved, but the
amino acid sequence identity of the ligand-binding
domain (LBD) is less conserved (59%). Despite these
differences, the two ligand-binding pockets are almost
identical, the principal difference being a somewhat
smaller internal volume for ERâ and the substitution
of just two amino acids, with Met421 in ERR being
replaced by Ile in ERâ and Leu384 in ERR being
replaced by Met in ERâ.9
The tissue distributions of ERR and ERâ are quite
different: ERR is predominant in the uterus, liver,
mammary gland, bone, and cardiovascular systems,
Figure 1.
whereas ERâ is highly expressed in the prostate, ovary,
and urinary tract.10 Both receptors are also present in
many tissues, including the brain, although in this
organ they are not always expressed in the same
regions.11,12 There is also evidence that the two ER
subtypes have distinct patterns of gene regulation.13-15
The discovery of the second estrogen receptor, togeth-
er with its distinct tissue distribution and patterns of
transcriptional regulation, has aroused strong interest
in the scientific community, because it opens new pos-
sibilities for the synthesis of interesting tissue- and cell-
selective estrogen pharmaceutical agents. In fact, ERâ-
selective ligands might maintain some of the benefits
of traditional hormone therapy without the undesired
stimulatory effects on uterine and breast tissues.
Although there are a number of estrogens with good
selectivity for ERR,16,17 relatively few ERâ-selective
compounds are known. Among natural products, the
isoflavone phytoestrogen genistein (1, Figure 1) is
notable for having a 20-fold ERâ selectivity;18 it was one
of the first ERâ-selective compounds characterized.18
Among synthetic estrogens, a 30-fold selectivity is
reported for compound 2,19 50-fold for derivative 3,20 and
70-fold for the nitrile compound 4 (DPN), the last being
* To whom correspondence should be addressed. Phone: 217 333
6310. Fax: 217 333 7325. E-mail: jkatzene@uiuc.edu.
† Department of Chemistry.
‡ Department of Molecular and Integrative Physiology.
10.1021/jm049223g CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/21/2005

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1133
Figure 2.
Scheme 1a
Figure 3. Indazole system for ERâ ligands.
a compound developed in our laboratories.21 Recently,
a number of new molecules bearing benzothiophene or
benzofuran scaffolds have also emerged as ERâ-selective
agents.22,23 Further investigations on similar structures,
such as benzothiazoles,24 benzimidazoles,25 and benzox-
azoles,26 have provided very promising results, as in the
case of derivative 5, which shows high binding affinity
and a 200-fold selectivity for ERâ.26 In these last
derivatives, the increase in ERâ selectivity is achieved
through the introduction of different polar and polariz-
able groups in the two phenyl rings, but for obvious
structural reasons, no substitution could be made in the
central part of the heterocyclic system.
We have developed a pharmacophore model for non-
steroidal estrogen receptor ligands in which two or three
aryl substituents (of which one or two are p-hydrox-
yphenyl rings) are attached to a central core structure
bearing various other substituents (Figure 2A).27 Using
this model as a guide, we were able to generalize ER
ligand development and to synthesize very good ERR-
selective ligands. The smaller ligand binding pocket of
ERâ, the substitution of Met421 and Leu384 in ERR
with Ile373 and Met336 in ERâ, and the observation
that variation of substituents on the central core could
lead to good ERâ-selective compounds, particularly
when certain polar or polarizable groups were intro-
duced,21 lead us to develop a different pharmacophore
model for ERâ (Figure 2B). The major differences
between the two pharmacophores are the lack of the
third aromatic substituent so that the ligand is smaller
in volume. To reduce ligand size further, one of the two
phenol rings has been fused to the heterocycle, although
this last feature is not essential, as demonstrated by
the activity shown by DPN (4). The nature of the
substituent in pharmacophore B should be such that it
would interact favorably with Ile373 or Met336 and/or
unfavorably with Met421 and Leu384, in this way
engendering better selectivity for ERâ.
a (a) NAHMDS, THF; (b) Pd(OAc)2, dppf, NaOt-Bu, toluene; (c)
BF3‚SMe2, CH2Cl2.
In this report, we describe the synthesis and biological
evaluation of a series of indazole compounds as potential
ERâ-selective ligands, and we identify a number of these
that show very good selectivity for ERâ in receptor
binding and potency in transcription assays.
Results
Chemical Synthesis. Synthesis of the indazole core
structure was accomplished following a known proce-
dure, as outlined in Scheme 1.28 Treatment of phenyl-
hydrazines 7a-c with sodium hexamethyl disilyl amide
followed by the o-bromobenzyl bromides 6a-c provided
the alkylated derivatives 8a-e. These were cyclized in
a palladium-catalyzed coupling reaction and were then
oxidized in situ to furnish the protected indazole deriva-
tives 9a-e (derivatives 9a,b and their precursors are
known compounds28). Deprotection gave the final prod-
ucts indazole phenols 10a-e. Compound 6c is not
commercially available, but it was obtained as previ-
ously reported.29
All the compounds presented herein can be divided
into two groups: analogues of 2-(4-hydroxyphenyl)-2H-
indazol-5-ol (10c), having the indazole hydroxyl on C-5,
and analogues of 2-(4-hydroxyphenyl)-2H-indazol-6-ol
(10d), having the indazole hydroxyl on C-6. As will be
noted below, analogues in the former class (10c) proved
to be more interesting for our purpose.
Following this pharmacophore model, then, we de-
cided to prepare compounds having a phenyl-2H-inda-
zole core structure (Figure 3). An attractive feature of
this particular heterocyclic system is that it is possible
to introduce different steric and polar groups at an
internal position of the heterocyclic system (C-3) and
thereby to further investigate the validity of our phar-
macophore model for ERâ-selective ligands, noted above.
To prepare analogues in the 5-OH (10c) series, we
developed methods to introduce substituents at C-3 that

1134 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
Scheme 2a
with yields that varied from 20 to 85%. These deriva-
tives were then deprotected with BF3‚SMe2 to give the
final products, 12a-f.
Compound 11e can be considered a key intermediate
because, through various palladium coupling reactions,
it was possible to replace the bromine group with many
substituents (Scheme 3). The isopropyl group (13a) was
introduced through a nickel-catalyzed Kumada reac-
tion,32 but curiously, all attempts to employ the same
reaction conditions for the synthesis of the correspond-
ing ethyl and propyl derivatives failed. For this reason,
we turned to the Stille coupling reaction to prepare the
vinyl and allyl derivatives (14, 15a)33 that in turn were
reduced to obtain the ethyl and propyl compounds (16a,
17a). For the synthesis of product 18a, we followed a
literature procedure described for the displacement of
an aromatic bromine group with the trifluoromethyl
moiety using an unusual fluorosulfonylfluoroacetate re-
agent as a precursor for the in situ generation of triflu-
oromethide species.34 Although examples of this reaction
have never been reported for our particular heterocyclic
system, we were able to obtain the desired compound
in moderate yield within a few hours.
In an initial study, derivative 20a was synthesized
through a Stille coupling reaction using phenyltrimethyl
tin as a source of the phenyl substituent. Although we
obtained the desired phenyl-substituted compound (20a)
as the major product, we observed significant formation
of the methyl-substituted product (19a). We tried to in-
crease the yield of 20a by reducing the reaction temper-
ature or changing the concentration of catalytic system,
but we continued to observe the formation of 19a, albeit
in smaller amounts. We were able to obtain derivatives
20a without the formation of any other byproducts, how-
a (a) NCS, CH3CO2H (for 11a-d); Br2, CH3CO2H (for 11e); I2,
KOH, DMF (11f); (b) BF3‚SMe2, CH2Cl2.
would contribute steric bulk and polarity at this position
in the heterocyclic system (Scheme 2). Since this posi-
tion could be halogenated easily, a series of halo
derivatives (11a-f) were synthesized. All of these
compounds were obtained following classical procedures
(NCS or Br2 in acetic acid for derivatives 11a-e, and
I2/sodium hydroxide in DMF for derivative 11f30,31) and
Scheme 3a
i
a (a) NiCl2(dppp), PrMgCl, THF; (b) vinylSnBu3, CsF, Pd2(dba)3, P(t-Bu)3, dioxane; (c) allylSnBu3, CsF, Pd2(dba)3, P(t-Bu)3, dioxane;
(d) FSO2CF2CO2CH3, CuI, DMF; (e) PhSn(Me)3, P(o-Tol)3, Pd2(dba)3, P(t-Bu)3, DMF (f) Pd2(dba)3, Dppf, Zn(CN)2, DMA; (g) BF3‚SMe2,
CH2Cl2; (h) BBr3, CH2Cl2; (i) Pd(OH)2/C, H2 (1 atm), EtOH.

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1135
Table 1. Relative Binding Affinity (RBA) Values for ERR and ERâ and the Selectivity for ERâ As Determined by â/R Ratioa
a Relative binding affinity (RBA) values are determined by competitive radiometric binding assays and are expressed as IC50
/
compound
estradiol
IC50
× 100 (RBA, estradiol ) 100%). In these assays, the Kd for estradiol is 0.2 nM on ERR and 0.5 nM on ERâ. For details, see the
Experimental Section.
ever, through a Suzuki coupling reaction between com-
pound 11e and phenylboronic acid (see the Experimen-
tal Section).
The cyano derivative 21a was also prepared using a
palladium coupling reaction, with good results being
obtained with Pd2(dba)3, dppf, and Zn(CN)2.35 All com-
pounds synthesized from derivative 11e were depro-
tected with BF3‚SMe2 (13b, 16b-21b) except for de-
rivatives 14 and 15a, which were cleaved using BBr3.
Although it was possible to isolate the deprotected allyl
derivative 15b, we were unable to characterize the
dihydroxy analogue of the vinyl derivative 14, presum-
ably because it decomposed under acidic conditions.
For the synthesis of the 6-OH series (10d) analogues,
we initially followed the same synthetic strategy: bromin-
ation at C-3 of derivative 9d and then introduction of

1136 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
Scheme 4a
Biological Results
Estrogen Receptor Binding Assays. The indazole
analogues were evaluated in competitive radiometric
binding assays to determine their affinities for human
ERR and ERâ. Binding affinities, expressed relative to
that of estradiol (100%), gave relative binding affinity
(RBA) values that are summarized in Table 1.
The nonsubstituted indazole derivatives (10a-d)
show, in general, low affinities for both ER subtypes,
with RBA values not exceeding 0.5% and selectivity for
ERâ less than 20-fold. The monohydroxyl derivatives
10a,b and 12a,b were prepared to investigate which one
of two phenyl rings mimicked the A-ring of estradiol;
the expectation was that deletion of the phenolic hy-
droxyl from the ring that mimicked the A-ring of
estradiol would result in a more marked reduction of
binding affinity. According to the results we obtained,
however, deletion of either hydroxy caused a large loss
of binding affinity (compare ERâ values of 10c with 10a
and 10b; 12c with 12a and 12b). Thus, both hydroxy
groups appear to play important roles in the ERâ
binding affinity of these indazoles, although, based on
the somewhat larger binding decrement that occurs
with deletion of the 4′-hydroxyl from the N-1 pendant
phenol (cf. Figure 2), it appears that it is the N-(4-
hydroxylphenyl) moiety that is the mimic of the A-ring
of estradiol.
a (a) Br2, CH3CO2H; (b) BF3‚SMe2, CH2Cl2.
Scheme 5a
A large number of 5-hydroxyl derivatives with differ-
ent C-3 substituentssalkyl, aryl, and polar groupsson
the 1-(p-hydroxyphenyl)indazole core were investigated.
