A new approach to desketoraloxifene analogs from oxygen-bearing 3-iodobenzo[b]thiophenes prepared via iodocyclization

Article abstract of DOI:10.1016/j.tetlet.2010.09.137

A formal total synthesis of the benzothiophene selective estrogen receptor modulator (SERM) desketoraloxifene and analogs has been accomplished from alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I₂. This approa

Full text of DOI:10.1016/j.tetlet.2010.09.137

Tetrahedron Letters 51 (2010) 6485–6488
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach to desketoraloxifene analogs from oxygen-bearing
3-iodobenzo[b]thiophenes prepared via iodocyclization
Chul-Hee Cho a, Dai-Il Jung a,b, Richard C. Larock a,
⇑
a Department of Chemistry, Iowa State University, Ames, IA 50011, United States
b Department of Chemistry, Dong-A University, Saha-Gu, Busan 604-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2010
Revised 17 September 2010
Accepted 27 September 2010
Available online 16 October 2010
A formal total synthesis of the benzothiophene selective estrogen receptor modulator (SERM) desketora-
loxifene and analogs has been accomplished from alkynes bearing electron-rich aromatic rings by
electrophilic cyclization using I2. This approach affords oxygen-bearing 3-iodobenzo[b]thiophenes in
excellent yields, which are easily further elaborated using a two-step approach involving Suzuki–Miyaura
and Mitsunobu coupling reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Iodocyclization
3-Iodobenzothiophene
Benzothiophene SERM
Desketoraloxifene
Cl
1. Introduction
H3C
HO
H3C
A
A
A
Early cancer drug discovery efforts focused on the design of
small molecule nonsteroidal estrogen receptor (ER) ligands with
antagonist properties against breast and other reproductive tis-
sues.1 Tamoxifen (I, Fig. 1) is the archetypal selective estrogen
receptor modulator (SERM).2–4 It was the first marketed drug to
be realized from these efforts, and while this compound and its
active metabolite, 4-hydroxytamoxifen (II, Fig. 1), are effective
antiestrogens on estrogen receptor positive breast tissue, they
subsequently were discovered to have undesirable estrogenic
properties on the endometrium.5 A third triphenylethylene com-
pound, toremifene (III, Fig. 1), has also been approved for the
treatment of breast cancer, although it too has been reported to
have undesirable uterine stimulatory activity.6 Because more po-
tent and safer chemotherapeutic agents are needed, due to the
potential side effects of tamoxifen I, considerable attention has
been paid to the development of less toxic SERMs.7 Many SERMs
in clinical use and clinical development are also highly suscepti-
ble to oxidative metabolism by electrophilic, redox active qui-
noids simply because they are based on polyaromatic phenol
scaffolds.8,9
B
B
B
O
CH3
O
CH3
O
CH3
N
N
CH3
N
CH3
toremifene (III)
CH3
tamoxifen (I)
4-hydroxytamoxifen (II)
HO
R2
S
6
A
R3
R4
R5
S
A
R1
5
2
B
R
B
X
3
R7
R6
O
O
N
N
X = CO; R = OH: raloxifene (IV)
X = O; R = OMe: arzoxifene (V)
desketoraloxifene analogs 3/4
(R1-R7=OH, OMe, H)
X = none; R = OH: desketoraloxifene (VI)
Figure 1. Chemical structures of tamoxifen (I), 4-hydroxytamoxifen (II), toremifene
(III), and representative synthetic benzothiophene SERMs [e.g., raloxifene (IV), arzox-
ifene (V), and desketoraloxifene (VI)] with A and B rings corresponding to tamoxifen.
⇑
Corresponding author. Tel.: +1 515 294 4660; fax: +1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.137

6486
C.-H. Cho et al. / Tetrahedron Letters 51 (2010) 6485–6488
SMe
2. Results and discussion
R''
S
R'
I2
R'
Our first goal was the efficient preparation of a variety of oxy-
gen-bearing 3-iodobenzo[b]thiophenes 1 (Scheme 2). In this series,
we proposed to initially change the substituents at the C-2, C-3,
C-5, and C-6 positions of the benzothiophene ring system. This
decision was based on the structure of desketoraloxifene (VI),
which has a para-phenol at the 2-position, a basic aliphatic amine
chain at the 3-position and a hydroxyl group at the 6-position of
the benzothiophene ring system.
DCM, r.t.
