Synthesis of estradiol backbone mimics via the Stille reaction using copper(II) oxide as co-reagent

Article abstract of DOI:10.1016/j.tetlet.2010.10.144

Sterically hindered biaryls and 2-phenylbenzo[b]thiophenes that can serve as templates for mimics of the estradiol backbone were prepared in modest to good yields by the Stille reaction using CuO as a co-reagent. Due to the neutral conditions applied in t

Full text of DOI:10.1016/j.tetlet.2010.10.144

Tetrahedron Letters 52 (2011) 209–211
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of estradiol backbone mimics via the Stille reaction using
copper(II) oxide as co-reagent
Erik Flöistrup a, Patrick Goede b, Roger Strömberg a, Johan Malm c,
⇑
a Department of Bioscience and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge, Sweden
b Department of Energetic Materials, Swedish Defence Research Agency FOI, Grindsjön Research Centre, SE-147 25 Tumba, Sweden
c Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box-574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Sterically hindered biaryls and 2-phenylbenzo[b]thiophenes that can serve as templates for mimics of the
estradiol backbone were prepared in modest to good yields by the Stille reaction using CuO as a co-
reagent. Due to the neutral conditions applied in the Stille reaction, protection strategies were unneces-
sary for hydroxy containing coupling partners. Ligandless coupling conditions were also evaluated.
Ó 2010 Published by Elsevier Ltd.
Received 29 April 2010
Revised 10 August 2010
Accepted 27 October 2010
Available online 31 October 2010
The synthesis of estrogenic mimetics is important due to the
inherent side effects, low efficacy, and low oral bioavailability asso-
ciated with the endogenous hormone estradiol (Fig. 1) in medicinal
therapy. It is known that certain estrogen mimetics can be
exploited as Selective Estrogen Receptor Modulators (SERMs), as
exemplified by raloxifen (Fig. 1).1 Furthermore, it has been shown
that hindered 40-hydroxy PCB’s can act as estradiol mimetics and
exhibit estradiol-like properties.2
The preparation of a number of different biphenyls using palla-
dium-catalyzed cross-coupling of aryl boronic acids with aryl ha-
lides and triflates, for the assembly of biaryls to mimic the
steroidal backbone of estradiol, has been reported.3 Yields were
low, especially when the halogen cross-coupling partner was
substituted at both ortho positions to give bis-ortho-substituted
biphenyl derivatives (e.g. as in the estradiol mimetic, Fig. 1).
An efficient method for palladium-catalyzed cross-coupling of
organostannanes with aryl- and heteroarylbromides (Stille reac-
tion) in the presence of metal oxides in stoichiometric quantities
(co-reagent) has been developed by us.4 This method is highly effi-
cient when the standard cross-coupling tends to be sluggish and
has for example been applied to the assembly of 5-heteroaryl
nucleosides,5 polythiophenes,6 heteroaryl ferrocenes,7 diphenylox-
azoles,8 and for the synthesis of a sterically-crowded atropisomeric
1,8-diacridylnaphthalenes,9 as well as in microwave-promoted flu-
orous phase conditions.10
This advantage is especially appealing when considering the
assembly of phenolic coupling partners. Organostannanes are usu-
ally stable to a wide variety of reaction conditions, have long shelf
lives, and are readily purified. It has also been shown that all
remaining traces of organostannanes can be removed completely
upon work-up in the presence of Et3Al or NaOH (aq).13
The first objective of the present research was to prepare 2-
phenylbenzo[b]thiophene derivatives, which could serve as a start-
ing point for the preparation of raloxifen and derivatives thereof.
The second objective was to carry out an investigation of whether
the present method could be applied to the preparation of hindered
biaryls that could serve as templates for mimics of steroidal back-
bone of estradiol. Apart from cross-coupling conditions using
Pd(0) with and without CuO (Method A),14 ligandless conditions
were employed. This technique15,16 requires use of a palladium cat-
alyst with more ‘loosely’ complexed ligands, in this case tris(diben-
zylideneacetone)dipalladium (Pd2dba3), and then exchanging those
ligands in situ with another type of ligand. Our ligand of choice for
the exchange was tri-furylphosphine (Method B).17
OH
Me
H
N
O
H
H
Even though organostannanes are known for their toxicity, and
boronic acids and boronic acid esters (Suzuki-coupling) have
emerged as the preferred coupling partners,11,12 a number of key
advantages of the use of stannanes can be identified. There is no
need to apply protection strategies for base-sensitive groups since
the Stille reaction conditions are usually non-aqueous and neutral.
HO
estradiol
O
OH
OH
Me
HO
S
raloxifen
HO
Me
estradiol mimetic
⇑
Corresponding author. Tel.: +46 18 4714124; fax: +46 18 4714474.
E-mail address: Johan.Malm@orgfarm.uu.se (J. Malm).
Figure 1. Chemical structures of estradiol, raloxifen, and an estradiol mimetic.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.10.144

