Synthesis of constrained raloxifene analogues by complementary use of Friedel-Crafts and directed remote metalation reactions

Article abstract of DOI:10.1021/jo034325k

New constrained heterocyclic analogues, 2a,b and 3, of Raloxifene (1) have been prepared by complementary Directed remote Metalation (DreM)/Friedel-Crafts cyclization approaches. Utilization of a benzylidene-thiolactone rearrangement was successfully impl

Full text of DOI:10.1021/jo034325k

Syn th esis of Con str a in ed Ra loxifen e An a logu es by
Com p lem en ta r y Use of F r ied el-Cr a fts a n d Dir ected Rem ote
Meta la tion Rea ction s
Alexey V. Kalinin,† Mark A. Reed,† Bryan H. Norman,‡ and Victor Snieckus*,†
Queen’s University, Department of Chemistry, Kingston, Ontario, Canada K7L 3N6, and Eli Lilly and
Company, Discovery Chemistry Research, Lilly Corporate Center, Indianapolis, Indiana 46285
snieckus@chem.queensu.ca
Received March 11, 2003
New constrained heterocyclic analogues, 2a ,b and 3, of Raloxifene (1) have been prepared by
complementary Directed remote Metalation (DreM)/Friedel-Crafts cyclization approaches. Utiliza-
tion of a benzylidene-thiolactone rearrangement was successfully implemented to construct
benzothiophenes 13a -c in good yields. Selective deprotection of 13a and 13b induced by
complexation followed by triflation gave 18 and 23, thereby allowing efficient Suzuki-Miyaura
cross coupling with borolane 16 to give biaryls 19 and 24. Treatment of 19 with BCl3 induced an
intramolecular para Fridel-Crafts cyclization and concomitant double deprotection to furnish
analogue 2a , a new 5,6,6,6-(C4S-C6-C6-C6) sulfur-containing heterocycle. Exposure of 25 with
excess LDA induced a DreM cyclization delivering the ortho-substituted 5,6,6,6-(C4S-C6-C6-C6)
heterocylic analogue 26 in 70% yield. Similar treatment of 13c and 27 afforded 30, representing
the novel 5,5,6,6-(C4S-C5-C6-C6) ring system, which was subjected to Suzuki-Miyaura cross
coupling with 16 to give the biaryl 31 in 93% yield; deprotection furnished the final constrained
analogue 3.
In tr od u ction
In 1984, Lilly scientists reported that [6-hydroxy-2-(4-
hydroxyphenyl)benzo[b]thien-3-yl]-[4-(2-(1-piperidinyl)-
ethoxy]phenyl]methanone exhibited strong estrogen
antagonist activity, an incisive discovery that eventually
led to the new commercial drug Raloxifene (1, Figure
1),1a-c which was approved by the U.S. Food and Drug
Administration for the prevention and treatment of
osteoporosis in postmenopausal women. Extensive re-
search and clinical trials are in progress to assess the
potential of Raloxifene for the prevention of breast
cancer,1d lower lipid production,1e control of uterine
cancer,1f,g and treatment of Alzheimer’s disease.1h
Molecular modeling studies at the Lilly Laboratories2a-d
posited the new constrained Raloxifene analogues
2a ,b and 3 as potential candidates for biological evalu-
ation. Herein we report the efficient syntheses of 2a ,b
and 3.
F IGURE 1. Raloxifene and constrained analogues synthe-
sized.
Resu lts a n d Discu ssion
The retrosynthetic plans for analogues 2 and 3 were
envisaged through a rational combination of Friedel-
* To whom correspondence should be addressed. Phone: (613) 533-
2239. Fax: (613) 533-2837.
(2) (a) Grese, T. A.; Sluka, J . P.; Bryant, H. U.; Cole, H. W.; Kim, J .
R.; Magee, D. E.; Rowley, E. R.; Sato, M. Bioorg. Med. Chem. Lett.
1996, 6, 903-908. (b) Grese, T. A.; Sluka, J . P.; Bryant, H. U.; Cullinan,
G. J .; Glasebrook, A. L.; J ones, C. D.; Matsumoto, K.; Palkowitz, A.
D.; Sato, M.; Termine, J . D.; Winter, M. A.; Yang, N. N.; Dodge, J . A.
Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 14105-14110. (c) Schmid, C.
R.; Sluka, J . P.; Duke, K. M.; Glasebrook, A. W. Bioorg. Med. Chem.
Lett. 1999, 9, 523-528. (d) Grese, T. A.; Pennington, L. D.; Sluka, J .
P.; Adrian, M. D.; Cole, H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D.
L.; Rowley, E. R.; Shetler, P. K.; Short, L. L.; Venugopalan, M.; Yang,
N. N.; Sato, M.; Glasebrook, A. L.; Bryant, H. U. J . Med. Chem. 1998,
41, 1272-1283.
† Queen’s University.
‡ Eli Lilly and Company.
(1) (a) J ones, C. D.; J evnikar, M. G.; Pike, A. J .; Peters, M. K.; Black,
L. J .; Thompson, A. R.; Falcone, J . F.; Clemens, J . A. J . Med. Chem.
1984, 27, 1057-1066. (b) J ordan, V. C. J . Med. Chem. 2003, 46, 883-
908. (c) J ordan, V. C. J . Med. Chem. 2003, 46, 1081-1111. (d) J ordan,
V. C. J . Steroid Biochem. Mol. Biol. 2002, 74, 269-277. (e) Rossouw,
J . E. Curr. Opin. Lipidol. 1999, 10, 429-434. (f) Goldfrank, D.;
Haytoglu, T.; Frishman, W. H.; Mohammad, Z. J . Clin. Pharmacol.
1999, 39, 767-774. (g) Gustafsson, J .-A. Nat. Med. 1998, 4, 152. (h)
McCormick, W. C.; Abrass, I. B. Lancet 1998, 352 (Suppl 4), 6.
10.1021/jo034325k CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/28/2003
5992
J . Org. Chem. 2003, 68, 5992-5999

New Constrained Raloxifene Analogues
SCHEME 1. Syn th esis of In ter m ed ia te 13 via a
Ben zylid en e-Th iola cton e Rea r r a n gem en ta
F IGURE 2. Retrosynthetic analysis for constrained analogues
2 and 3.
Crafts,3a Directed remote Metalation (DreM)3b and Su-
zuki-Miyaura cross-coupling4 reactions (Figure 2). Thus,
for 2a , dissection at the C6-C6a bond would predispose
Friedel-Crafts ring closure (path a, 4), favorably assisted
by the para orientation of the OR substituent over path
b, and the precursor 4-aryl benzothiophene derived by
the Suzuki-Miyaura cross-coupling reaction. On the
other hand, consideration of the DreM strategy implicates
cyclization driven by the OR-directed metalation group
(DMG), path c, 5, the alternate path d, is not DMG-
assisted and is therefore less likely.3 The approach to 3
may be envisaged by initial dissection to the Suzuki-
Miyaura precursor 6, which perforce avoids the above
dichotomy and allows consideration of regioselective,
DreM-induced five-memered ring cyclization of the ben-
zothiophene derivative 7 (path e).
The synthesis of 2 was initiated with the preparation
of the key intermediate benzothiophenes 13 (Scheme 1).
Use of the conditions developed by Ablenas5 converted
the readily available aldehydes 8 into the corresponding
hydroxythioacetamides 9 by reaction with lithio anion of
N,N-dimethylthioformamide. Dehydrative carbocationic
cyclization of 9, promoted by MeSO3H, resulted in forma-
tion of intermediate aminobenzothiophenes 10,5 which
were subjected to acid-catalyzed hydrolysis to deliver the
benzothiophenones 11. In contrast to the synthetic ap-
proach to a series of Raloxifene analogues with variable
2-aryl substituents via either aryl Grignard additions to
2-(dimethylamino)-3-aroylbenzothiophenes or Stille cou-
plings of crude 2-stannyl-3-aroylbenzothiophenes with
aryl bromides,2d,6 we pursued a modification of the
a
Reagents and conditions: (a) LDA, HC(S)NMe2, THF, -78 °C
to rt, 69% (a ), 41% (b), 50% (c); (b) MeSO3H, DCM 0 °C to rt; (c)
EtOH or MeOH, 3 N HCl, reflux/68% (a ), 59% (b), 62% (c); (d) 10
mol % C5H11N, 4-(i-PrO)C6H4CHO, HOAc, reflux and then cat 50%
aq KOH, MeOH, rt, 77%; (e) 10 mol % HNET2, 4-(BnO)C6H4CHO
(b) or 4-(MeO)C6H4CHO (c), HOAc, reflux and then HNET2, MeCN
or THF, reflux, 69% (b), 81% (c); (f) DDQ, PhH or PhMe, reflux,
92% (a ), 63% (b), 93% (c).
