Synthesis and binding affinities of fluoroalkylated raloxifenes

Article abstract of DOI:10.1016/S0968-0896(03)00362-6

Three fluoroalkylated derivatives (1-3) of the selective estrogen receptor modulator (SERM), raloxifene, have been synthesized. The key step in the synthesis is the C-C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C) using a Stille reaction. The in vitro binding affinities of the substituted raloxifenes 1-3 are 45, 60, 89%, respectively, relative to the affinity of estradiol, which is higher than the affinity of raloxifene itself (25%). When labeled with the positron-emitting radionuclide, these compounds might be useful as PET imaging agents for estrogen receptor-positive breast tumors.

Full text of DOI:10.1016/S0968-0896(03)00362-6

Bioorganic& Medicinal Chemistry 11 (2003) 3649–3658
Synthesis and Binding Affinities of Fluoroalkylated Raloxifenes
Kyo Chul Lee,a Byung Seok Moon,a Jae Hak Lee,a Kyoo-Hyun Chung,a
John A. Katzenellenbogenb,* and Dae Yoon Chia,*
aDepartment of Chemistry, Inha University, 253 Yonghyundong, Namgu, Inchon 402-751, South Korea
bDepartment of Chemistry, University of Illinois, Urbana, IL 61801, USA
Received 21 January 2003; accepted 23 May 2003
Abstract—Three fluoroalkylated derivatives (1–3) of the selective estrogen receptor modulator (SERM), raloxifene, have been
synthesized. The key step in the synthesis is the C–C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C)
using a Stille reaction. The in vitro binding affinities of the substituted raloxifenes 1–3 are 45, 60, 89%, respectively, relative to the
affinity of estradiol, which is higher than the affinity of raloxifene itself (25%). When labeled with the positron-emitting radio-
nuclide, these compounds might be useful as PET imaging agents for estrogen receptor-positive breast tumors.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
in the breast and uterus, yet possesses estrogen agonist-
like actions on bone and blood lipid profiles.6
The roles played by endogeneous estrogens, such as
17b-estradiol and estrone, as important regulators of
the development and maintenance of the female repro-
ductive organs and other sexual characteristics have
long been appreciated.1 More recently, their involve-
ment in maintaining the healthy function of a number
of other systems in humans, such as bone, the cardio-
vascular system, and the central nervous system, has
been recognized, as well.2 The decreased production of
ovarian steroids which occurs after menopause has been
linked to a number of pathologies, particularly osteo-
porosis and coronary artery disease, as well as with
changes in cognitive function.
Raloxifene binds with high affinity to the estrogen
receptor (ER).5a Thus, radiolabeled raloxifene deriva-
tives might be useful for imaging ER-positive breast
tumors in vivo, as has been done using several radio-
labeled steroidal estrogen agonists, including ones
labelled with fluorine-18.7 By contrast, receptor imaging
studies with estrogen antagonists have been limited, and
there have been only a few reports of imaging and tissue
Tamoxifen, an antiestrogen widely used for the treat-
ment of breast cancer, possesses mixed agonist–antago-
nist activities, thus limiting its efficiency as a blocker of
estrogen action.3 Recently, some groups have developed
molecules termed Selective estrogen receptor mod-
ulators (SERMs) that fully antagonize the effects of
estrogen on uterine and mammary tissue, while retain-
ing the effects of estrogen on bone and blood lipid pro-
file.4,5 Raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-
piperidin-1-yl)ethoxybenzoyl]benzo[b]thiophene, is
SERM that displays potent estrogen antagonist properties
a
*Corresponding author. Tel.:+82-505-8607-686; fax:+82-328-675-
604; e-mail: dychi@inha.ac.kr
0968-0896/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00362-6

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K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
distribution studies with radio-emitting tamoxifen deri-
vatives, many of which have low binding affinity for the
ER.8 In vivo tissue distribution studies of radiolabeled
raloxifene have not been reported.
we wish to report the synthesis and in vitro binding
affinities of these analogues. Further studies of their
labeling with fluorine-18 and in vivo studies will be
described elsewhere.
Radiopharmaceuticals labeled with fluorine-18 are
being increasingly used in clinical diagnosis.9 Although
fluorine-18 is the most attractive radionuclide for the
preparation of imaging agents for positron emission
tomography (PET), labeling of organiccompounds with
fluorine-18 is often difficult, particularly at aromatic
positions. Because fluorine-18 at the high specific activ-
ity level required for imaging receptors is only practi-
cally available in nucleophilic form (i.e., as fluoride ion),
direct arene labeling with fluorine requires nucleophilic
aromatic substitution, which further limits the scope of
systems that can be labeled easily.10
Results and Discussion
2-Arylbenzothiophene 4a5a and 4-(2-piperidin-1-yl)
ethoxybenzoyl chloride (5)5a were prepared according to
literature procedures. The Friedel–Crafts acylation of a
4a with 5 in chlorobenzene at 100 ꢀC provided 2-dime-
thylamino-6-methoxy-3-[4-(2-piperidin-1-yl)ethoxy-ben-
zoyl]benzo[b]thiophene (6a) in 64% isolated yield
(Scheme 1). 6-tert-Butyldiphenylsilyl (TPS) protected
derivatives 4b and 6b were also prepared by a similar
route.
An alternative way to label aromaticsystems with
fluorine-18 involves introduction of a fluoroalkyl group
on an aromaticposition, rather than labeling with a
fluorine atom directly.11 According to various in vivo
stability studies of [18F]fluoroalkyl aromaticocm-
pounds, as well as metabolism studies in vitro, the
[18F]fluoroethyl group appears to be the most stable,
with the in vivo stability of fluoroalkyl groups following
the order: fluoroethyl>fluoropropyl>fluoromethyl.12
Synthesis of fluoroalkylated aryl compounds for ring C.
Three fluoroalkylated aryl compounds 13, 20, and 25,
which are the precursors of the ring C part required for
the coupling reaction of rings B and C, were prepared
by different syntheticroutes, as shown in Schemes 2–4.
Synthesis of 2-(3-fluoropropyl)-4- (methoxymethoxy)-1-
trifluoromethanesulfonyloxy-benzene (13). Treatment of
hydroquinone with allyl bromide in anhydrous acetoni-
trile at reflux for 12 h provided monoallyl ether 8 in
If a fluoroalkyl group could be introduced into ralox-
ifene without compromising its high affinity binding to
the ER, this might provide a convenient strategy for
developing an easily radiolabeled raloxifene-based agent
for imaging estrogen receptor in vivo. In this report, we
describe our investigations of methods for preparing
raloxifene analogues containing fluoroalkyl groups that
might be readily labeled with fluorine-18. Our selection
of sites for fluoroalkyl substitution on raloxifene was
based on the known relative binding affinity (RBA) and
IC50 values of various substituted and modified ralox-
ifene analogues, through which it is known that the C-
ring is particularly tolerant of substitution (e.g., Fig. 1).5a
Therefore, we elected to introduce fluoroethyl and
fluoropropyl groups at the R1 and R2 positions. Herein,
Scheme 1. (a) Chlorobenzene, 100 ꢀC, 9 h, 6a: 64%; 6b; 68%.
Scheme 2. (a) Allyl bromide, K2CO3, CH3CN, reflux, 12 h, 92%; (b)
MOMCl, NaH, THF, 0 ꢀC to reflux, 1 h, 92%; (c) N,N-dimethylani-
line, reflux, 2 h, 80%; (d) borane–THF complex, H2O2, 4 N NaOH,
THF, 0 ꢀC, 1 h, 78%; (e) DAST, CH2Cl2, À78 ꢀC to rt, 30 min, 15%;
(f) Tf2O, 2,6-lutidine, CH2Cl2, 0 ꢀC to rt, N2, 30 min, 92%.
Figure 1. Estrogen receptor binding affinity of raloxifene derivatives
modified on the C ring (from ref 5a).

K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
3651
92% yield. After protection of the free phenol group
with methoxymethyl chloride (MOMCl), Claisen rear-
rangement reaction gave allylbenzene 10 in 80% yield.
