Short-step synthesis of droloxifene via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole

Article abstract of DOI:10.1016/j.tetlet.2005.12.117

A short-step route for the preparation of droloxifene has been established via the novel three-component coupling reaction among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and β-chlorophenetole, the successive installation of the side-chain part, and the base-induced migration of the double bond. The present synthesis of tetra-substituted ethylene moieties is a widely applicable strategy for producing a variety of SERMs (selective estrogen receptor modulators) and SARMs (selective androgen receptor modulators), such as tamoxifen, raloxifene, and other compounds that can lead to new drugs.

Full text of DOI:10.1016/j.tetlet.2005.12.117

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1631–1635
Short-step synthesis of droloxifene via the
three-component coupling reaction among aromatic aldehyde,
cinnamyltrimethylsilane, and b-chlorophenetole
Yoshiyuki Sano and Isamu Shiina*
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
Received 10 November 2005; revised 17 December 2005; accepted 21 December 2005
Available online 19 January 2006
Abstract—A short-step route for the preparation of droloxifene has been established via the novel three-component coupling reac-
tion among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and b-chlorophenetole, the successive installation of the side-
chain part, and the base-induced migration of the double bond. The present synthesis of tetra-substituted ethylene moieties is a
widely applicable strategy for producing a variety of SERMs (selective estrogen receptor modulators) and SARMs (selective andro-
gen receptor modulators), such as tamoxifen, raloxifene, and other compounds that can lead to new drugs.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
dration reaction of the resulting tertiary alcohols, which
are generated by the Grignard reaction of benzyl phenyl
ketones with aromatic nucleophiles,4 while (ii) the other
employs the reductive coupling reaction of unsymmetri-
cal aromatic carbonyl compounds using low-valent tita-
nium species to form the desired tetra-substituted
double bond.5 Although several approaches classified
into the above two typical strategies for the synthesis
of 1 have been developed, multiple synthetic steps are
required to produce 1 and its derivatives (Fig. 1).
Droloxifene (1), an estrogenic and anti-estrogenic active
compound, is known as one of the tamoxifen derivatives
used for the treatment and prevention of recurrence of
women’s breast cancer.1 It is also expected that 1 might
be a therapeutic drug candidate for postmenopausal and
senile osteoporosis, because 1 has a similar selective
activity to the estrogen receptor like that of 17b-
estradiol.2
NMe2
NMe2
Recently, we have established the novel three-compo-
nent coupling reaction, which can afford 3,4,4-trisubsti-
tuted butenes (B), through the allylation reaction of
aromatic aldehydes and successive Friedel–Crafts type
alkylation of the resulting homoallyl silyl ethers (A) with
aromatic nucleophiles (Ar3–H) in the presence of a
Lewis acid catalyst (Scheme 1).6 Furthermore, we have
shown that the synthetic intermediates (B) generated
via the three-component coupling reaction among benz-
aldehyde, cinnamyltrimethylsilane, and anisole could be
converted into tamoxifen, an anti-cancer drug widely
used all over the world, followed by the successive dou-
ble-bond migration reaction to form C corresponding to
the basic skeleton of tamoxifen.
O
O
HO
1′
1
Figure 1. Droloxifene (1), tamoxifen (2).
Two general synthetic pathways for the preparation of 1
have been reported according to the widely used tam-
oxifen synthesis;3 namely, (i) one of them includes the
formation of the double-bond functionalities by a dehy-
Initially, we planned to apply this strategy to the synthe-
sis of 1 as shown in Scheme 2. The three-component
coupling reaction among 3-pivaloyloxybenzaldehyde,
*
Corresponding author. Tel.: +81 3 5228 8263; fax: +81 3 3260
5609; e-mail: shiina@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.117

1632
Y. Sano, I. Shiina / Tetrahedron Letters 47 (2006) 1631–1635
O
+
Ar3
OSiMe3
Ar2
Ar3
Ar1
H
Ar3
H
Ar2
Ar2
Tamoxifen
derivatives
Ar1
Ar1
Ar1
Ar2
SiMe3
C
A
B
Three Component Coupling Reaction
Double bond migration
Scheme 1. A novel synthetic pathway to produce tamoxifen derivatives via the three-component coupling reaction.