method developed by Heindel for the synthesis of dihy-
dro- and benzothiophenes involving a base-catalyzed
benzylidene-thiolactone rearrangement.7 We found that
performing condensations of 11 with aromatic aldehydes
in refluxing HOAc catalyzed by bases such as piperidine
(for 11a ) or diethylamine (for 11b,c) was more efficient
than carrying out the reactions in anhydrous EtOH as
reported.5 Basification (catalytic amount of 50% aqueous
KOH solution) of a MeOH solution of the crude product
from the condensation of 11a and p-(i-PrO)benzaldehyde
produced methyl ester 12a as a single trans isomer in
77% yield. The relative trans stereochemistry of 12a was
assigned by NOE observations. Thus, irradiation at the
resonance frequency of H1 protons (δ 7.32) showed NOEs
for H2 (δ 5.21) and H3 (δ 4.35), while irradiation of H2
resulted in response from the H1 proton only.8 Similarly,
condensation of 11b and 11c with p-(BnO)- and p-(MeO)-
benzaldehyde, respectively, followed by treatment of the
intermediate benzylidenes7 with an excess of diethyl-
amine in refluxing MeCN or THF led directly to diethyl-
amides 12b and 12c, formed as mixtures of isomers in
81% and 69% yields, respectively. Oxidation of 12a -c
with DDQ completed the synthesis of the requisite
benzothiophenes 13a -c.7a
(3) (a) Olah, G. A. Friedel-Crafts Chemistry; New York: Wiley,
1973; Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chem-
istry: A Century of Discovery; Marcel Dekker: New York, 1984. (b)
Anctil, E. J .-G.; Snieckus, V. J . Organomet. Chem. 2002, 653, 150-
160. Snieckus, V. Chem. Rev. 1990, 90, 879-933. For an illustrative
example of DreM application in total synthesis, see: Chauder, B. A.;
Kalinin, A. V.; Taylor, N. T.; Snieckus, V. Angew. Chem., Int. Ed. 1999,
38, 1435-1438 and refs cited therein. For an application to bioactive
molecules, see: Ciske, F. L.; J ones, W. D., J r. Synthesis 1998, 1195-
1198.
(4) Suzuki, A. In Metal-catalysed Cross-coupling Reactions; Dieder-
ich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998, p 49. Suzuki,
A. J . Organomet. Chem. 2002, 653, 83-90.
(5) Ablenas, F. J .; George, B. E.; Maleki, M.; J ain, R.; Hopkinson,
Lee-Ruff, E. Can. J . Chem. 1987, 65, 1800-1803.
(6) Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; J ones, C. D.;
Lugar, C. W., III; Martin, M. J .; Matsumoto, K.; Pennington, L. D.;
Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D.
L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J . Med.
Chem. 1997, 40, 146-167. Bradley, D. A.; Godfrey, A. G.; Schmid, C.
R. Tetrahedron Lett. 1999, 40, 5155-5159.
The borolane 16, required for the proposed Suzuki-
Miyaura reaction, was prepared by sequential alkylation
of 3-bromophenol 14 with 1-(2-chloroethyl)piperidine
hydrochloride in aqueous NaOH solution9 to give ether
15 followed by sequential lithium-bromine exchange,
B(OMe)3 quench, and in situ re-esterification with pinacol
(7) (a) Conley, R. A.; Heindel, N. D. J . Org. Chem. 1976, 41, 3743-
3746. (b) Conley, R. A.; Heindel, N. D. J . Org. Chem. 1975, 40, 3169-
3173.
(8) See ref 7a for the corresponding assignments of H2 and H3.
(9) Mason, J . P.; Malkiel, S. J . Am. Chem. Soc. 1940, 62, 1448-
1450.
J . Org. Chem, Vol. 68, No. 15, 2003 5993

Kalinin et al.
SCHEME 4. Syn th esis of An a logu e 2b by a
SCHEME 2. Syn th esis of Bor ola n e Cr oss-Cou p lin g
P a r tn er 16a
Com bin ed Su zu k i-Miya u r a /Regioselective
Dir ected Rem ote Meta la tion Str a tegya
a
Reagents and conditions: (a) ClCH2CH2NC5H10 HCl, NaOH,
H20, reflux, 69%; (b) n-BuLi, THF, -78 °C and then B(OMe)3,
pinacol, rt, 74%.
SCHEME 3. Syn th esis of An a logu e 2a by
F r ied el-Cr a fts a n d An a logu e 21 by Dir ected
Rem ote Meta la tion Key Rea ction sa
a
Reagents and conditions: (a) 9-Br-9-BBN, DCM, -78 °C to
rt, 82%; (b) Tf20, TEA, DCM, 0 °C, 85%; (c) 16, DME-2 M Na2CO3,
5 mol % Pd(PPh3)4, reflux, 80%; (d) 1,4-cyclohexadiene, Pd-C,
EtOAc-HOAc, rt, and then TIPSCl, NEt(i-Pr)2, DMAP, DCM, rt,
82%; (e) LDA, THF, -40 to 0 °C, 70%; (f) TBAF, THF, rt, 86%.
the reaction at low concentration (c 0.025 M) appeared
to be crucial due to the limited solubilities of reaction
intermediates.11 The synthesis of analogue 2a was thus
achieved by a nine-step sequence in 14.1% overall yield
based on 8a .
As suggested in Figure 2, two modes of DreM-induced
cyclization may be envisaged for intermediate 4. In the
event, 19 upon treatment with excess LDA delivered 21,
the expected product of anionic cyclization ortho with
respect to the amino ether side chain, in 33% yield. Due
to the low yield and the problem of subsequent side chain
cleavage upon deprotection of the isopropyl groups, our
attention was turned to an alternative synthesis of
analogue 2b (Scheme 4). Commencing with 13b, treat-
ment (-78 °C/DCM) with 9-Br-BBN12 effected regiose-
lective C-4 debenzylation to furnish the phenol 22, which
was subsequently subjected to Tf2O/pyridine treatment
to afford the triflate 23. Suzuki-Miyaura coupling of 23
with borolane 16 under our standard conditions furnished
the biaryl 24. Treatment of 24 with LDA provided none
of the desired cyclized product. To overcome this observed
incompatibility of the benzyl protecting groups, a silicon
for benzyl protecting group interchange was envisaged.
Thus, exposure of 24 to catalytic transfer hydrogenation
conditions (1,4-cyclohexadiene and 10% Pd-C)13 gave the
intermediate diphenol which, upon treatment with tri-
isopropylsilyl chloride (3 equiv) in the presence of N,N-
diisopropylethylamine and catalytic DMAP furnished 25
in 82% yield over two steps. Subjection of 25 to 3 equiv
of LDA (THF/0 °C to room temperature/4 h) smoothly
delivered the DreM product 26 in 70% yield. Deprotection
with TBAF afforded the target analogue 2b in 13 steps
and 6.6% overall yield based on 8b.
a
Reagents and conditions: (a) BCl3, DCM, -78 to 0 °C, 96%,
(b) Tf2O, TEA, DCM, 0 °C, 83%; (c) 16, DME-2 M Na2CO3, 2 mol
% Pd(PPh3)4, reflux, 95%; (d) BCl3, DCM, 0 °C, 56% (2a ) and 15%
(20); (e) LDA, THF, -78 °C to rt, 33%.
(Scheme 2). Purification of borolane 16 by vacuum
distillation ensured its chemical purity and proved to be
more convenient than handling the corresponding boronic
acid.
Peri proximity of CO2Me to the 4-(i-PrO)-substituent
in 13a allowed the regioselective deisopropylation with
BCl3 at low temperature10 to give the phenol 17 (quan-
titative yield), which was converted into triflate 18 and
then subjected to Suzuki-Miyaura cross coupling with
1.2 equiv of 16, a reaction effectively catalyzed by 2 mol
% Pd(PPh3)4 and completed within 30 min to furnish the
biaryl 19 in 95% yield (Scheme 3). Completion of the
synthesis was achieved through a mild BCl3-mediated
one-pot electrophilic cyclization-double-deprotection se-
quence of 19 leading selectively to six-membered ketones
2a (56%) and 20 (15%) and reflecting a typical para:ortho
ratio observed for Friedel-Crafts reactions.3a Clearly,
side chain loss in the formation of 20 was induced by BCl3
coordination to the ortho-carbonyl group.10 Optimization
of the reaction conditions showed that 5 equiv of BCl3
were required to accomplish the reaction, and conducting
(11) Upon addition of more than 1 equiv of BCl3 to a solution of 20,
the reaction mixture immediately changes from colorless to a dark
green-blue, an observation that could be used for in situ confirmation
of BCl3 concentration.