Hydroboration of alkene 10 using borane–THF com-
plex and subsequent oxidation with alkaline peroxide
(MEMCl), hydroboration–oxidation, mesylation of the
terminal alcohol, fluorination, deprotection of the
MEM group and triflation gave 20, one of the C-ring
precursors. Yields and details for each step are shown in
Scheme 3.
gave the aliphaticaolchol
11; fluorination using
diethylaminosulfur trifluoride (DAST) gave the fluor-
opropyl compound 12, followed by trifluoro-
methanesulfonylation (triflation afforded triflate 13 as
shown in Scheme 2).
Synthesis of 2-(2-fluoroethyl)-1-trifluoromethanesulfonyl-
oxybenzene (25). After selective protection of phenol
21, using MEMCl, mesylated compound 23 was
obtained. However, fluorination of the phenethyl mesyl-
ate failed because of competitive elimination. Thus, the
phenethyl alcohol was fluorinated using DAST, and
triflation afforded triflate 25, as shown in Scheme 4.
The conventional method for fluorination is a nucleo-
philicdisplaecment of a methanesulfonate (mesylate)
using fluoride ion. However, our attempts at mesylation
of primary alcohol 11 failed because the phenol group
attacked the a-carbon of the mesylate, giving a cyclic
ether. Thus, the fluoropropyl compound 12 was pre-
pared using DAST. Before the triflate 13 was prepared,
the MOM protecting group was replaced by the methyl
ether derivative. As discussed later in detail, we were
unable to use the methylated derivative, because
defluorination occurred during the demethylation step.
Ring B and ring C coupling reactions
Synthesis of 2-(4-methoxy-2-fluoropropylphenyl)-3-[4-(2-
piperidin - 1 - yl)ethoxybenzoyl] - 6 - methoxybenzo[b]thie-
phene (27a). Two different methods were used to couple
rings B and C: a Stille coupling reaction and a Grignard
Synthesis of 2-(3-fluoropropyl)-1-trifluoromethanesulfo-
nyloxybenzene (20). From 2-allylphenol (14), protection
of the phenol using methoxyethoxymethyl chloride
Scheme 5. (a) LiMe3Sn, THF, À78ꢀC to rt, 5 h, 99%; (b) 2-(3-fluoro-
propyl)-4-methoxyphenylmagnesium bromide, THF, À78 ꢀC to rt, 2 h,
60%; (c) compound 13, Pd(PPh3)4, DMF, 120 ꢀC, 9 h, 57%; (d) BBr3,
CH2Cl2, rt, 1 h or AlCl3, CH3CH2SH, CH2Cl2, rt, 1 h or SiCl4, NaI,
CH2Cl2, rt, 1 h or CH3SiI, CHCl3, rt, 1 h.
Scheme 3. (a) MEMCl, NaH, THF, 0 ꢀC to reflux, 1 h, 82%; (b) bor-
ane–THF complexꢀ, H2O2, 4 N NaOH, THF, 0 ꢀC, 1 h, 48%; (c) MsCl,
.
Et3N, CH2Cl2, 0 C, 20 min, 56%; (d) n-Bu4NF xH2O, CH3CN,
110 ꢀC, 30 min, 74%; (e) concd HCl, MeOH, 60 ꢀC, 1 h, 90%; (f)
Tf2O, 2,6-lutidine, CH2Cl2, 0 ꢀC to rt, N2, 30 min, 82%.
Scheme 6. (a) TPSCl, imidazole, DMF, rt, 3 h, 99%; (b) N,N-dime-
thylthioformamide, LDA, THF/hexane (5:1), À100 to À78 ꢀC, 1 h,
57%; (c) methanesulfonic acid, CH2Cl2, À10 ꢀC, 10 min, 49%; (d)
compound 5, chlorobenzene, 100 ꢀC, 9 h, 68%; (e) LiMe3Sn, THF,
À78 ꢀC to rt, 5 h, 71%.
Scheme 4. (a) MꢀEMCl, NaH, THF, 0 ꢀC to reflux, 1 h, 70%; (b) MsCl,
ꢀ
.
Et3N, CH2Cl2, 0 C, 20 min, 82%; (c) n-Bu4NF xH2O, CH3CN, 110 C,
30 min, obtained vinyl compound; (d) (i) DAST, CH2Cl2, À78 ꢀC to rt,
30 min; (ii) Tf2O, 2,6-lutidine, CH2Cl2, 0 ꢀC to rt, N2, 30 min, 26%.

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K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
100%. Binding affinities to the purified human ERa and
ERb, as well as to the estrogen receptor from lamb
uterus (predominantly ERa),14 are shown in Table 1.
From literature precedent, it is known that introduction
of a methyl group on the C2 position of ring C results in
a slight increase in RBA value over that for raloxifene
itself, when affinities are measured in uterine cytosol,
whereas introducing a methyl group on the C3 position
of ring C decreases the RBA value (cf. Fig. 1).5a It was
on this basis that we designed the fluoroalkyl raloxifene
analogues 1–3.
Scheme 7. (a) Compound 13, 20 or 25, Pd(PPh3)4, DMF, 100 ꢀC, 12 h,
.
(b) n-Bu4NF xH2O, THF, rt, 1 min, 47% (compound 1; including
MOM deprotection, concd HCl in isopropanol, 60 ꢀC, 30 min), 68%
(compound 2) or 80% (compound 3).
Gratifyingly, all three compounds that we have pre-
pared show much better ER binding affinities than does
raloxifene (Table 1). The uterine cytosol RBA value of
compound 1 having both hydroxy and fluoropropyl
groups on ring C is somewhat elevated, but the deriva-
tives 2 and 3, with no hydroxy group on ring C, have
RBA values that are considerably higher than ralox-
ifene. Thus, considering binding values to this receptor
preparation, compound 3, the fluoroethyl derivative,
appears to be the most promising compound for further
study. The structure–binding affinity relationships with
pure human ERa and ERb are somewhat different, with
raloxifene and the three compounds having more com-
parable affinities on the a subtype, but the compounds
1–3 binding much better than raloxifene on the b sub-
type. Overall, we consider compound 3 to be the most
promising to investigate further for fluorine-18 labeling,
although there is not a great difference among the three
fluoroalkyl raloxifene derivatives.
reaction. Reaction of 6a with Me3SnLi, generated from
lithium metal and trimethylstannyl chloride in THF,
provided the aryl stannane 26a in quantitative yield.
The coupling reaction between stannane 26a and triflate
13 using Pd(PPh3)4 gave the protected raloxifene ana-
logue 27a in 57% yield. A Grignard reaction between
26a and 2-(3-fluoropropyl)-4-methoxyphenylmagnesium
bromide also afforded 27a in 78% yield. We encoun-
tered unexpected problems in the deprotection of the
two methyl groups in compound 27a. All well-known
deprotection reagents that we tried, such as BBr3, AlCl3
with ethane thiol and tetramethylsilyl iodide, gave
deprotected as well as defluorinated compound. Thus,
we were unable to obtain the demethylated compound
without losing the fluorine (Scheme 5).
At this point, an alternate function to protect the 6-
hydroxy group of the benzothiophene group was
required. In place of the methyl group, we considered
other groups, such as methoxymethyl (MOM) and tert-
butyldiphenylsilyl (TPS). When 4-hydroxybenzaldehyde
was treated with MOMCl, a quinone derivative was
obtained. Thus, we prepared 6b and 26b protected with
TPS, as shown in Scheme 6.
In conclusion, based on known structure affinity rela-
tionship data for raloxifene derivatives, we have
Synthesis of fluoroalkyl raloxifene derivatives 1, 2, and
3. Coupling reactions between 26b and 13, 20 or 25
were carried out using Pd(PPh3)4 in DMF at 100 ꢀC for
12 h (Scheme 7). While the fluorine group is lost under
conditions used to remove the methyl group, deprotec-
tion of the TPS groups by treatment with n-
.
