The synthesis and characterization of new triphenylethylene platinum(II) complexes

Article abstract of DOI:10.1016/S0020-1693(97)05514-X

In our search for a chemotherapeutic agent with a better therapeutic index and selectivity for the treatment of breast cancer, we have synthesized a series of cytotoxic analogs of tamoxifen. The new triphenylethylene platinum(II) derivatives were designed to possess binding affinity for the estrogen receptor. The synthesis of this type of compound is straightforward and efficient. The new complexes were fully characterized by their IR, ¹H NMR and ¹³C NMR spectra as well as their elemental analysis. The estrogen receptor binding affinity (RBA) of some of these triphenylethylenes was also evaluated and was found to be comparable to the affinity of the reference drug, i.e. tamoxifen, RBA=1.3%.

Full text of DOI:10.1016/S0020-1693(97)05514-X

Inorganica Chimica Acta 262 (1997) 139–145
The synthesis and characterization of new triphenylethylene
platinum(II) complexes
U
Gervais Be´rube´ , Yuehua He, Serge Groleau, Alexandre Se´ne´, He´le`ne-Marie The´rien,
Madeleine Caron
De´partement de Chimie-biologie, Universite´ du Que´bec a` Trois-Rivie`res, C.P. 500, Trois-Rivie`res, Que., G9A 5H7, Canada
Received 14 June 1996; revised 10 August 1996; accepted 6 December 1996
Abstract
In our search for a chemotherapeutic agent with a better therapeutic index and selectivity for the treatment of breast cancer, we have
synthesized a series of cytotoxic analogs of tamoxifen. The new triphenylethylene platinum(II) derivatives were designed to possess binding
affinity for the estrogen receptor. The synthesis of this type of compound is straightforward and efficient. The new complexes were fully
characterized by their IR, 1H NMR and 13C NMR spectra as well as their elemental analysis. The estrogen receptor binding affinity (RBA)
of some of these triphenylethylenes was also evaluated and was found to be comparable to the affinity of the reference drug, i.e. tamoxifen,
RBAs1.3%.
Keywords: Platinum complexes; Triphenylethylene complexes; Cytotoxic complexes
1. Introduction
In order to improve the low activity of platinum(II) com-
plexes against breast cancer [22], we investigated the cova-
lent attachment of dichloroplatinum to diamino analogs of
triphenylethylene. The choice of the triphenylethylene moi-
ety of structure 1 (see Scheme 1) was based on both the
structure of tamoxifen (3) and the triphenylacrylonitrile
derivatives (2). It was previously demonstrated that triphen-
ylacrylonitriles bearing two or three hydroxy groups, located
as presented on structure 2, possess high affinity for the estro-
gen receptor (ER) (receptor binding affinity (RBA)s
270%) [23–25]. We were hoping that such an arrangement
of hydroxy groups would confer to our new cytotoxic tri-
phenylethylenes high RBAs. These derivatives could also be
considered cytotoxic analogs of tamoxifen (3), the latter
being an efficient drug for the treatment [26] and potential
prevention [27,28] of breast cancer. The new compounds 1
were also synthesized on the structural basis of the steroidal
anti-estrogens ICI 164 384 (4) and ICI 182 780 (5), the side
chain being in the middle part of the molecule [29,30].
Therefore, considering the fact that hormonal therapy will be
ultimately followed by chemotherapy or a combination of
both therapies at the onset of treatment, we synthesized a
number of non-steroidal cytotoxic estrogens hoping to obtain
products with dual activity, i.e. anti-estrogenic and cytotoxic.
Moreover, these compounds might also be multidrug resis-
tance (MDR) modulators (chemosensitizers) as per their
Several platinum coordination complexes such as cis-
diamminedichloroplatinum(II) (cisplatin, 6) and carbopla-
tin (7) are currently used in the chemotherapy of neoplastic
diseases (Scheme 1) [1]. These complexes of a non-essen-
tial heavy metal exhibit a remarkable antitumor effectiveness
and a broad spectrum of activity. It is widely believed that
the antitumor activity of platinum drugs is a consequence of
their interaction with DNA [2,3]. Cisplatin binds readily to
guanine residues of DNA molecules [3]. Cisplatin has
proved very successful in the treatment of a variety of human
solid tumors such as genitourinary and gynecologic tumors
as well as head, neck and lung tumors [1]. Unfortunately,
the development of cellular resistance to cisplatin in mam-
malian cells is common [4–6] and is believed to occur via
four main mechanisms: (a) increased efficiency of repair of
platinum–DNA lesions [7–10]; (b) increased inactivation
of the drug by elevated levels of cellular low-molecular
weight thiols, particularly glutathione [11–13]; (c) metallo-
thionein [14–16]; (d) decreased cellular uptake of the drug
[17–21]. The clinical utility of the drug is also limited by its
toxic effects, particularly kidney toxicity [2].
