Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid

Article abstract of DOI:10.1021/jo0255328

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.

Full text of DOI:10.1021/jo0255328

4608
J . Org. Chem. 2002, 67, 4608-4611
only by preparative TLC using an elution system of
Syn th esis of (Z)-4-Hyd r oxyta m oxifen a n d
benzene/piperidine6 or by HPLC.2 To date, only two
stereospecific approaches to 4-hydroxytamoxifen have
been reported. One involves carbometalation of alkynyl-
silanes7 and the other, by Gauthier et al.,8 utilizes a
McMurry reaction between monopivaloated 4,4′-dihy-
droxybenzophenone and propiophenone as the key step
and furnishes a 14:1 E/Z ratio in favor of the desired
triarylethylene derivative. The final step of the latter
synthetic sequence requires removal of the pivaloyl ester
using MeLi at -78 °C. These conditions however, are not
compatible with the synthesis of a number of 4-hydroxy-
tamoxifen analogues, for example, those bearing acidic
side chains. This class of compounds has also been found
to have selective estrogenic activity, i.e., to prevent
against bone loss in ovariectomized (OVX) rats while
displaying estrogen antagonist activity in the uterus.9-12
(Z)-2-[4-[1-(p-Hyd r oxyp h en yl)-2-p h en yl]-1-
bu ten yl]p h en oxya cetic Acid
Anastasia Detsi, Maria Koufaki, and
Theodora Calogeropoulou*
Institute of Organic and Pharmaceutical Chemistry,
National Hellenic Research Foundation,
48 Vassileos Constantinou Avenue, 11635 Athens, Greece
tcalog@eie.gr
Received J anuary 18, 2002
Abstr a ct: The synthesis of (Z)-4-hydroxytamoxifen and (Z)-
2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyace-
tic acid was accomplished using a McMurry reaction as the
key step. The perfluorotolyl derivatives of the McMurry
products enabled the separation of the minor undesirable
geometrical isomer. The methodology proceeds without E,Z
isomerization, employs a very mild final debenzylation step
compatible with a large array of functional groups, and can
be applied to the generation of a variety of 4-hydroxytamox-
ifen analogues.
More recent attempts toward (Z)-4-hydroxytamoxifen
analogues employed benzylmonoprotected 4,4′-dihydroxy-
benzophenone (3) in the above-mentioned McMurry reac-
tion. However, they were not synthetically useful because
they resulted in mixtures of geometrical isomers that
could not be separated by trituration, recrystallization,
or column chromatography.10,13 We decided to focus our
efforts on investigating further this synthetic route, since
the benzyl protecting group could be removed in the final
step under mild conditions without cis-trans isomeriza-
tion and double-bond hydrogenation. Thus, coupling of
compound 3 with propiophenone under McMurry condi-
tions afforded the two isomeric triarylethylenes 4a and
4b in a 4:1 ratio, in 72% yield. We expected that the
isomer in excess had the desired E configuration since
previous work on hydroxytamoxifen analogues has iden-
tified the tendency of monoprotected 3,4′- or 4,4′-dihy-
droxybenzophenones used in the McMurry reaction with
propiophenone to favor the formation of that product that
has a trans arrangement of the ethyl side chain relative
to the phenolic system.14,15 We were very gratified to find
that when compounds 4a and 4b were transformed to
the corresponding perfluorotolyl ethers 5a and 5b, the
desired geometrical isomer 5a was obtained preferen-
tially by crystallization from pentane (Scheme 1).
Tamoxifen, (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-
N,N-dimethylethanamine (1), a selective estrogen recep-
tor modulator (SERM), is the treatment of choice for all
stages of hormone-responsive breast cancer and has
recently been approved by the FDA for the chemopre-
vention of this disease.1 (Z)-4-Hydroxytamoxifen (2) is the
active metabolite of tamoxifen; it possesses a high in vitro
potency for the estrogen receptor, but it is a weaker agent
than the parent compound in vivo, due to rapid clearance.
(Z)-4-Hydroxytamoxifen has an affinity for the estrogen
receptor about three times that of estradiol but it readily
equilibrates into a Z/E mixture, and the (E) isomer has
an affinity of only 5%.2
The geometry of the olefinic compound 5a was unam-
biguously confirmed by X-ray crystallographic analysis
(Figure 1).
(5) Olier-Reuchet, C.; Aitken, D. J .; Bucourt, R.; Husson, H. P.