Bu4NF xH2O was successful and provided compound 1,
2, or 3 in 47, 68, and 80% yields, respectively. To pro-
duce compound 1, the TPS group on the C6 position as
well as the MOM group on para position of the C ring
had to be removed. All modifications for the synthesis
of stannyl compound 26b protected with a TPS group
on the C6 position from p-hydroxybenzaldehyde 28
were done according the same route as that for the
methyl protected stannyl compound 26a, and the yields
of each step are shown in Scheme 6.
Figure 2. Structures of fluoroalkylated raloxifenes 1–3.
Table 1. Relative binding affinities (RBA) of fluoroalkylated ralox-
ifene derivatives 1–3a
Compd
Lamb uterine ER
RBA
Human ER a
RBA
Human ER b
RBA
Raloxifene
25Æ0
45
60
48Æ8
71
35
3.5Æ1.7
Estrogen binding affinities of raloxifene derivatives 1–3.
The in vitro binding affinity of raloxifene and the three
fluoroalkylated raloxifene derivatives 1–3 (Fig. 2) to the
ER was determined by a competitive radiometric bind-
ing assay, using established methods described pre-
viously.13 Affinity is expressed as relative binding
affinity (RBA) values, where the RBA of estradiol is
1
2
3
24
30
27
89
63
aRelative binding affinity (RBA) values in this study were determined
in a competitive radiometric binding assay. Values are expressed as
percentages relative to the affinity of the indicated tritium-labeled tra-
cer. For procedural details, see Methods.

K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
3653
designed three target compounds 1–3 bearing a fluoro-
alkyl substituent. Compound 1 has a hydroxyl group on
ring C, as is found in raloxifene, but the other two
compounds (2 and 3) lack this hydroxy group. As is
apparent from the binding affinity of our compounds, as
well as that for other raloxifene analogues,5a the
hydroxy group on ring C is not crucial, and introduc-
tion of the fluoroalkyl groups, especially the fluoroethyl
group, on ring C actually increases binding affinity to
the estrogen receptor. We anticipate that these sub-
stitutions will not have a major effect on the pharma-
cology or pharmacokinetics of these high affinity
raloxifene derivatives. Therefore, when labeled with
fluorine-18, these compounds may hold promise as a
PET imaging estrogen antagonist agent for ER-positive
tumors, particularly those rich in the ERa subtype.15
(1.35 g, 4.74 mmol) was converted to its acid chloride by
dissolving it in 1,2-dichloroethane and adding one drop
of DMF and SOCl2. The mixture was stirred at reflux
under a N2 atmosphere for 2 h and was then evaporated
in vacuo to obtain the tannic white crystalline acid
chloride. The acid chloride was dissolved in chlor-
obenzene was treated with 4a (653 mg, 3.16 mmol) and
warmed to 100–105 ꢀC for 9 h. The mixture was then
allowed to cool to rt resulting in complete solidification.
The solid was broken up and treated with saturated
Na2CO3 (4 mL), water (2 mL), CH2Cl2 (2 mL) and 50%
aqueous NaOH (1 mL). After stirring for a short per-
iod, the mixture was diluted with CH2Cl2 and water.
The layers were separated and the organiclayer was
washed with 50% saturated Na2CO3. The organiclayer
was dried (Na2SO4), decanted and concentrated under
reduced pressure. Purification via flash chromatography
(0–5% MeOH/CH2Cl2) provided 6a (1.33 g, 64%) as a
1
thick dark oil: H NMR (200 MHz, CDCl3) d 1.30–1.40
Experimental
(m, 2H), 1.50–1.60 (m, 4H), 2.50–2.52 (m, 4H), 2.70 (t,
J=5.9 Hz, 2H), 2.76 (s, 6H), 3.70 (s, 3H), 4.07 (t, J=5.9
Hz, 2H), 6.73 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=8.8
Hz, 2H), 7.03 (d, J=2.4 Hz, 1H), 7.29 (d, J=8.9 Hz,
1H), 7.76 (d, J=8.8 Hz, 2H); 13C NMR (50 MHz,
CDCl3) d 23.8, 25.5, 44.6, 54.7, 55.2, 57.4, 65.8, 104.9,
111.2, 113.9, 121.8, 131.4, 131.5, 132.0, 133.2, 155.3,
160.8, 162.1, 190.8. The experiment data is in agreement
with in the literature.5a
2-Dimethylamino-6-methoxybenzo[b]thiophene (4a). a-
Hydroxythioacetamide (0.316 mmol) was dissolved in
dichloromethane (10 mL) and cooled to À10 ꢀC.
Methansulfonicacid (0.10 mL, 1.54 mmol) was added,
resulting in a green-brown solution that turned colorless
within 10 min, when TLC analysis indicated the absence
of starting material. The solution was washed with
saturated sodium bicarbonate solution (10 mL), water
(10 mL), dried (MgSO4), filtered, and solvent removed
to yield the arene, which was recrystallized from 95%
ethanol or flash chromatography (5% EtOAc/hexane)
to give a pale yellow crystalline solid (52.4 mg, 80%);
mp 69–70 C; H NMR (200 MHz, CDCl3) d 2.95 (s,
6H), 3.80 (s, 3H), 5.95 (s, 1H), 6.85 (dd, J=8.6, 2.3 Hz,
1H), 7.10 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H);
13C NMR (50 MHz, CDCl3) d 40.3, 53.3, 94.4, 103.2,
110.9, 118.5, 131.4, 132.7, 152.4, 153.6. The spectro-
scopic data is in agreement with that in the literature.5a
3-[4-(2-piperidin-1-yl)ethoxybenzoyl]-6-methoxy-2-tribu-
tylstannylbenzo[b]thiophene (26a). Lithium metal (7.1 g,
1.02 mol) was suspended in THF (100 mL) and treated
with trimethylstannyl chloride (1.0 M in THF, 103 mL,
103 mmol) dropwise at 0 ꢀC. After warming to rt, the
mixture was allowed to stir overnight. An aliquot of the
resulting Me3SnLi solution (0.507 M in THF, 19.4 mL,
9.85 mmol) was added dropwise to a solution of 6a (2.4
g, 5.47 mmol) in THF (48 mL) at À78 ꢀC. The mixture
was allowed to slowly warm to rt over 5 h. The reaction
quenched rapidly by pouring into a mixture of ice-cold
saturated, and the quenched product was extracted with
CH2Cl2 and water. The organiclayer was dried
(Na2SO4) and concentrated in vacuo to provide com-
pound 26a (3.2 g, 99%) as a brown oil; 1H NMR
(200 MHz, CDCl3) d 0.34 (s, 9H), 1.40–1.60 (m, 2H),
1.60–1.80 (m, 4H), 2.60–2.80 (m, 4H), 2.83 (t, J=5.9
Hz, 2H), 3.86 (s, 3H), 4.20 (t, J=5.9 Hz, 2H), 6.84 (dd,
J=8.9, 2.3 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.24–7.28
(m, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.6 Hz,
2H). The spectroscopic data is in agreement with that in
the literature.5a
ꢀ
1
4-(2-Piperidin-1-yl-ethoxy)benzoic acid monohydro-
chloride. The crude methyl 4-(2-piperidin-1-yl-ethox-
y)benzoate was hydrolyzed by dissolving the oil in
MeOH, adding 5 N NaOH, and allowing the reaction
mixture to stirring under N2 atmosphere for 48 h. The
mixture was then evaporated to remove most of the
MeOH, and the residue was diluted with water to make
a total volume of 200 mL. The resulting solution was
cooled to 5 ꢀC and acidified by the gradual addition of
6 N HCl, while the temperature was maintained below
À10 ꢀC. The white crystals that precipitated were col-
lected and washed with cold MeOH. The product was
then recrystallized from MeOH to provide a white
1
crystalline solid (11.54 g, 67%): H NMR (200 MHz,
2-(4-Methoxy-2-fluoropropylphenyl)-3-[4-(2-piperidin-1-
yl)ethoxybenzoyl]-6-methoxybenzo[b]thiophene (27a)
Method A (Stille reaction). A solution of 23 (2.5 g,
5.47 mmol), 4-bromo-2-fluoropropylanisole (3.75 g,
16.41 mmol) and Pd(PPh3)4 (0.41 g, 0.4 mmol) in anhy-
drous DMF (20 mL) was heated at 100 ꢀC for 12 h.