Introduction of halogen groups (compounds 12c,e,f) led
to an increase in the affinity for ERâ, with RBA values
ranging from 8% to 32%, whereas their affinity for ERR
is always less than 0.3%. These derivatives are, there-
fore, strongly affinity selective for ERâ: compound 12f
is 50-fold selective with an 8.5% ERâ RBA, derivative
12e is 102 times more selective with an 18% ERâ RBA,
and compound 12c is 107-fold selective with a 32% ERâ
RBA. The introduction of other polar groups such
trifluoro methyl (18b) and cyano (21b) also gave a large
increase in activity, but with some reduction in ERâ
affinity selectivity. Nevertheless, it should be pointed
out that the trifluoromethyl derivative 18b, with a 69%
ERâ RBA, is the highest affinity compound of this series.
The substitution of the indazole system at C-3 with
alkyl or arylsrather than polarsgroups, led to a
dramatic reduction in affinity and sometimes also in
selectivity. Usually bulky substituents, such as isopropyl
(13b), propyl (17b), allyl (15b), and phenyl (20b), are
not well-tolerated inside the ligand-binding pocket of
ERâ; in fact, all of these compounds show RBA values
that are less than 1% and generally have low ERâ
affinity selectivity (9-13-fold). The C-3 methyl (19b)
and ethyl (16b) derivatives are different and are ca. 40-
fold affinity selective for ERâ, with RBA values between
1 and 3%, the ethyl derivative 16b being the better of
the two.
a (a) TfN3, CuSO4, CH2Cl2, MeOH; (b) SOCl2, p-anisidine; (c)
benzene, SOCl2; (d) BF3‚SMe2, CH2Cl2.
different alkyl and polar groups. The bromination of der-
ivative 9d, however, did not give the 3-bromo derivative
22, but resulted, rather, in the formation of the 7-bromo
compound 23, which was subsequently deprotected to
give 24 (Scheme 4).
To introduce a halogen group in the desired position,
we followed a different synthetic strategy. It is known
from the literature that 2-azido-N-phenyl-benzamide,
when treated with a large excess of thionyl chloride,
undergoes cyclization to form 3-chloro-2-phenyl-2H-inda-
zole.36 Following this procedure, we treated compound
27 (Scheme 5) with SOCl2 in benzene, and we obtained
the desired 3-chloro derivative 28 as well as the 3,7-di-
chloro compound 29 as a byproduct. Compound 27, the
key intermediate for this synthesis, is not commercially
available but was readily synthesized as indicated in
Scheme 5. Starting from the methoxyanthranilic acid
25,37 we prepared the corresponding azide (26) according
to a literature precedent38 that avoided traditional
diazonium salt formation and strong acid hydrolysis. By
this alternative method, we could produce the azide 26
in good yield within 1 h. The desired anilide 27 was
easily prepared from derivative 26 by standard methods.
The chloro compounds 28 and 29 were deprotected as
previously reported to give the 6-OH isomeric deriva-
tives 30 and 31. Because these products showed lower
ER binding affinities and lower ERâ selectivity when
compared to their corresponding 5-hydroxy isomers
(Table 1), no further 6-OH derivatives were prepared.
The binding data for a few 6-hydroxyl analogues (10d,
24, 30, and 31) are also reported in Table 1. In general,
these derivatives are of lower affinity and sometimes
lower selectivity compared to their 5-hydroxyl counter-
parts (10d vs 10c, and 30 vs 12c). The best compound
of this series is the 3-chloro analogue (30), but its ERâ

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1137
Figure 4. Transcriptional activation by ERR and ERâ in response to estradiol (E2), 12c,e,f, 18b, and 21b. Human endometrial
cancer (HEC-1) cells were transfected with expression vectors for ERR or ERâ and the estrogen responsive gene 2EREp-S2-Luc
and were incubated with the indicated concentrations of estradiol or ligands 12c,e,f, 18b, and 21b for 24 h. Value are expressed
as percent of the ERR or ERâ response with 10-6 M estradiol.
Table 2. Transcriptional Efficacy of Estradiol (E2) and Some
Indazole Derivatives at 10-8 and 10-6 M on ERR, ERâ
affinity is still 5 times lower than that of its 5-hydroxyl
analogue 12c.
The following conclusions can be drawn from these
data: (1) Only small C-3 alkyl groups are tolerated by
ERâ; (2) C-5 is the favored position for the hydroxyl
group on the indazole system; (3) high affinity and
particularly high ERâ selectivity are found with polar
and/or polarizable groups at the C-3 position, with the
best examples being the halogenated derivatives 12c
and 12e, which have ERâ affinity selectivities of over
100-fold and RBA values of ca. 20-30%. Although these
two can be considered lead compounds in this series, it
is important to note that a large number of other
indazole compounds show very pronounced ERâ affinity
selectivity, even though their absolute affinities are
lower than those reported for 12c and 12e.
Activity of Indazole Compounds on Gene Tran-
scription. The transcriptional activities of some inda-
zole derivatives were assayed in human endometrial
cancer (HEC-1) cells transfected with expression pla-
mids for ERR and ERâ and an estrogen-responsive
reporter gene. Activities were normalized to that re-
ported for 10-6 M estradiol, which is set to 100. Eleven
derivatives were selected for this transcriptional assay
(12c,e,f, 16b, 18b, 19b, 20b, 21b, and 24). In an initial
screening study, the efficacy of these compounds was
determined at two different concentrations, 10-8 and
10-6 M; the results of these assays are summarized in
Table 2. In general, compound potency and ERâ selec-
tivity in these assays nicely reflected their behavior in
the binding assays.
% efficacy on ERR
% efficacy on ERâ
compd
10-8
M
10-6
M
10-8
M
10-6
M
E2
77
100
1.5
83
47
1.7
88
66
85
63
78
57
11
82
1.4
100
10c
10d
12c
12e
12f
16b
18b
19b
20b
21b
24
0.6
90
75
89
67
58
0.23
0.18
45
0.06
0.03
0.01
0.6
42
40
20
100
74
87
28
56
29
5.6
58
0.6
0.5
1.7
52
0.3
0.02
0.08
0.5
assay: the most active derivatives on ERâ are 12c,e,f,
18b, and 21b; these have an efficacy level that is close
to that reported for estradiol, but they show weak or
negligible activity on ERR. Good potency for ERâ is also
observed for the derivatives 10c, 16b, and 19b, whereas
derivatives 10d, 20b, and 24 were the least potent and
selective compounds of this series.
When these derivatives were tested at 10-6 M, all of
the compounds show efficacy through ERâ, with the low-
affinity compounds 20b and 24 being least efficacious.
At this concentration, considerable ERR activity is
found, but only with the compounds that have signifi-
cant affinity for ERR (12c,e,f, 18b, and 21b).
More extensive dose-response curves were then
obtained for some of the most interesting compounds
(12c,e,f, 18b, 21b; Figure 4). From these data one can
clearly see that all of these compounds have high ERâ
All of the compounds tested showed agonist activity
at 10-8 M, as expected from their affinity in the binding

1138 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
°C and methoxy-2-bromobenzyl bromide (15 mmol) was added.
The reaction mixture was stirred at room temperature for 1 h
and then quenched with water. The mixture was extracted
with ethyl acetate (three times), and the organic extracts were
dried over Na2SO4 and concentrated in a vacuum. The crude
product was purified by flash chromatography (30% EtOAc/
hexanes). The purified product (1.2 mmol) was dissolved in
toluene (4 mL), and Pd(OAc)2 (5 mol %), dppf (7.5 mol %), and
NaOtBu (1.5 mmol) were added. The reaction mixture was
stirred at 90 °C in a sealed tube for 15 h. The reaction mixture
was filtered off, and the crude product purified by flash
chromatography (30% EtOAc/hexanes).
potency selectivity: With four of them (10c,d, 12c,e,f,
21b), full activation of ERâ is achieved at concentrations
30-100-fold below that at which one begins to see
activation of ERR. Thus, these agents are clean phar-
maceutical modulators of the ERâ subtype, capablesat
an appropriate dosesof full activation of ERâ with no
activation of ERR.
Conclusion
In summary, we have prepared novel ligands for the
estrogen receptor â (ERâ) having a phenyl-2-H-indazole
core structure. Most of the compounds prepared showed
good selectivity for ERâ in terms of binding affinity and
transcriptional potency; in particular, derivatives 12c
and 12e can be considered the lead compounds of this
series (RBA for ERâ between 18 and 32% and affinity
selectivity over 100-fold). In the transcriptional assay,
all the active compounds tested are agonists. Because
of their good potency and efficacy through ERâ, coupled
with their weak-to-negligible potency through ERR,
these compounds are very promising agents for the
selective activation of the ERâ. As such, they should
prove to be useful pharmacological probes to define the
biological importance and physiological roles of ERâ.
This study also advances further our pharmacophore
model for ERâ-selective ligands (Figure 2B) that embod-
ies a structurally slender core having phenolic hydroxyl
groups at both ends and incorporating polar or polariz-
able groups in the interior of the ligand; it highlights,
in particular, the importance of the electronic nature
of the internal substituent. While this pharmacophore
is clearly not the only one capable of encompassing ERâ-
selective ligands, it appears to be a valid one and thus
can serve as a productive basis for the design of ligands
having high selectivity for this ER subtype.
N-(2-Bromo-5-methoxybenzyl)-N-(4-methoxyphenyl)-
hydrazine (8c). Product 8c was obtained as orange oil that
solidified on standing (630 mg, 3.6 mmol, 55% yield). The
product was then recrystallized in ethyl acetate/hexane to give
a pale yellow solid (mp 53-54 °C): 1H NMR (400 MHz, CDCl3)
δ 7.46 (d, J ) 8.5, 1H), 7.02 (AA′ of AA′XX′ JAX ) 6.9, JAA′
)
2.4, 2H), 6.95 (d, J ) 3.0, 1H), 6.85 (XX′ of AA′XX′ JAX ) 6.9,
JXX′ ) 2.4, 2H), 6.72 (dd, J ) 8.8, 2.9, 1H), 4.51 (s, 2H), 3.77
(s, 3H), 3.73 (s, 3H), 3.63 (bs, 2H); 13C NMR (400 MHz, CDCl3)
δ 159.3, 153.4, 146.3, 138.0, 133.6, 115.7, 115.1, 114.6, 114.5,
114.1, 62.7, 55.8, 55.6; MS (EI) m/z 337 (M+, 15).
N-(2-Bromo-6-methoxybenzyl)-N-(4-methoxyphenyl)-
hydrazine (8d). Product 8d was obtained as orange oil that
solidified on standing (700 mg, 2.5 mmol, 44% yield). The
product was then recrystallized in ethyl acetate/hexane to give
a pale yellow solid (mp 83-84 °C): 1H NMR (400 MHz, CDCl3)-
δ 7.24 (d, J ) 8.8, 1H), 7.14 (d, J ) 2.8, 1H), 7.045 (AA′ of
AA′XX′ JAX ) 6.8, JAA′ ) 2, 2H), 6.86-6.81 (m, 3H), 4.73 (s,
2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.54 (bs, 2H); 13C NMR (400
MHz, CDCl3) δ 159.4, 153.4, 146.3, 130.6, 128.6, 124.4, 118.3,
116.0 114.5, 113.7; MS (EI) m/z 337 (M+, 10).
N-(2-Bromo-5-methoxybenzyl)-N-(3-chloro-4-methox-
yphenyl)hydrazine (8e). Product 8e was obtained as orange
oil that solidified on standing (1.55 g, 4.1 mmol, 48% yield).
