Triaryl (Z)-olefins suitable for radiolabeling with iodine-124 or fluorine-18 radionuclides for positron emission tomography imaging of estrogen positive breast tumors

Article abstract of DOI:10.1016/j.bmcl.2010.12.091

A group of (Z)-1,2-diphenyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl] but-1-enes were synthesized using methodologies that will allow incorporation of a [¹²⁴I]iodine substituent at the para-position of either the C-1 phenyl ring or the C-2

Full text of DOI:10.1016/j.bmcl.2010.12.091

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1195–1198
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triaryl (Z)-olefins suitable for radiolabeling with iodine-124 or fluorine-18
radionuclides for positron emission tomography imaging of estrogen
positive breast tumors
⇑
Khaled R. A. Abdellatif, Carlos A. Velázquez, Zhangjian Huang, Morshed A. Chowdhury, Edward E. Knaus
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
a r t i c l e i n f o
a b s t r a c t
Article history:
A group of (Z)-1,2-diphenyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]but-1-enes were synthe-
sized using methodologies that will allow incorporation of a [124I]iodine substituent at the para-position
of either the C-1 phenyl ring or the C-2 phenyl ring, or a [18F]OCH2CH2F substituent at the para-position of
the C-2 phenyl ring. These [124I] and [18F] radiotracers are designed as potential radiopharmaceuticals to
image estrogen positive breast tumors using positron emission tomography (PET).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 December 2010
Revised 15 December 2010
Accepted 16 December 2010
Available online 23 December 2010
Keywords:
Tricyclic (Z)-olefins
Estrogen positive breast tumors
Positron emission tomography imaging
Tamoxifen (1) is a non-steroidal triphenylbut-1-ene anti-estro-
genic drug used extensively to treat hormone-responsive human
breast cancer1,2 that is believed to act3 primarily by competing with
estradiol for its estrogen receptor (ER). The basic aminoalkyloxy
moiety present in tamoxifen (OCH2CH2NMe2) is a major determi-
nant of receptor binding affinity (RBA) where the relative binding
profile with respect to the amino group is 4-methylpiperazin-1-
yl > pyrrolidin-1-yl > NEt2 > NMe2 > piperidin-1-yl > morpholin-4-
yl.4 Decreasing the basicity of the protonated amino group (cationic
site)is believedto diminishthebindinginteractionwithAsp351(an-
ionic carboxylate site) on the estrogen receptor.5 Although replace-
ment of the –CH2CH3 substituent in tamoxifen (1) by a –CH2CH2F
substituent does not change the RBA,6 there is the possibility for
elimination of HF to furnish the respective vinyl (–CH@CH2) prod-
uct.6,7 The 4-hydroxytamoxifen metabolite 2, which shows a higher
in vitro anti-estrogenic potency than tamoxifen, is less potent than
tamoxifen in vivo owing to rapid glucuronidation of the hydroxyl
group and subsequentexcretion.8,9 4-Iodotamoxifen (3)9,10 is a more
potent in vitro inhibitor of MCF-7 cancer cell growth than tamoxi-
fen9 (see structures 1–3 in Fig. 1).
Me2N
O
Et
R1
Figure 1. Structures of tamoxifen (1, R1 = H), 4-hydroxytamoxifen (2, R1 = OH) and
4-iodotamoxifen (3, R1 = I).
prompted us to design candidate imaging agents having a 4-meth-
ylpiperazin-1-yl moiety (see structures in Fig. 2). It was envisioned
that the 4-position on the C-1 phenyl ring would be a suitable loca-
tion to position a longer half-life 124I (t1/2 = 4.18 days) radionuclide
since 4-iodotamoxifen (3)9,10 is a more potent in vitro inhibitor of
MCF-7 cancer cell growth than tamoxifen.9 Access to [124I]radiotra-
cers with a longer radionuclide half-life is highly relevant since it
provides an extended time period, relative to [11C] and [18F], during
which optimal imaging can be carried out based on the biodistribu-
tionandeliminationpropertiesof theradiotracerbeinginvestigated.
Furthermore, placement of an iodine radionuclide at this position
would result in metabolic halogenic obstruction preventing forma-
tion of a putative 4-hydroxy metabolite that was observed in the
The most common positron emitting radionuclides include 11C
(t1/2 = 20.4 min) and 18F (t1/2 = 109.6 min). The radiosynthesis of
[
11C]tamoxifen having the short half-life 11C label in one of the
N–11CH3 substituents has been reported.11 The observation that
replacement of the –NMe2 group in tamoxifen by a 4-methylpipera-
zin-1-yl ring resulted in a fivefold enhancement in estrogen RBA4
⇑
Corresponding author. Tel.: +1 780 492 5993; fax: +1 780 492 1217.
E-mail address: eknaus@pharmacy.ualberta.ca (E.E. Knaus).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.091