U Corresponding author. Tel.: (819) 376-5170, ext: 3353; fax: (819)
376-5084; e-mail: Gervais Berube@uqtr.uquebec.ca
0020-1693/97/$17.00 q 1997 Elsevier Science S.A. All rights reserved
PII S0020-1693(97)05514-X

140
G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
been distilled. Melting points (m.p.) were recorded on an
Electrothermal 9100 apparatus and are uncorrected. IR spec-
tra were taken on a Nicolet model 205 FT-IR, or on a Perkin-
Elmer model 2000 FT-IR spectrophotometer. Mass spectral
assays (MS, m/e) were obtained using a VG Micromass
7070 HS instrument using an ionization energy of 70 eV.
Elemental analyses were conducted by Microanalysis Labo-
ratories Limited, Markham, Ontario. Nuclear magnetic res-
onance (NMR) spectra were obtained in CDCl3 solution,
unless otherwise noted, on a General Electric GE 300-NB
(300 MHz) or a Bruker AMX-2 (500 MHz) instrument:
chemical shifts were measured relative to internal standards:
1
tetramethylsilane (TMS, d 0.0 ppm) for H and CDCl3 (d
77.0 ppm) for 13C NMR. Multiplicities are described by the
following abbreviations: s (singlet), d (doublet), q (quar-
tet), p (pentet), m (multiplet), dd (double doublet), tq (tri-
ple quartet), and so on. The NMR assignments were assisted
by 13C–1H correlation (HET-CORR) 2-D spectra.
2.2. General procedure for the conversion of
bromoalcohols to iodotetrahydropyranyl ethers
2.2.1. 1-Tetrahydropyranyloxy-n-bromoalkane (9)
A solution of bromoalcohol 8 (27.6 mmol), dihydropyran
(2.57 g, 30.6 mmol) and pyridinium p-toluenesulfonate
(PPTS, 10 mg, 0.04 mmol) in dichloromethane (CH2Cl2, 50
ml) was stirred for 5 h under nitrogen. Afterwards, sodium
bicarbonate (NaHCO3, 500 mg) and MgSO4 (5.0 g) were
added to the reaction mixture and stirred for 15 min before
being filtered on a short pad of Celite/silica gel (1 cm/4 cm)
using CH2Cl2 as eluent. The filtrate was evaporated to a
viscous oil 9 (98% yield), which was used without further
purification in the next step.
Scheme 1.
lipophilic character [31,32]. The present paper describes in
detail the synthesis of eleven members of this new family of
cytotoxic triphenylethylenes [33] and the RBA of several of
these derivatives.
The spectroscopic data for derivatives 9a–c were reported
earlier [36].
2. Experimental
2.1. Synthesis of Pt(II) complexes
2.2.2. 1-Tetrahydropyranyloxy-11-bromoundecane (9d)
IR, nmax (thin film): 1170–1000 (C–O) cmy1. 1H NMR
(d ppm): 4.58 (1H, t, Js3.5 Hz, –OCHO–), 3.87, 3.73, 3.50
and 3.38 (4H, 4xm, –CH2OCHOCH2–), 3.41 (2H, t, Js6.8
Hz, –CH2Br), 1.2–2.0 (24H, m, –CH2–). MS (m/e): 335
(Mqq1), 233 (MqyOTHP).
2.1.1. Materials
Anhydrous reactions were performed under aninertatmos-
phere, the set-up assembled and cooled under dry nitrogen.
Unless otherwise noted, starting material, reactant and sol-
vents were obtained commercially and were used as such or
purified and dried by standard means [34]. Organic solutions
were dried over magnesium sulfate (MgSO4), and evapo-
rated on a rotatory evaporator and under reduced pressure.