Tetrahedron Lett. 1995, 36, 8221.
(6) Robertson, D. W.; Katzenellenbogen, J . A. J . Org. Chem. 1982,
47, 2387.
(7) Al-Hassan, M. I. Synth. Commun. 1989, 19, 1619.
(8) Gauthier, S.; Mailhot, J .; Labrie, F. J . Org. Chem. 1996, 61, 3890.
(9) Ruenitz, P. C.; Bourne, C. S.; Sullivan, K. J .; Moore, S. A. J .
Med. Chem. 1996, 39, 4853.
(10) Kraft, K. S.; Ruenitz, P. C.; Bartlett, M. G. J . Med. Chem. 1999,
42, 3126.
(11) Rubin, V. N.; Ruenitz, P. C.; Boudinot F. D.; Boyd J . L. Bioorg.
Med. Chem. 2001, 9, 1579.
(12) Willson, T. M.; Norris, J . D.; Wagner, B. L.; Asplin, I.; Baer,
P.; Brown, H. R.; J ones, S. A.; Henke, B.; Sauls, H.; Wolfe, S.; Morris,
D. C.; McDonnell, D. P. Endocrinology 1997, 138, 3901.
(13) Chu, G.-H.; Peters, A.; Selcer, K. W.; Li, P.-K. Bioorg. Med.
Chem. Lett. 1999, 9, 141.
We were interested in synthesizing analogues of (Z)-
4-hydroxytamoxifen that would retain the beneficial
characteristics and would be devoid of the metabolic
disadvantages of the parent compound. Several strategies
have been devised for the synthesis of 4-hydroxytamox-
ifen, the majority of which results in the generation of
an equimolar mixture of geometrical isomers3-5 separable
(1) J ordan, V. C. J . Steroid Biochem. Mol. Biol. 2000, 74, 269.
(2) Robertson, D. W.; Katzenellenbogen, J . A.; Long, D. J .; Rorke,
E. A.; Katzenellenbogen, B. S. J . Steroid Biochem. 1982, 16, 1.
(3) McCague, R. J . Chem. Res., Synop. 1986, 58.
(14) Coe, P. L.; Scriven, C. E. J . Chem. Soc., Perkin Trans. 1 1986,
475.
(4) Foster, A. B.; J arman, M.; Leung, O. T.; McCague, R.; Leclercq,
G.; Devleeschouwer, N. J . Med. Chem. 1985, 28, 1491.
(15) Gauthier, S.; Sanceau, J .-Y.; Mailhot, J .; Caron, B.; Cloutier,
J . Tetrahedron 2000, 56, 703.
10.1021/jo0255328 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/16/2002

Notes
J . Org. Chem., Vol. 67, No. 13, 2002 4609
Sch em e 2
F igu r e 1. ORTEP diagram of perfluorotolyl derivative (E)-
1-[4-(benzyloxy)phenyl]-1-[4-(perfluorotolyloxy)phenyl]-2-phe-
nylbut-1-ene (5a ).
Sch em e 3
Sch em e 1
sis resulted in fully hydrogenated products when MeOH
was used as the solvent, while in THF the reaction was
not always reproducible.
To investigate whether we can improve the ratio of the
desired compound 5a , we performed the McMurry reac-
tion using 4-benzyloxy-4′-perfluorotolyloxybenzophenone
(7) and propiophenone. Unfortunately, this reaction gave
a mixture of 5a and 5b in a 1:2 ratio (Scheme 3).
The observed stereoselectivity of the McMurry reaction
between 4-benzyloxy-4′-hydroxybenzophenone and pro-
piophenone could be explained by the following mecha-
nism. Reduction of the ketones by metallic titanium to
give a radical anion species is followed by homolytic
coupling of the mixed carbonyl compounds, and subse-
quent deoxygenation of the pinacolic intermediate gives
the desired olefin. Due to steric hindrance, the bulkier
benzyloxyphenyl substituent and the ethyl group should
lie on the same side, thus leading to the preferential
formation of derivative 4a (Figure 2). In the case of the
McMurry coupling between 4-benzyloxy-4′-perfluorotoly-
loxybenzophenone (7) and propiophenone, the steric bulk
of the benzyl group and the perfluorotolyl group is
slightly different leading to a preference for triaryleth-
ylene derivative 5b but only in a 2-fold excess (Figure
2).