1196
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1195–1198
Me
erazinyl product (Z)-8a (54%) and (Z)-8b (59%). Stereoisomer
N
assignments were made based on 1H NMR chemical shifts from pub-
N
lished information.4,6,8,12,13
O
R2
A
McMurry olefination reaction employing the Zn–TiCl4
catalyzed reductive cross-coupling of 4-(2-chloroethoxy)benzophe-
none (5a) with 4-hydroxypropiophenone (9) yielded a 1:1 mixture
(1H NMR integrals) of the 1-(4-chloroethoxyphenyl)-2-(4-hydroxy-
phenyl)-1-phenylbut-1-ene (Z)-10a and (E)-10b stereoisomers in
44% yield as illustrated in Scheme 2. Attempts to separate these
(Z)-10a and (E)-10b stereoisomers by fractional crystallization from
solvents of varied polarity (diethyl ether, ethyl acetate, isopropanol
and ethanol) were unsuccessful. Therefore, the mixture of (Z)-10a
and (E)-10b, without separation, was reacted with N-methylpipera-
zineto givea1:1mixtureofthe (Z)-11aand(E)-11bstereoisomersin
90% yield (1.05 g). Repeated fractional crystallization of this mixture
from methanol furnished 170 mg of (Z)-11a. Condensation of the
para-hydroxyphenyl (Z)-11a stereoisomer with 2-fluoroethyl p-tol-
uenesulfonate in the presence of K2CO3 and Kryptofix 222 with
CH3CN as solvent yielded the target fluoroethoxy (Z)-12 product
(35% yield). In contrast, an attempted methylation of the para-
hydroxyphenyl (Z)-11a stereoisomer with CH3I in DMF using NaH
or 5 N NaOH as base resulted in loss of the N-methylpiperazine
moiety.
Et
R1
4
R1 = *I, R2 = H
R1 = H, R2 = *I
R1 = H, R2 = OCH2CH2*F
*Indicates position suitable for labelling
with a [124I] or [18F] radionuclide
Figure 2. Putative positions (⁄) where
a [ [
124I]- or 18F]-radionuclide may be
incorporated for assessment as PET radiopharmaceuticals to image estrogen-
responsive breast tumors.
The stereochemical integrity of electron-rich tetra-substituted
olefinic bonds is frequently compromised under both alkaline
and acidic conditions.14 It was recently reported14 that (Z)-4-hy-
droxy-N-desmethyltamoxifen (endoxifen) could be readily sepa-
rated from the corresponding (E)-stereoisomer by preparative
RP-HPLC with isocratic elution using a buffer containing 50% of
20 mM triethylammonium bicarbonate in MeCN at pH 8.8. Accord-
ingly, it is possible that the (Z)- and (E)-stereoisomer mixtures (10a
and 10b; 11a and 11b) could also be separated using this RP-HPLC
methodology. Separation of (Z)- and (E)-4-hydroxy-N-desmethyl-
tamoxifen stereoisomers worked well even at significant column
overload since the retention times of the two stereochemical iso-
mers differed by 28 min.
case of tamoxifen.8,9 Alternatively, a [124I], or [18F]OCH2CH2F, substi-
tuent could be placed at the para-position of the C-2 phenyl ring. We
now describe non-radioactive synthetic methodologies that will be
applicable to the future radiochemical synthesis of the three puta-
tive radiopharmaceuticals illustrated in Figure 2 employing reaction
conditions and reagents that employ the corresponding [124I]- or
[
18F]-reagents. These putative radiopharmaceuticals will warrant
future assessment as PET imaging agents targeted to the detection
of estrogen positive breast tumors.
The (Z)-1-[4-(2-chloroethoxy)phenyl]-2-(4-iodophenyl)-1-phe-
nylbut-1-ene [(Z)-7a] was synthesized using a McMurry olefination
reaction by Zn–TiCl4 catalyzed reductive cross-coupling of 4-(2-
chloroethoxy)benzophenone (5a) with 4-iodopropiophenone (6a)
in 35% yield as illustrated in Scheme 1. The (Z)-7a product was the
sole stereoisomer obtained after silica gel column chromatography
and recrystallization from EtOH. A similar cross-coupling reaction
of the iodobenzophenone analog 5b with propiophenone (6b)
afforded the (Z)-1-[4-(2-chloroethoxy)phenyl]-1-(4-iodophenyl)-
2-phenylbut-1-ene [(Z)-7b] regioisomer (20%). Subsequent reaction
of the chloroethoxy (Z)-7a and (Z)-7b regioisomers with N-methyl-
piperazine in EtOH at reflux furnished the respective N-methylpip-
Access to [124I] (t1/2 = 4.18 days) and [18F] (t1/2 = 109.6 min)
radiotracers with a longer radionuclide half-life is highly relevant
since it provides an extended time period, compared to [11C] with
a t1/2 = 20.4 min, during which optimal imaging can be carried out
based on the biodistribution and elimination (background wash-
out) properties of the radiotracer being investigated. In this regard,
[
124I] analogs of the iodophenyl (Z)-8a and (Z)-8b regioisomers will
be accessible using a CuSO4 catalyzed iodine isotope exchange
reaction using [124I]NaI.15 Alternatively, elaboration of the unla-
beled iodophenyl (Z)-8a and (Z)-8b regioisomers to the respective
Me
N
Cl
Cl
N
O
2
2
O
R
O
R
2
R
+
a
b
O
Et
Et
O
Et
1
R
5a, R1= H
5b, R1= I
6a, R2= I
1
1
R
6b, R2= H
R
(Z )-7a, R1= H, R2= I
(Z )-8a, R1= H, R2= I
(Z )-7b, R1= I, R2= H
(Z )-8b, R1= I, R2= H
Scheme 1. Reagents and conditions: (a) Zn, TiCl4, THF, reflux 3.5 h; (b) N-methylpiperazine, EtOH, reflux 24 h.