OMe
OMe
OMe
O
i
ii
PivO
H
SiMe3
+
+
PivO
HO
OMe
OH
OTBS
OTBS
iv
iii
v
vi
DNBO
DNBO
DNBO
HO
DNB = 3,5-dinitrobenzoyl
OTBS
NMe2
OH
O
viii
ix
x
vii
1
PivO
PivO
PivO
Scheme 2. A preliminary synthetic route for the preparation of droloxifene using the three-component coupling reaction. Regents and conditions: (i)
HfCl4 (1 equiv), TMSOTf (0.5 equiv), 72%; (ii) t-BuOK, DMSO, 89%; (iii) 3,5-dinitrobenzoyl chloride, NaH, DMF, 85%; (iv) BBr3, CH2Cl2, 89%; (v)
TBSOTf, pyridine, 99%; (vi) K2CO3, MeOH, 86%; (vii) Pivaloyl chloride, NaH, DMF, 74%; (viii) KF, HBr, DMF, quant.; (ix) N,N-
dimethylaminoethyl chloride, K2CO3, acetone–H2O, 46%; (x) MeLi, THF, 61%.5
cinnamyltrimethylsilane, and anisole proceeded as well
as the case for the synthesis of tamoxifen, and the corre-
sponding 3,4,4-trisubstituted butene was obtained in a
satisfactory yield. However, the chemoselective installa-
tion of the N,N-dimethylaminoethyl side chain to the
framework of 1 required a complicated roundabout
pathway due to the existence of a deprotecting step for
cleaving the O-methyl group that originated from the
anisole moiety under the severe reaction conditions.
with a secondary dialkylamine before carrying out the
olefin migration promoted by the basic catalyst. This
synthetic approach would be practically applicable for
the effective production of novel tamoxifen-type drugs,
that is, the so-called SERMs (selective estrogen receptor
modulators) and SARMs (selective androgen receptor
modulators) having activities against hormonal distur-
bances. In this letter, a new and concise method for
the preparation of 1 using the improved three-compo-
nent coupling reaction among an aromatic aldehyde,
cinnamyltrimethylsilane, and b-chlorophenetole by the
promotion of Lewis acid catalysts, and the successive
double-bond migration reaction promoted by a basic
catalyst is described.
After the preliminary study of the synthesis of 1 using
the three-component coupling reaction among 3-piva-
loyloxybenzaldehyde, cinnamyltrimethylsilane, and
anisole, it was again planned to use b-chlorophenetole
(2-chloroethyl phenyl ether) as a second nucleophile
instead of anisole to produce the intermediary homoallyl
silyl ethers (A) in order to decrease the total steps for the
synthesis of 1 from the starting materials. It seems that
the chloroethoxy group will be easily converted to the
corresponding dialkylaminoethoxy group by treatment
2. Results and discussion
First, the amount of the co-catalyst was screened for the
reaction of 3-pivaloyloxybenzaldehyde with cinnamyltri-

Y. Sano, I. Shiina / Tetrahedron Letters 47 (2006) 1631–1635
1633
Table 1. The three-component coupling reaction among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and b-chlorophenetole using HfCl4
and TMSOTf as catalysts
Cl
O
HfCl4
O
TMSOTf
PivO
O
SiMe3
H
Cl
3-PivOC6H4CH(C6H4OCH2CH2Cl)2
+
+
+
PivO
rt, 2 h
(solvent)
5
2
3
4
Entry
Catalyst (equiv)
TMSOTf
Mol. ratio of 2/3
Yield of 4/%
Yield of 5/%
HfCl4
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
1/1
1/1
1/1
1/1
1/1
1/1
1/1.5
1/2
12
26
27
21
19
Trace
38
Trace
21
15
23
26
30
5
18
0.05
0.1
0.2
0.3
0.5
0.1
0.1
43
methylsilane in b-chlorophenetole solvent to optimize
the suitable ratio of TMSOTf to HfCl4. When no co-cat-
alyst was added to the reaction system, a large amount of
starting 3-pivaloyloxybenzaldehyde was recovered and
the corresponding homoallyl alcohol derived from the