The minor geometrical Z isomer 5b could potentially
afford 2 by sequential debenzylation, alkylation, and
removal of the perfluorotolyl group. This would give the
opportunity to utilize both products of the McMurry
coupling to obtain the desired (Z)-4-hydroxytamoxifen (2).
However, catalytic hydrogenolysis of compound 5b in
ethyl acetate resulted both in debenzylation and partial
double-bond hydrogenation.
The perfluorotolyl group has been previously employed
by McCague et al. for the separation of the geometrical
isomers of triarylethylenes.16,17 However, compounds 5a
and 5b have not been prepared previously. The singlets
corresponding to the benzylic protons are very charac-
teristic for the two geometrical isomers of triarylethylenes
4a and 4b or 5a and 5b. The peak corresponding to the
benzylic CH2 of the triarylethylene isomer that eventually
leads to (Z)-4-hydroxytamoxifen appears more downfield
(5.07 ppm) than the one of the undesired geometrical
isomer (4.92 ppm).
Compound 5a was treated with NaOMe in DMF to
remove the perfluorotolyl function without any cis-trans
isomerization. Alkylation of the resulting alcohol 4a with
2-chloro-N,N′-dimethylethylamine afforded 4-benzyl-
oxytamoxifen (6), which upon removal of the benzyl group
by catalytic hydrogenolysis gave (Z)-4-hydroxytamoxifen
(2) in pure stereochemical configuration (Scheme 2). It
is worth noting that the debenzylation reaction proceeds
smoothly, in quantitative yield, when it is performed in
ethyl acetate. Previous reports9 of debenzylation reactions
of triarylethylene analogues using catalytic hydrogenoly-
In addition, as an example of the application of our
approach in the synthesis of (Z)-4-hydroxytamoxifen
analogues bearing acidic side chains, compound 9 was
(16) J arman, M.; McCague, R. J . Chem. Res., Synop. 1985, 116.
(17) McCague, R. J . Chem. Res., Synop. 1986, 58.

4610 J . Org. Chem., Vol. 67, No. 13, 2002
Notes
analogues of (Z)-4-hydroxytamoxifen, and it can be stored
until further modifications are required without E/ Z
interconversion. The methodology proceeds without double-
bond isomerization, employs a very mild final debenzy-
lation step which is compatible with a large array of
functional groups, and can be scaled up to produce gram
quantities of the desired products.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. NMR spectra were measured at
300 MHz (1H), 75 MHz (13C), and 282 MHz (19F) in CDCl3 unless
otherwise specified. Chemical shifts for 19F are reported relative
to trifluoromethyl benzene as external standard (δ ) -73.732
ppm). Reactions requiring air-sensitive manipulations were
conducted under argon. Unless stated otherwise, all reagents
were purchased from commercial sources and used without
additional purification. THF was freshly distilled from Na/
benzophenone and DMF was dried over molecular sieves (3 Å).
Analytical thin-layer chromatography was carried out using
precoated silica gel plates Merck F254. Analytical visualization
was accomplished with ultraviolet light and/or 7% phosphoro-
molybdic acid in ethanol stain with heating. Flash column
chromatography was performed with silica gel (200-400 mesh).
Melting points are reported in degrees Celsius and are uncor-
rected.
F igu r e 2. Proposed intermediates of the McMurry coupling
of 4-benzyloxy-4′-hydroxybenzophenone and 4-benzyloxy-4′-
perfluorotolyloxybenzophenone with propiophenone.
4-Ben zyloxy-4′-h yd r oxyben zop h en on e (3). To a solution
of 4,4′-dihydroxybenzophenone (2 g, 9.4 mmol) in dry DMF (20
mL) were added benzyl bromide (1.22 mL, 10.2 mmol) and
K2CO3 (1.4 g, 10.2 mmol), and the mixture was heated at 60 °C
for 48 h. After being cooled to room temperature, the mixture
was filtered, and the filtrate was concentrated under reduced
pressure. The residue was dissolved in EtOAc, and the solution
was washed with 1 M HCl and brine, dried (Na2SO4), and
concentrated in vacuo. The resulting crude product was purified
by flash column chromatography (8:2 petroleum ether 40-60°/
acetone) to afford 4-benzyloxy-4′-hydroxybenzophenone (3) (2.1
g, 6.8 mmol, 72%) as a white solid: mp 158-160 °C; 1H NMR δ
8.62 (s, 1H), 7.64 (d, J ) 8.5 Hz, 2H), 7.59 (d, J ) 8.5 Hz, 2H),
7.33-7.20 (m, 5H), 6.90 (d, J ) 8.5 Hz, 2H), 6.81 (d, J ) 8.5 Hz,
2H), 5.02 (s, 2H).