210
E. Flöistrup et al. / Tetrahedron Letters 52 (2011) 209–211
Table 1
with hindered Halophenols is greatly improved when the co-
reagent CuO is used. Comparing the two Methods A and B also sug-
gests the use of tetrakis(triphenylphosphine)palladium(0) rather
than ‘ligandless’ conditions for Stille cross-coupling reactions of
hindered biaryls. We think that these results will help in selecting
conditions for the preparation of biologically active and selective
estradiol mimetics.
Palladium-catalyzed cross-coupling of 2-trimethylstannyl-6-methoxybenzo[b]thio-
phene with arylhalides.a
R3
R3
R2
R2
R1
X
Pd(0)
R1
SnMe3
+
S
S
MeO
MeO
Me
Me
Entry
R1
R2
R3
X
Yielda (%)
Acknowledgments
1
2
3
4
H
H
OH
OH
H
H
H
Me
H
Br
Br
Br
I
98
Me
Me
H
61 (0)
37 (0)
46
The authors acknowledge the Swedish Research Council and the
Foundation for Knowledge and Competence Development (the KK-
foundation) for the financial support.
a
Yields refer to isolated yields. Reactions were heated at 95-100 °C over night.
Method A was used and conducted as described in reference 14. Yield in brackets
refers to runs without CuO.
Supplementary data
Supplementary data (experimental procedures and data for new
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.10.144.
Table 2
Palladium-catalyzed cross-coupling of arylstannanes with arylbromides
R2
Me
Me
R2
Br
References and notes
"Pd"
+
R1
Me3Sn
Me
1. Raloxifen displays estrogen agonist-like actions on bone tissues and serum
lipids while displaying potent estrogen antagonist properties in the breast and
uterus. See for example: Dodge, J. A.; Lugar, C. W.; Cho, S.; Short, L. L.; Sato, M.;
Yang, N. N.; Spangle, L. A.; Martin, M. J.; Phillips, D. L.; Glasebrook, A. L.;
Osborne, J. J.; Frolik, C. A.; Bryant, H. U. J. Steroid Biochem. Mol. Biol. 1997, 61,
97–106.
R1
Me
Entry
R1
R2
Methoda
Reaction timeb (h)
Yieldc (%)
1
2
3
4
5
OH
OBn
OH
OBn
OH
CHO
CHO
CHO
CHO
COOH
A
A
B
B
A
20 (102)
18 (23)
69 (30)
96 (50)
28 (20)
94, 80d (51)
47 (45)
25 (5)
2. Korach, K. S.; Chae, K.; McLachlan, J.; McKinney, J. D. Mol. Pharmacol. 1988, 61,
120–126.
8 (9)
3. Lesuisse, D.; Albert, E.; Bouchoux, F.; Cerede, E.; Lefrancois, J.-M.; Levif, M.-O.;
Tessier, S.; Tric, B.; Teutsch, G. Bioorg. Med. Chem. Lett. 2001, 11, 1709–1712.
4. (a) Malm, J.; Björk, P.; Gronowitz, S.; Hörnfeldt, A.-B. Tetrahedron Lett. 1992, 33,
2199–2202; (b) Gronowitz, S.; Björk, P.; Malm, J.; Hörnfeldt, A.-B. J. Organomet.
Chem. 1993, 460, 127–129; (c) Malm, J.; Björk, P.; Gronowitz, S.; Hörnfeldt, A.-B.
Tetrahedron Lett. 1994, 35, 3195–3196; (d) Björk, P.; Malm, J.; Hörnfeldt, A.-B.;
Gronowitz, S. Heterocycles 1997, 44, 237–253.
No yield
a
Methods A and B were as described in Refs. 14 and 17, with and without CuO
present.
b
Reaction times were monitored by TLC and determined as the time required for
all the starting material to be consumed. Reaction times in brackets refer to runs
without CuO.
5. Guitierrez, A. J.; Terhost, T. J.; Matteucci, M. D.; Froehler, B. C. J. Am. Chem. Soc.
1994, 116, 5540–5544.
c
Yields were estimated by HPLC analysis of the crude products as described in
6. McCullough, R. D.; Ewbank, P. C.; Loewe, R. S. J. Am. Chem. Soc. 1997, 119, 633–
634.
Ref. 14. Yields in brackets refer to runs without CuO.
d
Isolated yield in a separate synthesis.
7. Liu, C.-M.; Chen, B.-H.; Liu, W.-Y.; Wu, X.-L.; Ma, Y.-X. J. Organomet. Chem. 2000,
598, 348–352.
8. Clapham, B.; Sutherland, A. J. J. Org. Chem. 2001, 66, 9033–9037.
9. Mei, X.; Martin, R. H.; Wolf, C. J. Org. Chem. 2006, 71, 2854–2861.
10. Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J. Org. Chem.
1997, 62, 5583–5587.
11. Reviews: (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (b) Stanforth, S. P.
Tetrahedron 1998, 54, 263–303.
12. Applications employing highly active Suzuki catalysts: (a) Yin, J.; Matthew, M.
P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162–1163; (b)
Dupuis, C.; Adiey, K.; Charruault, L.; Michelet, V.; Savignac, M.; Genet, J.-P.
Tetrahedron Lett. 2001, 42, 6523–6526.
Method A was applied to the synthesis of hindered analogs of 2-
phenyl-6-methoxybenzo[b]thiophene (Table 1). Strikingly, the
presence of CuO was mandatory in order to obtain the desired