After cooling to rt, the mixture was concentrated, and
the residue was purified via flash chromatography (50%
EAOAc/hexane, 0–1% MeOH) to provide the title
DMSO-d6) d 1.36 (br s, 1H), 1.62–1.76 (m, 5H), 2.97 (br
s, 2H), 3.41 (br s, 4H), 4.48–4.51 (m, 2H), 7.04 (d, J=8.4
Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 11.28 (brs, 1H); 13C
NMR (50 MHz, DMSO-d6) d 20.19, 21.20, 51.49, 53.41,
61.58, 113.49, 122.73, 130.33, 160.03, 165.80. The spec-
troscopic data is agreement with that in the literature.5a
2-Dimethylamino-6-methoxy-3-[4-(2-piperidin-1-yl)ethox-
ybenzoyl]benzo[b]thiophene (6a). A portion of 4-(2-
piperidin-1-yl-ethoxy)benzoic acid monohydrochloride
1
compound (1.7 g, 57%): H NMR (200 MHz, CDCl3) d
1.42–1.45 (m, 2H), 1.57–1.65 (m, 4H), 1.72–1.92 (m,

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K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
2H), 2.46–2.63 (m, 6H), 2.74 (t, J=6.0 Hz, 2H), 3.75 (s,
3H), 3.87 (s, 3H), 4.08 (t, J=5.9 Hz, 2H), 4.30 (dt,
J=47.4, 6.1 Hz, 2H), 6.67–6.77 (m, 3H), 6.95 (dd,
J=9.2, 2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.23–7.31
(m, 2H), 7.56 (d, J=9.2 Hz, 1H), 7.75 (d, J=7.0 Hz,
2H).
(FAB) m/z 450 (MH+). HRMS calcd for
C26H32NO2SSi 450.1923, found 450.1919.
6-(tert-Butyldiphenylsilyloxy)-2-dimethylaminobenzo[b]-
thiophene (4b). a-Hydroxythioacetamide 30 (3.0 g, 6.65
mmol) was dissolved in dichloromethane and cooled to
À10 ꢀC. Methansulfonicaicd (2.15 mL, 33.25 mmol)
was added. After warming to rt, the reaction mixture
was stirred for 4 h and then recooled, and the reaction
quenched with saturated NaHCO3. The solution was
washed with saturated sodium bicabonate solution,
water, dried (Na2SO4), filtered, and solvent removed to
give the title compound. The desired product 4b was
purified flash chromatography (1–5% EtOAc/hexane)
producing a yellow oil (1.41 g, 49%): 1H NMR
(200 MHz, CDCl3) d 1.10 (s, 9H), 2.86 (s, 6H), 5.83 (s,
1H), 6.70 (dd, J=8.8, 2.0 Hz, 1H), 7.02 (d, J=8.8 Hz,
1H), 7.12 (d, J=8.8 Hz, 1H), 7.28–7.49 (m, 6H), 7.62–
7.74 (m, 4H); 13C NMR (50 MHz, CDCl3) d 19.46,
26.55, 42.63, 96.67, 111.92, 117.58, 120.41, 127.68,
129.75, 133.16, 133.32, 135.22, 135.50, 150.18, 156.08;
MS (FAB) m/z 431 (MH+). HRMS calcd for
C26H29NOSSi 431.1739, found 431.1738.
Method B (Grignard reaction). A solution of 6a (1.5 g,
3.4 mmol) in THF (20 mL) at 0 ꢀC was treated portion-
wise with a 1 M THF solution of 4-methoxy-2-(3-fluor-
opropyl)phenylmagnesium bromide (10 mL, 10 mmol),
which was prepared from magnesium turnings and 4-
bromo-3-(3-fluoropropyl)anisole (Due to the defluor-
ination during the deprotection of methyl group, the
preparation of this compound is not described in this
report.). After warming to rt, the reaction mixture was
stirred for 90 min and then recooled and quenched with
ice water. The mixture was extracted with CH2Cl2, and
the combined organic layers were washed with brine,
dried (Na2SO4), concentrated and purified by flash
chromatography (0–10% MeOH/CH2Cl2) to give the
title compound (1.11 g, 60%).
4-(tert-Butyldiphenylsilyloxy)benzaldehyde (29). To a
stirred solution of the 4-hydroxybenzaldehyde (28, 5.0
g, 41 mmol) in DMF were added imidazole (4.2 g, 61.35
mmol) and tert-butyldiphenylsilyl chloride (12.8 mL,
49.1 mmol) at rt. The reaction mixture was stirred at the
same temperature for 3 h. After dilution with brine, the
aqueous layer was extracted with ether. The combined
organicextracts were washed water, dried (Na 2SO4) and
concentrated to afforded an oily residue, which was
purified by silica gel column chromatography (5%
EtOAc/hexane) to give the silyl ether 28 (22.12 g, 99%)
as white crystals: 1H NMR (200 MHz, CDCl3) d 1.11 (s,
9H), 6.86 (d, J=8.8 Hz, 2H), 7.31–7.47 (m, 6H), 7.60–
7.76 (m, 6H), 9.81 (s, 1H); 13C NMR (50 MHz, CDCl3)
d 17.04, 23.96, 117.86, 125.55, 127.82, 129.26, 129.51,
132.95, 158.76, 188.39; MS (FAB) m/z 361 (MH+).
HRMS calcd for C23H25O2Si 361.1624, found
361.1611.
6-(tert-Butyldiphenylsilyloxy)-2-dimethylamino-3-[4-(2-
piperidin-1-yl)ethoxybenzoyl]benzo[b]thiophene (6b). A
portion of 4-(2-piperidin-1-yl-ethoxy)benzoiciadc
monohydrochloride (2.0 g, 7.0 mmol) was converted to
its acid chloride by dissolving it in 1,2-dichloroethane
and adding one drop of DMF and SOCl2. The mixture
was stirred at reflux under a N2 atmosphere for 2 h and
was then evaporated in vacuo to obtain the off-white
crystalline acid chloride 5. The acid chloride was dis-
solved in chlorobenzene, treated with 4b (1.6 g, 3.5
mmol), and then warmed to 100–105 ꢀC for 9 h. The
mixture was then allowed to cool to rt, resulting in
complete solidification. The solid was broken up and
treated with saturated Na2CO3, water, CH2Cl2 and 50%
aqueous NaOH. After stirring for a short period, the
mixture was diluted with CH2Cl2 and water. The layers
were separated and the organiclayer was washed with
50% saturated Na2CO3. The organiclayer was dried
over Na2SO4, decanted and concentrated under reduced
pressure to thick dark oil. Purification via flash chro-
matography (2% MeOH/CH2Cl2) provided 6b (1.58 g,
2-[4-(tert-Butyldiphenylsilyloxy)phenyl]-2-hydroxy-N,N-
dimethylthioacetamide (30). To a stirred solution of
LDA (2 M solution in THF, 10 mL) in THF/hexane was
added a solution of N,N-dimethylthioformamide (1.65
mL, 20 mmol) over a 1-min period at À100 ꢀC. After 3
min, the yellow reaction solution is treated with a solu-
tion of 29 (1.65 mL, 20 mmol), and the bath tempera-
ture is allowed to rise to À78 ꢀC over a period of 1 h.
The reaction mixture was then neutralized with glacial
acetic acid (3 mL) and then extracted with CH2Cl2, and
the combined extracts were dried over sodium sulfate,
and evaporated under reduced pressure. The desired
product 30 was purified flash chromatography (15%
EtOAc/hexane) to produce pale yellow crystals (5.13 g,
1
68%) as a yellow oil: H NMR (200 MHz, CDCl3) d
1.09 (s, 9H), 1.41–1.54 (m, 2H), 1.51–1.66 (m, 4H),
2.41–2.54 (m, 4H), 2.58–2.92 (m, 8H), 4.15 (t, J=6.0
Hz, 2H), 6.67 (dd, J=8.8, 2.0 Hz, 1H), 6.89 (dd, J=7.0,
1.8 Hz, 2H), 6.98 (d, J=2.2 Hz, 1H), 7.16 (d, J=8.8 Hz,
1H), 7.31–7.47 (m, 6H), 7.68–7.86 (m, 6H); 13C NMR
(50 MHz, CDCl3) d 19.42, 24.03, 25.78, 26.52, 44.85,
55.01, 57.69, 66.09, 111.51, 114.13, 118.01, 121.76,
127.69, 129.79, 131.38, 131.73, 132.26, 132.95, 133.71,
135.46, 151.15, 161.21, 162.34, 191.25; MS (FAB) m/z
662 (MH+). HRMS calcd for C40H46N2O3SSi 662.2999,
found 662.2993.