(12) Bhatt, M. V. J . Organomet. Chem. 1978, 156, 221-226.
(13) Felix, A. M.; Heimer, E. P.; Lambros, T. J .; Tzougraki, X. C.;
Meienhofer, J . J . Org. Chem. 1978, 43, 4194-4196.
(10) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett.
1981, 22, 899-902.
5994 J . Org. Chem., Vol. 68, No. 15, 2003

New Constrained Raloxifene Analogues
SCHEME 5. Syn th esis of An a logu e 3 by a
Com bin ed Su zu k i-Miya u r a /Regioselective
Dir ected Rem ote Meta la tion Str a tegya
°C/5 h) provided 3 in 59% yield, thus concluding the
synthetic objective in an 11-step protocol and ∼4.7%
overall yield based on 8c.
In summary, the synthesis of three novel heterocylic
analogues 2a ,b and 315 of the drug Raloxifene (1) has
been accomplished by routes involving key directed
remote metalation (DreM) and electrophilic cyclization
strategies combined with Suzuki-Miyaura cross-coupling
processes. The cyclization precursors 25 and 13c (or 27)
underwent LDA-mediated regioselective ring closure to
give 2b and 3, respectively (paths c and e, Figure 2), while
treatment of 19 with BCl3 induced a Friedel-Crafts
cyclization (path a) followed by concomitant global depro-
tection to give 2a . In view of the efficient and contra-
Friedel-Crafts nature of the anionic reactions, the
broader use of DreM as a pivotal strategy for the
construction of complex aromatics and heteroaromatics
may be anticipated.
Exp er im en ta l Section
All reactions requiring anhydrous conditions were carried
out using syringe-septum cap techniques in flame-dried
glassware under a positive argon/nitrogen atmosphere. Sol-
vents and anhydrous liquid reagents were purified and dried
according to established procedures.
a
Meth yl 4-Hyd r oxy-6-iso-p r op oxy-2-(4-iso-p r op oxyp h e-
n yl)ben zo[b]th iop h en e-3-ca r boxyla te (17). To a cooled
(-78 °C) solution of 13a (4.74 g, 10.71 mmol) in CH2Cl2 (200
mL) was added slowly BCl3 (11.2 mL, 1 M solution in heptane).
The reaction mixture was stirred for 1 h at -78 °C, warmed
to 0 °C over 30 min, and stirred for an additional 30 min, and
the reaction was quenched with saturated Rochell’s salt
solution (100 mL). After 1 h stirring at room temperature,
EtOAc (200 mL) was added and the organic layer was
separated, dried (Na2SO4) and concentrated in vacuum. The
resulting residue was passed through a short column (silica
gel, EtOAc-hexanes 1:4) affording 17 (4.10 g, 10.24 mmol, 96%
yield) as a pale yellowish solid: mp 129-130 °C (hexanes); IR
(KBr) υmax 1654, 1614, 1557, 1459, 1363, 1284, 1216, 1117,
Reagents and conditions: (a) BCl3, DCM, 0 °C to rt, 75% (27),
95% (29); (b) LDA, THF, 0 °C to rt, 65%; (c) LDA, THF, 0 °C to
reflux, 79%; (d) Tf2O, Py, 0 °C to rt, 61%; (e) 16, DME-2 M
Na2CO3, 5 mol % Pd(PPh3)4, reflux, 93%; (f) NaSEt, DMF, 100 °C,
59%.
The synthesis of analogue 3 commenced with 13c and
implemented two variations of the LDA-induced anionic
cyclization,3b both of which delivered the key intermedi-
ate 29 (Scheme 5). In the first variant, exposure of 13c
to 3 equiv of LDA (THF/0 °C to room temperature/3 h)
cleanly furnished the 10H-benzo[b]indeno[2,1-d]thiophen-
10-one 28 in 65% yield after recrystallization (Scheme
5, Z ) Me). Proximity of the C-10-(CdO) and the 9-(OMe)
groups resulted in a high-yielding BCl3-induced regiose-
lective demethylation10 to give compound 29. The second
variant of the DreM reaction3b was conducted on the
corresponding phenol 27, obtained similarly to 29 by
selective C-4 demethylation of 13c with BCl3.10 In the
case of 27, the use of 4 equiv of LDA at higher reaction
temperatures (THF/reflux/5 h) was found to be obligatory
to achieve good conversion, presumably due to internal
complexation of neighboring OZ (Z ) Li) and CONEt2
groups. However, these admittedly harsh conditions gave
29 in 79% yield. With the synthesis of 29 achieved by
two different routes, qualitative NOE studies were
performed to confirm the positions of two methoxy and
phenolic functionalities. Irradiation of both methoxy
groups with the center at δ 3.78 ppm showed a clear NOE
effect with protons H1 (δ 6.97), H3 (δ 6.89), H6 (δ 7.12),
and H8 (δ 6.43), thus unequivocally establishing the
substitution pattern of 29.
1
1013, 951 cm-1; H NMR (250 MHz, CDCl3) δ 11.11 (s, 1H),
7.32-7.26 (m, 2H), 6.94-6.87 (m, 2H), 6.79 (d, J ) 2.1 Hz,
1H), 6.56 (d, J ) 2.1 Hz, 1H), 4.66-4.53 (m, 2H), 3.65 (s, 3H),
1.39-1.34 (comp, 12H); 13C NMR (63 MHz, CDCl3) δ 168.3,
158.4, 157.7, 154.1, 152.0, 141.1, 130.5, 126.7, 120.3, 120.2,
115.2, 102.9, 98.9, 70.4, 70.0, 52.4, 22.1 (2), 22.0 (2); EI MS
(m/z, relative intensity) 402 (M+ + 2, 5), 401 (M+ + 1, 14), 400
(M+, 59), 326 (16), 285 (18), 284 (100), 283 (10), 255 (13); EI
HRMS (calcd for C22H24O5S) 400.1344, found 400.1342. Anal.
Calcd for C22H24O5S: C, 65.98; H, 6.04; S, 8.01. Found: C,
66.20; H, 6.13; S, 8.07.
Meth yl 6-iso-P r op oxy-2-(4-iso-p r op oxyp h en yl)-4-{[(tr i-
flu or om eth yl)su lfon yl]oxy}ben zo[b]-th ioph en e-3-car box-
yla te (18). To a cooled (ice bath) solution of 17 (4.00 g, 10.00
mmol) and NEt3 (2.80 mL, 20.00 mmol) in CH2Cl2 (150 mL)
was slowly added Tf2O (2.0 mL, 12.00 mmol). The reaction
mixture was stirred for 30 min at the ice bath temperature
and then for an additional 30 min at room temperature,
washed with H2O (200 mL), dried (Na2SO4), and concentrated
in a vacuum. The resulting residue was purified by column
chromatography (silica gel, EtOAc-hexanes 1:9) to give 18
(4.42 g, 8.30 mmol, 83% yield) as colorless needles: mp 119-
120 °C (hexanes); IR (KBr) υmax 2985, 1724, 1613, 1536, 1500,
Triflation of 29 under typical conditions (Tf2O/pyridine)
afforded the dark-red benzoindenothiophenone 30, which
was subjected to standard Suzuki-Miyaura conditions
using 1.5 equiv of coupling partner 16 to afford 31 in 93%
yield. Demethylation of 31 with NaSEt14 in DMF (100
(15) Compounds 2a , 2b, and 3 were tested in an estrogen receptor
(ER) binding assay to determine their ability to displace 3H-estradiol
at the ERR and ERâ receptors. For a complete description of the assay
details, see: Wallace, O. B. PCT Int. App. WO 0294788, 2002. While
2a and 2b showed no binding affinity at either receptor (up to 10 uM),
3 demonstrated some binding affinity at both receptors: Ki ERR ) 82.6
( 4.6 nM.; Ki ERâ ) 274 ( 17 nM.
(14) Feutrill, G. I.; Mirrington, R. N. Aust. J . Chem. 1972, 25, 1719-
1729, 1731-1735.
J . Org. Chem, Vol. 68, No. 15, 2003 5995

Kalinin et al.
1466, 1427, 1278, 1231, 1139, 1107, 1007 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.44 (d, J ) 8.8 Hz, 2H), 7.24 (d, J ) 2.0 Hz,
1H), 7.00 (d, J ) 2.0 Hz, 1H), 6.92 (d, J ) 8.8 Hz, 2H), 4.65-
4.54 (m, 2H), 3.83 (s, 3H), 1.38 (d, J ) 6.0 Hz, 6H), 1.37 (d, J
) 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 165.7, 158.8, 155.7,
for C21H12O4S + 0.5H2O: C, 68.28; H, 3.55; S, 8.68. Found:
C, 68.79; H, 3.67; S, 8.82.