R''
I
R', R'': H, OMe, SMe, SO2Me, NMe2, etc.
Scheme 1. Synthesis of 3-iodobenzo[b]thiophenes by iodocyclization.
The cyclization proceeds smoothly when the substituent on the
distal end of the alkyne is an electron-rich methoxy-aryl group.
These 3-iodobenzo[b]thiophenes 1 are easily further elaborated
using a two-step approach involving Suzuki–Miyaura and Mitsun-
obu coupling reactions to give desketoraloxifene analogs 3. The
first step, the palladium-catalyzed Suzuki–Miyaura coupling of
the 3-iodobenzo[b]thiophenes 1 with a tetrahydropyranyl (THP)
ether-protected boronic acid, for example, p-THPOC6H4B(OH)2,
for 6–8 h, followed by aqueous HCl deprotection, afforded the de-
sired phenolic oxygen products 215 in high yield (Scheme 2).
In the second step, amine-coupled SERM precursors have been
produced by reaction of the phenolic oxygen species 2 with 1-(2-
hydroxyethyl)piperidine under Mitsunobu reaction conditions,17
using Ph3P and diethyl azodicarboxylate (DEAD), to afford the deske-
toraloxifene analogs 3 in good yields. The use of multimethoxy-
A benzothiophene SERM, raloxifene (IV, Fig. 1), is in clinical use
for the prevention and treatment of postmenopausal osteoporosis
and is currently in clinical trials for the chemoprevention of breast
cancer.4,10 Another benzothiophene SERM, arzoxifene (V, Fig. 1), is
a structural analog of raloxifene in which the carbonyl hinge has
been replaced by an ether linkage and the 40-hydroxy group
is methylated. This SERM is currently in clinical trials for the
treatment of breast cancer, and since it has similar structural
characteristics to tamoxifen I, it has the potential to form
quinoids.7,11
Interestingly, removal of the ketone moiety in raloxifene results
in a benzothiophene analog SERM desketoraloxifene (VI, Fig. 1),
which is more planar and conformationally more similar to
4-hydroxytamoxifen (II). Desketoraloxifene (VI) has been found
to be a much stronger activator of the Activator Protein-1 (AP-1)
substituted desketoraloxifene analogs
3 affords considerable
site by ER
a than ERb, and mimics 4-hydroxytamoxifen (II) more
diversity. The final step in our synthesis delivers hydroxy-substituted
desketoraloxifene analogs 4 using BBr3. The results are summarized
in Table 1.
than raloxifene (IV).10,12,13 With this information in hand, a set of
desketoraloxifene analogs 3/4 was designed based on the struc-
tures of 4-hydroxytamoxifen (II) and raloxifene (IV).
As illustrated in Table 1, entry 10, desketoraloxifene (VI) itself
has been synthesized using the approach outlined. The desired
dimethoxy-substituted desketoraloxifene analog 3e was obtained
from compound 2e using 1-(2-hydroxyethyl)piperidine under the
general Mitsunobu coupling conditions in 83% yield. Compound
3e was then converted by demethylation using BBr3 into the corre-
sponding desketoraloxifene 4e (VI) in 78% yield. In a similar man-
ner a variety of desketoraloxifene analogs 3 and 4 have been
prepared in good yields and a minimum of steps.
In summary, a number of benzothiophene SERM analogs and the
desketoraloxifene analogs 3/418 have been successfully synthesized
starting from various oxygen-bearing 3-iodobenzo[b]thiophenes 1
by a two-step approach involving sequential Suzuki–Miyaura and
Mitsunobu couplings. We believe that this approach to oxygen-
bearing 3-iodobenzo[b]thiophenes 1 should readily afford many
other functionalized desketoraloxifene analogs 3/4 using known
chemistry and parallel synthesis strategies.
Previously, we have developed a general synthesis of 2,3-disub-
stituted benzo[b]thiophenes by the palladium/copper-catalyzed
cross-coupling of various o-iodothioanisoles and terminal alkynes,
followed by electrophilic cyclization under mild reaction condi-
tions (Scheme 1).14 Very recently, a simple and efficient method
for the parallel synthesis of multi-substituted benzo[b]thiophenes
has also been described via known palladium-catalyzed couplings
for generation of a diverse set of building blocks starting from
3-iodobenzo[b]thiophenes.15,16
We wish to report herein a new efficient method for the
preparation of oxygen-functionalized 3-iodobenzo[b]thiophenes 1
by electrophilic cyclization using I2 and their further elaboration
to desketoraloxifene analogs 3/4 (Scheme 2 and Table 1). The
3-iodobenzo[b]thiophenes 1, having oxygen substituents at the
C-5 and/or C-6 benzothiophene positions, are promising precursors
to a wide variety of desketoraloxifene analogs 3/4.