1
57%): H NMR (200 MHz, CDCl3) d 1.10 (s, 9H), 3.01
(s, 3H), 3.46 (s, 3H), 5.24 (q, 2H), 6.74 (d, J=8.8 Hz,
2H), 7.11 (d, J=8.8 Hz, 2H), 7.31–7.52 (m, 6H), 7.58–
7.74 (m, 4H); 13C NMR (50 MHz, CDCl3) d 19.30,
26.38, 40.90, 45.38, 73.22, 119.50, 127.65, 128.34,
129.83, 132.28, 132.52, 135.34, 155.56, 203.65; MS
6-(tert-Butyldiphenylsilyloxy)-3-[4-(2-piperidin-1-yl)eth-
oxybenzoyl]-2-tributylstannylbenzo[b]thiophene
Lithium metal (710 mg, 0.10 mol) was suspended in
THF (10 mL) and treated with trimethylstannyl chlor-
ide (1.0 M in THF, 10 mL, 10 mmol) dropwise at 0 ꢀC.
(26b).

K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
3655
After warming to rt, the mixture was allowed to stir
overnight. An aliquot of the Me3SnLi solution prepared
above (0.507 M in THF, 2.0 mL, 1.04 mmol) was added
dropwise to a solution of 6b (360 mg, 0.52 mmol) in
THF (15 mL) at À78 ꢀC. The mixture was allowed to
slowly warm to rt over 5 h. The reaction quenched
rapidly by pouring into a mixture of ice-cold saturated
NaHCO3 (100 mL), dried (Na2SO4). Purification by
flash chromatography (100% EtOAc) provided 26b (290
Hz), 3.48 (s, 3H), 5.10 (s, 2H), 5.16–5.18 (m, 2H), 5.27
(bs, 1H), 5.89–6.10 (m, 1H), 6.71–6.83 (m, 3H); 13C
NMR (50 MHz, CDCl3) d 35.02, 55.80, 95.43, 115.72,
116.36, 118.76, 126.71, 136.16, 149.11, 151.27; MS (EI)
m/z 194 (M+). HRMS calcd for C11H14O3 194.0943,
found 194.0942.
2-(3-Hydroxypropyl)-4-(methoxymethoxy)phenol
(11).
To 2-allylphenol 10 (545 mg, 2.81 mmol) was added
borane–THF complex (3.37 mL, 3.37 mmol) in dried
THF at 0 ꢀC over 5 min. After 1 h, water was added
cautiously to decompose excess hydride. Oxidation was
carried out by adding 3.37 mL of 4 N NaOH, followed
by dropwise addition of 3.37 mL of 30% hydrogen
peroxide. Flash column chromatography (40% EtOAc/
hexane) provided alcohol 11 (341 mg, 57%) as a pale
1
mg, 71%) as a brown oil; H NMR (200 MHz, CDCl3)
d 0.30 (s, 9H), 1.11 (s, 9H), 1.45–1.47 (m, 2H), 1.56–1.69
(m, 4H), 2.60–2.80 (m, 4H), 2.52 (t, J=5.2 Hz, 4H), 2.79 (t,
J=6.1 Hz, 2H), 4.16 (t, J=6.1 Hz, 2H), 6.73 (dd, J=8.8,
2.2 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.12 (d, t, J=8.8 Hz,
1H), 7.20 (d, J=2.2 Hz, 1H), 7.31–7.43 (m, 6H), 7.69–7.76
(m, 6H); 13C NMR (50MHz, CDCl3) d 7.36, 14.09,
19.35, 24.07, 25.86, 26.45, 54.96, 57.64, 66.26, 111.40,
114.08, 118.09, 123.64, 127.69, 129.85, 131.59, 132.01,
132.58, 133.55, 135.36, 143.04, 145.91, 152.56, 162.62,
192.24; MS (FAB) m/z 784 (MH+). HRMS calcd for
C41H50NO3S SiSn 784.2302, found 784.2322.
1
yellow oil: H NMR (200 MHz, CDCl3) d 1.85 (q, 2H,
J=6.3 Hz), 2.73 (t, 2H, J=7.0 Hz), 3.48 (s, 3H), 3.62 (t,
2H, J=5.9 Hz), 5.09 (s, 2H), 6.78–6.84 (m, 3H); 13C
NMR (50 MHz, CDCl3) d 25.50, 32.20, 55.83, 60.85,
95.44, 115.60, 116.71, 118.69, 128.41, 149.58, 151.26;
MS (EI) m/z 212 (M+). HRMS calcd for C11H16O4
212.1049, Found 212.1043.
4-Allyloxyphenol (8). A mixture of hydroquinone (7,
10.0 g, 90.82 mmol) of allyl bromide (5.50 mL, 22.70
mmol), anhydrous potassium carbonate (3.13 g, 22.70
mmol), and dried acetonitrile (20 mL) was refluxed for
12 h and cooled. Flash column chromatography (20%
EtOAc/hexane) provided allyl substituted 8 (3.14 g,
2-(3-Fluoropropyl)-1-hydroxy-4-(methoxymethoxy)ben-
zene (12). A solution of DAST (226 mL, 1.71 mmol) in
dichloromethane (2 mL) was added dropwise to a solu-
tion of 11 (362 mg, 1.71 mmol) in dichloromethane (3
mL) and stirred at À78 ꢀC for several minutes. The
reaction mixture was stirred at rt for 30 min. and 10 mL
of water added. The organiclayer was separated and the
1
92%) as a brown oil: H NMR (200 MHz, CDCl3) d
4.48 (d, 2H, J=6.6 Hz), 4.56 (bs, 1H), 5.34 (dd, 2H,
J=28.2, 21.2 Hz), 5.95–6.11 (m, 1H), 6.72–6.84 (m, 4H);
13C NMR (50 MHz, CDCl3) d 67.30, 113.64, 115.00,
131.17, 134.11, 147.31, 150.35; MS (EI) m/z 150 (M+).
HRMS calcd for C9H10O2 150.0681, found 150.0687.
organiclayer was dried (Na SO4) and evaporated; flash
2
column chromatography (10% EtOAc/hexane) pro-
1
vided fluoride 12 (55 mg, 15%) as a pale yellow oil: H
NMR (200 MHz, CDCl3) d 2.00 (dq, 2H, J=25.6, 5.9
Hz), 2.71 (t, 2H, J=7.5 Hz), 3.48 (s, 3H), 4.48 (dt, 2H,
J=47.2, 5.9 Hz), 4.80 (bs, 1H), 5.10 (s, 2H), 6.67 (d, 1H,
J=8.4 Hz), 6.76–6.84 (m, 2H); 13C NMR (50 MHz,
CDCl3) d 25.78 (J=5.7 Hz), 30.37 (J=19.8 Hz), 55.85,
83.39 (J=163.1 Hz), 95.43, 97.93, 115.41, 116.05,
118.85, 128.24, 148.71, 151.34; MS (CI) m/z 214
(MH+). HRMS calcd for C11H15FO3 214.1005, found
215.1083.
1-Allyloxy-4-(methoxymethoxy)benzene (9). A solution
of 4-allyloxyphenol (8, 3.34 g, 22.24 mmol) in 10 mL
of dried THF at 0 ꢀC was treated with NaH (1.43 g,
37.14 mmol) in several portions over 5 min. After 10
min, chloromethylmethyl ether (2.53 mL, 33.36
mmol) was added. The reaction mixture was refluxed
for 1 h and cooled. The reaction mixture was quen-
ched by the slow addition of 10 mL of H2O. The
aqueous layer was extracted with ethyl acetate. The
organiclayers were ocmbined, washed with 10%
aqueous NaHCO3 and H2O, dried over Na2SO4, and
evaporated. Flash column chromatography (5%
EtOAc/hexane) provided MOM protected 9 (3.98 g,
2-(3-Fluoropropyl)-4-(methoxymethoxy)-1-(trifluorome-
thanesulfonyloxy)benzene
(13).