The MeOH fraction was acidified with concentrated HCl and
evaporated to dryness, and the resulting solid residue was
redissolved in MeOH. Et2O was added, and the resulting
precipitate was collected and washed (acetone, Et2O) to give
hydrochloride monohydrate 2a (328 mg, 0.624 mmol, 56%
yield) as a yellow-orange solid: mp > 300 °C (dec); IR (KBr)
1
144.7, 143.7, 142.2, 130.1, 124.4, 121.6, 118.6 (q, J C-F ) 321
Hz), 115.8, 108.7, 106.8, 70.0, 52.7, 22.0 (2), 21.8 (2); EI MS
(m/z, relative intensity) 534 (M+ + 2, 10), 533 (M+ + 1, 20),
532 (M+, 76), 501 (8), 447 (8), 400 (31), 399 (100), 357 (71),
315 (89), 286 (22), 284 (30), 255 (17), 171 (11); EI HRMS (calcd
for C23H23O7F3S2) 532.0837, found 532.0811.
υmax 3680-2400 (br), 1630, 1607, 1487, 1436, 1346, 1279, 1225,
1208, 1174, 1120 cm-1; 1H NMR (250 MHz, DMSO-d6) δ 10.90
(br s, 1H, concentration-dependent δ; exchange with D2O),
10.23 (s, 1H, exchange with D2O), 10.16 (s, 1H, exchange with
D2O), 8.23 (d, J ) 8.8 Hz, 1H), 7.92 (d, J ) 1.4 Hz, 1H), 7.84
(d, J ) 2.0 Hz, 1H), 7.77 (d, J ) 8.6 Hz, 2H), 7.55 (d, J ) 1.4
Hz, 1H), 7.18 (dd, J ) 8.8, 2.0 Hz, 1H), 6.89 (d, J ) 8.6 Hz,
2H), 4.68 (br s, 2H), 3.53 (br s, 4H), 3.03 (br s, 2H), 2.39 (s,
1H, exchange with D2O), 1.82 (br s, 6 H), 1.68 (br s, 1H), 1.39
(br s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 161.5, 159.4,
156.4, 154.8, 137.1 (2), 131.3, 130.3, 129.5, 127.2, 126.7, 123.1,
122.3, 116.0, 115.0, 110.3, 108.6, 107.5, 62.7, 54.5, 52.5, 22.3,
21.2; EI MS (m/z, relative intensity) (M+ not registered), 447
(53), 446 (100), 260 (5), 223 (12), 184 (7), 168 (15), 141 (15),
115 (14); ES HRMS (calcd for C28H26NO4S - Cl) 472.1583,
found 472.1574.
Meth yl 6-iso-P r op oxy-2-(4-iso-p r op oxyp h en yl)-4-[3-(2-
p ip er id in oeth oxy)p h en yl]ben zo[b]-th iop h en e-3-ca r box-
yla te (19). To a degassed solution of 18 (1.065 g, 2.00 mmol),
16 (0.795 g, 2.40 mmol), and Pd(PPh3)4 (46 mg, 0.04 mmol) in
DME (25 mL) was added 2 M Na2CO3 solution (20 mL), and
the reaction mixture was refluxed under argon for 30 min,
cooled to room temperature, and concentrated in vacuum to
remove most of the DME. The formed residue was partitioned
between Et2O (100 mL) and H2O (50 mL), and the whole was
stirred for 30 min. The organic layer was separated, and the
aqueous layer was extracted with Et2O (2 × 50 mL). The
combined extract was dried (Na2SO4) and concentrated in
vacuum, and the resulting residue was purified by column
chromatography (silica gel, EtOAc-hexanes-TEA 1:1:0.05) to
give 19 (1.119 g, 1.90 mmol, 95% yield) as a colorless glass:
IR (film) υmax 2975, 2933, 1726, 1591, 1494, 1446, 1246, 1206,
2-iso-P r op oxy-5-(4-iso-p r op oxyp h en yl)-7-(2-p ip er id i-
n oet h oxy)-6H-p h en a n t h r o[1,10-bc]t h iop h en -6-on e (21).
To a cooled (-78 °C) solution of 19 (346 mg, 0.589 mmol) in
THF (6 mL) was cannulated a solution of LDA [2.94 mmol;
prepared from HN(i-Pr)2 (0.41 mL) and n-BuLi (2.10 mL, 1.38
M in hexane)] in THF (4 mL). The mixture was stirred for 30
min at -78 °C followed by 1 h at 0 °C and 2 h at room
temperature before the reaction was quenched with saturated
NH4Cl solution (20 mL). The mixture was extracted with Et2O
(4 × 20 mL); the combined organic extract was evaporated in
vacuum, and the resulting residue was redissolved in Et2O,
loaded on silica gel, and purified by column chromatography
(silica gel, EtOAc-hexanes-NEt3 70:25:5) followed by recrys-
tallization to afford 21 (108 mg, 0.194 mmol, 33% yield) as
yellow crystals: mp 159-161 °C (hexanes); IR (KBr) υmax 2930,
1648, 1591, 1478, 1438, 1252, 1182, 1107, 1027 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.87 (d, J ) 8.9 Hz, 2H), 7.80 (d, J ) 8.1
Hz, 1H), 7.69 (d, J ) 1.9 Hz, 1H), 7.57 (t, J ) 8.1 Hz, 1H),
7.34 (d, J ) 1.9 Hz, 1H), 7.06 (d, J ) 8.1 Hz, 1H), 6.94 (d, J )
8.9 Hz, 2H), 4.75-4.60 (m, 2H), 4.27 (t, J ) 6.5 Hz, 2H), 2.92
(t, J ) 6.5 Hz, 2H), 2.60-2.50 (m, 4H), 1.65-1.55 (m, 4H),
1.55-1.45 (m, 2H), 1.42 (d, J ) 6.0 Hz, 6H), 1.39 (d, J ) 6.0
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 179.7, 161.7, 159.2,
156.5, 154.4, 137.9, 137.5, 133.3, 131.4, 131.3, 127.9, 125.2,
124.8, 123.5, 115.5, 115.1, 114.0, 111.5, 107.9, 71.2, 69.9, 67.8,
57.6, 55.2, 26.0, 24.2, 22.1 (2); EI MS (m/z, relative intensity)
556 (M+, 2), 555 (M - 1+, 5), 446 (10), 445 (28), 444 (77), 402
(12), 361 (16), 360 (54), 359 (35). Anal. Calcd for (C34H37NO4S)
C, 73.48; H, 6.71; N, 2.52. Found: C, 73.29; H, 6.80; N, 2.46.
N,N-Dieth yl 6-(Ben zyloxy)-2-[4-(ben zyloxy)p h en yl]-4-
h ydr oxyben zo[b]th ioph en e-3-car boxam ide (22). To a cooled
(-78 °C) solution of 13b (1.70 g, 2.71 mmol) in CH2Cl2 (30 mL)
was slowly added 9-Br-BBN (2.84 mL, 1 M CH2Cl2 solution).
The solution was slowly allowed to warm to room temperature
(∼6 h) and the reaction sequentially slowly quenched with
saturated NaHCO3 solution (30 mL) and ethanolamine (0.33
g, 5.42 mmol). This mixture was stirred for an additional 2 h
and extracted with CH2Cl2 (3 × 75 mL). The combined organic
extract was concentrated in vacuum, and the resulting solid
residue was recrystallized from MeOH to furnish 22 (1.19 g,
2.22 mmol, 82% yield) as a colorless microfine crystalline
solid: mp 218 °C (MeOH); IR (KBr) υmax 3168 br, 1611, 1570,
1500, 1422, 1378, 1289, 1243, 1180, 1133, 1020 cm -1; 1H NMR
(400 MHz, CDCl3) δ 8.50 (br s, 1H), 7.50-7.30 (m, 12H), 7.01
(d, J ) 8.7 Hz, 2H), 6.94 (d, J ) 1.2 Hz, 1H), 6.55 (s, 1H), 5.10
(s, 4H), 3.85-3.75 (m, 1H), 3.35-3.15 (m, 2H), 2.85-2.75 (m,
1H), 1.10 (t, J ) 7.0 Hz, 3H), 0.63 (t, J ) 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 169.9, 159.4, 158.3, 153.3, 141.2,
1
1160, 1112 cm-1; H NMR (500 MHz, CDCl3) δ 7.41 (d, J )
8.5 Hz, 2H), 7.28 (t, J ) 7.9 Hz, 1H), 7.25 (d, J ) 2.3 Hz, 1H),
6.96 (d, J ) 7.5 Hz, 1H), 6.94-6.88 (m, 3H), 6.86 (d, J ) 8.5
Hz, 2H), 4.65-4.58 (m, 1H), 4.58-4.51 (m, 1H), 4.20-4.10 (m,
2H), 3.07 (s, 3H), 2.79-2.70 (m, 2H), 2.55-2.45 (m, 4H), 1.63-
1.55 (m, 4H), 1.45-1.36 (m, 2H), 1.36 (d, J ) 6.0 Hz, 6H), 1.33
(d, J ) 6.1 Hz, 6H); 13C NMR (63 MHz, CDCl3) δ 166.4, 158.6,
158.4, 155.2, 142.9, 142.3, 141.1, 138.9, 130.3, 129.7, 129.1,
125.2, 124.9, 121.0, 118.2, 115.5, 114.4, 114.1, 106.3, 70.6, 69.8,
65.8, 57.8, 54.9, 51.4, 25.7, 24.0, 21.9 (4); EI MS (m/z, relative
intensity) 588 (M+ + 1, 5), 587 (M+, 14), 586 (M+ - 1, 1), 476
(9), 392 (11), 345 (6), 112 (5), 99 (16), 98 (100); EI HRMS (calcd
for C35H41NO5S) 587.2705, found 587.2731.