The product was then recrystallized in ethyl acetate/hexane
to give a pale yellow solid (mp 99-100 °C): 1H NMR (400 MHz,
CDCl3) δ 7.48 (d, J ) 8.8, 1H), 7.19 (d, J ) 2.0, 1H), 6.88-
6.84 (m, 3H), 6.72 (dd, J ) 8.8, 2.8, 1H), 4.51 (s, 2H), 3.84 (s,
3H), 3.71(s, 3H), 3.63 (bs, 2H); 13C NMR (400 MHz, CDCl3) δ
159.4, 148.4, 146.6, 137.4, 133.8, 116.5, 115.0, 114.5, 114.0,
113.4, 113.0; 61.9, 56.9, 55.6; MS (EI) m/z 371 (M+, 10).
5-Methoxy-2-(4-methoxyphenyl)-2H-indazole (9c). Prod-
uct 9c was obtained as a white solid (122 mg, 0.48 mmol, 40%
yield) recrystallized from EtOAc/hexanes (mp 154-155 °C):
1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.74 (AA′ of AA′XX′
JAX ) 6.7, JAA′ ) 2.4, 2H), 7.66 (d, J ) 9.6, 1H), 7.03-6.98 (m,
3 H), 6.87 (d, J ) 2.4, 1H), 3.84 (s, 3H), 3.83 (s, 3H); 13C NMR
(400 MHz, CDCl3), δ 159.1, 155.5, 146.5, 134.3, 122.7, 122.1,
121.6, 119.3, 119.2, 114.6, 96.4, 55.6, 55.4; MS (EI) m/z 254
(M+, 100).
6-Methoxy-2-(4-methoxyphenyl)-2H-indazole (9d). Prod-
uct 9d was obtained as a white solid (260 mg, 1.02 mmol, 50%
yield) recrystallized from EtOAc/hexanes (mp 143-144 °C):
1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.76 (AA′ of AA′XX′
JAX ) 6.5, JAA′ ) 2, 2H), 7.56 (d, J ) 8.5, 1H), 7.02-7.00 (m,
3H), 6.80 (dd, J ) 9, 2, 1H), 3.88 (s, 3H), 3.86 (s, 3H); 13C NMR
(400 MHz, CDCl3) δ 159.3, 159.1, 150.8, 134.3, 122.1, 121.2,
120.4, 118.5, 117.6, 114.7, 94.7, 55.7, 55.3; MS (EI) m/z 254
(M+, 100).
5-Methoxy-2-(3-chloro-4-methoxyphenyl)-2H-inda-
zole (9e). Product 9e was obtained as a white solid (100 mg,
0.35 mmol, 35% yield) that was recrystallized from EtOAc/
hexanes (mp 175-177 °C): 1H NMR (400 MHz, CDCl3) δ 8.21
(s, 1H), 7.09 (d, J ) 2.4, 1H), 7.67-7.63 (m, 2H), 7.02-6.69
(m, 2H), 6.84 (d, J ) 2.4, 1H), 3.92 (s, 3H), 3.82 (s, 3H); 13C
NMR (400 MHz, CDCl3) δ 155.6, 154.4, 146.7, 134.3, 123.3,
122.9, 122.7, 122.2, 119.7, 119.2, 112.3, 96.2, 56.5, 55.4; MS
(EI) m/z 288 (M+, 100).
Experimental Section
Materials and Methods. All reagents and solvents were
obtained from Aldrich or Fisher. Tetrahydrofuran, diethyl
ether, toluene, and dichloromethane were dried by the solvent
delivery system (SDS) (neutral alumina columns) designed by
Meyer. Glassware was oven-dried, assembled while hot, and
cooled under an inert atmosphere. Unless otherwise stated,
all reactions were conducted in an inert atmosphere. Reactions
using moisture- or air-sensitive reagents were performed in
anhydrous solvents. Reaction progress was monitored using
analytical thin-layer chromatography (TLC) on 0.25 mm Merck
F-254 silica gel glass plates. Visualization was achieved by
either UV light (254 nm) or potassium permanganate indica-
tor. Flash chromatography was performed with Woelm silica
gel (0.040-0.063 mm) packing.
1H NMR and 13C NMR spectra were obtained on a 400 or
500 MHz instrument. The chemical shifts are reported in ppm
and are referenced to either tetramethylsilane or the solvent.
Mass spectra were recorded under electron impact conditions
at 70 eV. Melting points were obtained on a Thomas-Hoover
MelTemp apparatus and are uncorrected. Elemental analyses
were performed by the Microanalytical Service Laboratory of
the University of Illinois. Those final components that did not
give satisfactory combustion analysis gave satisfactory exact
mass determinations and were found to be at least 96% pure
by HPLC analysis.
General Procedure for the Synthesis of the 2-Arylin-
dazole Ring System. Compounds 9a and 9b are known,28
and derivatives 9c-e were synthesized following the same
procedure: to a solution of NaHMDS (30 mmol) at 0 °C was
added phenylhydrazine hydrochloride (15 mmol). The reaction
mixture was stirred at 0 °C for 15 min and then at room
temperature for 1 h. The reaction mixture was recooled at 0
General Method for Deprotection of Methoxy Groups
with BF3‚SMe2. The methyl ether protected compound (0.5
mmol) was dissolved in CH2Cl2 (1 mL), and BF3‚SMe2 (15
mmol) was added. The reaction mixture was stirred at room

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1139
temperature for 24 h. If after that time starting material was
not totally consumed, an additional amount of BF3‚SMe2 (15
mmol) was added and the reaction mixture was stirred for
another 24 h. The reaction mixture was quenched with water
(10 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over Na2SO4 and concentrated in a
vacuum.
4-Indazol-2-ylphenol (10a). Compound 10a was purified
by flash chromatography (40% EtOAc/hexanes) to give a white
solid (63 mg, 0.30 mmol, 96% yield) that was recrystallized
from EtOAc (mp 193-194 °C): 1H NMR (400 MHz, acetone-
d6) δ 8.77 (s, OH), 8.71 (s, 1H), 7.90 (AA′ of AA′XX′ JAX ) 6.9,
JAA′ ) 3.4, 2H), 7.72 (d, J ) 8.5, 1H), 7.66 (d, J ) 8.8, 1H),
7.28-7.24 (m, 1H), 7.07-7.00 (m, 3H);); 13C NMR (400 MHz,
acetone-d6) δ 158.0, 150.1, 134.2, 126.9, 123.7, 122.8, 122.6,
121.4, 121.1, 118.3, 116.7; MS (EI) m/z 210 (M+, 100); HRMS
(EI) calcd for C13H10N2O 210.0793, found 210.0800. Anal.
(C13H10N2O) C, H, N.
(m, 1H), 7.17-7.14 (m, 1H), 7.05 (d, J ) 8.8, 2H), 3.88 (s, 3H);
13C NMR (500 MHz, CDCl3) δ 160.2, 148.5, 131.6, 127.5, 127.1,
122.7, 119.8, 119.7, 119.1, 118.2, 114.4, 55.7; MS (EI) m/z 258
(M+, 100).
3-Chloro-5-methoxy-2-phenyl-2H-indazole (11b). Com-
pound 9b (45 mg, 0.2 mmol) was dissolved in acetic acid (2
mL), and N-chlorosuccinimide (26 mg, 0.2 mmol) was added.
The reaction mixture was stirred at room temperature for 24
h. The reaction mixture was quenched with water (5 mL) and
extracted with EtOAc (3 × 5 mL). The organic extracts were
washed twice with NaOH (1 M), dried over Na2SO4, and
concentrated in a vacuum. The crude product was purified by
flash chromatography (20% EtOAc/hexanes) to give a white
solid (11 mg, 0.04 mmol, 22%) that was essentially pure: 1H
NMR (500 MHz, CDCl3) δ 7.70-7.47 (m, 5H), 7.06 (dd, J )
8.4, 2.4, 1H); 6.77 (d, J ) 2.4, 1H), 3.89 (s, 3H); 13C NMR (500
MHz, CDCl3) δ 156.04, 145.6, 138.7, 129.2, 129.0, 125.7, 123.1,
120.0, 119.8, 94.7, 55.6; MS (EI) m/z 258 (M+, 100).
2-Phenyl-2H-indazol-5-ol (10b). Compound 10b was puri-
fied by flash chromatography (30% EtOAc/hexanes) to give a
white solid (40 mg, 0.19 mmol 86% yield) that was recrystal-
lized from EtOAc/hexanes (mp 168-169 °C, dec): 1H NMR
(400 MHz, acetone-d6) δ 8.62 (s, 1H), 8.30 (bs, OH), 8.05 (AA′
of AA′XX′ JAX ) 7.1, JAA′ ) 3.4, 2H), 7.61-7.54 (m, 3H), 7.42-
7.38 (m, 1H), 7.03-6.97 (m, 2H); 13C NMR (400 MHz, MeOH-
d4) δ 153.7, 147.6, 141.7, 130.7, 128.8, 124.7, 123.1, 121.7,
121.2, 119.2, 100.8; MS (EI) m/z 210 (M+, 100); HRMS (EI)
calcd for C13H10N2O 210.0793, found 210.0800. Anal. (C13H10-
N2O) C, H, N.
3-Chloro-5-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (11c). Compound 9c (100 mg, 0.4 mmol) was suspended
in acetic acid (4 mL), and N-chlorosuccinimide (53 mg, 0.4
mmol) was added. The reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was quenched with
water (10 mL) and extracted with EtOAc (3 × 10 mL). The
organic extracts were washed twice with NaOH (1 M), dried
over Na2SO4, and concentrated in a vacuum. The crude product
was purified by flash chromatography (20% EtOAc/hexanes)
to give a white solid (50 mg, 0.17 mmol, 44%) that was
recrystallized from EtOAc/hexanes (mp 134-135 °C): 1H NMR
(500 MHz, CDCl3) δ 7.61-7.56 (m, 3H), 7.07-7.03 (m, 3H),
6.76 (d, J ) 2.4, 1H), 3.88 (s, 6H); 13C NMR (500 MHz, CDCl3)
δ 160.1, 156.0, 145.0, 131.5, 127.0, 123.1, 119.7, 119.5, 118.6,
114.4, 94.7, 55.7, 55.6; MS (EI) m/z 288 (M+, 100).
3-Chloro-5-methoxy-2-(3-chloro-4-methoxyphenyl)-2H-
indazole (11d). Compound 9e (100 mg, 0.35 mmol) was
dissolved in acetic acid (3 mL), and N-chlorosuccinimide (47
mg, 0.35 mmol) was added. The reaction mixture was stirred
at room temperature for 12 h. The reaction mixture was then
quenched with water (10 mL) and extracted with EtOAc (3 ×
10 mL). The organic extracts were washed twice with NaOH
(1 M), dried over Na2SO4, and concentrated in a vacuum. The
crude product was purified by flash chromatography (20%
EtOAc/hexanes) to give a white solid (40 mg, 0.12 mmol, 35%)
that was recrystallized from EtOAc/hexanes (mp 179-181
°C): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J ) 2.4, 1H), 7.59-
7.53 (m, 2H), 7.035 (AA′ of AA′XX′ JAX ) 8.4, JAA′ ) 2.4, 2H),
6.73 (d, J ) 2, 1H), 3.97 (s, 3H), 3.87 (s, 3H); 13C NMR (500
MHz, CDCl3) δ 156.0, 155.5, 145.5, 131.9, 127.6, 125.0, 123.3,
122.9, 119.8, 119.7, 118.2, 111.8, 94.6, 56.6, 55.6; MS (EI) m/z
323 (M+, 16).