R3
R4
R6
R2
R1
SMe
R7
R2
R1
S
R3
R7
R4
R6
R3
R6
R
5
(HO)2B
OTHP
R2
R1
6
5
I2
S
2
R4
R5
R5
DCM, r.t.
R7
(i) 5 mol % Pd(PPh3)4,K2CO3
toluene/EtOH/H2O, 80 oC.
(ii) 10 % aq HCl, THF, r.t.
3
I
OH
2
1
1a: R1,R5 = MeO/R2,R3,R4,R6,R7 = H (94%)
1b: R1,R4 = MeO/R2,R3,R5,R6,R7 = H (89%)
1c: R1,R3 = MeO/R2,R3,R4,R6,R7 = H (94%)
2a: 89%
2b: 86%
2c: 91%
2d: 83%
2e: 81%
2f: 78%
1d: R1,R4,R6 = MeO/R2,R3,R5,R7 = H (88%)
1e: R2,R5 = MeO/R1,R3,R4,R6,R7 = H (95%)
1f: R1,R2,R5 = MeO/R3,R4,R6,R7 = H (89%)
Scheme 2. Various 2,3-disubstituted benzo[b]thiophenes 2 via Suzuki–Miyaura reactions.

C.-H. Cho et al. / Tetrahedron Letters 51 (2010) 6485–6488
6487
Table 1
Synthesis of desketoraloxifene analogs 3 and 4a
R3
R4
(OH)
S
R2
R1
S
HO
N
(HO)
R5
BBr3
R6
N
2
DIAD, PPh3
THF, rt
R7
DCM, rt
N
O
O
3
4
Entry
2
R
Product
3/4
3a
Yieldd (%)
S
R5
1
2
2a
2a
R1, R5 = OMe
R1, R5 = OH
89
58
R1
4ab
N
O
R4
S
3
4
2b
2b
R1, R4 = OMe
R1, R4 = OH
3b
86
61
R1
4bb
N
O
R3
S
S
5
6
2c
2c
R1, R3 = OMe
R1, R3 = OH
3c
87
52
R1
4cb
N
O
O
R4
7
8
2d
2d
R1, R4, R6 = OMe
R1, R4, R6 = OH
3d
83
39
R1
R6
N
4dc
R2
S
S
R5
9
2e
R2, R5 = OMe
3e
83
b
10
11
12
2e
2f
2f
R2, R5 = OH
4e (VI)
3f
78
76
41
N
N
O
O
R2
R1
R1, R2, R5 = OMe
R1, R2, R5 = OH
R5
4fc
a
Reagents and conditions: (i) Mitsunobu coupling: 2 (0.2 mmol), alkylaminoethanol (1.5 equiv), DIAD (1.5 equiv), PPh3 (2.0 equiv), THF (2.0 mL), rt, 24–36 h. (ii)
Demethylation: 3 (0.1 mmol), BBr3, CH2Cl2 (1.0 mL), rt, N2, 3 h.
b
4.0 equiv of BBr3 used.
6.0 equiv of BBr3 used.
c
d
Isolated yields after column chromatography. All isolated products were characterized by 1H and 13C NMR spectroscopy (see Supplementary data).

6488
C.-H. Cho et al. / Tetrahedron Letters 51 (2010) 6485–6488
CDCl3) d 55.5, 55.8, 78.8, 108.4, 114.0 (ꢀ2), 115.7, 123.0, 127.1, 131.1 (ꢀ2),
Acknowledgments
131.3, 143.2, 143.5, 158.6, 160.2; HRMS calcd for C16H13IO2S [M+], 395.9681,
found 395.9684.
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the National Institutes of Health
Kansas University Chemical Methodologies and Library Devel-
opment Center of Excellence (GM069663) for support of this
research; Johnson Matthey, Inc. for donation of tetrakis(triphenyl-
phosphine)palladium(0) and Frontier Scientific, Inc. for donation of
4-[(tetrahydro-2H-pyran-2-yl)oxy]benzeneboronic acid.