2-Hydr oxy-5-(4-h ydr oxyph en yl)-9-(2-piper idin oeth oxy)-
6H-p h en a n th r o[1,10-bc]th iop h en -6-on e Hyd r och lor id e
(2a ) a n d 2,7-Dih yd r oxy-5-(4-h yd r oxyp h en yl)-6H-p h en a n -
th r o[1,10-bc]th iop h en -6-on e (20). To a cooled (ice bath)
solution of 19 (657 mg, 1.12 mmol) in CH2Cl2 (45 mL) was
added slowly BCl3 (5.80 mL, 1 M solution in heptane). The
reaction mixture was stirred for 1 h at 0 °C; the reaction was
slowly quenched with saturated NaHCO3 solution (30 mL), and
the whole was extracted with 1:1 EtOAc-THF mixture (5 ×
75 mL). The combined organic extract was concentrated in
vacuum, and the resulting solid residue was dissolved in 1:1
MeOH-acetone mixture (∼100 mL) and treated with 5 g of
Florisil. The resulting suspension was evaporated in vacuum,
and the Florisil absorbent was placed in a column and eluted
sequentially with acetone (∼200 mL) and MeOH (∼200 mL).
The acetone fraction was evaporated in vacuum and redis-
solved in acetone, and the resulting precipitate was collected
and combined with the MeOH fraction. The filtrate was
concentrated in a vacuum. The resulting residue was purified
by column chromatography (silica gel, hexanes-EtOAc 1:1 to
EtOAc) to give 20 as a brown-red solid (62 mg, 0.172 mmol,
15% yield): mp > 300 °C; IR (KBr) υmax 3353 (br), 1606, 1593,
1
1503, 1448, 1356, 1256, 1175, 822 cm-1; H NMR (250 MHz,
DMSO-d6) δ 13.87 (s, 1H, exchange with D2O), 10.12 (br s, 2H,
exchange with D2O), 7.85-7.76 (m, 4H), 7.69 (t, J ) 8.0 Hz,
1H), 7.54 (d, J ) 1.6 Hz, 1H), 6.98 (d, J ) 8.1 Hz, 1H), 6.90 (d,
J ) 8.6 Hz, 2H); 13C NMR (63 MHz, DMSO-d6) δ 184.2, 164.3,
159.6, 157.6, 156.5, 137.0, 136.1, 135.9, 131.4, 128.5, 126.5,
122.9, 121.5, 116.7 (CH and C), 115.1, 113.8, 110.1, 108.9; EI
MS (m/z, relative intensity) 361 (M+ + 1, 24), 360 (M+, 100),
359 (M+ - 1, 65), 331 (10), 180 (8), 157 (11), 245 (5); EI HRMS
(calcd for C21H12O4S) 360.0456; found 360.0452. Anal. Calcd
5996 J . Org. Chem., Vol. 68, No. 15, 2003

New Constrained Raloxifene Analogues
138.2, 136.9, 136.5, 129.9, 128.7, 128.6, 128.2, 128.0, 127.5 (2),
126.3, 123.3, 122.4, 115.4, 102.2, 98.7, 70.4, 70.1, 43.7, 39.9,
13.2, 12.0; FAB MS (m/z, relative intensity) 540 (MH+ + 2, 1),
539 (MH+ + 1, 4), 538 (MH+, 11), 537 (MH+ - 1, 2), 392 (3),
391 (9), 277 (8), 185 (100), 167 (8), 149 (30), 132 (14), 113 (7);
ES HRMS (calcd for C33H32NO4S, M + 1) 538.2052, found
538.2055. Anal. Calcd for C33H31NO4S: C, 73.72; H, 5.81; N,
2.61. Found: C, 73.47; H, 5.86; N, 2.65.
ature for 3 days and then passed through a small pad of silica,
which was then washed with EtOH (∼15 mL). The filtrate was
concentrated in vacuum, ensuring complete removal of sol-
vents, and the residue was redissolved in CH2Cl2 (5 mL). To
this stirred solution was added i-Pr2EtN (0.39 mL, 2.22 mmol)
followed by triisopropylsilyl chloride (0.31 mL, 1.48 mmol) and
then DMAP (70 mg, 0.057 mmol). The reaction mixture was
stirred for 4 h and diluted with saturated NH4Cl (5 mL), and
the whole was extracted with CH2Cl2 (2 × 20 mL), dried (Na2-
SO4), filtered, and concentrated in vacuum. The residue was
purified by column chromatography (silica gel, EtOAc-hex-
anes-NEt3 9:88:3) followed by recrystallization to give 25 as
a colorless solid (0.21 g, 0.245 mmol, 82% yield): mp 116-
118 °C (acetone); IR (film) υmax 2941, 2867, 1631, 1603, 1584,
1495, 1443, 1388, 1265 cm-1; 1H NMR (500 MHz, 80 °C, DMF-
d7) δ 7.57 (d, J ) 8.3 Hz, 2H), 7.53 (s, 1H), 7.28 (t, J ) 7.7 Hz,
1H), 7.00-6.90 (comp, 5H), 6.85 (s, 1H), 4.28-4.20 (m, 1H),
4.20-4.33 (m, 1H), 3.10-2.95 (m, 3H), 2.78-2.70 (m, 3H),
2.70-2.60 (m, 1H), 2.55-2.49 (m, 4H), 1.58-1.51 (m, 4H),
1.45-1.27 (m, 8H), 1.17 (d, J ) 7.3 Hz, 18H), 1.13 (d, J ) 7.3
6-(Ben zyloxy)-2-[4-(ben zyloxy)p h en yl]-3-[(d ieth yla m i-
n o)ca r bon yl]ben zo[b]th iop h en -4-yl Tr iflu or om eth a n e-
su lfon a te (23). To a cooled (ice bath) solution of 22 (0.52 g,
0.97 mmol) and NEt3 (0.27 mL, 1.94 mmol) in CH2Cl2 was
slowly added triflic anhydride (0.19 mL, 1.16 mmol). The
reaction mixture was stirred for 1.5 h at 0 °C, warmed to room
temperature, washed with cold H2O, dried (Na2SO4), and
concentrated in vacuum. The resulting residue was purified
by column chromatography (silica gel, EtOAc-hexanes 1:4)
followed by recrystallization to give 23 (0.55 g, 0.82 mmol, 85%
yield) as colorless light needles: mp 150 °C (EtOAc-hexanes);
IR (KBr) υmax 2982, 1627, 1536, 1499, 1458, 1426, 1274, 1216,
1139, 1104, 1023, 814 cm -1; 1H NMR (500 MHz, CDCl3) δ 7.57
(d, J ) 8.8 Hz, 2H), 7.49-7.30 (m, 11H), 7.07 (d, J ) 1.9 Hz,
1H), 6.95 (d, J ) 8.8 Hz, 2H), 5.12 (s, 2H), 5.10 (s, 2H), 4.05-
3.95 (m, 1H), 3.12-2.91 (m, 3H), 1.11 (t, J ) 7.2 Hz, 3H); 0.65
(t, J ) 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.3, 159.4,
156.5, 144.2, 142.7, 139.3, 136.5, 135.8, 130.0, 128.8, 128.6,
Hz, 18H), 0.80 (t, J ) 7.0 Hz, 3H), 0.61 (t, J ) 7.0 Hz, 3H); 13
C
NMR (125 MHz, 80 °C, DMF-d7) δ 166.2, 158.8, 157.0, 153.4,
141.6, 141.4, 140.1, 138.0, 130.9, 130.5, 129.8, 128.9, 127.4,
122.2, 121.6, 120.5, 116.7, 114.7, 111.6, 67.0, 58.4, 55.3, 44.2,
39.8, 26.5, 24.7, 18.00, 17.9, 13.6, 13.12, 13.07, 12.8; FAB MS
(m/z, relative intensity) 859 (MH+ + 1, 3), 858 (MH+, 6), 857
(MH+ - 1, 8), 146 (5), 133 (24), 112 (100); ES HRMS (calcd for
C50H77N2O4SSi2, M + 1) 857.5142, found 857.5147. Anal. Calcd
for C50H76N2O4SSi2: C, 70.04; H, 8.93; N, 3.27. Found: C,
70.09; H, 8.89; N, 3.25.