2-(4-Hydroxyphenyl)-2H-indazol-5-ol (10c). Compound
10c was purified by flash chromatography (50% EtOAc/
hexanes) to give a white solid (13 mg, 0.06 mmol, 97% yield)
that was recrystallized from EtOAc (mp >230 °C dec): 1H
NMR (400 MHz, acetone-d6) δ 8.70 (bs, OH), 8.44 (s, 1H), 8.18
(bs, OH), 7.83 (AA′ of AA′XX′ JAX ) 6.9, JAA′ 3.4, 2H), 7.55
)
(d, J ) 8.8, 1H), 7.00-6.95 (m, 4H); 13C NMR (400 MHz,
acetone-d6) δ 157.7, 153.1, 146.8, 134.4, 124.2, 122.4, 121.4,
119.6, 119.1. 116.6, 100.4; MS (EI) m/z 226 (M+, 100); HRMS
(EI) calcd for C13H10N2O2 226.0742, found 216.0745. Anal.
(C13H10N2O2‚0.2 H2O) C, H, N.
2-(4-Hydroxyphenyl)-2H-indazol-6-ol (10d). Compound
10d was purified by flash chromatography (30% EtOAc/
hexanes) to give a white solid (50 mg, 0.22 mmol, 94% yield)
that was recrystallized from EtOAc (mp >200 °C dec): 1H
NMR (400 MHz, acetone-d6) δ 8.71 (bs, OH), 8.58 (s, 1H), 8.45
(s, OH), 7.82 (d, J ) 9, 2H), 7.60 (d, J ) 9, 1H), 7.00-6.92 (m,
3H), 6.77 (d, J ) 1.9, 1H); 13C NMR (400 MHz, acetone-d6) δ
157.6, 156.9, 151.4, 134.3, 122.4, 122.3, 120.9, 119.2, 117.2,
116.6, 98.3; MS (EI) m/z 226 (M+, 100); HRMS (EI) calcd for
C13H10N2O2 226.0742, found 216.0745. Anal. (C13H10N2O2) C,
H, N.
2-(3-Chloro-4-hydroxyphenyl)-2H-indazol-5-ol (10e).
Compound 10e was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (30 mg, 0.11 mmol, 82%
yield) that was recrystallized from EtOAc (mp >250 °C dec):
1H NMR (500 MHz, acetone-d6) δ 8.54 (s, 1H), 8.03 (d, J ) 3,
1H), 7.83 (dd, J ) 8.8, 2.6, 1H), 7.56 (d, J ) 8.8, 1H), 7.17 (d,
J ) 8.8, 1H), 7.00 (dd, J ) 9.2, 2.2, 1H), 6.95 (d, J ) 2.1, 1H);
13C NMR (500 MHz, acetone-d6) δ 153.3, 153.2, 134.8, 124.4,
122.5, 122.0, 121.6, 120.6, 119.7, 119.4, 117.9, 100.4; MS (EI)
m/z 260 (M+, 100); HRMS (EI) calcd for C13H9ClN2O2 260.0353,
found 260.0352. Anal. (C13H9ClN2O2) C, H, N.
3-Chloro-2-(4-methoxyphenyl)-2H-indazole (11a). Com-
pound 9a (45 mg, 0.2 mmol) was dissolved in acetic acid (2
mL), and N-chlorosuccinimide (27 mg, 0.2 mmol) was added.
The reaction mixture was heated under reflux overnight. The
reaction mixture was quenched with water (5 mL) and
extracted with EtOAc (3 × 5 mL). The organic extracts were
washed twice with NaOH (1 M), dried over Na2SO4, and
concentrated in a vacuum. The crude product was purified by
flash chromatography (20% EtOAc/hexanes) to give a white
solid (45 mg, 0.17 mmol, 87% yield) that was recrystallized
from EtOAc/hexanes (mp 105-106 °C): 1H NMR (500 MHz,
CDCl3) δ 7.71 (d, J ) 8.8, 1H), 7.63-7.59 (m, 3H), 7.36-7.33
3-Bromo-5-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (11e). Compound 9c (60 mg, 0.23 mmol) was suspended
in acetic acid (1 mL), and a solution of bromine (12 µL, 0.23
mmol) in acetic acid (1.5 mL) was added dropwise at room
temperature for 4 h. After the addition was complete, the
reaction mixture was stirred at room temperature for another
12 h. The reaction mixture was quenched with water (10 mL)
and extracted with EtOAc (3 × 10 mL). The organic extracts
were washed twice with NaOH (1 M), dried over Na2SO4, and
concentrated in a vacuum. The crude product was purified by
flash chromatography (20% EtOAc/hexanes) to give a white
solid (47 mg, 0.14 mmol, 61%) that was recrystallized from
EtOAc/hexanes (mp 148-149 °C): 1H NMR (400 MHz, CDCl3)-
δ 7.62 (d, J ) 9.2, 1H), 7.55 (AA′ of AA′XX′ JAX ) 7.0, JAA′
)
2.0, 2H), 7.06-7.01 (m, 3H), 6.71 (d, J ) 2.4, 1H), 3.88 (s, 6H);
13C NMR (400 MHz, CDCl3) δ 160.0, 156.0, 145.9, 132.5, 127.4,
122.8, 122.7, 119.6, 114.2, 104.8, 95.4, 55.7, 55.6; MS (EI) m/z
333 (M+, 18).
3-Iodo-5-methoxy-2-(4-methoxyphenyl)-2H-indazole
(11f). Iodine (190 mg, 0.75 mmol) and KOH in pellets (42 mg,
0.75 mmol) were added at room temperature to a solution of
compound 9c (50 mg, 0.19 mmol) in DMF (1 mL). The reaction
mixture was stirred at the same temperature for another 12
h. The reaction mixture was quenched with 10 mL of NaHCO3

1140 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
(sat. solution) and extracted with diethyl ether (3 × 10 mL).
The organic extracts were dried over Na2SO4 and concentrated
in a vacuum. The crude product was purified by flash chro-
matography (20% EtOAc/hexanes) to give a white solid (43 mg,
0.11 mmol, 60%) that was recrystallized from EtOAc/hexanes
(mp 150-151 °C): 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J )
9.5, 1H), 7.52 (AA′ of AA′XX′ JAX ) 6.8, JAA′ ) 2.3, 2H), 7.07-
7.02 (m, 3H), 6.63 (d, J ) 2.5, 1H), 3.90 (s, 3H), 3.89 (s, 3H);
13C NMR (500 MHz, CDCl3) δ 160.1, 156.3, 146.7, 133.8, 128.2,
128.0, 122.7, 119.7, 114.7, 114.2, 97.0, 74.6, 55.7, 55.6; MS (EI)
m/z 380 (M+, 100).
the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 12f was purified by flash chromatography (70%
EtOAc/hexanes) to give a white solid (25 mg, 0.07 mmol, 79%)
that was recrystallized from EtOAc (mp 170-174 °C dec): 1H
NMR (400 MHz, acetone-d6) δ 8.9 (bs, 1H), 8.3 (bs, OH), 7.55
(d, J ) 9.2, 1H), 7.46 (AA′ of AA′XX′ JAX ) 6.6, JAA′ ) 2.2,
2H), 7.05-7.01 (m, 3H), 6.70 (d, J ) 2.4, 1H); 13C NMR (400
MHz, acetone-d6) δ 158.9, 154.0, 147.0, 134.0, 129.4, 128.8,
122.4, 120.3, 116.1, 100.9, 74.4; MS (EI) m/z 352 (M+, 100);
HRMS (EI) calcd for C13H9IN2O 351.9709, found 351.9711;
purity > 96% (HPLC).
4-(3-Chloroindazol-2-yl)phenol (12a). Compound 11a (40
mg, 0.15 mmol) was deprotected according to the procedure
described above with BF3‚SMe2 in CH2Cl2. Compound 12a was
purified by flash chromatography (50% EtOAc/hexanes) to give
a white solid (25 mg, 0.1 mmol, 68%) that was recrystallized
from EtOAc/hexanes (mp 194-195 °C): 1H NMR (500 MHz,
acetone-d6) δ 9.01 (bs, OH), 7.67-7.62 (m, 2H), 7.57 (dd, J )
6.7, J ) 3.4, 2H), 7.38-7.35 (m, 1H), 7.20-7.17 (m, 1H), 7.06
(dd, J ) 6.8, 3.2, 2H); 13C NMR (500 MHz, acetone-d6) δ 159.1,
149.0, 131.5, 128.1, 127.9, 123.4, 120.3, 119.5, 118.9, 116.4;
MS (EI) m/z 244 (M+, 100); HRMS (EI) calcd for C13H9ClN2O
244.0403, found 244.0409. Anal. (C13H9ClN2O) C, H, N.
3-Chloro-2-phenyl-2H-indazol-5-ol (12b). Compound 11b
(8 mg, 0.03 mmol) was deprotected according to the procedure
described above with BF3‚SMe2 in CH2Cl2. Compound 12b was
purified by flash chromatography (40% EtOAc/hexanes) to give
a white solid (5 mg, 0.02 mmol, 68% yield, mp >200 °C dec):
1H NMR (500 MHz, acetone-d6) δ 8.57 (bs, OH), 7.73-7.56 (m,
6H), 7.07 (d, J ) 9.2, 1H), 6.82 (d, J ) 2, 1H); 13C NMR (500
MHz, acetone-d6) δ 153.9, 145.9, 139.7, 129.9, 129.7, 126.3,
123.0, 121.0, 120.5, 98.1; MS (EI) m/z 244 (M+, 100); HRMS
(EI) calcd for C13H9ClN2O 244.0403, found 244.0405. Anal.
(C13H9ClN2O) C, H, N.
3-Chloro-2-(4-hydroxyphenyl)-2H-indazol-5-ol (12c).
Compound 11c (45 mg, 0.15 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 12c was purified by flash chromatography (70%
EtOAc/hexanes) to give a white solid (38 mg, 0.13 mmol, 95%)
that was recrystallized from EtOAc (mp >195 °C dec): 1H
NMR (500 MHz, acetone-d6) δ 8.92 (bs, OH), 8.50 (bs, OH),
7.55-7.03 (m, 3H), 7.04-7.02 (m, 3H), 6.8 (d, J ) 2.2, 1H);
13C NMR (500 MHz, acetone-d6) δ 159.0, 153.9, 145.1, 131.4,
127.9, 123.0, 120.7, 120.1, 117.6, 116.4, 98.4; MS (EI) m/z 260
(M+, 100); HRMS (EI) calcd for C13H9ClN2O2 260.0353, found
260.0353. Anal. (C13H9ClN2O2) C, H, N.
3-Chloro-2-(3-Chloro-4-hydroxyphenyl)-2H-indazol-5-
ol (12d). Compound 11d (50 mg, 0.15 mmol) was deprotected
according to the procedure described above with BF3‚SMe2 in
CH2Cl2. Compound 12d was purified by flash chromatography
(60% EtOAc/hexanes) to give a white solid (40 mg, 0.13 mmol,
90% yield; mp 204-205 °C dec): 1H NMR (500 MHz, acetone-
d6) δ 9.0 (bs, OH), 7.74 (d, J ) 2.4, 1H), 7.57-7.53 (m, 2H),
7.23 (d, J ) 8.5, 1H), 7.07 (dd, J ) 9.2, J ) 2.1, 1H), 6.81 (d,
J ) 2.4, 1H); 13C NMR (500 MHz, acetone-d6) δ 154.5, 153.9,
145.7, 132.2, 128.1, 126.4, 123.1, 121.137, 120.8, 120.4, 117.4,
117.1, 98.2; MS (EI) m/z 294 (M+, 100); HRMS (EI) calcd for
C13H9ClN2O 293.9963, found 293.9955. Anal. (C13H9ClN2O·
0.7H2O) C, H, N.