General procedure for Suzuki–Miyaura coupling to form compounds 2. To
a
solution of 1 (1.0 mmol) and 5 mol % Pd(PPh3)4 in toluene (10 mL) was added
K2CO3 (2.5 mmol) under an Ar atmosphere. To the resulting mixture was added
p-THPOC6H4B(OH)2 (1.5 mmol), dissolved in ethanol (2 mL) and water
(0.5 mL), and the reaction mixture was heated to 80 °C for 6–8 h with
vigorous stirring. After concentration of the solvent under reduced pressure,
10% aq HCl was added to the crude product in THF (0.1 M) at room temperature
and stirred for 1 h. The mixture was then extracted by EtOAc (2 ꢀ 20 mL), and
the aqueous phase was also extracted with EtOAc or CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4 and concentrated under a
vacuum to yield the crude product, which was purified by flash
chromatography using EtOAc/hexanes as the eluent to afford the
corresponding products 2.
Supplementary data
3-(4-Hydroxyphenyl)-5-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene
The product was obtained as
pale yellow oil (89% yield): 1H NMR
(400 MHz, CDCl3) 3.78 (s, 3H), 3.78 (s, 3H), 5.12 (br s, 1H), 6.78 (d,
(2a).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.137.
a
d
J = 8.7 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.96–7.03 (m, 2H), 7.20 (d, J = 8.5 Hz,
2H), 7.23 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 55.5, 55.8, 105.8, 114.0 (ꢀ2), 114.3, 115.9 (ꢀ2), 122.9, 127.1, 128.3, 130.8
(ꢀ2), 131.1, 131.85 (ꢀ2), 131.89, 140.7, 142.4, 155.0, 157.8, 159.2; HRMS calcd
for C22H18O3S [M+], 362.0977, found 362.0983.
General procedure for the Mitsunobu reaction to form compounds 3. To a solution
of 2 (0.2 mmol), triphenylphosphine (PPh3) (0.4 mmol), and alkylaminoethanol
(0.3 mmol) in anhydrous THF (2 mL) was added diisopropyl azodicarboxylate
(DIAD) (0.3 mmol) with stirring at 0–5 °C. The resulting solution was stirred at
room temperature for 24–32 h (monitored by TLC until completion) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using methanol/ethyl acetate/hexanes as the
eluent to afford the corresponding products 3.
6-Methoxy-2-(4-methoxyphenyl)-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}benzo[b]-
thiophene (3e). The product was obtained as a pale yellow oil (83% yield): 1H
NMR (400 MHz, CDCl3) d 1.40–1.50 (m, 2H), 1.58–1.66 (m, 4H), 2.55 (br s, 4H),
2.81 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.89 (s, 3H), 4.15 (t, J = 6.0 Hz, 2H), 6.78 (d,
J = 8.9 Hz, 2H), 6.90–6.97 (m, 1H), 6.92 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.8 Hz,
4H), 7.32 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.4, 26.1 (ꢀ2), 55.3 (ꢀ2), 55.4, 55.9, 58.2, 66.1, 104.8, 114.0 (ꢀ2), 114.3,
114.9 (ꢀ2), 124.0, 127.2, 128.2, 130.7 (ꢀ2), 131.6 (ꢀ2), 131.7, 135.5, 136.4,
139.9, 157.5, 158.2, 159.0; HRMS calcd for C29H31NO3S [M+], 473.2025, found
473.2029.
References and notes
1. Lerner, L. J.; Holthaus, J. F.; Thompson, C. R. Endocrinology 1958, 63, 295.
2. Harper, M. J.; Walpole, A. L. Nature 1966, 212, 87.
3. Jordan, V. C. Nat. Rev. Drug Discov. 2003, 2, 205.
4. Jordan, V. C.; Phelps, E.; Lindgren, J. U. Breast Cancer Res. Treat. 1987, 10, 31.
5. Killackey, M. A.; Hakes, T. B.; Pierce, V. K. Cancer Treat. Rep. 1985, 69, 237.
6. Robinson, S. P.; Goldstein, D.; Witt, P. L.; Borden, E. C.; Jordan, V. C. Breast Cancer
Res. Treat. 1990, 15, 95.
7. Liu, H.; Liu, J.; van Breemen, R. B.; Thatcher, G. R. J.; Bolton, J. L. Chem. Res.
Toxicol. 2005, 18, 162.