All reactions were monitored by thin-layer chromatography
(TLC). The plates were visualized by UV fluorescence, or
by staining with iodine or spraying with an aqueous solution
of phosphomolybdic acid followed by heating the plate at
;1358C. Commercial TLC plates were Sigma T 6145 (poly-
2.2.3. 1-Tetrahydropyranyloxy-n-iodoalkane (10)
Sodium iodide (6.07 g, 40.5 mmol) was added to a solu-
tion of the crude bromide 9 (27 mmol) in dried acetone. The
reaction mixture was stirred at 228C for 5 h. Then, most of
the solvent was evaporated and the residue was transferred
to an extraction flask with ether (150 ml) and water (100
ml). The organic phase was washed with water (6=50 ml),
dried, filtrated and concentrated to a viscous liquid. Thecrude
iodide 10 (98% yield) was used as such at the alkylation
step.
˚
ester silica gel 60 A, 0.25 mm). Preparative TLC was per-
˚
formed on 1 mm silica gel 60 A, 20=20 plates (Whatman,
4861 840). Flash chromatography was performed according
to the method of Still et al. on Merck grade 60 silica gel, 230–
400 mesh [35]. All solvents used in chromatography had
The spectroscopic data for derivatives10a–c werereported
earlier [36].

G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
141
2.2.4. 1-Tetrahydropyranyloxy-11-iodoundecane (10d)
IR, nmax (thin film): 1170–1000 (C–O) cmy1. 1H NMR
(d ppm): 4.58 (1H, t, Js3.5 Hz, –OCHO–), 3.87, 3.73, 3.50
and 3.38 (4H, 4=m, –CH2OCHOCH2–), 3.19 (2H, t, Js7.0
Hz, –CH2I), 1.2–2.0 (24H, m, –CH2–). MS (m/e): 381
(MqyH), 281 (MqyOTHP).
3.34 (4H, 4=m, –CH2OCHOCH2–), 3.79 (3H, s, –OCH3),
2.23–1.18 (16H, m, –CH2–). 13C NMR (d ppm): 198.44,
163.12, 140.17, 130.82(2), 129.84, 128.69(2), 128.03(2),
126.73, 113.56(2), 98.73, 67.48, 62.24, 55.30, 53.17, 33.97,
30.70, 29.59, 29.40, 27.62, 25.99, 25.42, 19.60. MS (m/e):
no Mq, 326 (MqyDHP), 239 (MqyC5H10OTHP).
2.3. General procedure for the conversion of benzyl-
4-hydroxyphenyl ketone to bihydroxy and bimethoxy
triphenylethylene platinum(II) complexes 1Ba–e and 17
2.3.4. Synthesis of x-phenyl-y,y-bis(49-methoxyphenyl)-
x-alken-1-ol (13B)
A Grignard reagent, p-methoxyphenyl magnesium bro-
mide was prepared from magnesium (432 mg, 18.0 mmol)
and 4-methoxyphenylbromide (2.81 g, 15.0 mmol) in the
presence of a crystal of iodine in 100 ml of dry ether. The
Grignard reagent was usually ready after stirring at room
temperature (228C) overnight (18 h), but sometimes
required heating at reflux to initiate the reaction. A solution
of the ketone 12B (3.0 mmol) in dry ether was treated with
excess of the Grignard reagent for 6 h under nitrogen at room
temperature (228C) and was then hydrolyzed with 50 ml of
10% aqueous ammonium chloride. The ether phase was
washed with water (5=50 ml), dried and evaporated to give
the crude tertiary alcohol intermediate. The oily residue was
dehydrated and deprotected in 100 ml 95% ethanol in the
presence of PPTS (100 mg, 0.40 mmol) at reflux for 3 h.
After evaporation of the solvent, the residue was taken with
ether and extracted with water (5=50 ml). The ethereal
phase was dried and evaporated to an oil. Flash column chro-
matography (hexane:acetone, 7:1) gave pure 13B in 85%
average yield as a viscous oil.
2.3.1. Synthesis of benzyl-4-methoxyphenyl ketone (11B)
Benzyl-4-hydroxyphenyl ketone (2.12 g, 10 mmol) and
sodium hydroxide (0.60 g, 15 mmol) were dissolved in 250
ml ethanol by heating. Dimethyl sulfate (1.51 g, 12 mmol)
was added dropwise to the initial solution. The reaction mix-
ture was refluxed for 4 h. After evaporation, the residue was
diluted with ether (200 ml) and washed with water (5=50
ml). The ethereal phase was dried and evaporated to give a
white powder which was purified by flash column chroma-
tography (hexane:acetone, 9:1). The yield was 80% (98%
taking in consideration the hydroxy-ketone recovered). M.p.