3-Isopropyl-5-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (13a). Compound 11e (66 mg, 0.2 mmol) was dissolved
in THF (1 mL), and Ni(dppp)Cl2 (11 mg, 10 mol %) was added.
i
The reaction mixture was cooled at 0 °C, and PrMgBr (2 M
solution in THF, 0.28 mmol) was added. The reaction mixture
was gently allowed to reach room temperature and stirred at
this temperature for 30 min. The reaction mixture was
quenched with water (10 mL) and extracted with EtOAc (3 ×
10 mL). The organic extracts were dried over Na2SO4 and
concentrated in a vacuum. The crude product was purified by
flash chromatography (30% EtOAc/hexanes) to give a white
solid (15 mg, 0.05 mmol, 26%) that was recrystallized from
EtOAc/hexanes (mp 181-185 °C): 1H NMR (500 MHz, CDCl3)-
δ 7.61 (d, J ) 9.3, 1H), 7.38 (AA′ of AA′XX′ JAX ) 6.7, JAA′
)
2.3, 2H), 7.03-6.99 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.88-
3.28 (m, 1H), 1.44 (d, J ) 7.1, 6H); 13C NMR (500 MHz, CDCl3)
δ 159.9, 154.1, 154.7, 140.8, 133.3, 127.7, 121.1, 119.3, 118.6,
114.3, 97.4, 55.7, 55.5, 26.9, 22.2; MS (EI) m/z 296 (M+, 70).
3-Vinyl-5-methoxy-2-(4-methoxyphenyl)-2H-indazole
(14). Compound 11e (100 mg, 0.3 mmol) was dissolved in
dioxane (2.5 mL), and the following reagents were added: Pd2-
(dba)3 (12 mg, 4.5 mol %), PtBu3 (11 mg, 18 mol %), CsF (100
mg, 0.66 mmol), and vinyltributyltin (87 µL, 0.3 mmol). The
reaction mixture was heated in a sealed tube at 100 °C for 2
h. The reaction mixture was filtered, the solvent removed in
a vacuum, and the crude product purified by flash chroma-
tography (30% EtOAc/hexanes) to give a white solid (63 mg,
0.22 mmol, 75%) that was recrystallized from EtOAc/hexanes
(mp 86-88 °C): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J )
9.2, 1H), 7.47 (d, J ) 8.8, 2H), 7.08-7.01 (m, 4H), 6.76 (dd, J
) 17.8, 11.6, 1H), 5.87 (dd, J ) 17.9, 1H), 5.45 (d, J ) 11.8,
1H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (400 MHz) δ 159.8,
156.1, 145.5, 133.0, 132.3, 127.4, 125.4, 121.3, 120.2, 119.5,
116.2, 114.3, 97.2, 55.7, 55.5; MS (EI) m/z 280 (M+, 100).
3-Allyl-5-methoxy-2-(4-methoxyphenyl)-2H-indazole
(15a). Compound 11e (100 mg, 0.3 mmol) was dissolved in
dioxane (2.5 mL), and the following reagents were added: Pd2-
(dba)3 (12 mg, 4.5 mol %), PtBu3 (11 mg, 18 mol %), CsF (100
mg, 2.2 mmol), and allyltributyltin (92 µL, 0.3 mmol). The
reaction mixture was heated in a sealed tube at 100 °C for 2
h. The reaction mixture was filtered off, the solvent removed
in a vacuum, and the crude product purified by flash chroma-
tography (30% EtOAc/hexanes) to give a white solid (70 mg,
0.23 mmol, 79%) that was recrystallized from EtOAc/hexanes
(mp 96-97 °C): 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J )
9.5, 1H), 7.44 (AA′ of AA′XX′ JAX ) 6.8, JAA′ ) 2.3, 2H), 5.98-
592 (m, 1H), 5.12 (d, J ) 10.3, 1H), 4.99 (d, J ) 17.1, 1H),
3.86 (s, 3H), 3.84 (s, 3H), 3.71-3.69 (m, 2H); 13C NMR (500
MHz) δ 159.8, 154.7, 145.4, 134.0, 133.0, 132.0, 127.1, 121.5,
121.2, 119.1, 117.0, 114.2, 96.2, 55.6, 55.4, 29.6; MS (EI) m/z
294 (M+, 100).
3-Bromo-2-(4-hydroxyphenyl)-2H-indazol-5-ol (12e).
Compound 11e (45 mg, 0.13 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 12e was purified by flash chromatography (70%
EtOAc/hexanes) to give a white solid (35 mg, 0.11 mmol, 85%)
that was recrystallized from EtOAc (mp 195-196 °C dec): 1H
NMR (500 MHz, acetone-d6) δ 9.0 (bs, OH), 7.56 (d, J ) 9,
1H), 7.49 (AA′ of AA′XX′ JAX ) 6.8, JAA′ ) 2, 2H), 7.06-7.01
(m, 3H), 6.77 (d, J ) 2, 1H); 13C NMR (500 MHz, acetone-d6)
δ 158.9, 153.9, 146.2, 132.5, 128.3, 132.8, 122.6, 120.3, 116.2,
103.7, 99.1; MS (EI) m/z 305 (M+, 20); HRMS (EI) calcd for
C13H9CBrN2O: 303.9847, found 303.9853. Anal. C13H9BrN2O
C, H, N.
5-Methoxy-2-(4-methoxyphenyl)-3-ethyl-2H-indazole
(16a). Compound 14 (70 mg, 0.25 mmol) was dissolved in
EtOH (2 mL), and Pd(OH)2 (20 mg) was added. The reaction
mixture was stirred at room temperature under hydrogen
atmosphere (1 atm), for 24 h. The reaction mixture was filtered
off, the organic solvent removed in a vacuum, and the crude
product purified by flash chromatography (20% EtOAc/hex-
anes) to give a white solid (55 mg, 0.19 mmol, 78% yield) that
was recrystallized from EtOAc/hexanes (mp 134-136 °C): 1H
NMR (500 MHz, CDCl3) δ 7.61 (d, J ) 9.2, 1H), 7.41 (AA′ of
AA′XX′ JAX ) 6.8, JAA′ ) 2.2, 2H), 7.03-7.00 (m, 3H), 6.84 (d,
J ) 2.0, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.98 (q, J ) 7.7, 2H),
3-Iodo-2-(4-hydroxyphenyl)-2H-indazol-5-ol (12f). Com-
pound 11f (35 mg, 0.09 mmol) was deprotected according to

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1141
1.23 (t, J ) 7.7, 3H); 13C NMR (500 MHz, CDCl3) δ 159.8, 154.4,
145.4, 136.8, 133.2, 127.2, 121.4, 120.1, 119.0, 114.3, 96.3, 55.6,
55.5, 18.7, 14.0; MS (EI) m/z 282 (M+, 98).
extracted with EtOAc (3 × 10 mL). The organic extracts were
dried over Na2SO4 and concentrated in a vacuum. The crude
product was purified by flash chromatography (30% EtOAc/
hexanes) to give a white solid (30 mg, 0.1 mmol, 53%) that
was recrystallized from EtOAc/hexanes (mp 147-148 °C): 1H
NMR (500 MHz, CDCl3) δ 7.77-7.75 (m, 3H), 7.12-7.06 (m,
3H), 6.96 (d, J ) 2.3, 1H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR
(500 MHz, CDCl3) δ 160.5, 158.5, 145.3, 132.4, 128.4, 125.1,
123.0, 120.5, 114.8, 112.2, 105.4, 94.8, 55.8; MS (EI) m/z 279
(M+, 100).
2-(4-Hydroxyphenyl)-3-isopropyl-2H-indazol-5-ol (13b).
Compound 13a (30 mg, 0.10 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 13b was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (20 mg, 0.07 mmol, 75%
yield; mp >270 °C dec): 1H NMR (500 MHz, methanol-d4) δ
7.43 (d, J ) 9.1, 1H), 7.27 (AA′ of AA′XX′ JAX ) 6.7, JAA′ ) 2.1,
2H), 7.05 (d, J ) 2.2, 1H), 6.97-6.93 (m, 3H), 3.21 (m, 1H),
1.41 (d, J ) 7.1, 6H); 13C NMR (500 MHz, methanol-d4) δ 159.8,
152.2, 146.1, 142.0, 132.7, 129.0, 122.1, 120.2, 118.8, 116.6,
101.6, 28.2, 22.2; MS (EI) m/z 268 (M+, 72); HRMS (EI) calcd
for C16H16N2O2 268.1212, found 268.1207; purity > 95%
(HPLC).
3-Allyl-2-(4-hydroxyphenyl)-2H-indazol-5-ol (15b). Com-
pound 15a (20 mg, 0.07 mmol) was dissolved in CH2Cl2 (0.5
mL), and BBr3 (3 mmol) was added. The reaction mixture was
stirred at room temperature for 24 h and then quenched with
water (3 mL). The inorganic phase was extracted with EtOAc
(3 × 5 mL), and the combined organic extracts were dried on
Na2SO4 and concentrated in a vacuum. Compound 15b was
purified by flash chromatography (60% EtOAc/hexanes) to give
a white solid (13 mg, 0.04 mmol, 65% yield, mp 210 °C dec):
1H NMR (500 MHz, acetone-d6) δ 8.87 (bs, OH), 8.11 (bs, OH),
7.50 (d, J ) 9.0 1H), 7.40 (AA′ of AA′XX′ JAX ) 6.7, JAA′ ) 2.0,
2H), 7.02-6.97 (m, 3H), 6.91 (d, J ) 2.3, 1H), 5.99-5.91 (m,
1H), 5.06 (d, J ) 10.0, 1H), 4.97 (d, J ) 17.0), 3.72-3.70 (m,
2H); 13C NMR (500 MHz, methanol-d4) δ 159.7, 152.8, 145.9,
135.2, 133.7, 132.5, 128.5, 122.7, 122.5, 118.6, 117.2, 116.6,
100.7, 30.2; MS (EI) m/z 266 (M+, 100); HRMS (EI) calcd for
C16H14N2O2 266.1055, found 266.1078. Anal. (C16H14N2O2·
0.3H2O) C, H, N.
2-(4-Hydroxyphenyl)-3-ethyl-2H-indazol-5-ol (16b). Com-
pound 16a (55 mg, 0.19 mmol) was deprotected according to
the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 16b was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (42 mg, 0.16 mmol, 85%)
that was recrystallized from EtOAc (mp >230 °C dec): 1H
NMR (500 MHz, acetone-d6) δ 8.8 (bs, OH), 8.2 (bs, OH), 7.47
(d, J ) 9.2, 1H), 7.39 (AA′ of AA′XX′ JAX ) 6.7, JAA′ ) 2.1,
2H), 7.02-6.94 (m, 4H), 2.96 (q, J ) 7.6, 2H), 1.17 (t, J ) 7.7,
3H); 13C NMR (500 MHz, acetone-d6) δ 158.5, 152.0, 145.7,
136.2, 133.3, 128.1, 121.5, 121.3, 119.3, 116.3, 100.3, 19.0, 14.0;
MS (EI) m/z 254 (M+, 100); HRMS (EI) calcd for C15H14N2O2
254.1055, found 254.1061. Anal. (C15H14N2O2·0.2H2O) C, H, N.