Sch em e 4
(E,Z)-1-[4-(Ben zyloxy)p h en yl]-1-(4-h yd r oxyp h en yl)-2-
p h en ylbu t-1-en e (4). TiCl4 (2.86 mL, 26 mmol) was added to a
stirred suspension of zinc powder (3.4 g, 53 mmol) in dry THF
(60 mL), under Ar, at -10 °C. When the addition was complete,
the mixture was warmed to room temperature and then refluxed
for 2 h. To the cooled suspension of the titanium reagent was
added a solution of 4-benzyloxy-4′-hydroxybenzophenone (2 g,
6.6 mmol) and propiophenone (2.6 mL, 19.7 mmol) in dry THF
(125 mL) at 0 °C, and the mixture was refluxed in the dark for
2.5 h. After cooling, the reaction mixture was poured into 10%
aqueous potassium carbonate and extracted with EtOAc. The
organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography (9:1
petroleum ether 40-60°/acetone) afforded 4 (1.91 g, 4.7 mmol,
72%) as a 4:1 mixture of (E)-4a /(Z)-4b isomers: mp 126-129
°C; 1H NMR δ 7.47-7.34 (m, 5H), 7.22-7.11 (m, 7H), 6.99 (d, J
) 7.9 Hz, 1.6H), 6.82 (d, J ) 8.5 Hz, 0.8H), 6.66 (d, J ) 8.5 Hz,
0.4H), 6.76 and 6.49 (d, J ) 7.9 Hz, 1.6H each), 5.75 (bs, 1H),
5.09 and 4.93 (s, 1.6 and 0.4, 2H), 2.53 (q, J ) 7.3 Hz, 2H), 0.97
(t, J ) 7.3 Hz, 3H).
(E,Z)-1-[4-(Ben zyloxy)p h en yl]-1-[4-(p er flu or otolyloxy)-
p h en yl]-2-p h en ylbu t-1-en e (5). A mixture of 4 (700 mg, 1.7
mmol), octafluorotoluene (0.25 mL, 1.75 mmol), tetrabutylam-
monium hydrogen sulfate (290 mg, 0.85 mmol), CH2Cl2 (15 mL),
and aqueous sodium hydroxide (1 M, 15 mL) was stirred at room
temperature for 1 h. The organic phase was separated, and the
aqueous phase was acidified with aqueous hydrochloric acid
(10%) and extracted with CH2Cl2. The organic phases were
combined, dried (Na2SO4), and concentrated in vacuo. The
yellowish residue was washed with 2:1 petroleum ether 40-60°/
diethyl ether (3 × 20 mL), and the ethereal washings were
evaporated in vacuo. The solid product (5a :5b 4:1, 950 mg, 1.5
mmol, 90%) was dissolved in the minimum volume of CH2Cl2,
60 mL of pentane was added, and the solution was kept in the
synthesized in excellent yield as the pure Z geometrical
isomer. Previous attempts to generate compound 9 or
other related derivatives always resulted in an equimolar
mixture of the two geometrical isomers that could not
be separated.9-11 Thus, the biological evaluation was
carried out with the mixture and the effect of geometric
isomerism on estrogen receptor affinity or bioactivity
could not be deciphered. We opted to use benzyl 2-bro-
moacetate as the alkylating agent for the phenolic
derivative 4a since catalytic hydrogenolysis would re-
move both the benzyl ether and the benzyl ester func-
tionalities and would generate the desired hydroxytri-
arylethylene oxyalkanoic acid in one step. As planned,
(E)-1-(4-hydroxyphenyl)-1-(4-benzyloxyphenyl)-2-phenyl-
but-1-ene (4a ) was treated with benzyl 2-bromoacetate
and K2CO3 to afford the triarylethylene oxyalkanoic acid
benzyl ester derivative 8 in quantitative yield without
double-bond isomerization. Treatment with H2 and 10%
Pd/C at 1 atm in ethyl acetate/methanol (6/1) removed
both benzyl groups and afforded hydroxy-triarylethylene
oxyalkanoic acid 9 in quantitative yield as the pure (Z)-
geometrical isomer (Scheme 4).