1
128.4, 128.1, 127.6, 127.5, 125.4, 125.0, 124.7, 119.3 (q, J C-F
) 319 Hz), 115.2, 107.5, 105.7, 71.1, 70.1, 43.7, 39.7, 13.4, 12.4;
FAB MS (m/z, relative intensity) 671 (MH+ + 1, 4), 670 (MH+,
9), 669 (M+ - 1, 2), 391 (8), 285 (16), 284 (73), 185 (76), 148
(45), 132 (100), 114 (18); ES HRMS (calcd for C34H31F3NO6S2,
7-(2-P iper idin oeth oxy)-2-[(1,1,1-tr i-iso-pr opylsilyl)oxy]-
5-4-[(1,1,1-tr i-iso-p r op ylsilyl)oxy]p h en yl-6H-p h en a n th r o-
[1,10-bc]th iop h en -6-on e (26). To a cooled solution (-40 °C)
of 25 (300 mg, 0.35 mmol) in THF (5 mL) was slowly added a
solution of LDA (1.50 mL, 1.05 mmol, 0.70 M in THF). The
solution was allowed rise to 0 °C over 5 h; the reaction was
quenched with saturated NHCl4 (15 mL), and the whole was
extracted with EtOAc (3 × 20 mL). The combined organic
extract was dried (Na2SO4) and subjected to filtration, and the
filtrate was concentrated in vacuum. The resulting residue was
purified by column chromatography (silica gel, EtOAc-hex-
anes-NEt3 40:60:2.5) to give 26 as a bright yellow glass (192
mg, 0.245 mmol, 70% yield); IR (film) υmax 2942, 2866, 1654,
1591, 1464, 1267 cm-1; 1H NMR (300 MHz, acetone-d6) δ 7.95
(d, J ) 8.0 Hz, 1H), 7.88-7.83 (m, 3H), 7.66 (t, J ) 8.2 Hz,
1H), 7.60 (d, J ) 1.8 Hz, 1H), 7.21 (d, J ) 8.2 Hz, 1H), 7.01 (d,
J ) 8.7 Hz, 2H), 4.20 (t, J ) 5.8 Hz, 2H), 2.77 (t, J ) 5.8 Hz,
2H), 2.63-2.50 (m, 4H); 1.60-1.45 (m, 4H), 1.45-1.30 (m, 8H),
1.18 (d, J ) 7.3, 18H), 1.16 (d, J ) 7.3 Hz, 18H); 13C NMR (75
MHz, acetone-d6) δ 179.5, 162.6, 158.3, 155.6, 154.2, 138.3,
138.2, 134.5, 132.25, 132.22, 128.8, 127.0, 125.8, 124.1, 1201,
116.3, 115.2, 114.6, 113.4, 69.4, 58.5, 55.9, 27.0, 25.1, 18.4, 18.3,
13.4; FAB MS (m/z, relative intensity) 785 (MH+ + 1, 3), 784
(M+, 5), 112 (100); ES HRMS (calcd for C46H66NO4SSi2, M +
1) 784.4251, found 784.4251.
M + 1) 670.1545, found 670.1547. Anal. Calcd for C34H30
-
NO6S2: C, 60.97; H, 4.51; N, 2.09. Found: C, 60.92; H, 4.40;
N, 2.12.
N,N-Dieth yl 6-(Ben zyloxy)-2-[4-(ben zyloxy)p h en yl]-4-
[3-(2-piper idin oeth oxy)ph en yl]ben zo[b]-th ioph en e-3-car -
boxa m id e (24). To a solution of 23 (0.635 g, 0.95 mmol), 16
(0.315 g, 1.11 mmol), and Pd(PPh3)4 (55 mg, 0.05 mmol) in
DME (15 mL) was added 2 M Na2CO3 solution (8 mL). The
mixture was refluxed for 3 h, cooled to room temperature, and
concentrated in vacuum to remove most of the DME; the
resulting slurry was partitioned between Et2O (40 mL) and
H2O (20 mL), and the whole was stirred for 30 min. The
organic layer was separated, and the aqueous layer was
extracted with Et2O (3 × 30 mL). The combined extract was
dried (Na2SO4) and concentrated in vacuum, and the resulting
residue was purified by column chromatography (silica gel,
EtOAc-hexanes-NEt3 3:7:0.06) to give 24 (0.55 g, 0.76 mmol,
80% yield) as a colorless glass; IR (film) υmax 2936, 1633, 1496,
1452, 1239,1026 cm-1; 1H NMR (500 MHz, acetone-d6) δ 7.60
(d, 1H, J ) 2.4 Hz), 7.60-7.56 (m, 2H), 7.51 (d, 2H, J ) 7.3
Hz), 7.46 (d, 2H, J ) 7.2 Hz), 7.41-7.28 (comp, 6H), 7.23 (t,
1H, J ) 7.9 Hz), 7.04 (d, 2H, J ) 8.8 Hz), 6.91 (d, 1H, J ) 2.4
Hz), 6.92-6.85 (br m, 3H), 5.24 (s, 2H), 5.14 (s, 2H), 4.35-
4.15 (br m, 1H), 4.12-4.05 (m, 1H), 3.05-2.90 (m, 2H), 2.85-
2.40 (m, 8H), 1.55-1.50 (m, 4H), 1.42-1.35 (m, 2H), 0.75 (t,
3H, J ) 7.2 Hz), 0.55 (t, 3H, J ) 7.2 Hz); 13C NMR (125 MHz,
acetone-d6) δ 165.6, 159.1, 158.1, 156.1, 141.1, 140.8, 139.6,
137.3, 137.2, 129.9, 129.0, 128.44, 128.40, 127.84, 127.79,
127.63, 127.59, 126.4, 117.4 (2), 115.5, 114.9, 105.2, 70.0, 69.6,
65.9, 58.0, 54.8, 43.9, 39.6, 26.0, 24.2, 13.3, 12.5; FAB MS (m/
z, relative intensity) 726 (MH+ + 1, 4), 725 (MH+, 7), 635 (2),
369 (5), 277 (22), 185 (100), 167 (6), 133 (11), 112 (52); ES
2-Hydr oxy-5-(4-h ydr oxyph en yl)-7-(2-piper idin oeth oxy)-
6H-p h en a n th r o[1,10-bc]th iop h en -6-on e (2b). To a stirred
solution of 26 (200 mg, 0.267 mmol) in THF (3 mL) was added
TBAF (0.58 mmol, 1 M solution in THF), which was ac-
companied by an immediate color change to a dark violet. The
mixture was stirred at room temperature for 2 h and concen-
trated in vacuum without heating, and the resulting residue
was treated with MeOH (10 mL) and H2O (10 mL). The formed
red precipitate was collected by filtration and washed succes-
sively with H2O (2 × 10 mL), 1% aq NH4OH (5 mL), H2O (2 ×
10 mL), and acetone (2 × 5 mL). Drying in a vacuum gave a
monohydrate of 2b (108 mg, 0.229 mmol, 86% yield) as a red-
brown solid: mp > 180 °C sublm; IR (KBr) υmax 3435 br, 2933
br, 1708, 1591, 1453 br, 1350, 1259, 1169 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 10.30-9.50 (br s, 2H), 7.89 (d, J ) 7.9 Hz,
1H), 7.74-7.62 (comp, 4H), 7.42 (d, J ) 1.2 Hz, 1H), 7.20 (d,
J ) 8.2 Hz, 1H), 6.86 (d, J ) 8.6 Hz, 2H), 4.17 (t, J ) 5.8 Hz,
HRMS (calcd for
725.3399.
C46H49N2O4S, M + 1) 725.3413, found
N,N-Dieth yl 4-[3-(2-P ip er id in oeth oxy)p h en yl]-6-[(1,1,1-
tr i-iso-p r op ylsilyl)oxy]-2-4-[(1,1,1-tr i-iso-p r op ylsilyl)oxy]-
p h en ylben zo[b]th iop h en e-3-ca r boxa m id e (25). To a so-
lution of 24 (0.22 g, 0.30 mmol) and 10% w/w Pd-C (0.66 g,
∼30% substrate by weight) in a mixture of 3:2 EtOH-HOAc
(5 mL) was added 1,4-cyclohexadiene (0.14 mL, 1.50 mmol).