8. Macgregor, J. I.; Jordan, V. C. Pharmacol. Rev. 1998, 50, 151.
9. Bolton, J. L.; Yu, L.; Thatcher, G. R. J. Methods Enzymol. 2004, 378, 110.
10. Weatherman, R. V.; Carroll, D. C.; Scanlan, T. S. Bioorg. Med. Chem. Lett. 2001, 11,
3129.
11. Suh, N.; Glasebrook, A. L.; Palkowitz, A. D.; Bryant, H. U.; Burris, L. L.; Starling, J.
J.; Pearce, H. L.; Williams, C.; Peer, C.; Wang, Y.; Sporn, M. B. Cancer Res. 2001,
61, 8412.
12. Grese, T. A.; Sluka, J. P.; Bryant, H. U.; Cullinan, G. J.; Glasebrook, A. L.; Jones, C.
D.; Matsumoto, K.; Palkowitz, A. D.; Sato, M.; Termine, J. D.; Winter, M. A.;
Yang, N. N.; Dodge, J. A. Proc. Nat. Acad. Sci. U.S.A. 1997, 94, 14105.
13. Carta, G.; Knox, A. J. S.; Lloyd, D. G. J. Chem. Inf. Model. 2007, 47, 1564.
14. Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
General procedure for the demethylation of 3e to form 6-hydroxy-2-(4-
hydroxyphenyl)-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}benzo[b]thiophene (desket-
15. Cho, C.-H.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem.
2009, 11, 900.
oraloxifene, 4e). To
a solution of compound 3e (0.095 mmol, 45 mg) in
anhydrous CH2Cl2 (2 mL) cooled in an ice water bath under N2 was added
BBr3 (0.38 mL, 0.38 mmol) while stirring. The solution turned orange in color.
This solution was stirred for 3 h after slowly warming to room temperature.
The reaction was quenched with satd aq NaHCO3 (2 ꢀ 2 mL) and the product
was extracted with 5% CH3OH/CHCl3 (3 ꢀ 5 mL). The combined organic layers
were dried over anhydrous MgSO4 and concentrated under a vacuum to yield
the crude product, which was purified by column chromatography using 5–
10% CH3OH/CHCl3 as the eluent to provide 33 mg (78%) of desketoraloxifene
(4e) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 1.34–1.43 (m, 2H), 1.48–
1.57 (m, 4H), 2.72 (br s, 2H), 3.35 (br s, 4H), 4.10 (t, J = 5.7 Hz, 2H), 6.67 (d,
J = 8.7 Hz, 2H), 6.84 (dd, J = 2.2, 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 7.05 (d,
J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 2.2 Hz,
1H), 9.62 (s, 1H), 9.65 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 23.7, 25.3 (ꢀ2),
54.3 (ꢀ2), 57.2, 65.3, 107.0, 114.6, 114.7 (ꢀ2), 115.3 (ꢀ2), 123.2, 124.6, 127.4,
130.1 (ꢀ2), 130.7, 131.0 (ꢀ2), 133.5, 134.8, 138.8, 155.1, 156.9, 157.6; HRMS
calcd for C27H27NO3S [M+], 445.1712, found 445.1725.
16. Cho, C.-H.; Neuenswander, B.; Larock, R. C. J. Comb. Chem. 2010, 12, 278.
17. Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
18. General procedure for iodocyclization using I2 to form compounds 1. To a solution
of 5.0 mmol of the alkyne and 20 mL of CH2Cl2 was added gradually 1.2 equiv
of I2 dissolved in 30 mL of CH2Cl2. The reaction mixture was allowed to stir at
room temperature for up to 10 min. The reaction was monitored by TLC to
establish completion. The remaining I2 was removed by washing with satd aq
Na2S2O3. The mixture was then extracted by EtOAc (2 ꢀ 100 mL). The
combined organic layers were dried over anhydrous MgSO4 and
concentrated under a vacuum to yield the crude product, which was purified
by flash chromatography using EtOAc/hexanes as the eluent to afford the
corresponding products 1.
3-Iodo-5-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (1a). The product
was obtained as
a pale yellow solid (94% yield): mp 114–115 °C
(uncorrected); 1H NMR (400 MHz, CDCl3) d 3.83 (s, 3H), 3.90 (s, 3H), 6.95–
7.00 (m, 3H), 7.24 (d, J = 2.4 Hz, 1H), 7.58–7.60 (m, 3H); 13C NMR (100 MHz,