intermediate alkyl silyl ether was mainly obtained (Table
1, entry 1). In entries 5 and 6, a large amount of triaryl-
methanes (5), which were produced from a 1 molar
amount of 3-pivaloyloxybenzaldehyde and 2 molar
amounts of b-chlorophenetole, was preferentially pro-
duced by the addition of 30–50 mol % of the co-catalyst
to the reaction mixture because the aldehyde was over-
activated by TMSOTf. On the other hand, the desired
three-component coupling product (4) was obtained in
a better yield when 10 mol % of TMSOTf was addition-
ally used with a stoichiometric amount of HfCl4 as
shown in entry 3. The yield of the desired three-compo-
nent coupling product was finally improved up to 43%
using a twofold amount of cinnamyltrimethylsilane to
3-pivaloyloxybenzaldehyde (entry 8). It was also rev-
ealed that all of the reaction afforded nearly stoichiome-
tric amounts of the syn- and anti-diastereomers of the
3,4,4-trisubstituted butenes by careful analysis using
HPLC–MS; however, these compounds could be con-
verted to the identical 1,1,2-trisubstituted butene after
the double-bond migration. Therefore, it is not required
to separate these compounds in our short-step strategy
for the synthesis of 1. Furthermore, no more than 10%
of the o-isomers originated from the nucleophilic substi-
tution of b-chlorophenetole with the intermediary homo-
allyl silyl ethers were also detected by the HPLC–MS
analysis.
Next, the N,N-dimethylamination was successfully
accomplished by heating the three-component coupling
product (4) with 30% dimethylamine in ethanol at
110 ꢁC in a sealed vessel for 8 h to produce a mixture
of the syn- and anti-3,4,4-trisubstituted butenes having
the side chain (6) in good yield (Scheme 3). The pivaloyl
protective group was simultaneously removed under
these reaction conditions. Although the syn- and anti-
isomers are separable at this stage by silica gel column
chromatography, further purification was not carried
out since it is unnecessary to separate these compounds
for preparing the identical 1,1,2-trisubstituted butene, a
precursor of 1, by the double-bond migration in the next
step.
Finally, the desired (E)-1 was prepared in 49% yield
from the 3,4,4-trisubstituted butenes by treating with
an excess amount of t-BuOK in DMSO at 50 ꢁC via
the base-catalyzed double-bond migration reaction
established for the synthesis of tamoxifen (Scheme 4).6
Although this olefin transformation was accompanied
by the formation of a nearly stoichiometric amount of
(Z)-1 with the formation of (E)-1, the isomers are easily
Cl
O
NMe2
O
30% Dimethylamine
EtOH
PivO
HO
110 C, 8 h
˚
81%
syn/anti-4
syn/anti-6
Scheme 3. Side-chain installation to form the precursor of droloxifene using dimethylamine in ethanol.

1634
Y. Sano, I. Shiina / Tetrahedron Letters 47 (2006) 1631–1635
NMe2
viscous colorless oil (308 mg, 43%, the ratio of p/o is
O
>9:1, the ratio of syn/anti is ca 6:4 from HPLC analysis).
tert-BuOK/DMSO
(Z
)-1
+
syn /anti-6
5. Typical experimental procedure for N,N-dimethyl-
amination of 4 (Scheme 3)
50 C, 2 h
HO
˚
38%
A solution of the product obtained from the former
reaction (421 mg, 0.909 mmol) in 30% dimethylamine-
ethanol (3 mL) was heated for 8 h at 110 ꢁC in a sealed
vessel. The reaction mixture was concentrated under re-
duced pressure and the residue was purified by TLC
(chloroform–methanol 9:1) to afford the amination
product (6) as a colorless oil (285 mg, 81%).