In summary, we presented the synthesis of (Z)-4-
hydroxytamoxifen and (Z)-4-hydroxytamoxifen acetic acid
analogue 9 in pure stereochemical form employing a
McMurry reaction as the key step and using the perfluo-
rotolyl group as a means to remove the minor undesirable
geometrical isomer. The intermediate perfluorotolyl de-
rivative 5a allows the synthesis of a variety of side-chain

Notes
J . Org. Chem., Vol. 67, No. 13, 2002 4611
refrigerator overnight to afford 5a as a white solid (622 mg, 1
mmol, 59%). Evaporation of the mother liquor afforded a 4:1
mixture of 5b/5a (328 mg, 0.5 mmol, 31%), which was subjected
to column chromatography (8:2 petroleum ether 40-60°/ CH2-
Cl2) to afford pure 5b (262 mg, 0.4 mmol, 25%).
completion of the reaction (ca 2.5 h). The reaction mixture was
filtered through Celite, and the filtrate was concentrated in
vacuo to afford (Z)-hydroxytamoxifen (2) (280 mg, 0.73 mmol,
100%): 1H NMR δ 7.16-7.02 (m, 7H), 6.76 (d, J ) 7.9 Hz, 2H),
6.67 and 6.23 (d, J ) 8.5 Hz, 2H each), 3.90 (t, J ) 5.5 Hz, 2H),
2.75 (t, J ) 5.5 Hz, 2H), 2.49 (q, J ) 7.3 Hz, 2H), 2.36 (s, 6H),
0.90 (t, J ) 7.3 Hz, 3H).
(E)-1-[4-(Ben zyloxy)p h en yl]-1-[4-(p er flu or otolyloxy)p h e-
n yl]-2-p h en ylbu t-1-en e (5a ): TLC (7:3 petroleum ether 40-
1
60°/ CH2Cl2) Rf ) 0.57; mp 165-167 °C; H NMR δ 7.47-7.33
4-Ben zyloxy-4′-per flu or otolyloxyben zoph en on e (7). Com-
pound 7 was prepared following the procedure described for the
synthesis of compound 5, using 4-benzyloxy-4′-hydroxyben-
zophenone (3) (500 mg, 1.64 mmol), octafluorotoluene (0.25 mL,
1.75 mmol), tetrabutylammonium hydrogen sulfate (290 mg, 0.85
mmol), CH2Cl2 (15 mL), and aqueous sodium hydroxide (1 M,
15 mL): yield 740 mg, 0.14 mmol, 87%; mp 160-162 °C; 1H NMR
δ 7.80 (m, 4H), 7.45-7.37 (m, 5H), 7.08-7.03 (m, 4H), 5.15 (s,
2H); 13C NMR δ 194.05, 162.60, 159.05, 136.21, 134.56, 132.50,
(m, 5H), 7.17-7.06 (m, 7H), 6.97 (d, J ) 8.5 Hz, 2H), 6.84 and
6.63 (d, J ) 8.5 Hz, 2H each), 5.08 (s, 2H), 2.50 (q, J ) 7.9 Hz,
2H), 0.94 (t, J ) 7.3 Hz, 3H); 13C NMR δ 157.74, 154.38, 142.54,
142.05, 139.89, 137.04, 135.81, 132.25, 130.60, 129.63, 128.60,
127.98, 127.92, 127.53, 126.24, 114.98, 114.46, 70.04, 28.99,
13.53; 19F NMR δ -162.9 (m, 2F), -151.6 (m, 2F), -66.8 (t, J )
23.5 Hz, 3F).18 Anal. Calcd for C36H25F7O2: C, 69.45; H, 4.05.
Found: C, 69.19; H, 4.17.
132.27, 130.21, 128.79, 128.35, 127.55, 115.41, 114.57, 70.17; 19
F
(Z)-1-[4-(Ben zyloxy)p h en yl]-1-[4-(p er flu or otolyloxy)p h e-
n yl]-2-p h en ylbu t-1-en e (5b): TLC (7:3 petroleum ether 40-
NMR δ -162.30 (s, 2F), -150.54 (d, J ) 24.4 Hz, 2F), -66.90
(d, J ) 24.4 Hz, 3F).