76.2–77.08C. IR, nmax (KBr): 1680 (C_O), 1600 (C_C),
1254 (C–O) cmy1. 1H NMR (d ppm): 7.98, 6.90 (4H, 2=d
apparent, Js8.87 Hz, H in para-substituted anisyl group),
7.30–7.21 (5H, m, Ar–H), 4.20 (2H, s, –CH2–), 3.80 (3H,
s, –OCH3). 13C NMR (d ppm): 196.06, 163.37, 134.83,
130.79(2), 129.44, 129.25(2), 128.48(2), 126.63,
113.65(2), 55.32, 45.11. MS (m/e): 226 (Mq), 135
(MqyCH2C6H5).
2.3.5. 7-Phenyl-8,8-bis(49-methoxyphenyl)-7-octen-1-ol
(13Ba)
2.3.2. Synthesis of 1-(49-methoxyphenyl)-2-phenyl-n-tetra-
hydropyranyl-oxy-alkanone (12B)
IR, nmax (thin film): 3640–3150 (OH), 1600 (C_C),
1
To a stirred suspension of sodium hydride (448 mg, 11.2
mmol, 60% dispension in mineral oil) in dry tetrahydrofuran
(THF, 150 ml) was added rapidly ketone 11B (2.30 g, 10.2
mmol). The reaction mixture was heated (508C) in a water
bath for 1 h under a nitrogen atmosphere. After cooling, 1-
tetrahydropyranyloxy-n-iodoalkane (10) (11.2 mmol) was
added dropwise and the resulting mixture stirred overnight
(18 h) at room temperature (228C). Most of the solvent was
then evaporated and the residue was diluted with ether (200
ml) and treated with water (50 ml). The ethereal phase was
washed thoroughly with water (6=50 ml), dried and evap-
orated to give an oil that was purifed by flash column chro-
matography (hexane:acetone, 95:5). A viscous oil was
obtained. The average yield was 75% (98% taking into
account the alkyl iodide 10 recovered).
1240 (C–O) cmy1. H NMR (d ppm): 7.18–7.05 (7H, m,
Ar–H), 6.87 (2H, d apparent, Js8.72 Hz, H in para-substi-
tuted anisyl group), 6.77, 6.53 (4H, 2=d apparent, Js8.82
Hz, H in para-substituted anisyl group), 3.82, 3.66 (6H,
2=s, 2=–OCH3), 3.55 (2H, t, Js6.60 Hz, –CH2OH), 2.43
(2H, m, –C_C–CH2–), 1.65 (1H, br s, –OH), 1.50 (2H, p,
Js7.30 Hz, –CH2CH2OH), 1.30–1.10 (6H, m, –(CH2)3–).
13C NMR (d ppm): 158.16, 157.37, 142.87, 139.73, 138.06,
136.25, 135.73, 131.84(2), 130.56(2), 129.54(2),
127.80(2), 125.85, 113.39(2), 112.66(2), 62.91, 55.18,
54.95, 35.85, 32.60, 29.42, 28.82, 25.32. MS (m/e): 416
(Mq), 329 (MqyC5H10OH).
2.3.6. Synthesis of 1-bromo-x-phenyl-y,y-bis(49-methoxy-
phenyl)-x-alkene (14B)
A solution of the alcohol 13B (2.25 mmol), carbon tetra-
bromide (2.98 g, 9.00 mmol) and triphenylphosphine (2.36
g, 9.00 mmol) in dry ether (100 ml) was stirred at room
temperature (228C) for 24 h under a nitrogen atmosphere.
The triphenylphosphine oxide precipitate was filtrated and
the resulting solution was washed thoroughly with water
(5=25 ml), dried and evaporated to an oil. The crude
material was purified by flash column chromatography
2.3.3. 1-(49-Methoxyphenyl)-2-phenyl-8-tetrahydropyranyl-
oxy-octanone (12Ba)
IR, nmax (thin film): 1680 (C_O), 1600 (C_C), 1254
1
(C–O) cmy1. H NMR (d ppm): 7.95, 6.85 (4H, 2=d
apparent, Js8.93 Hz, H in para-substituted anisyl group),
7.32–7.14 (5H, m, Ar–H), 4.55 (1H, t, Js3.51 Hz,
–OCHO–), 4.49 (1H, t, Js7.25 Hz, –CH–), 3.84, 3.69, 3.48,

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G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
(hexane:acetone, 95:5) to give the bromide 14B in 85%
yield.
allowed to warm to room temperature (228C) and was stirred
for 18 h. The mixture was refluxed for 2 h. The reaction was
cooled down with an ice bath before adding 10 ml methanol.