Trifluoromethane-
sulfonicanhydride (48 mL, 0.28 mmol) was added
dropwise to a solution of 12 (55 mg, 0.26 mmol) in di-
chloromethane (3 mL) and 2,6-lutidine (75 mL, 0.64
mmol) and stirred at 0ꢀC to rt for 30 min. The reaction
mixture quenched with a small amount of water. The
organiclayer was separated and the organiclayer was
dried (Na2SO4) and evaporated. Flash column chroma-
tography (5% EtOAc/hexane) provided triflate 13 (84
1
92%) as a colorless oil: H NMR (200 MHz, CDCl3) d
3.47 (s, 3H), 4.49 (d, 2H, J=3.6 Hz), 5.10 (s, 2H), 5.34
(dd, 2H, J=29.0, 19.2 Hz), 5.95–6.14 (m, 1H), 6.82–6.99
(m, 4H); 13C NMR (50 MHz, CDCl3) d 55.82, 69.36,
95.24, 115.59, 117.50, 133.50, 151.41, 153.71; MS (EI)
m/z 194 (M+). HRMS calcd for C11H14O3 194.0942,
found 194.0948.
1
mg, 92%) as a yellow oil: H NMR (200 MHz, CDCl3)
d 2.02 (dq, 2H, J=25.8, 5.7 Hz), 2.81 (t, 2H, J=7.9 Hz),
3.48 (s, 3H), 4.48 (dt, 2H, J=46.8, 5.7 Hz), 5.16 (s, 2H),
6.91–6.99 (m, 2H), 7.17 (d, 1H, J=8.8 Hz); 13C NMR
(50 MHz, CDCl3) d 26.12 (J=5.7 Hz), 30.46 (J=19.8
Hz), 56.12, 82.78 (J=165.0 Hz), 94.64, 115.31, 118.50,
121.78, 122.42, 135.28, 142.23, 156.76; MS (CI) m/z 346
(MH+). HRMS calcd for C12H14F4O5S 346.0498,
found 346.0498.
2-Allyl-4-(methoxymethoxy)phenol (10). A mixture of
allyl ether (3.10 g, 15.98 mmol) and N,N-dimethylani-
line (5 mL) was cautiously brought to boiling in a
round-bottom flask, refluxed for 2 h, and cooled. Flash
column chromatography (20% EtOAc/hexane) pro-
vided 2-allylphenol 10 (2.47 g, 80%) as a dark yellow
1
oil: H NMR (200 MHz, CDCl3) d 3.36 (d, 2H, J=6.2

3656
K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
1-Allyl-2-[(2-methoxyethoxy)methoxy]benzene (15).
A
2.75 (t, 2H, J=7.5 Hz), 3.38 (s, 3H), 3.56 (t, 2H, J=4.7
Hz), 3.83 (t, 2H, J=4.7 Hz), 4.46 (dt, 2H, J=47.2, 6.0
Hz), 5.30 (s, 2H), 6.90–6.98 (m, 1H), 7.10–7.17 (m, 3H);
13C NMR (50 MHz, CDCl3) d 26.07 (J=6.1 Hz), 30.68
(J=19.4 Hz), 58.95, 67.76, 71.68, 83.49 (J=163.9 Hz),
93.61, 114.15, 121.71, 127.38, 130.12, 155.32; MS (CI)
m/z 242 (MH+). HRMS calcd for C13H19FO3 242.1318,
found 242.1320.
solution of 2-allylphenol (14, 1.00 g, 7.45 mmol) in 5 mL
of dried THF at 0 ꢀC was treated with NaH (418 mg,
12.45 mmol) in several potions over 5 min. After 10
min, 2-methoxyethoxymethyl chloride (1276 mL, 11.18
mmol) was added. The reaction mixture was refluxed
for 1 h and cooled. Flash column chromatography
(10% EtOAc/hexane) provided MEM protected 15
(1.35 g, 82%) as a yellow oil: 1H NMR (200 MHz,
CDCl3) d 3.38 (s, 3H), 3.41 (s, 2H), 3.56 (t, 2H, J=4.8
Hz), 3.83 (t, 2H, J=4.7 Hz), 5.00–5.08 (m, 2H), 5.29 (s,
2H), 5.89–6.09 (m, 1H), 6.88–6.99 (m, 1H), 7.10–7.18
(m, 3H); 13C NMR (50 MHz, CDCl3) d 34.34, 58.93,
67.70, 71.67, 93.61, 114.23, 115.28, 121.77, 127.34,
129.25, 129.95, 136.98, 155.02; MS (EI) m/z 222
(M+). HRMS calcd for C13H18O3 222.1250, found
222.1253.
2-(3-Fluoropropyl)phenol (19). To MEM protected 18
(534 mg, 2.21 mmol) in methanol (5 mL) was added 6N
HCl (3 mL) and heated at 60 ꢀC for 1 h. Methanol was
removed under vacuum, and and the reaction mixture
was extracted with ethyl acetate and washed (H2O,
brine) and the organiclayer was dried (Na SO4) and
2
evaporated. Flash column chromatography (10%
EtOAc/hexane) provided the deprotected phenol 19
(512 mg, 74%) as a pale yellow oil: 1H NMR (200 MHz,
CDCl3) d 2.01 (dq, 2H, J=26.0, 6.5 Hz), 2.74 (t, 2H,
J=7.4 Hz), 4.47 (dt, 2H, J=47.2, 5.7 Hz), 5.35 (bs, 1H),
6.76–6.90 (m, 2H), 7.10 (t, 2H, J=8.2 Hz); 13C NMR
(50 MHz, CDCl3) d 23.15 (J=5.7 Hz), 27.98 (J=19.4
Hz), 81.16 (J=162.7 Hz), 113.00, 118.40, 124.68,
125.05, 128.05, 151.28; MS (EI) m/z 154 (M+). HRMS
calcd for C9H11FO 154.0794, found 154.0797.
2-(3-Hydroxypropyl)-1-[(2-methoxyethoxy)methoxy]ben-
zene (16). According to the procedure for the prepara-
tion of compound 11 described above, to 8.83 g (39.79
mmol) of olefin 15 was added to 47.75 mL (47.75 mmol)
of borane–THF complex in dried THF at 0 ꢀC over 5
min. After 1 h, water was added cautiously to decom-
pose excess hydride. Oxidation was carried out by add-
ing 47.75 mL of 4N NaOH, followed by dropwise
addition of 47.75 mL of 30% hydrogen peroxide. Flash
column chromatography (30% EtOAc/hexane) pro-
1-(3- Fluoropropyl)- 2- (trifluoromethanesulfonyloxy)ben-
zene (20). Trifluoromethanesulfonicanhydride (367 mL,
2.18 mmol) was added dropwise to a solution of 49 (305
mg, 1.98 mmol) in dichloromethane (3 ꢀmL) and 2,6-
lutidine (277 mL, 2.38 mmol) stirred at 0 C to rt for 30
min. Flash column chromatography (5% EtOAc/hex-
ane) provided triflate 20 (462 mg, 82%) as a colorless
oil: 1H NMR (200 MHz, CDCl3) d 2.03 (dq, 2H,
J=28.2, 5.7 Hz), 2.87 (t, 2H, J=7.7 Hz), 4.50 (dt, 2H,
J=47.2, 5.7 Hz), 7.29–7.34 (m, 4H); 13C NMR
(50 MHz, CDCl3) d 25.90 (J=5.7 Hz), 30.53 (J=20.1
Hz), 82.77 (J=165.4 Hz), 115.45, 121.49, 121.81,
128.17, 128.46, 131.40, 133.90, 148.07; MS (CI) m/z 286
(MH+). HRMS calcd for C10H10F4O3S 286.2442,
found 287.0358.