product (entries 2 and 3). Yields were lower when the R1-position
was substituted with a hydroxy group. Boronic acids were also
evaluated as coupling partners using a wide variety of conditions,
but resulted in complex reaction mixtures and low yields of the de-
sired products.
13. Renaud, P.; Lacôte, E.; Quaranta, L. Tetrahedron Lett. 1998, 39, 2123–2126.
14. Method A: A stirred mixture of the appropriate bromophenol (2.0 mmol), with
or without CuO (2.0 mmol), tetrakis(triphenylphosphine)palladium(0)
(0.1 mmol), and DMF (9.0 mL) was purged with argon for 15 min after which
the appropriate stannane (2.5 mmol) in DMF (1.0 mL) was added via a syringe
to the mixture. The reaction mixture was stirred at 95–100 °C until the starting
materials were consumed. The reaction mixture was filtered through a short
pad of Celite (1 cm) on silica (1 cm) in a glass filter funnel that was then
washed with ethyl acetate. The filtrate was washed with water, dried over
MgSO4, and concentrated in vacuo. The benzothiophene isolated products
(Table 1) were purified on a chromatotron (silica, 99:1, petroleum ether/ethyl
acetate). The isolated product from Table 2, entry 1 was purified by flash
chromatography (silica, 19:1, toluene/acetonitrile). Other products in Table 2
The cross-coupling of arylstannanes with aryl bromides was
evaluated by HPLC analysis of the reaction mixtures and the results
from these biaryl couplings are shown in Table 2. The presence of
the R2-formyl group represents the synthetic precursor of the
hydroxymethyl group shown in the estradiol mimetic (Fig. 1).
When Method A was applied for the palladium-catalyzed cross-
coupling, it was generally more effective with CuO than without
CuO (Tables 1 and 2). Addition of CuO in Method A resulted in
higher yields as well as a substantially shorter reaction time in
the reaction with the unprotected phenol (Table 2, entry 1), and
with the benzothiophenes there was no detectable product without
CuO. When a protected phenol (–OBn) was used as the coupling
partner, CuO-addition only resulted in a slight improvement
(Table 2, entry 2). Ligandless conditions (Method B) gave quite inef-
ficient cross-coupling of these substances, for both unprotected and
protected phenols (Table 2, entries 3 and 4), both with and without
CuO. Attempts to cross-couple the benzoic acid stannane only
resulted in a complex reaction mixture.
were isolated from
a part of the crude product of entries 1 and 2, for
characterization and to obtain HPLC reference material for co-injection.
Reversed Phase (RP) HPLC analyses of crude product mixtures (Table 2) were
carried out with a gradient of 75–100% of solvent B in Solvent A over 18 min
after an initial 0.1 min isocratic part with 75%
B (Reprosil RP-18 5 mm,
4.6 ꢀ 250 mm, mL/min; solvent A: 30% H2O in methanol, B: 25% isopropanol in
methanol). The response areas in the HPLC analysis (UV 260 nm) of the desired
biaryl peak in the crude product and in the crude product spiked with a known
amount of isolated biaryl compound were determined and the amount of
biaryl compound in the crude product was determined from the difference
between the spiked and non-spiked samples.
In summary, we have shown that the Stille palladium-catalyzed
cross-coupling of benzo[b]thiophene and benzaldehyde stannanes
15. Beletskaya, I. P. J. Organomet. Chem. 1983, 250, 551–564.
16. Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.

E. Flöistrup et al. / Tetrahedron Letters 52 (2011) 209–211
211
17. Method B:
A
stirred mixture of bromo component (2.0 mmol),
observed (TLC), ethyl acetate and activated carbon were added and the mixture
was set to reflux for 15 min, after which it was filtered through a short pad of
Celite (1 cm) on silica (1 cm) in a glass filter funnel. The filtrate was evaporated
and the residue was further purified on HPLC. Yields were determined using
HPLC as described above under Method A.
tris(dibenzylidene-acetone)dipalladium (0.1 mmol) and trifurylphosphine
(0.4 mmol, 5 mol %) in DMF (8 mL) was purged with argon for 10 min. 4-
trimethyl-stannylbenzaldehyde (0.67 g, 2.5 mmol) was added to the reaction
mixture and heating was set to 65 °C. When no further development could be