The resulting solution was concentrated to 2–3 ml, treated
with saturated NaHCO3 solution (30 ml), and extracted with
ethyl acetate (5=30 ml). The crude yield is around 60–80%.
The diol-diamine was used without further purification in the
next step.
A solution of potassium tetrachloroplatinate(II) (219 mg,
0.528 mmol) in 7.5 ml of a mixture of DMF and water (2:1)
was added to a warm (358C) solution of the crude diol-
diamine (0.528 mmol)in5mlofDMF. Theresultingmixture
(pHs9–10) was stirred in the dark for 2–3 days until the
pH value reached 4–5. Then, 1 drop of N,N-dimethyl sulf-
oxide was added and the stirring was continued for 2 h. The
solvent was evaporated and the residue was suspended in
saturated potassium chloride solution (30 ml). A vigorous
stirring was essential in order to pulverize the lumps of pre-
cipitated platinum(II) complex 1B. The resulting suspension
was filtered, washed with water (100–250 ml) and dried
in a desiccator. The product was further purified either by
flash column chromatography or by preparative TLC
(CH2Cl2:CH3OH, 95:5). The crude yield was around 80%.
2.3.7. 1-Bromo-7-phenyl-8,8-bis(49-methoxyphenyl)-
7-octene (14Ba)
IR, nmax (thin film): 1600 (C_C), 1240 (C–O) cmy1
.
1H NMR (d ppm): 7.18–7.05 (7H, m, Ar–H), 6.88 (2H, d
apparent, Js8.73 Hz, H in para-substituted anisyl group),
6.77, 6.53 (4H, 2=d apparent, Js8.81 Hz, H in para-sub-
stituted anisyl group), 3.82, 3.66 (6H, 2=s, 2=–OCH3),
3.32 (2H, t, Js6.86 Hz, –CH2Br), 2.43 (2H, m, –C_C–
CH2–), 1.74 (2H, p, Js7.30 Hz, –CH2CH2Br), 1.40–1.18
(6H, m, –(CH2)3–). 13C NMR (d ppm): 158.23, 157.40,
142.81, 139.59, 138.20, 136.20, 135.69, 131.84(2),
130.54(2), 129.54(2), 127.84(2), 125.89, 113.43(2),
112.67(2), 55.20, 54.96, 35.77, 33.91, 32.62, 28.75, 28.65,
27.80. MS (m/e): 478 (Mq), 480 (Mqq2), 329
(MqyC5H10Br).
2.3.8. Synthesis of 1-[(29-aminoethyl)amino]-x-phenyl-
y,y-bis(49-methoxyphenyl)-x-alkene (15B)
Under a nitrogen atmosphere, ethylenediamine (900 mg,
15.0 mmol) was added to a solution of the bromide 14B
(1.50 mmol) in 80 ml of dry methanol. After boiling for 2
days under reflux (sometimes a longer reaction period was
required), the solvent was evaporated. The resulting residue
was dissolved in ether (150 ml) and washed with a solution
of NaHCO3 (30 ml, 5% aqueous) and with water (5=30
ml). The ethereal phase was dried and evaporatedtoaviscous
oil 15B. The yield was 90%.
2.3.11. 1-{Cis-[(29-aminoethyl)amino]dichloro-
platinum(II)}-7-phenyl-8,8-bis(49-hydroxyphenyl)-7-octene
(1Ba)
M.p.)1388C (dec.). IR, nmax (KBr): 3400–3100 (O–H,
N–H), 1600 (C_C), 1225 (C–O) cmy1. 1H NMR (acetone-
d6, d ppm): 8.32, 8.09 (2H, 2=br s, 2=Ar–OH), 7.20–7.10
(5H, m, Ar–H), 7.07, 6.86 (4H, 2=d apparent, Js8.52 Hz,
H in para-substituted phenol), 6.71, 6.48 (4H, 2=d appar-
ent, Js8.62 Hz, H in para-substituted phenol), 5.68, 5.11,
4.98 (3H, 3=br s, –NH– and –NH2), 3.21, 3.06, 2.77, 2.67
(6H, 4=br s, –CH2NHCH2CH2NH2), 2.46 (2H, m, –C_C–
CH2–), 1.78, 1.56 (2H, 2=br s, –CH2CH2NH–), 1.40–1.10
(6H, m, –(CH2)3–). 13C NMR (acetone-d6, d ppm): 156.88,
156.07, 143.94, 139.72(2), 135.93, 135.62, 132.62(2),
131.30(2), 130.41(2), 128.07(2), 126.55, 115.73(2),
114.93(2), 56.12, 53.42, 47.78, 36.33, 27.64, 26.82 (N.B.