1
60°/ CH2Cl2) Rf ) 0.54; mp 120-122 °C; H NMR δ 7.36-7.10
(m, 12H), 6.98 (d, J ) 8.5 Hz, 2H), 6.77 and 6.64 (d, J ) 8.5 Hz,
2H each), 4.92 (s, 2H), 2.47 (q, J ) 7.3 Hz, 2H), 0.93 (t, J ) 7.3
Hz, 3H); 13C NMR δ 156.90, 155.19, 142.15, 141.99, 140.21,
136.94, 135.39, 131.93, 131.02, 129.60, 128.50, 127.92, 127.53,
126.17, 115.66, 113.72, 69.79, 29.02, 13.59; 19F NMR δ -162.7
(m, 2F), -151.3 (m, 2F), -66.8 (t, J ) 22.3 Hz, 3F).18 Anal. Calcd
for C36H25F7O2: C, 69.45; H, 4.05. Found: C, 69.08; H, 4.28.
(E)-1-[4-(Ben zyloxy)p h en yl]-1-(4-h yd r oxyp h en yl)-2-p h e-
n ylbu t-1-en e (4a ). Compound 5a (600 mg, 0.96 mmol,) and
freshly prepared MeONa (5.18 g, 96 mmol) were dissolved in
dry DMF (90 mL), and the mixture was stirred in the dark for
1.5 h. The mixture was diluted with water (30 mL), acidified
with aqueous hydrochloric acid (10%), and extracted with diethyl
ether (5 × 30 mL). The combined extracts were dried (Na2SO4),
and the solvent was evaporated in vacuo to afford 4a (388 mg,
0.96 mmol, 100%): 1H NMR δ 7.44-7.35 (m, 5H), 7.16-7.10 (m,
7H), 6.95 (d, J ) 8.5 Hz, 2H), 6.72 and 6.46 (d, J ) 7.9 Hz, 2H
each), 5.07 (s, 2H), 2.48 (q, J ) 6.7 Hz, 2H), 0.92 (t, J ) 6.7 Hz,
3H);13C NMR δ 157.55, 156.74, 142.64, 141.15, 137.75, 137.04,
136.56, 135.94, 132.23, 130.69, 129.79, 128.68, 128.06, 127.90,
127.66, 125.99, 114.37, 114.28, 70.01, 28.91, 13.49. Anal. Calcd
for C29H26O2: C, 85.68; H, 6.45. Found: C, 85.71; H, 6.69.
(E)-1-[4-(Ben zyloxy)p h en yl]-1-[4-(2-d im et h yla m in oet -
h oxy)p h en yl)]-2-p h en ylbu t-1-en e (6). Preparation of 2-chloro-
N,N-dimethylethylamine: 2-(dimethylamino)ethyl chloride hy-
drochloride (552 mg, 3.84 mmol) was treated with K2CO3 (1.06
g, 7.68 mmol) in a solution of 19:1 acetone-water (40 mL). The
mixture was stirred at 0 °C for 0.5 h.
Compound 4a (380 mg, 0.94 mmol) was dissolved in 20 mL
of the above solution, K2CO3 (312 mg, 2.26 mmol) was added,
and the mixture was refluxed in the dark for 4 h. The solids
were filtered off, and the filtrate was concentrated in vacuo. The
yellowish oily product was purified by flash column chromatog-
raphy (98:2 CH2Cl2/MeOH) to afford 6 (352 mg, 0.74 mmol,
73%): 1H NMR δ 7.48-7.34 (m, 5H), 7.18-7.10 (m, 7H), 6.96
(d, J ) 8.5 Hz, 2H), 6.77 and 6.56 (d, J ) 8.5 Hz, 2H each), 5.07
(s, 2H), 3.94 (t, J ) 6.1 Hz, 2H), 2.66 (t, J ) 6.1 Hz, 2H), 2.50 (q,
J ) 7.3 Hz, 2H), 2.30 (s, 6H), 0.94 (t, J ) 7.3 Hz, 3H); 13C NMR
δ 157.52, 156.68, 142.60, 141.05, 137.78, 137.07, 136.56, 135.84,
131.93, 130.60, 129.66, 128.56, 127.79, 127.53, 125.85, 114.30,
113.33, 70.01, 65.61, 58.3, 45.85, 28.99, 13.59. Anal. Calcd for
C33H25NO2: C, 82.98; H, 7.39; N, 2.93. Found: C, 83.30; H, 7.64;
N, 2.89.