5-Methoxy-2-(4-methoxyphenyl)-3-propyl-2H-inda-
zole (17a). Compound 15a (60 mg, 0.2 mmol) was dissolved
in EtOH (2 mL), and Pd(OH)2 (13 mg) was added. The reaction
mixture was stirred at room temperature under hydrogen at-
mosphere (1 atm), for 15 h. The reaction mixture was filtered
off, the organic solvent removed in a vacuum, and the crude
product purified by flash chromatography (20% EtOAc/hexanes)
to give a white solid (40 mg, 0.13 mmol, 66% yield) that was
recrystallized from EtOAc/hexanes (mp 95-97 °C): 1H NMR
(500 MHz, CDCl3) δ 7.60 (d, J ) 9.3, 1H), 7.40 (AA′ of AA′XX′
JAX ) 6.8, JAA′ ) 2.2, 2H), 7.03-7.00 (m, 3H), 6.82 (d, J ) 2.1,
1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.92 (t, J ) 7.7, 2H), 1.63 (m,
2H), 0.89 (t, J ) 7.4, 3H); 13C NMR (500 MHz, CDCl3)δ 159.8,
154.5, 145.3, 135.7, 133.2, 127.4, 121.4, 120.6, 119.0, 114.3,
96.5, 55.6, 55.5, 27.2, 22.7, 14.0; MS (EI) m/z 296 (M+, 90).
5-Methoxy-2-(4-methoxyphenyl)-3-trifluoromethyl-2H-
indazole (18a). Compound 11e (66 mg, 0.2 mmol) was
dissolved in DMF (1 mL), and FSO2CF2CO2CH3 (127 µL, 1
mmol), followed by the addition of CuI (38 mg, 0.2 mmol), was
added. The reaction mixture was heated at 80 °C and stirred
at this temperature for 2 h. The reaction mixture was filtered
off, the DMF solvent removed in a vacuum, and the crude
product purified by flash chromatography (30% EtOAc/hex-
anes) to give a white solid (22 mg, 0.06 mmol, 34%) that was
recrystallized from EtOAc/hexanes (mp 128-129 °C): 1H NMR
(500 MHz, CDCl3) δ 7.67 (d, J ) 9.5, 1H), 7.47 (AA′ of AA′XX′
JAX ) 6.7, JAA′ ) 2.3, 2H), 7.10 (dd, J ) 9.2, 2.4, 1H), 7.01
(XX′ of AA′XX′ JAX ) 6.8, JXX′ ) 2.2, 2H), 6.95 (d, J ) 2.1, 1H),
3.89 (s, 3H), 3.88 (s, 3H); 19F NMR (500 MHz, CDCl3) δ -54.9;
MS (EI) m/z 322 (M+, 100).
3-Methyl-5-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (19a). Compound 19a was obtained as a byproduct in
the synthesis of product 20a. Product 20a was more conve-
niently synthesized by following the experimental procedure
reported below (20a). Compound 11e (80 mg, 0.24 mmol) was
dissolved in DMF (2 mL), and the following reagents were
added: Pd2(dba)3 (4 mg, 6 mol %), P(o-tolyl)3 (8.8 mg, 12 mol
%), and phenyltrimethyltin (87 µL, 0.48 mmol). The reaction
mixture was stirred at 80 °C for 3 h. The reaction mixture
was filtered off, the solvent removed in a vacuum, and the
crude product purified by flash chromatography (30% EtOAc/
hexanes) to give compound 19a (19 mg, 0.07 mmol, 30% yield)-
as white solid (mp 122-123 °C) and compound 20a (26 mg,
0.07 mmol, 33% yield): 1H NMR (400 MHz, CDCl3) δ 7.60 (d,
J ) 9.3, 1H), 7.44 (AA′ of AA′XX′ JAX ) 6.8, JAA′ ) 2.4, 2H),
7.04-7.01 (m, 3H), 6.79 (d, J ) 2.4, 1H), 3.88 (s, 3H), 3.87 (s,
3H), 2.57 (s, 3H); 13C NMR (400 MHz) δ 159.6, 154.6, 145.4,
133.2, 130.7, 126.9, 121.6, 121.1, 119.0, 114.3, 96.2, 55.6, 55.5,
11.1; MS (EI) m/z 268 (M+, 100).
5-Methoxy-2-(4-methoxyphenyl)-3-phenyl-2H-inda-
zole (20a). Compound 11e (70 mg, 0.21 mmol) was dissolved
in DMF (2 mL), and the following reagents were added: Pd-
(PPh3)4 (12 mg, 5 mol %), Cs2CO3 (96 mg, 0.3 mmol), and
phenylboronic acid (31 mg, 0.25 mmol). The reaction mixture
was stirred at 80 °C for 4 h. The reaction mixture was filtered
off, the solvent removed in a vacuum, and the crude product
purified by flash chromatography (30% EtOAc/hexanes) to give
a white solid (31 mg, 0.09 mmol, 45%) that was recrystallized
from EtOAc/hexanes (mp 138-140 °C): 1H NMR (500 MHz,
CDCl3) δ 7.69 (d, J ) 9.2, 1H), 7.46-730 (m, 7H), 7.04 (dd, J
2-(4-Hydroxyphenyl)-3-propyl-2H-indazol-5-ol (17b).
Compound 17a (30 mg, 0.10 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 17b was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (22 mg, 0.08 mmol, 82%)
that was recrystallized from EtOAc/acetone (mp >240 °C
dec): 1H NMR (500 MHz, acetone-d6) δ 8.5 (bs, OH), 7.46 (d,
J ) 9.2, 1H), 7.36 (AA′ of AA′XX′ JAX ) 6.7, JAA′ ) 2.1, 2H),
7.00 (XX′ of AA′XX′ JAX ) 6.8, JXX′ ) 2.2, 2H), 6.96 (dd, J )
9.2, 2.2, 2H), 6.91 (d, J ) 2.2, 1H), 2.91 (t, J ) 7.7, 2H), 1.60-
1.56 (m, 2H), 0.83 (t, J ) 7.3, 3H); 13C NMR (500 MHz, acetone-
d6) δ 158.5, 152.0, 145.7, 134.8, 133.5, 128.2, 122.1, 121.2,
119.4, 116.3, 100.5, 27.5, 23.1, 14.0; MS (EI) m/z 268 (M+, 66);
HRMS (EI) calcd for C16H16N2O2 268.1212, found 268.1210.
Anal. (C16H16N2O2‚0.1 H2O) C, H, N.
) 9, 2.4, 1H), 6.90-6.86 (m, 3H), 3.83 (s, 3H), 3.82 (s, 3H); 13
C
NMR (500 MHz, CDCl3) δ 159.3, 155.9, 145.8, 134.3, 133.6,
130.5, 129.7, 128.9, 128.1, 127.1, 121.9, 121.5, 119.2, 114.2,
96.4, 55.6, 55.6; MS (EI) m/z 330 (M+, 35).
5-Methoxy-2-(4-methoxyphenyl)-2H-indazole 3-carbo-
nitrile (21a). Compound 11e (66 mg, 0.2 mmol) was dissolved
in dimethylacetamide (1 mL), and the following reagents were
added: Pd2(dba)3 (7.2 mg, 4 mol %), Dppf (8.8 mg, 8 mol %),
Zn powder (1.5 mg, 24 mol %), and Zn(CN)2 (23 mg, 0.2 mmol).
The reaction mixture was stirred at 120 °C for 6 h. The
reaction mixture was quenched with water (10 mL) and
2-(4-Hydroxyphenyl)-3-trifluoromethyl-2H-indazol-5-
ol (18b). Compound 18a (30 mg, 0.09 mmol) was deprotected
according to the procedure described above with BF3‚SMe2 in
CH2Cl2. Compound 18b was purified by flash chromatography
(60% EtOAc/hexanes) to give a white solid (23 mg, 0.08 mmol,

1142 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
85%) that was recrystallized from EtOAc/hexanes (mp 224-
225 °C dec): 1H NMR (500 MHz, acetone-d6) δ 8.98 (s, OH),
7.86 (AA′ of AA′XX′ JAX ) 6.6, JAA′ ) 2.1, 2H), 7.60 (d, J ) 8.8,
1H), 7.01 (XX′ of AA′XX′ JAX ) 6.8, JXX′ ) 2.3, 2H), 6.89 (d, J
) 9.0, 1H); 13C NMR (500 MHz, acetone-d6) δ 157.3, 152.8,
149.0, 133.3, 122.0, 122.0, 120.9, 119.0, 116.3, 116.1, 92.6; MS
(EI) m/z 305 (M+, 3); HRMS (EI) calcd for C13H9BrN2O2
303.9847, found 303.9844. Anal. (C13H9BrN2O2·0.5H2O) C, H,
N.
8.71 (s, OH), 7.68 (d, J ) 9.4, 1H), 7.44 (XX′ of AA′XX′ JAX
)
6.8, JXX′ ) 2.2, 2H), 7.11 (dd, J ) 9.2, 2.3, 1H), 7.04-7.02 (m,
3H); 19F NMR (500 MHz, acetone-d6) δ -55.4; MS (EI) m/z
294 (M+, 100); HRMS (EI) calcd for C14H9F3N2O2 294.0616,
found 294.0612. Anal. (C14H9F3N2O2·0.1H2O) C, H, N.
2-(4-Hydroxyphenyl)-3-methyl-2H-indazol-5-ol (19b).
Compound 19a (19 mg, 0.07 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 19b was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (14 mg, 0.05 mmol, 82%
yield, mp >200 °C dec): 1H NMR (500 MHz, acetone-d6) δ 8.8
(bs, OH), 8.2 (bs, OH), 7.46-7.42 (m, 3H), 7.01 (AA′ of AA′XX′
JAX ) 6.6, JAA′ ) 2.2, 2H), 6.95 (dd, J ) 9.2, 2.2, 1H), 6.86 (d,
J ) 2.1, 1H), 2.50 (s, 3H); 13C NMR (500 MHz, acetone-d6) δ
158.2, 152.0, 145.7, 133.4, 130.0, 127.7, 121.3, 119.3, 116.3,
100.2, 10.9; MS (EI) m/z 240 (M+, 100); HRMS (EI) calcd for
C14H12N2O2 240.0899, found 240.0901. Anal. (C14H12N2O2·
0.3H2O) C, H, N.
2-Azido-4-methoxybenzoic Acid (26). Compound 25 (500
mg, 3 mmol) was dissolved in CH2Cl2 (2 mL), and Et3N (1.25
mL, 9 mmol) and CuSO4 (24 mg, 5 mol %) were added. The
reaction mixture was cooled at 0 °C and a freshly prepared
solution of TfN3 (9 mmol in 9 mL of CH2Cl2) was added. The
solution was brought to homogeneity by adding MeOH (2 mL)
and allowed to warm to room temperature. After 1 h of stirring
at this temperature, the reaction mixture was quenched with
water (10 mL), acidified with HCl (1 M), and extracted with
CH2Cl2 (3 × 15 mL). The organic extracts were dried over Na2-
SO4 and concentrated in a vacuum. The crude product was
purified by flash chromatography (90% CH2Cl2/MeOH) to give
a pale brown solid (550 mg, 2.8 mmol, 94% yield) that was
essentially pure (mp >140 °C dec): 1H NMR (500 MHz,
acetone-d6) δ 7.94 (d, J ) 8.5, 1H), 6.85 (dd, J ) 8.7, 2.2, 1H),
6.81 (d, J ) 2, 1H), 3.91 (s, 3H); 13C NMR (500 MHz, acetone-
d6) δ 165.8, 164.5, 142.9, 134.9, 115.9, 111.6, 106.8, 56.1; MS
(EI) m/z 193 (M+, 5).