2 carbons are hidden by acetone). Anal. Calc. for
C28H34Cl2N2O2PtP2H2O: C, 45.68; H, 5.26; N, 3.80. Found:
C, 45.72; H, 5.28; N, 3.70%.
2.3.9. 1-[(29-Aminoethyl)amino]-7-phenyl-8,8-bis-
(49-methoxyphenyl)-7-octene (15Ba)
IR, nmax (thin film): 3560–3130 (N–H), 1600 (C_C),
1240 (C–O) cmy1. 1H NMR (d ppm): 7.18–7.05 (7H, m,
Ar–H), 6.87 (2H, d apparent, Js8.65 Hz, H in para-substi-
tuted anisyl group), 6.77, 6.53 (4H, 2=d apparent, Js8.75
Hz, H in para-substituted anisyl group), 3.82, 3.67 (6H,
2=s, 2=–OCH3), 2.79, 2.64 (4H, 2=t, Js5.92 Hz,
–NHCH2CH2NH2), 2.54 (2H, t, Js7.25 Hz, –CH2NH–),
2.43 (2H, m, –C_C–CH2–) 1.78 (3H, br s, –NH– and
–NH2), 1.43–1.18 (8H, m, –(CH2)4–). 13C NMR (d ppm):
158.14, 157.33, 142.86, 139.76, 137.99, 136.23, 135.73,
131.84(2), 130.55(2), 129.53(2), 127.78(2), 125.81,
113.37(2), 112.63(2), 55.16, 54.93, 52.42, 49.74, 41.58,
35.88, 29.90, 29.60, 28.86, 26.99. MS (m/e): 458 (Mq),
428 (MqyCH2NH2), 415 (MqyCH2CH2NH), 329
(MqyC5H10NHCH2CH2NH2).
2.3.12. Synthesis of 1-{cis-[(29-aminoethyl)amino]-
dichloroplatinum(II)}-12-phenyl-13,13-bis(49-methoxy-
phenyl)-12-tridecene (17)
The platinum(II) complex 17 was obtained following the
same procedure as for compound 1B taking 16 as the starting
material (see Scheme 4). The crude yield was around 80%.
The product can be further purified either by flash column
chromatography or by preparative TLC (CH2Cl2:CH3OH,
98:2). M.p.)1738C (dec.). IR, nmax (KBr): 3560–3140
2.3.10. Synthesis of 1-{cis-[(29-aminoethyl)amino]-
dichloroplatinum(II)}-x-phenyl-y,y-bis(49-hydroxyphenyl)-
x-alkene (1B)
A solution of 15B (0.665 mmol) in dry CH2Cl2 (30 ml)
was treated with a solution of boron tribromide (1 M in
CH2Cl2, 1.60 ml, 1.60 mmol) at y608C, under nitrogen
atmosphere. After the addition, the reaction mixture was
1
(N–H), 1600 (C_C), 1240 (C–O) cmy1. H NMR (d
ppm): 7.16–7.08 (7H, m, Ar–H), 6.86 (2H, d apparent,
Js8.62 Hz, H in para-substituted anisyl group), 6.76, 6.53

G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
143
(4H, 2=d apparent, Js8.73 Hz, H in para-substitutedanisyl
group), 5.65, 5.05, 4.92 (3H, 3=br s, –NH– and –NH2),
3.80, 3.66 (6H, 2=s, 2=–OCH3), 4.05, 3.18, 2.95, 2.75
(6H, 4=br s, –CH2NHCH2CH2NH2), 2.43 (2H, m, –C_C–
CH2–), 1.75, 1.52 (2H, 2=br s, –CH2CH2NH–), 1.40–1.06
(16H, m, –(CH2)8–). 13C NMR (d ppm): 158.15, 157.34,
142.93, 139.90, 137.93, 136.28, 135.81, 131.88(2),
130.61(2), 129.58(2), 127.80(2), 125.83, 113.40(2),
112.67(2), 55.45, 55.22, 54.98, 53.47, 46.93, 35.98, 29.78,
29.55(2), 29.45, 29.34, 29.24, 28.97, 27.41, 26.56. Anal.
Calc. for C35H48Cl2N2O2Pt: C, 52.89; H, 6.09; N, 3.52.
Found: C, 52.83; H, 6.06; N, 3.51%.