(
E
)-1
49%
TfOH/CH2Cl2
C, 2 h
0
˚
recovery: (
E
)-1 37%
(
Z )-1 36%
Scheme 4. Double-bond migration reaction to form droloxifene and
isomerization between (E)-1 and (Z)-1.
6. Typical experimental procedure for double-bond
migration (Scheme 4)
A solution of 6 (199 mg, 0.512 mmol) in dimethylsulfox-
ide (1 mL) was added to a solution of t-BuOK (373 mg,
3.32 mmol) in dimethylsulfoxide (1 mL), and stirred at
50 ꢁC for 2 h. The reaction mixture was poured into a sat-
urated NH4Cl solution (30 mL), then extracted with ethyl
ether (30 mL · 3). The combined organic phase was dried
(Na2SO4) and concentrated. The residue was purified by
TLC (ammoniacal chloroform–methanol 19:1) to give
the (E)-droloxifene and (Z)-droloxifene as colorless sol-
ids (97.4 mg, 49%; 74.5 mg, 38%, respectively).
separable by silica gel chromatography or fractional
crystallization of the corresponding acid salts. Further-
more, each isomer could be easily transformed into a
mixture of (E)-1 and (Z)-1 again by the treatment with
trifluoromethanesulfonic acid (TfOH) in CH2Cl2.
Therefore, the combined yield of (E)-1 could be in-
creased to nearly 70% involving this isomerization
procedure.
3. Conclusion
7. Typical experimental procedure for E/Z isomerization
(Scheme 4)
Thus, we developed a new synthetic route for producing
droloxifene (1) in only three steps; that is, the sequential
one-pot allylation and Friedel–Crafts type alkylation
using Lewis acid catalysts (43%), installation of the side
chain (81%) and the base-induced double-bond migra-
tion (>49%). This synthetic strategy seems to serve as
a new and practical pathway to prepare not only dro-
loxifene, but also the other SERMs and SARMs, includ-
ing the estrogen-dependent breast cancer agents such as
tamoxifen and its derivatives.
To a solution of (Z)-droloxifene (73.0 mg, 0.158 mmol)
in CH2Cl2 (2 mL), trifluoromethanesulfonic acid
(140 lL, 1.58 mmol) was added at 0 ꢁC under argon
atmosphere, and then stirred at the same temperature
for 2 h. A saturated NaHCO3 solution (20 mL) was
added to the reaction mixture, then extracted with
CH2Cl2 (10 mL · 3). The organic phase was dried
(Na2SO4) and concentrated. The residue was purified
by TLC (ammoniacal chloroform–methanol 19:1) to
afford (E)-droloxifene (26.7 mg, 37%). (Z)-droloxifene
was also recovered (26.4 mg, 36%).
4. Typical experimental procedure for the three-
component coupling reaction among 3-pivaloyloxybenz-
aldehyde, cinnamyltrimethylsilane, and b-chlorophenetole
(Table 1, entry 8)
References and notes
To a suspension of HfCl4 (490 mg, 1.53 mmol) in
b-chlorophenetole (1 mL), trimethylsilyl trifluoro-
methanesulfonate (34.0 mg, 0.153 mmol) was added as
a co-catalyst, then a solution of (E)-cinnamyltrimethyl-
silane7 (583 mg, 3.06 mmol) and 3-pivaloyloxybenzalde-
hyde (316 mg, 1.53 mmol) in b-chlorophenetole (1 mL)
was slowly added at room temperature under argon
atmosphere. The mixture was stirred for 2 h, then
poured into a saturated NaHCO3 solution (50 mL)
and extracted with Et2O (30 mL · 1, 10 mL · 2). The
combined organic phase was dried (Na2SO4) and con-
centrated. The residue was purified by silica gel column
chromatography (hexane–ethyl acetate 9:1) and succes-
sive thin-layer chromatography (toluene–hexane 17:1)
to afford the corresponding coupling product (4) as a
1. (a) Hasmann, M.; Lo¨ser, R.; Kohr, A.; Seibel, K. Onkologie
1994, 17, 22; (b) Biedermann, E.; Lo¨ser, R.; Hasmann, M.