The reaction mixture was allowed to stir at ambient temper-
J . Org. Chem, Vol. 68, No. 15, 2003 5997

Kalinin et al.
2H), 3.40-3.05 (br s, 4H), 2.73 (t, J ) 5.8 Hz, 2H), 1.54-1.45
(m, 4H), 1.42-1.33 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
179.5, 161.9, 159.8, 157.1, 153.3, 137.9, 137.7, 134.6, 131.8,
130.1, 128.0, 124.9, 124.3, 123.5, 116.3, 115.9, 115.2, 110.7,
109.1, 68.7, 58.0, 55.3, 26.5, 24.7; FAB MS (m/z, relative
intensity) 474 (MH+ + 2, 4), 473 (MH+ + 1, 10) 472 (MH+,
24), 391 (4), 242 (7), 185 (31), 149 (16), 133 (35), 112 (100); ES
HRMS (calcd for C28H26NO4S, M + 1) 472.1582, found 472.1573.
Anal. Calcd for C28H25NO4S‚H2O: C, 68.69; H, 5.56; N, 2.86.
Found: C, 68.52; H, 5.33; N, 2.97.
mL) and n-BuLi (1.42 mL, 1.77 M in hexane)] in THF (5 mL)
was added a solution of 27 (243 mg, 0.63 mmol) in THF (15
mL). The reaction mixture was stirred at room temperature
(1 h), refluxed (5 h), and cooled in an ice bath, and the reaction
was quenched with saturated NH4Cl solution (20 mL). The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (4 × 15 mL). The combined organic
extract was concentrated in vacuum; the resulting residue was
dissolved in CH2Cl2, and this solution was passed through a
short silica gel column (CH2Cl2 eluent) to give 29 (156 mg, 0.50
mmol, 79% yield) as a black solid; mp 218-220 °C (EtOAc);
IR (KBr) υmax 3274 br, 2935, 2835, 1672, 1617, 1602, 1571,
1469, 1433, 1283, 1202, 1128, 1080, 1028 cm-1; 1H NMR (250
MHz, DMSO-d6) δ 9.08 (s, 1H), 7.32 (d, J ) 8.0 Hz, 1H), 7.12
(d, J ) 1.9 Hz, 1H), 6.97 (d, J ) 2.3 Hz, 1H), 6.89 (dd, J ) 8.0,
2.3 Hz, 1H), 6.43 (d, J ) 1.9 Hz, 1H), 3.80 (s, 3H), 3.76 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 186.5, 160.7, 159.4,
159.3, 152.3, 145.4, 137.5, 133.1, 130.4, 121.6, 116.4, 116.2,
111.7, 100.7, 98.7, 55.8, 55.6; EI MS (m/z, relative intensity)
314 (M+ + 2, 17), 313 (M+ + 1, 28), 312 (M+, 100), 298 (19),
297 (60), 269 (20), 254 (12), 226 (19), 198 (12), 156 (20), 117
(18); EI HRMS (calcd for C17H12O4S) 312.0456, found 312.0466.
F r om 28. To a cooled (ice bath) solution of 28 (825 mg, 2.53
mmol) in CH2Cl2 (50 mL) was added BCl3 (5.30 mL, 1 M
solution in heptane). The reaction mixture was stirred at 0
°C (15 min) and then at room temperature (24 h), and the
reaction was quenched with 5% NaHCO3 solution (50 mL). The
organic layer was separated, the aqueous layer was extracted
with CH2Cl2 (4 × 75 mL), and the combined organic extract
was dried (Na2SO4) and concentrated in vacuum. The resulting
residue was recrystallized from EtOAc to give 29 (749 mg,
2.399 mmol, 95% yield), which was shown by physical and
spectroscopic comparison to be identical to the material
obtained from 27.
N,N-Dieth yl 4-Hyd r oxy-6-m eth oxy-2-(4-m eth oxyp h e-
n yl)ben zo[b]th iop h en e-3-ca r boxa m id e (27). To a cooled
(ice bath) solution of 13c (1.199 g, 3.00 mmol) in CH2Cl2 (30
mL) was added a solution of BCl3 (6.10 mL, 1 M solution in
heptane). The reaction mixture was stirred at 0 °C (0.5 h), at
room temperature (3 h), and cooled in the ice bath and the
reaction quenched by slow addition of saturated Rochell’s salt
solution (30 mL). EtOAc (40 mL) was added, and the hetero-
geneous mixture was stirred for 2 h. The organic layer was
separated, and the aqueous layer was extracted with a mixture
of 4:1 EtOAc-CH2Cl2 (4 × 25 mL). The combined organic
extract was dried (Na2SO4), subjected to filtration, and evapo-
rated in vacuum. The resulting solid residue was recrystallized
to afford 27 (872 mg, 2.26 mmol, 75% yield) as pale yellow
crystals: mp 171-172 °C (EtOAc-hexanes); IR (KBr) υmax
3191 br, 1606, 1577, 1533, 1506, 1460, 1425, 1294, 1250, 1142,
1032 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.50 (s, 1H), 7.43 (d,
J ) 8.7 Hz, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 6.86 (d, J ) 2.1 Hz,
1H), 6.55 (d, J ) 2.1 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.86-
3.75 (m, 1H), 3.35-3.15 (m, 2H), 2.85-2.70 (m, 1H), 1.16 (t, J
) 7.1 Hz, 3H), 0.65 (t, J ) 7.1 Hz, 3H); 13C NMR (63 MHz,
CDCl3) δ 170.0, 160.2, 159.2, 153.2, 141.2, 137.9, 129.9, 126.0,
123.3, 122.2, 114.4, 101.4, 97.4, 55.6, 55.4, 43.7, 39.9, 13.2, 12.0;
EI MS (m/z, relative intensity) 387 (M+ + 2, 3), 386 (M+ + 1,
9), 385 (M+, 41), 314 (8), 313 (26), 312 (100), 297 (19), 282 (5),
2,7-Dim e t h oxy-10-oxo-10H -b e n zo[b]in d e n o[2,1-d ]-
th iop h en -9-yl Tr iflu or om eth a n esu lfon a te (30). To a cooled
(ice bath) solution of 29 (229 mg, 0.73 mmol) in pyridine (15
mL) was added Tf2O (0.19 mL, 1.10 mmol). The resulting
solution was stirred at 0 °C (0.5 h) and then at room
temperature (1 h) and cooled in the ice bath, and the reaction
was quenched with 50% citric acid solution (50 mL). CH2Cl2
(50 mL) was added, and the organic phase was separated, dried
(Na2SO4), and concentrated in a vacuum. The residue was
purified by column chromatography (CH2Cl2 eluent) to give
30 (199 mg, 0.45 mmol, 61% yield) as a red solid; mp 213-
214 °C (EtOAc); IR (KBr) υmax 1708, 1618, 1599, 1558, 1476,
1428, 1341, 1269, 1242, 1138, 1068, 1025, 961 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.24 (d, J ) 2.0 Hz, 1H), 7.12 (d, J ) 2.4
Hz, 1H), 7.05 (d, J ) 8.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1H),
6.77 (dd, J ) 8.0, 2.4 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 183.6, 167.4, 162.2, 155.7, 147.0,
269 (10), 242 (7), 241 (7), 129 (5); EI HRMS (calcd for C21H23
NO4S) 385.1348, found 385.1342. Anal. Calcd for C21H23
-
-
NO4S: C, 65.43; H, 6.01; N, 3.63; S, 8.32; Found: C, 65.36; H,
6.07; N, 3.60; S, 8.26.
2,7,9-tr im eth oxy-10H-ben zo[b]in d en o[2,1-d ]th iop h en -
10-on e (28). To a cooled (ice bath) solution of LDA [10.00
mmol; prepared from HN(i-Pr)2 (1.41 mL) and n-BuLi (7.00
mL, 1.43M in hexane)] in THF (25 mL) was added a solution
of 13c (1.336 g, 3.34 mmol) in THF (15 mL). The reaction
mixture was stirred at 0 °C (0.5 h) and then at room
temperature (2.5 h) and cooled in the ice bath, and the reaction
was quenched with saturated NH4Cl solution (50 mL). CH2-
Cl2 (20 mL) was added, and the reaction mixture was stirred
for 1 h, the organic phase was separated, and the aqueous
phase was extracted with a mixture of 4:1 EtOAc-DCM (4 ×
25 mL). The combined organic extract was concentrated in
vacuum, and the resulting residue was dissolved in CH2Cl2.