The conversion of desoxybenzoin and desoxyanisoin to
triphenylethylene platinum(II) complexes 1Aa–c and 1Cd,e
was done in a similar fashion as for the synthesis of plati-
num(II) complexes 1Ba–e described above.
3. Results and discussion
3.1. Synthesis of triphenylethylene platinum(II) complexes
1Aa–c, 1Ba—e, 17 and 1Cd,e
Scheme 3. Reagents: (a) NaH, I–(CH2)n-OTHP, THF:DMSO, 258C, 17 h,
75%; (b) R9C6H4MgBr, Et2O, 258C, 17 h; (c) crude tertiary alcohol, PPTS
or pTSA, EtOH, reflux, 5 h, 85% from 12; (d) CBr4, Ph3P, Et2O, 258C, 24
h, 85%; (e) H2NCH2CH2NH2, CH3OH, reflux, 24 h, 95%;(f)BBr3,CH2Cl2,
y60 to 258C, 15 h to reflux 2 h; (g) K2PtCl4, DMF:H2O, 48 h, 60% from
15.
The appropriate iodotetrahydropyranyl ethers 10a–e were
prepared in high yield as described previously (Scheme 2)
[36]. As shown in Scheme 3, five new platinum(II) com-
plexes 1Ba–e (RsR9sOH; R0sH) were obtained with a
30% overall yield from commercially available benzyl-4-
hydroxyphenyl ketone, after eight steps. Benzyl-4-hydroxy-
phenyl ketone was initially protected as a methyl ether 11
(RsOCH3; R0sH) by using dimethylsulfate and sodium
hydroxide [37]. The yield for this reaction was 80%.
Alkylation of 11 with the iodotetrahydropyranyl ethers
10a–e was achieved using sodium hydride in tetrahydrofuran
to give compounds 12Ba–e with an average yield of 75%
(98% based on recovered alkyliodide 10). Addition of an
excess of p-methoxyphenylmagnesium bromide to the
ketones 12Ba–e and subsequent treatment of the crude terti-
ary alcohol intermediates with pyridinium-p-toluenesulfon-
ate (PPTS) in ethanol at refluxaffordedthetriphenylethylene
alcohols 13Ba–e as the result of dehydration of the tertiary
alcohols and simultaneous deprotection of the tetrahydro-
pyranyl ethers (85% average yield for the two steps).
With the desired triphenylethylenes 13Ba–e in hand, sim-
ple functional group transformations were carried out in the
following sequence of reactions. Initially, alcohols 13Ba–e
were transformed to the bromides 14Ba–e with carbon tetra-
bromide and triphenylphosphine in dry diethyl ether (85%
average yield). The amines 15Ba–e were obtained with an
Scheme 4.
average yield of 90% by refluxing the bromides 14Ba–e in
the presence of an excess of ethylenediamineindrymethanol.
Finally, demethylation with boron tribromide gave the inter-
mediate bis-phenols, which, upon treatment with potassium
tetrachloroplatinate(II) in a mixture of dimethylformamide
(DMF) and water, led to the desired platinum(II)complexes
1Ba–e (RsR9sOH; R0sH) (60% average yield for the
two steps) [36]. As presented in Scheme 4, the platinum(II)
complex 17 was easily obtained by reacting the amine 16
with potassium tetrachloroplatinate(II) in a mixture of DMF
and water for 48 h (80% yield).
The triphenylethylene platinum(II) complexes 1Aa–c
(RsR9sR0sH) were synthesized from commercially
available starting material deoxybenzoin 11 (RsR0sH), in
a similar sequence of reactions as used earlier for compounds
1Ba–e. However, p-toluenesulfonic acid (PTSA) was used
instead of PPTS for the dehydration step. The total yield
Scheme 2.

144
G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
One reaction which we would like to emphasize here is the
dehydration and deprotection of the tertiary alcohol 18 as
presented in Scheme 5. Initially, we followed the same pro-
cedure as for the dehydration and deprotection of the tertiary
alcohol intermediate 20 (Scheme 6). The tertiary alcohol 18
was allowed to react in the presence of PPTS in 95% ethanol
at reflux for 8 h (Scheme 5). We expected simultaneous
dehydration of tertiary alcohol and deprotection of THP ether
to form the alkylalcohol 13Ac. Unfortunately, it was not the
case. Instead, we obtained the diol 19 which was confirmed
1
by its IR, H NMR 13C NMR and mass spectra. Further
treatment of 19 with a stronger acidic catalyst, i.e. PTSA, in
toluene at reflux produced the desired compound 13Ac, the
structure of which was also confirmed by spectroscopy. This
interesting result can be explained easily, if we compare the
structure of the substances 18 and 20. An electron-donating
group is present on compound 20, i.e. a methoxy group which
can assist the dehydration reaction to give derivative 13Bc
(Scheme 6). Therefore, compound 18 without an electron-
donating group on its aromatic rings needs a stronger acidic
catalyst PTSA and higher reaction temperature to achieve the
same reaction.