1
vided alcohol 16 (4.59 g, 48%) as a white oil: H NMR
(200 MHz, CDCl3) d 1.84 (q, 2H, J=7.0 Hz), 2.28 (bs,
1H), 2.72 (t, 2H, J=7.5 Hz), 3.37 (s, 3H), 3.55–3.64 (m,
4H), 3.83 (t, 2H, J=4.7 Hz), 5.29 (s, 2H), 6.89–6.97 (m,
1H), 7.11–7.16 (m, 3H); 13C NMR (50 MHz, CDCl3) d
26.17, 32.93, 58.79, 61.90, 67.68, 71.54, 93.62, 114.07,
121.73, 127.73, 129.97, 130.70, 155.12; MS (EI) m/z 240
(M+). HRMS calcd for C13H20O4 240.1361, found
240.1353.
1-(3-Methanesulfonyloxypropyl)-2-[(2-methoxyethoxy)-
methoxy]benzene (17). To alcohol 16 (1.21 g, 5.05
mmol) in dichloromethane (10 mL) was added triethyl-
amine (1056 mL, 7.58 mmol) and methanesulfonyl chlo-
ride (430 mL, 5.56 mmol) at 0 ꢀC for 20 min. Flash
column chromatography (30% EtOAc/hexane) pro-
1-(2-Hydroxyethyl)-2-[(2-methoxyethoxy)methoxy]ben-
zene (22). A solution of 2-(2-hydroxyethyl)phenol (21,
3.93 g, 28.46 mmol) in 15 mL of dried THF at 0 ꢀC was
treated with NaH (1.15 g, 34.16 mmol) in several
potions over 5 min. After 10 min, 2-methoxyethoxy-
methyl chloride (3.25 mL, 28.46 mmol) was added. The
reaction mixture was refluxed for 1 h and cooled. Flash
column chromatography (40% EtOAc/hexane) pro-
vided MEM protected 22 (4.51 g, 70%) as a pale yellow
oil: 1H NMR (200 MHz, CDCl3) d 2.05 (bs, 1H), 2.91 (t,
2H, J=6.6 Hz), 3.36 (s, 3H), 3.55 (t, 2H, J=4.2 Hz),
3.80–3.84 (m, 4H), 5.29 (s, 2H), 6.95 (t, 1H, J=7.1 Hz),
7.10–7.19 (m, 3H); 13C NMR (50 MHz, CDCl3) d 34.03,
58.89, 62.72, 67.81, 71.61, 93.63, 114.26, 121.81, 127.72,
130.82; MS (EI) m/z 226 (M+). HRMS calcd for
C12H18O4 226.1205, found 226.1202.
1
vided mesylate 17 (906 mg, 56%) as a yellow oil: H
NMR (200 MHz, CDCl3) d 2.06 (q, 2H, J=7.0 Hz),
2.76 (t, 2H, J=7.4 Hz), 2.99 (s, 3H), 3.38 (s, 3H), 3.56
(t, 2H, J=4.6 Hz), 3.83 (t, 2H, J=4.6 Hz), 4.24 (t, 2H,
J=6.4 Hz), 5.30 (s, 2H), 6.90-6.98 (m, 1H), 7.10–7.18
(m, 3H); 13C NMR (50 MHz, CDCl3) d 26.46, 29.34,
37.36, 58.92, 67.80, 69.62, 71.62, 93.53, 114.10, 121.68,
127.57, 129.26, 130.05, 155.16; MS (CI) m/z 318
(MH+). HRMS calcd for C14H22O6S 318.1137, found
318.1140.
1-(3 - Fluoropropyl) - 2 -[(2 - methoxyethoxy)methoxy]ben-
zene (18). To mesylate 17 (906 mg, 2.85 mmol) in ace-
tonitrile (3 mL) was added tetra-n-butylammonium
fluoride hydrate (897 mg, 2.85 mmol) and heated at
110 ꢀC for 30 min in a pressure bottle. Flash column
chromatography (10% EtOAc/hexane) provided fluor-
1-(2-Methanesulfonyloxyethyl)-2-[(2-methoxyethoxy)me-
thoxy]benzene (23). According to the procedure of 17
described above, to alcohol 21 (2.76 g, 12.22 mmol) in
dichloromethane (10 mL) was added triethylamine (2.56
1
ide 18 (512 mg, 74%) as a pale yellow oil: H NMR
(200 MHz, CDCl3) d 1.98 (dq, 2H, J=25.6, 6.2 Hz),

K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
3657
mL, 18.33 mmol) and methanesulfonyl chloride (1.04
mL, 13.44 mmol) at 0 ꢀC for 20 min. Flash column
chromatography (50% EtOAc/hexane) provided mesyl-
ate 23 (3.05 g, 82%) as a yellow oil: 1H NMR (200 MHz,
CDCl3) d 2.83 (s, 3H), 3.09 (t, 2H, J=6.9 Hz), 3.38 (s,
3H), 3.56 (t, 2H, J=4.5 Hz), 3.84 (t, 2H, J=4.6 Hz), 4.43
(t, 2H, J=7.0 Hz), 5.32 (s, 2H), 6.91–6.99 (m, 1H), 7.12–
7.27 (m, 3H); 13C NMR (50 MHz, CDCl3) d 30.80, 37.24,
58.93, 67.93, 69.26, 71.61, 93.52, 114.08, 121.79, 128.52,
131.03, 155.40; MS (CI) m/z 304 (MH+). HRMS calcd
for C13H20O6S 304.0980, found 304.0986.
2-[2-(3-Fluoropropyl)phenyl]-3-[4-(2-piperidin-1-yl)ethox-
ybenzoyl]-6-hydroxybenzo[b]thiohene (2). According to
the procedure of 24 described above, a solution of 32
(200 mg, 0.26 mmol), 50 (206 mg, 0.77 mmol) and
Pd(PPh3)4 (6 mg, 0.005 mmol) in anhydrous DMF (10
mL) was heated at 100 ꢀC for 12 h. Protected crude
fluoropropyl compounds, separated by silica gel column
chromatography (5% MeOH/CH2Cl2), was treated
tetra-n-butylammonium fluoride hydrate (2 equiv) in
THF at rt for 1 min. The reaction mixture was quen-
ched by water, and extacted with EtOAc. The organic
layer was dried with sodium sulfate, and evaporated.
Flash column chromatography (10% MeOH/CH2Cl2)
1-(2-Fluoroethyl)-2-(trifluoromethanesulfonyloxy)benzene
(25). A solution of DAST (963 mL, 7.29 mmol) in di-
chloromethane (5 mL) was added dropwise to a solution
of 21 (1.0 g, 7.29 mmol) in dichloromethane (10 mL)
1
provided 3 (88 mg, 68%) as a pale yellow oil: H NMR
(200 MHz, CDCl3) d 1.47–1.49 (m, 2H), 1.67 (bs, 4H),
1.93 (dq, 2H, J=24.8, 6.0 Hz), 2.61 (bs, 4H), 2.74 (t,
2H, J=7.9 Hz), 2.84 (t, 2H, J=5.3 Hz), 4.13 (t, 2H,
J=5.5 Hz), 4.32 (dt, 2H, J=47.2, 6.0 Hz), 6.37 (bs, 1H),
6.64 (d, 2H, J=8.8 Hz), 6.83 (dd, 1H, J=8.8, 2.2 Hz),
7.06–7.26 (m, 5H), 7.39 (d, 1H, J=8.8 Hz), 7.64 (d, 2H,
J=8.8 Hz); 13C NMR (50 MHz, CDCl3) d 23.85, 25.26,
28.85, 31.43 (J=19.8 Hz), 54.96, 57.62, 65.36, 83.31
(J=163.9 Hz), 107.27, 113.97, 115.33, 124.57, 125.75,
128.96, 129.12, 130.92, 131.57, 132.11, 132.44, 133.58,
140.39, 140.82, 142.10, 154.68, 162.60, 192.18; MS
(FAB) m/z 518 (MH+). HRMS calcd for C31H32FNO3S
517.2087, found 518.2161.