P r ep a r a tion of 5a a n d 5b fr om Com p ou n d 7. McMurry
reaction of compound 7 (500 mg, 0.96 mmol) and propiophenone
(0.4 mL, 2.8 mmol) following the procedure described for the
synthesis of compound 4 afforded a mixture of 5a and 5b in 1:2
ratio (358 mg, 0.58 mmol, 60%).
(Z)-2-[4-[1-(p-Hyd r oxyp h en yl)-2-p h en yl]-1-bu ten yl]p h e-
n oxya cetic Acid Ben zyl Ester (8). Benzyl 2-bromoacetate
(0.25 mL, 1.6 mmol) and K2CO3 (100 mg, 0.75 mmol) were added
to a solution of 6 (130 mg, 0.3 mmol) in acetone (4 mL), and the
mixture was refluxed in the dark for 1 h. Excess solids were
filtered off, and the solvent was evaporated in vacuo. Addition
of 1:1 diethyl ether/petroleum ether 40-60 °C to the oily residue
afforded 8 as a white solid (143 mg, 0.26 mmol, 86%): mp 138-
140 °C; 1H NMR δ 7.47-7.32 (m, 10H), 7.16-7.09 (m, 7H), 6.95
(d, J ) 8.5 Hz, 2H), 6.76 and 6.53 (d, J ) 8.5 Hz, 2H each), 5.18
(s, 2H), 5.07 (s, 2H), 4.52 (s, 2H), 2.48 (q, J ) 7.3 Hz, 2H), 0.92
(t, J ) 7.3 Hz, 3H); 13C NMR δ 168.81, 157.55, 155.61, 142.41,
141.41, 137.53, 137.04, 136.88, 136.33, 135.13, 131.99, 130.60,
129.66, 128.66, 128.60, 128.50, 128.40, 127.98, 127.82, 127.56,
125.98, 114.30, 113.46, 70.01, 66.91, 65.26, 29.02, 13.63. Anal.
Calcd for C38H34O4: C, 82.28; H, 6.18. Found: C, 82.49; H, 6.35.
(Z)-2-[4-[1-(p-Hyd r oxyp h en yl)-2-p h en yl]-1-bu ten yl]p h e-
n oxya cetic Acid (9). To a solution of 8 (140 mg, 0.25 mmol) in
EtOAc (25 mL) and MeOH (2.5 mL) was added 10% palladium
on carbon (70 mg). The suspension was stirred under 1 atm of
hydrogen gas for ca. 40 min in the dark (the reaction was
monitored by TLC). The reaction mixture was filtered through
Celite, which was washed with EtOAc and MeOH, and the
solvents were evaporated in vacuo to afford pure (Z)-2-[4-[1-(p-
hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid (9) (116
mg, 0.25 mmol, 100%): 1H NMR (acetone-d6) δ 7.18-7.06 (m,
7H), 6.86 (d, J ) 8.5, 2H), 6.81 (d, J ) 8.5, 2H), 6.60 (d, J ) 8.5
Hz, 2H), 4.58 (s, 2H), 2.49 (q, J ) 7.3 Hz, 2H), 0.91 (t, J ) 7.3
Hz, 3H). Anal. Calcd for C24H22O4: C, 76.99; H, 5.92. Found: C,
76.65; H, 6.18.
Ack n ow led gm en t. We thank Dr. Aris Terzis (X-ray
laboratory, NCSR “Demokritos”) for the X-ray crystal-
lographic analysis and the Greek General Secretariat
for Research and Technology (PENED 99ED 181 and
99ED 136) for financial support.
(Z)-1-[4-(2-Dim eth yla m in oeth oxy)p h en yl)]-1-(4-h yd r oxy-
p h en yl)-2-p h en ylbu t-1-en e ((Z)-4-Hyd r oxyta m oxifen ) (2).
To a solution of 6 (350 mg, 0.73 mmol) in EtOAc (25 mL) was
added of 10% palladium on carbon (175 mg). The suspension
was stirred under 1 atm of hydrogen gas in the dark until
Su p p or tin g In for m a tion Ava ila ble: Tables, in CIF
format, of positional parameters, bond lengths, and bond
angles of compound 5a . This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) Ayanbadejo, F. A. Spectrochim. Acta, Sect. A 1969, 25, 1009.
J O0255328