Scheme 5.
Scheme 6.
This result emphasizes that a very subtle change inreaction
conditions and the chemical structure of the substrate may
drastically change the outcome of a chemical reaction. More-
over, the availability of a derivative such as 19 (present as a
mixture of four isomers) could lead to the development of
interesting new platinum(II) complexes in the future.
exceeded 40%. These are the reference derivatives which
should not show affinity for the estrogenreceptor(ER).Also,
two new derivatives 1Cd,e were made from desoxyanisoin
as described previously for compounds 1Ca–c in order to
complete the series [36].
It is noteworthy that all our platinum(II) complexes were
purified using flash column chromatography instead of
recrystallization. Chromatography was possible due to the
substantial organic portion of the molecules. This method-
ology yielded very pure platinum(II) complexes, homoge-
neous on thin-layer chromatography. All new compounds
obtained were characterized by their IR, 1H NMR, 13C NMR
and mass spectra. The final products 1Aa–c, 1Ba–e, 17 and
1Cd,ehave good elementalanalysiswithrespecttocalculated
values (Table 1).
3.2. Estrogen receptor binding affinity
The RBAs of derivatives 1Aa–c, 1Ba–c and 1Ca–c for the
ER were determined by a competitive cytosolicbindingassay
[38]. The binding affinity for estradiol (E2) was set to 100%.
As expected, compounds 1Aa–c do not bind to the ER
(RBAs0%). Derivatives containing two or three hydroxy
groups possess the following RBA values: 1Bas1.1%,
1Bbs1.4%, 1Bcs0.8%, 1Cas0.2%, 1Cbs0.8%, 1Ccs
Table 1
Elemental analysis data of platinum complexes and melting point
Complex
CaaHbbClcNdOePt
Found (Calc.) (%)
M.p. (8C)
C
H
N
1Aa
1Ab
1Ac
1Ba
1Bb
1Bc
1Bd
1Be
1Cd
1Ce
17
C28H34Cl2N2Pt
C30H38Cl2N2Pt
C32H42Cl2N2Pt
C28H34Cl2N2O2PtP2H2O
C30H38Cl2N2O2PtP2H2O
C32H42Cl2N2O2PtP2H2O
C33H44Cl2N2O2PtP2H2O
C34H46Cl2N2O2PtP2H2O
C33H44Cl2N2O3PtP2H2O
C34H46Cl2N2O3Pt
50.63 (50.60)
52.05 (52.01)
53.28 (53.32)
45.72 (45.68)
47.40 (47.37)
48.65 (48.73)
49.32 (49.38)
49.93 (49.98)
48.36 (48.39)
51.25 (51.23)
52.83 (52.89)
5.20 (5.17)
5.51 (5.54)
5.90 (5.89)
5.28 (5.26)
5.62 (5.57)
5.78 (5.88)
6.08 (6.03)
6.21 (6.17)
5.94 (5.91)
5.79 (5.82)
6.06 (6.09)
4.19 (4.22)
4.02 (4.05)
3.92 (3.89)
3.70 (3.80)
3.73 (3.68)
3.61 (3.55)
3.52 (3.49)
3.41 (3.43)
3.44 (3.42)
3.49 (3.52)
3.51 (3.52)
)210 dec.
)210 dec.
)210 dec.
)138 dec.
)138 dec.
)138 dec.
)138 dec.
)138 dec.
)162 dec.
)170 dec.
)173 dec.
C35H48Cl2N2O2Pt
dec.sdecomposition.

G. Be´rube´ et al. / Inorganica Chimica Acta 262 (1997) 139–145
145
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The present report describes the synthesis of eleven mem-
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Acknowledgements
We are grateful to Dr B. Gregory, Ms M. Baggs and Ms
N. Brunet, Department of Chemistry, Memorial University
of Newfoundland, as well as Dr G. Sauve´, Institut Armand-
1
Frappier, for the H and 13C NMR spectra. This work was
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