ꢀ
and stirred at À78 C for several minutes. The reaction
mixture was stirred at rt for 30 min and 10 mL of water
added. The organiclayer was separated and the organic
layer was dried (Na2SO4) and evaporated. Tri-
fluoromethanesulfonicanhydride (500 mL, 2.97 mmol)
was added dropwise to a solution of crude fluoride in
dichloromethane (10 mL) and 2,6-lutidine (472 mL, 4.05
ꢀ
mmol) and stirred at 0 C to rt for 30 min. Flash col-
umn chromatography (5% EtOAc/hexane) provided
1
triflate 25 (516 mg, 26%) as a pale yellow oil: H NMR
(200 MHz, CDCl3) d 3.12 (dt, 2H, J=24.6, 6.0 Hz), 4.67
(dt, 2H, J=46.8, 6.2 Hz), 7.27–7.45 (m, 4H); 13C NMR
(50 MHz, CDCl3) d 30.98 (J=21.2 Hz), 82.22 (J=168.8
Hz), 109.32, 115.42, 120.29, 121.49, 121.77, 124.89,
127.89, 128.49, 128.77, 130.22 (J=4.6 Hz), 131.92,
148.04; MS (CI) m/z 273 (MH+). HRMS calcd for
C9H8F4O3S 272.0130, found 272.0130.
2-[2-(3-Fluoroethyl)phenyl]-3-[4-(2-piperidin-1-yl)ethoxy-
benzoyl]-6-hydroxybenzo[b]thiephene (3). According to
the procedure of 24 described above, a solution of 32
(120 mg, 0.15 mmol), 55 (117 mg, 0.46 mmol) and
Pd(PPh3)4 (4 mg, 0.003 mmol) in anhydrous DMF (8
mL) was heated at 100 ꢀC for 12 h. Flash chromato-
graphy (10% MeOH/CH2Cl2) provided 4 (62 mg, 80%)
as a pale yellow oil: 1H NMR (200 MHz, CDCl3) d
1.47–1.49 (m, 2H), 1.67 (bs, 4H), 2.60 (bs, 4H), 2.74 (t,
2H, J=7.9 Hz), 2.83 (t, 2H, J=5.4 Hz), 3.07 (dt, 2H,
J=22.8, 6.6 Hz), 4.12 (t, 2H, J=5.5 Hz), 4.56 (dt, 2H,
J=47.2, 6.6 Hz), 6.64 (d, 2H, J=8.8 Hz), 6.82 (dd, 1H,
J=8.8, 1.8 Hz), 7.07–7.27 (m, 5H), 7.37 (d, 1H, J=8.8
Hz), 7.63 (d, 2H, J=8.8 Hz); 13C NMR (50 MHz,
CDCl3) d 23.85, 25.21, 34.17 (J=20.5 Hz), 54.93, 57.60,
65.26, 83.51 (J=168.0 Hz), 107.28, 114.01, 115.45,
124.56, 126.30, 128.99, 129.69, 130.80, 131.51, 132.09,
132.83, 133.79, 136.55 (J=6.1 Hz), 140.87, 141.44,
154.85, 162.65, 192.16; MS (FAB) m/z 504 (MH+).
HRMS calcd for C30H30FNO3S 503.1930, found
504.1988.
2-[2-(3-Fluoroethyl)-4-hydroxyphenyl]-3-[4-(2-piperidin-
1-yl)ethoxybenzoyl]-6-hydroxybenzo[b]thiophene (1). A
solution of 13 (94 mg, 0.27 mmol), 26b (75 mg, 0.096
mmol), and Pd(PPh3)4 (2 mg, 0.002 mmol) in anhydrous
DMF (10 mL) was heated at 100 ꢀC for 12 h. The pro-
tected crude coupled product, separated by silica gel
column chromatography (5% MeOH/CH2Cl2), was
treated tetra-n-butylammonium fluoride hydrate (2
equiv) in THF at rt for 1 min. The crude mixture iso-
lated by silica gel flash column chromatography (10%
MeOH/CH2Cl2) was treated with three drops of concd
HCl in isopropanol (10 mL) at 60 ꢀC for 30 min. The
reaction mixture was extracted with EtOAc (10 mL) and
water (20 mL) and dried over Na2SO4. Flash column
chromatography (12% MeOH/CH2Cl2) gave 1 (24 mg,
47%) as a pale yellow oil: 1H NMR (200 MHz,
CD3OD) d 7.62 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz,
1H), 7.25 (d, J=2.2 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H),
6.90 (d, J=2.2 Hz, 1H), 6.82 (d, J=8.6 Hz, 2H), 6.54–
6.46 (m, 2H), 4.42 (t, J=6.1 Hz, 1H), 4.21–4.12 (m, 3H),
2.83 (t, J=5.3 Hz, 2H), 2.65–2.57 (m, 6H), 1.89–1.48
(m, 7H); 13C NMR (50 MHz, CD3OD) d 194.6, 164.0,
159.1, 156.7, 143.9, 143.1, 142.0, 134.2, 133.9, 133.2,
132.2, 125.1, 124.6, 116.7, 116.0, 115.1, 113.9, 107.6,
84.1 (d, J=163 Hz, 1C), 66.2, 58.4, 55.7, 32.7 (d, J=20.
Hz, 1C), 30.7, 30.1 (d, J=6 Hz), 26.1, 24.7; MS (FAB)
m/z 534 (M++H), 386, 371, 231, 154, 117 (100), 91.
HRMS (FAB) calcd for C31H32FNO4S 534.2036, found
534.2065.
Estrogen receptor binding affinity assays
Relative binding affinities were determined by a compe-
titive radiometricbinding assay as previously desrci-
bed,13 using 10 nM [3H]estradiol as tracer ([6,7-3H]estra-
1,3,5,(10)-triene-3,17-b-diol, 51-53 Ci/mmol, Amersham
BioSciences, Piscataway, NJ, USA) and either lamb
uterine cytosol (containing mostly ERa) or purified full
length human ERa and ERb receptor purchased from
Pan Vera (Madison, WI, USA). Incubations were for 18–
24 h at 0 ꢀC. With the uterine cytosol, charcoal–dextran
was used to adsorb free ligand and was pelleted by cen-
trifugation,13a and with the purified ER hydroxyapatite

3658
K. C. Lee et al. / Bioorg. Med. Chem. 11 (2003) 3649–3658
(BioRad, Hercules, CA, USA) was used to absorb the
receptor–ligand complexes, and free ligand was washed
away.13b The binding affinities are expressed as relative
binding affinity (RBA) values with the RBA of estradiol
set to 100%. The values given for raloxifene are the
averageÆrange or SD of 2–3 independent determina-
tions. The other values are for single determinations. It
should be noted that in this series of compounds, bind-
ing affinity determinations are highly reproducible, with
coefficient of variations being typically 0.15. This is
exemplified by the small SD values for the multiple
determinations for raloxifene on all three receptor sys-
tems. Estradiol binds to ERa with a Kd of 0.2 nM and
to ERb with a Kd of 0.5 nM, and to the estrogen recep-
tor in lamb uterine cytosol with a Kd of 0.17 nM.
6. (a) Palkowitz, A. D.; Glasebrook, A. L.; Thrasher, K. J.;
Hauser, K. L.; Short, L. L.; Phillips, D. L.; Muehl, B. S.; Sato,
M.; Shetler, P. K.; Cullinan, G. J.; Pell, T. R.; Bryant, H. U. J.
Med. Chem. 1997, 40, 1407. (b) Takeuchi, K.; Kohn, T. J.;
Sall, D. J.; Denney, M. L.; McCowan, J. R.; Smith, G. F.;
Gifford-Moore, D. S. Bioorg. Med. Chem. Lett. 1999, 9, 759.
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Their Antagonists, Pavlik, E. J., Ed.; Birkhauser: Boston, 1996;
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Griffeth, L. K.; Bonasera, T. J.; Fusselman, M. J.; Detert,
D. D.; Cutler, P. D.; Katzenellenbogen, J. A.; Welch, M. J. J.
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Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2000-015-DP0274). We thank
Kathryn Carlson for the binding affinity determinations.
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