2-Azido-4-methoxy-N-(4-methoxyphenyl)benzamide
(27). Compound 26 (100 mg, 0.5 mmol), was dissolved in
benzene (1 mL), and SOCl2 (375 µL, 10 mmol) was added. The
reaction mixture was stirred under refluxed for 2 h. After the
removal of SOCl2 by distillation, a solution of p-anisidine (63
mg, 0.5 mmol) in pyridine (1 mL) was added. After 15 min of
stirring at room temperature, the reaction mixture was
quenched with water (10 mL) and extracted with EtOAc (3 ×
10 mL). The organic extracts were washed twice with HCl (1
M), dried over Na2SO4, and concentrated in a vacuum. The
crude product was purified by flash chromatography (40%
EtOAc/hexanes) to give a white solid (110 mg, 0.21 mmol, 71%)
that was recrystallized from EtOAc/hexanes (mp 154-155 °C
dec): 1H NMR (500 MHz, CDCl3) δ 9.23 (s, NH), 8.19 (d, J )
9, 1H), 7.54 (d, J ) 8.8, 2H), 6.87 (d, J ) 8.8, 2H), 6.78 (dd, J
) 8.8, 2.2, 1H), 6.66 (d, J ) 2.1, 1H), 3.85 (s, 3H), 3.78 (s, 3H);
13C NMR (500 MHz, acetone-d6) δ 163.0, 162.3, 156.5, 138.3,
134.5, 131.3, 122.3, 117.9, 114.2, 110.6, 104.2, 55.7, 55.7; MS
(EI) m/z 298 (M+, 8).
3-Chloro-6-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (28). Compound 27 (100 mg, 0.33) was dissolved in
benzene (1.5 mL) and SOCl2 (1 mL) was added. The reaction
mixture was stirred under reflux for 3 h. After this time the
excess of SOCl2 was removed by distillation and the crude
product dissolved in EtOAc. The organic phase was washed
twice with NaHCO3 (sat. solution), dried over Na2SO4, and
concentrated in a vacuum. The crude product was purified by
flash chromatography (30% EtOAc/hexanes) to give a white
solid (50 mg, 0.17 mmol, 51%) that was recrystallized from
EtOAc/hexanes (mp 97-100 °C dec): 1H NMR (500 MHz,
CDCl3) δ 7.55 (d, J ) 9.0, 1H), 7.45 (d, J ) 9.2, 2H), 7.02 (d,
J ) 8.8, 2H), 6.90 (d, J ) 1.9, 1H), 6.81 (dd, J ) 9.1, 2.0, 1H),
3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (500 MHz, CDCl3) δ 159.96,
159.91, 149.5, 131.7, 126.9, 119.9, 119.7, 118.1, 115.6, 114.3,
94.7, 55.7, 55.4; MS (EI) m/z 288 (M+, 100).
3,7-Dichloro-6-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (29). Compound 29 was obtained as byproduct in the
synthesis of derivative 28. Using the same reaction conditions
and the same purification method, it was possible to obtained
29 (40 mg, 0.12 mmol, 35% yield) as a white solid which was
recrystallized from EtOAc/hexanes (mp 119-120 °C dec): 1H
NMR (400 MHz, CDCl3) δ 7.56 (d, J ) 9.1, 2H), 7.50 (d, J )
9.3, 1H), 7.03-7.00 (m, 3H), 3.99 (s, 3H), 3.86 (s, 3H); 13C NMR
(500 MHz, CDCl3) δ 160.2, 154.0, 146.8, 131.3, 127.3, 120.8,
118.5, 116.8, 114.4, 114.3, 113.0, 107.6, 57.7, 55.7; MS (EI)
m/z 322 (M+, 100).
2-(4-Hydroxyphenyl)-3-phenyl-2H-indazol-5-ol (20b).
Compound 20a (30 mg, 0.09 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 20b was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (23 mg, 0.07 mmol, 77%)
that was recrystallized from EtOAc (mp >250 °C dec): 1H
NMR (500 MHz, acetone-d6) δ 8.5 (bs, OH), 7.59 (d, J ) 9.3,
1H), 7.44-7.34 (m, 5H), 7.25 (AA′ of AA′XX′ JAX ) 6.8, JAA′
)
2.1, 2H), 7.05 (dd, J ) 9.2, 2.1, 1H), 6.95 (d, J ) 1.8, 1H), 6.87
(XX′ of AA′XX′ JAX ) 6.7, JXX′ ) 2.1, 2H); 13C NMR (500 MHz,
acetone-d6) δ 158.1, 153.6, 146.1, 133.7, 133.7, 131.6, 130.2,
129.5, 128.5, 128.1, 122.7, 121.6, 119.8, 116.1, 100.1; MS (EI)
m/z 302 (M+, 100); HRMS (EI) calcd for C19H14N2O2 302.1055,
found 302.1050. Anal. (C19H14N2O2·0.1H2O) C, H, N.
5-Hydroxy-2-(4-hydroxyphenyl)-2H-indazole-3-carbo-
nitrile (21b). Compound 21a (17 mg, 0.06 mmol) was depro-
tected according to the procedure described above with
BF3‚SMe2 in CH2Cl2. Compound 21b was purified by flash
chromatography (60% EtOAc/hexanes) to give a white solid
(14 mg, 0.05 mmol, 93%) that was recrystallized from EtOAc
(mp >280 °C dec): 1H NMR (500 MHz, acetone-d6) δ 9.06 (bs,
OH), 7.79 (d, J ) 9.2, 1H), 7.72 (AA′ of AA′XX′ JAX ) 6.7, JAA′
) 2.3, 2H), 7.16 (dd, J ) 9.3, 2.2, 1H), 7.09 (XX′ of AA′XX′ JAX
) 6.7, JXX′ ) 2.1, 2H), 7.02 (d, J ) 2.3, 1H);13C NMR (500 MHz,
acetone-d6) δ 159.4, 156.7, 145.5, 132.3, 129.0, 126.3, 122.7,
121.4, 116.7, 112.4, 105.3, 98.5; MS (EI) m/z 251 (M+, 100);
HRMS (EI) calcd for C14H9N3O2 251.0695, found 251.0696;
purity > 96% (HPLC).
7-Bromo-6-methoxy-2-(4-methoxyphenyl)-2H-inda-
zole (23). Compound 9d (60 mg, 0.23 mmol) was suspended
in acetic acid (1 mL) and a solution of bromine (12 µL, 0.23
mmol) in acetic acid (1.5 mL) was added dropwise at room
temperature for 4 h. After the addition was complete, the
reaction mixture was stirred at room temperature for another
12 h. The reaction mixture was quenched with water (10 mL)
and extracted with EtOAc (3 × 10 mL). The organic extracts
were washed twice with NaOH (1 M), dried over Na2SO4, and
concentrated in a vacuum. The crude product was purified by
flash chromatography (20% EtOAc/hexanes) to give a white
solid (65 mg, 0.19 mmol, 85%) that was recrystallized from
EtOAc/hexanes (mp 147-148 °C): 1H NMR (500 MHz, CDCl3)-
δ 8.34 (s, 1H), 7.80 (AA′ of AA′XX′ JAX ) 6.5, JAA′ ) 2.0, 2H),
7.63 (d, J ) 9, 1H), 7.00 (XX′ of AA′XX′ JAX ) 6.5, JXX′ ) 2.0,
2H), 6.97 (dd, J ) 9, 1H), 4.0 (s, 3H), 3.86 (s, 3H); 13C NMR
(500 MHz, CDCl3) δ 159.3, 154.6, 149.1, 133.8, 122.5, 121.6,
120.4, 119.4, 114.5, 112.4, 96.5, 57.5, 55.5; MS (EI) m/z 333
(M+, 100).
7-Bromo-2-(4-hydroxyphenyl)-2H-indazol-6-ol (24). Com-
pound 23 (60 mg, 0.18 mmol) was deprotected according to
the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 24 was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (35 mg, 0.11 mmol, 63%)
that was recrystallized from EtOAc/hexanes (mp 160-165 °C
dec): 1H NMR (500 MHz, acetone-d6) δ 8.7 (s, OH), 8.5 (s, OH),
3-Chloro-2-(4-hydroxyphenyl)-2H-indazol-6-ol (30). Com-
pound 28 (95 mg, 0.33 mmol) was deprotected according to
the procedure described above with BF3‚SMe2 in CH2Cl2.

Indazole Estrogens
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1143
Compound 30 was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (70 mg, 0.26 mmol, 81%)
that was recrystallized from EtOAc/hexanes (mp 236-238 °C
dec): 1H NMR (500 MHz, acetone-d6) δ 8.7 (bs, OH), 7.53-
7.48 (m, 3H), 7.03 (d, J ) 8.8, 2H), 6.87-6.85 (m, 2H); 13C
NMR (500 MHz, acetone-d6) δ 158.8, 157.8, 150.1, 131.5, 127.9,
120.5, 119.4, 118.2, 116.3, 115.8, 98.3; MS (EI) m/z 260 (M+,
100); HRMS (EI) calcd for C13H9ClN2O2 260.0353, found
260.0348. Anal. (C13H9ClN2O2) C, H, N
3,7-Chloro-2-(4-hydroxyphenyl)-2H-indazol-6-ol (31).
Compound 29 (30 mg, 0.09 mmol) was deprotected according
to the procedure described above with BF3‚SMe2 in CH2Cl2.
Compound 31 was purified by flash chromatography (60%
EtOAc/hexanes) to give a white solid (17 mg, 0.05 mmol, 63%
yield) that was essentially pure (mp >240 °C dec): 1H NMR
(500 MHz, acetone-d6) δ 8.7 (bs, OH), 7.56 (d, J ) 8.8, 2H),
7.49 (d, J ) 9.0, 1H), 7.06 (d, J ) 8.6, 2H), 7.02 (d, J ) 8.8,
2H); 13C NMR (500 MHz, acetone-d6) δ 159.0, 152.7, 147.3,
131.3, 128.0, 120.7, 119.0, 118.0, 116.6, 116.3, 104.2; MS (EI)
m/z 294 (M+, 100); HRMS (EI) calcd for C13H8Cl2N2O2 293.9963,
found 293.9959. Purity > 96% (HPLC).
Estrogen Receptor Binding Affinity Assays. Relative
binding affinities were determined by a competitive radiomet-
ric binding assay as previously described,39,40 using 10 nM [3H]-
estradiol as tracer ([6,7-3H]estra-1,3,5,(10)-triene-3,17-â-diol,
51-53 Ci/mmol, Amersham BioSciences, Piscataway, NJ), and
purified full-length human ERR and ERâ were purchased from
PanVera (Madison, WI). Incubations were for 18-24 h at 0
°C. Hydroxyapatite (Bio-Rad, Hercules, CA) was used to absorb
the receptor-ligand complexes, and free ligand was washed
away. The binding affinities are expressed as relative binding
affinity (RBA) values with the RBA of estradiol set to 100%.
The values given are the average ( range or SD of two or three
independent determinations. Estradiol binds to ERR with a
Kd of 0.2 nM and to ERâ×e2 with a Kd of 0.5 nM.
24, 30, 31. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Turner, R. T.; Rickard, D.; Spelsberg, T. C.; Sibonga, J. D. The
basic biology of estrogen and bone. Osteoporosis; Humana
Press: 2002; pp 309-330.
(2) Maran, A.; Turner, R. T. Effects of estrogen on bone. Recent
Research Developments in Endocrinology; 2001; p 327.
(3) Mendelsohn, M. E.; Karas, R. H. The protective effects of
estrogen on the cardiovascular system. N. Engl. J. Med. 1999,
340, 1801-1811.
(4) Mendelsohn, M. E. Protective effects of estrogen on the cardio-
vascular system. Am. J. Cardiol. 2002, 89, 12E-17E; discussion
17E-18E.
(5) Behl, C. Oestrogen as a neuroprotecitve hormone. Nature Rev.
Neurosci. 2002, 3, 433-442.