This solution was subjected to filtration; the filtrate was passed
through a silica gel column (CH2Cl2 eluent), and the red band
fraction was collected. Evaporation of the collected fraction
followed by recrystallization provided 28 (711 mg, 2.18 mmol,
65% yield) as deep red crystals; mp 185-186 °C (benzene-
MeOH); IR (KBr) υmax 1703, 1586, 1459, 1441, 1328, 1275,
1
144.2, 138.6, 129.4, 129.1, 123.5, 121.8, 118.8 (q, J C-F ) 322
Hz), 116.9, 111.6, 104.7, 57.5, 55.8; EI MS (m/z, relative
intensity) 446 (M+ + 2, 7), 445 (M+ + 1, 12), 444 (M+, 51), 313
(19), 312 (48), 311 (100), 297 (41), 283 (18), 269 (11), 268 (40),
253 (15), 240 (15), 225 (17), 169 (8); EI HRMS (calcd for
C
18H11F3O6S2) 443.9949, found 443.9957. Anal. Calcd for
C18H11F3O6S2: C, 48.65; H, 2.50. Found: C, 48.91; H, 2.67.
1208, 1145, 1077, 1029 cm-1 1H NMR (250 MHz, CDCl3) δ
;
2,7-Dim eth oxy-9-[3-(2-p ip er id in oeth oxy)p h en yl]-10H-
ben zo[b]in d en o[2,1-d ]th iop h en -10-on e (31). To a stirred
suspension of 30 (603 mg, 1.36 mmol) and 16 (676 mg, 2.04
mmol) in a degassed DME-2 M Na2CO3 mixture (20:15 mL)
was added Pd(PPh3)4 (81 mg, 0.07 mmol), and the mixture was
refluxed for 2 h under argon and cooled to room temperature.
The organic phase was separated; the aqueous phase was
extracted with EtOAc (3 × 15 mL), and the combined organic
extract was evaporated in vacuum to give a residue that was
dissolved in EtOAc, dried (Na2SO4), subjected to filtration, and
then concentrated in vacuum. Purification of the residue by
column chromatography (EtOAc-hexanes-NEt3 1:1:0.05) gave
31 (631 mg, 1.26 mmol, 93% yield) as a red solid: mp 149-
150 °C (hexanes, note: very low solubility); IR (KBr) υmax 2930,
7.04 (d, J ) 2.4 Hz, 1H), 6.97 (d, J ) 8.0 Hz, 1H), 6.79 (d, J )
1.9 Hz, 1H), 6.72 (dd, J ) 8.0, 2.4 Hz), 6.44 (d, J ) 1.9 Hz,
1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H); 13C NMR (63 MHz,
CDCl3) δ 184.8, 160.9, 159.7, 159.0, 155.7, 145.3, 138.5, 133.8,
130.5, 119.7, 118.3, 115.7, 111.0, 98.0, 97.5, 55.8, 55.6 (2); EI
MS (m/z, relative intensity) 328 (M+ + 2, 13), 327 (M+ + 1,
21), 326 (M+, 100), 312 (17), 311 (62), 283 (11), 268 (19), 253
(11), 240 (6), 225 (9), 163 (9); EI HRMS (calcd for C18H14O4S)
326.0613, found 326.0615. Anal. Calcd for C18H14O4S: C, 66.24;
H, 4.32; S, 9.83; Found: C, 66.22; H, 4.36; S, 9.56.
9-Hyd r oxy-2,7-d im eth oxy-10H-ben zo[b]in d en o[2,1-d ]-
th iop h en -10-on e (29): F r om 27. To a cooled (ice bath)
solution of LDA [2.52 mmol; prepared from HN(i-Pr)2 (0.35
5998 J . Org. Chem., Vol. 68, No. 15, 2003

New Constrained Raloxifene Analogues
1708, 1591, 1560, 1473, 1433, 1284, 1223, 1090 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.36 (t, J ) 7.8 Hz, 1H), 7.23 (d, J ) 2.4
Hz, 1H), 7.05-6.89 (comp, 6H), 6.71 (dd, J ) 8.0, 2.4 Hz, 1H),
4.14 (t, J ) 6.2 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 2.78 (t, J )
6.2 Hz, 2H), 2.60-2.45 (m, 4H), 1.65-1.50 (m, 4H), 1.50-1.40
(m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 184.3, 162.1, 161.1,
158.3, 157.0, 145.1, 142.7, 139.0, 138.6, 133.8, 130.2, 128.6,
126.0, 121.8, 120.1, 116.8, 116.1, 115.6, 113.9, 110.7, 105.7,
65.8, 58.0, 55.7, 55.6, 55.0, 26.0, 24.2; EI MS (m/z, relative
intensity) 501 (M+ + 2, 2), 500 (M+ + 1, 6), 499 (M+, 19), 388
a blue powder (181 mg, 0.344 mmol, 59% yield): mp 180-185
°C (dec); IR (KBr) υmax 3680-2400 br, 1694, 1615, 1576 cm-1
;
1H NMR (250 MHz, DMSO-d6) δ 10.12 (s, 1H, exchange with
D2O), 9.98 (s, 1H, exchange with D2O), 9.97 (br s, 1H, exchange
with D2O), 7.37 (d, 1H, J ) 2.1 Hz), 7.33 (t, 1H, J ) 8.2 Hz),
7.17 (d, 1H, J ) 7.8 Hz), 7.05-6.90 (comp, 3H), 6.77 (d, 1H, J
) 2.1 Hz), 6.72-6.63 (comp, 2H), 4.37 (br s, 2H), 3.60-3.40
(br s, 4H), 3.32 (s, 1H, H2O), 3.15-2.85 (m, 2H), 1.90-1.60
(m, 5H), 1.50-1.25 (1H, m); 13C NMR (50 MHz, DMSO-d6) δ
184.0, 161.9, 159.3, 156.8, 154.9, 145.0, 142.6, 137.9, 137.6,
132.4, 128.8, 127.8, 123.7, 122.0, 121.1, 117.7, 117.6, 115.6,
113.9, 111.5, 108.4, 62.1, 54.6, 52.5, 22.3, 21.1; EI MS (m/z,
relative intensity) (as free amine: C28H25NO4S): (M+ not
registered), 447 (20), 446 (65), 326 (7), 312 (50), 297 (34), 269
(10), 111 (28), 98 (10). Anal. Calcd for C28H26ClNO4S+H2O:
C, 63.93; H, 5.37; N, 2.66; S, 6.10. Found: C, 63.44; H, 5.33;
N, 2.65; S, 6.13.
(11), 373 (5), 99 (10), 98 (100); EI HRMS (calcd for C30H29
NO4S) 499.1817, found 499.1796. Anal. Calcd for C30H29
-
-
NO4S: C, 72.12; H, 5.85; N, 2.80. Found: C, 72.31; H, 5.86;
N, 2.79.
2,7-Dih yd r oxy-9-[3-(2-p ip er id in oeth oxy)p h en yl]-10H-
ben zo[b]in den o[2,1-d]th ioph en -10-on e Hydr och lor ide (3).
To a cooled (ice bath) suspension of 31 (293 mg, 0.586 mmol)
and NaH (141 mg, 3.53 mmol, 60% w/w suspension in mineral
oil) in DMF (8 mL) was carefully added EtSH (0.26 mL, 3.53
mmol), which was accompanied by an intensive gas evolution.
The reaction mixture was stirred at 100-110 °C under an
argon atmosphere for 5 h, cooled to room temperature, and
diluted with EtOAc (20 mL), and the reaction was quenched
with saturated NH4Cl (10 mL). The organic layer was sepa-
rated; the aqueous layer was extracted with a mixture of 1:1
EtOAc-THF (4 × 20 mL), and the combined organic extract
was evaporated in vacuum. The resulting residue was redis-
solved in MeOH, and the solution was loaded on silica gel.
Column chromatography (silica gel, DCM-MeOH-NEt3 90:
5:5) afforded a solid that was redissolved in MeOH, and the
resulting solution was acidified with concentrated HCl. Solvent
evaporation in vacuum gave 3 hydrochloride monohydrate as
Ack n ow led gm en t. We are grateful to Eli Lilly and
Company, and particularly Dr. Homer Pierce, for the
incentive to undertake this synthetic work and for
financial support. We thank Dr. Marijan Stefinovic for
preliminary observations.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for synthesis of compounds 8-13, 15, and 16, copies
of NMR spectra of compounds 16, 19, 2a , 20, 21, 24-26, 2b,
31, and 3, and NOE experiment of compound 29. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O034325K
J . Org. Chem, Vol. 68, No. 15, 2003 5999