Onkologie 1994, 17, 17; (c) Rauschning, W.; Pritchard, K. I.
Breast Cancer Res. Treat. 1994, 31, 83; (d) Gradishar, W. J.;
Jordan, V. C. J. Clin. Oncol. 1997, 15, 840.
2. (a) Ke, H. Z.; Chen, H. K.; Simmons, H. A.; Pirie, C. M.;
Ma, Y. F.; Jee, W. S. S.; Thompson, D. D. Bone 1995, 16,
99S; (b) Chen, H. K.; Ke, H. Z.; Jee, W. S. S.; Ma, Y. F.;
Pirie, C. M.; Simmons, H. A.; Thompson, D. D. J. Bone
Miner. Res. 1995, 10, 1256; (c) Ke, H. Z.; Chen, H. K.; Qi,
H.; Pirie, C.; Simmons, H. A.; Ma, Y. F.; Jee, W. S. S.;
Thompson, D. D. Bone 1995, 17, 491; (d) Chen, H. K.; Ke,
H. Z.; Lin, C. H.; Ma, Y. F.; Qi, H.; Crawford, D. T.; Pirie,
C. M.; Simmons, H. A.; Jee, W. S. S.; Thompson, D. D.
Bone 1995, 17, 175S; (e) Ke, H. Z.; Chen, H. K.; Simmons,
H. A.; Qi, H.; Crawford, D. T.; Pirie, C. M.; Chidsey-Frink,

Y. Sano, I. Shiina / Tetrahedron Letters 47 (2006) 1631–1635
1635
K. L.; Ma, Y. F.; Jee, W. S. S.; Thompson, D. D. Bone
1997, 20, 31.
3. For the examples of tamoxifen synthesis recently reported.
See: Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765,
and references cited therein.
O.-T., ; McCague, R.; Leclercq, G.; Devleeschouwer, N.
J. Med. Chem. 1985, 28, 1491; (e) Chen, Y.; Xia, P.; Zhang,
Q.; Zheng, Y.-h.; Xia, Y.; Yang, Z.-y. Acta Pharm. Sinica
2000, 35, 902.
´
5. Gauthier, S.; Sanceau, J.-Y.; Mailhot, J.; Caron, B.;
4. (a) Ruenitz, P. C.; Bagley, J. R.; Mokler, C. M. J. Med.
Chem. 1982, 25, 1056; (b) Schickaneder, H.; Loeser, R.;
Grill, H. Eur. Patent EP 54168, 1982; Chem. Abstr. 1982,
97, 215730; (c) Loeser, R.; Grill, H.; Schickaneder, H.;
Seibel, K. Ger. Patent DE 3425413, 1986; Chem. Abstr.
1986, 105, 42468; (d) Foster, A. B.; Jarman, M.; Leung,
Cloutier, J. Tetrahedron 2000, 56, 703.
6. (a) Shiina, I.; Suzuki, M.; Yokoyama, K. Tetrahedron Lett.
2002, 43, 6395; (b) Shiina, I.; Suzuki, M.; Yokoyama, K.
Tetrahedron Lett. 2004, 45, 965.
7. Andreini, B. P.; Carpita, A.; Rossi, R.; Scamuzzi, B.
Tetrahedron 1989, 45, 5621.