(6) Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen receptor subtypes
alpha and beta contribute to neuroprotection and increased Bcl-2
expression in primary hippocampal neurons. Brain Res. 2004,
1010, 22-34.
(7) Mosselman, S.; Polman, J.; Dijkema, R. ERb: Identification and
characterization of a novel human estrogen receptor. FEBS Lett.
1996, 392, 49-53.
(8) Kuiper, G. G.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.;
Gustafsson, J. A. Cloning of a novel receptor expressed in rat
prostate and ovary. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 5925-
5930.
(9) Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.;
Thorsell, A.-G.; Engstrom, O.; Ljunggren, J.; Gustafsson, J.-A.;
Carlquist, M. Structure of the ligand-binding domain of oestro-
gen receptor beta in the presence of a partial agonist and a full
antagonist. EMBO J. 1999, 18, 4608-4618.
(10) Weihua, Z.; Andersson, S.; Cheng, G.; Simpson Evan, R.; Warner,
M.; Gustafsson, J.-A. Update on estrogen signaling. FEBS Lett.
2003, 546, 17-24.
(11) Mitra, S. W.; Hoskin, E.; Yudkovitz, J.; Pear, L.; Wilkinson, H.
A.; Hayashi, S.; Pfaff, D. W.; Ogawa, S.; Rohrer, S. P.; Schaeffer,
J. M.; McEwen, B. S.; Alves, S. E. Immunolocalization of
Estrogen Receptor {beta} in the Mouse Brain: Comparison with
Estrogen Receptor {alpha}. Endocrinology 2003, 144, 2055-
2067.
Cell Culture and Transient Transfections. Human
endometrial cancer (HEC-1) cells were maintained in mini-
mum essential medium (MEM) plus phenol-red supplemented
with 5% calf serum and 5% fetal calf serum. Cells were plated
in phenol-red-free improved MEM and 5% charcoal dextran-
treated calf serum (CDCS) and were given fresh medium 24 h
before transfection. Transfection assays were performed in 24-
well plates using a mixture of 0.35 mL of serum-free improved
MEM medium and 0.15 mL of Hank’s balanced salt solution
containing 5 µL of lipofectin (Life Technologies, Inc., Gaith-
ersburg, MD), 1.6 µg of transferrin (Sigma, St. Louis, MO),
200 ng of pCMV â-galactosidase as internal control, 1 µg of
2ERE-pS2-Luc, and 100 ng of ER expression vector per well.
The cells were incubated at 37 °C in a 5% CO2-containing
incubator for 5 h. The medium was then replaced with fresh
improved MEM supplemented with 5% CDCS plus the desired
concentrations of ligands. Cells were harvested 24 h later.
Luciferase and â-galactosidase activity were assayed as de-
scribed.41
(12) Shughrue, P. J.; Lane, M. V.; Merchenthaler, I. Comparative
distribution of estrogen receptor-alpha and -beta mRNA in the
rat central nervous system. J. Comput. Neurol. 1997, 388, 507-
525.
(13) Stossi, F.; Barnett, D. H.; Frasor, J.; Komm, B.; Lyttle, C. R.;
Katzenellenbogen, B. S. Transcriptional profiling of estrogen-
regulated gene expression via estrogen receptor (ER) alpha or
ERbeta in human osteosarcoma cells: Distinct and common
target genes for these receptors. Endocrinology 2004, 145, 3473-
3486.
(14) Kian, T. M.; Rogatsky, I.; Tzagarakis-Foster, C.; Cvoro, A.; An,
J.; Christy, R. J.; Yamamoto, K. R.; Leitman, D. C. Estradiol
and selective estrogen receptor modulators differentially regulate
target genes with estrogen receptors alpha and beta. Mol. Biol.
Cell 2004, 15, 1262-1272.
(15) Monroe, D. G.; Getz, B. J.; Johnsen, S. A.; Riggs, B. L.; Khosla,
S.; Spelsberg, T. C. Estrogen receptor isoform-specific regulation
of endogenous gene expression in human osteoblastic cell lines
expressing either ERalpha or ERbeta. J. Cell. Biochem. 2003,
90, 315-326.
(16) Sun, J.; Meyers, M. J.; Fink, B. E.; Rajendran, R.; Katzenellen-
bogen, J. A.; Katzenellenbogen, B. S. Novel ligands that function
as selective estrogens or antiestrogens for estrogen receptor-
alpha or estrogen receptor-beta. Endocrinology 1999, 140, 800-
804.
(17) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Synthesis and
biological evaluation of a novel series of furans: Ligands
selective for estrogen receptor alpha. J. Med. Chem. 2001, 44,
3838-3848.
(18) Kuiper, G. G.; Carlsson, B.; Grandien, K.; Enmark, E.; Haggblad,
J.; Nilsson, S.; Gustafsson, J. A. Comparison of the ligand
binding specificity and transcript tissue distribution of estrogen
receptors alpha and beta. Endocrinology 1997, 138, 863-870.
(19) Henke, B. R.; Consler, T. G.; Go, N.; Hale, R. L.; Hohman, D.
R.; Jones, S. A.; Lu, A. T.; Moore, L. B.; Moore, J. T.; Orband-
Miller, L. A.; Robinett, R. G.; Shearin, J.; Spearing, P. K.;
Stewart, E. L.; Turnbull, P. S.; Weaver, S. L.; Williams, S. P.;
Wisely, G. B.; Lambert, M. H. A new series of estrogen receptor
modulators that display selectivity for estrogen receptor beta.
J. Med. Chem. 2002, 45, 5492-5505.
(20) Yang, C.; Edsall, R., Jr.; Harris, H. A.; Zhang, X.; Manas, E. S.;
Mewshaw, R. E. ERbeta ligands. Part 2: Synthesis and struc-
ture-activity relationships of a series of 4-hydroxy-biphenyl-
carbaldehyde oxime derivatives. Bioorg. Med. Chem. 2004, 12,
2553-2570.
Acknowledgment. We are grateful for support of
this research through grants from the National Insti-
tutes of Health [PHS 5R37 DK15556 (J.A.K.) and 5R01
CA19118 (B.S.K.)]. NMR spectra were obtained in the
Varian Oxford Instrument Center for Excellence in
NMR Laboratory. Funding for this instrumentation was
provided in part from the W. M. Keck Foundation, the
National Institutes of Health (PHS 1 S10 RR104444-
01), 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
Institutes of Health (RR 01575), and the National
Science Foundation (PCM 8121494).
Supporting Information Available: HPLC and elemen-
tal analysis of compounds 10a-e, 12a-f, 13b, 15b, 16b-21b,

1144 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
De Angelis et al.
(21) Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenel-
lenbogen, B. S.; Katzenellenbogen, J. A. Estrogen receptor-beta
potency-selective ligands: Structure-activity relationship stud-
ies of diarylpropionitriles and their acetylene and polar ana-
logues. J. Med. Chem. 2001, 44, 4230-4251.
(22) Schopfer, U.; Schoeffter, P.; Bischoff, S. F.; Nozulak, J.; Feuer-
bach, D.; Floersheim, P. Toward selective ERbeta agonists for
central nervous system disorders: Synthesis and characteriza-
tion of aryl benzthiophenes. J. Med. Chem. 2002, 45, 1399-1401.
(23) Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.;
Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R.
A.; Keith, J. C., Jr.; Harris, H. A. Design and synthesis of aryl
diphenolic azoles as potent and selective estrogen receptor-beta
ligands. J. Med. Chem. 2004, 47, 5021-5040.
(24) Barlaam, B.; Bernstein, P.; Dantzman, C.; Warwick, P. Prepara-
tion of benzoxazoles and benzothiazoles as selective ligands for
human b-estrogen receptor. An 2002:504768, WO02/051821,
2002.
(25) Barlaam, B.; Dock, S.; Folmer, J. Preparation of benzimidazoles
as selective estrogen receptor-b ligand. An 2002:449659, WO02/
046168, 2002.
(26) Harris, H. A.; Albert, L. M.; Leathurby, Y.; Malamas, M. S.;
Mewshaw, R. E.; Miller, C. P.; Kharode, Y. P.; Marzolf, J.;
Komm, B. S.; Winneker, R. C.; Frail, D. E.; Henderson, R. A.;
Zhu, Y.; Keith, J. C., Jr. Evaluation of an estrogen receptor-
beta agonist in animal models of human disease. Endocrinology
2003, 144, 4241-4249.
(27) Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Novel structural templates for estrogen-
receptor ligands and prospects for combinatorial synthesis of
estrogens. Chem. Biol. 1999, 6, 205-219.
(28) Song, J. J.; Yee, N. K. A novel synthesis of 2-aryl-2H-indazoles
via a palladium-catalyzed intramolecular amination reaction.
Org. Lett. 2000, 2, 519-521.
(31) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Suzuki-type
cross-coupling reaction of 3-iodoindazoles with aryl boronic
acids: A general and flexible route to 3-arylindazoles. Tetrahe-
dron 1999, 55, 6917-6922.
(32) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. Alkyl group
isomerization in the cross-coupling reaction of secondary alkyl
Grignard reagents with organic halides in the presence of nickel-
phosphine complexes as catalysts. J. Am. Chem. Soc. 1972, 94,
9268-9269.
(33) Littke, A. F.; Schwarz, L.; Fu, G. C. Pd/P(t-Bu)(3): A mild and
general catalyst for Stille reactions of aryl chlorides and aryl
bromides. J. Am. Chem. Soc. 2002, 124, 6343-6348.
(34) Chen, Q.-Y. Trifluoromethylation of organic halides with difluo-
rocarbene precursors. J. Fluorine Chem. 1995, 72, 241-246.
(35) Jin, F.; Confalone, P. N. Palladium-catalyzed cyanation reactions
of aryl chlorides. Tetrahedron Lett. 2000, 41, 3271-3273.
(36) Ardakani, M. A.; Smalley, R. K.; Smith, R. H. A New Synthesis
of 2-Aryl-3-chloro-2H-indazoles. Synthesis 1979, 4, 308-310.
(37) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A.
Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-diones. Library
Preparation and Demonstration of Synthesis Generality. J. Org.
Chem. 1997, 62, 1240-1256.
(38) Liu, Q.; Tor, Y. Simple conversion of aromatic amines into azides.
Org Lett 2003, 5, 2571-2572.
(39) Katzenellenbogen, J. A.; Johnson, H. J., Jr.; Myers, H. N.
Photoaffinity labels for estrogen binding proteins of rat uterus.
Biochemistry 1973, 12, 4085-4092.
(40) Carlson, K. E.; Choi, I.; Gee, A.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Altered ligand binding properties and
enhanced stability of a constitutively active estrogen receptor:
Evidence that an open pocket conformation is required for ligand
interaction. Biochemistry 1997, 36, 14897-14905.
(41) McInerney, E. M.; Tsai, M. J.; O’Malley, B. W.; Katzenellenbo-
gen, B. S. Analysis of estrogen receptor transcriptional enhance-
ment by a nuclear hormone receptor coactivator. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 10069-10073.
(29) Ghosh, A. K.; Mukhopadhyaya, J. K.; Ghatak, U. R. Regiose-
lective aryl radical cyclisation. Part 2. Synthesis of octahydro-
1H-dibenzo[a,d]cycloheptenes through 7-endo ring closure. J
Chem Soc, Perkin Trans 1 1997, 18, 2747-2756.
(30) Waalwijk, P. S.; Cohen-Fernandes, P.; Habraken, C. L. Indazole
studies. 3. The bromination of 2-phenyl-2H-indazole. Formation
and structure determination of mono-, di-, and tribromo-2-
phenyl-2H-indazoles. J. Org. Chem. 1984, 49, 3404-3403.
JM049223G