K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1195–1198
1197
Cl
Cl
OH
O
OH
O
OH
a
+
+
Et
Et
O
Et
O
Cl
O
(Z )-10a
(E)-10b
5a
9
(Z )-10a:(E)-10b = 1:1
OH
Me
N
N
b
O
OH
+
Et
Et
Me
N
N
O
(E)-11b
(Z )-11a
(Z )-11a:(E)-11b = 1:1
repeated fractional crystalization from
methanol
(Z )-11a
c
d
Me
N
N
F
O
O
Decomposition (loss of methylpiperazine
peaks in the NMR spectrum)
Et
(Z )-12
Scheme 2. Reagents and conditions: (a) Zn, TiCl4, THF, reflux 3.5 h; (b) 1-methylpiperazine, EtOH, reflux 24 h; (c) (i) K2CO3, Kryptofix 222, CH3CN, 50 °C, 15 min;
(ii) TsOCH2CH2F, reflux 10 min; (d) 5 N NaOH, CH3I, DMF, 60 °C, 3 min, or NaH, CH3I, DMF, 60 °C, 5 min.
tributylstannyl derivative and then treatment with [124I]ICl will
References and notes
provide high specific activity [124I)-labeled (Z)-8a and (Z)-8b
(-I?-SnBu3 + [124I]ICl?-[124I]).16 Reaction of the para-hydroxy-
1. Magarian, R. A.; Overacre, L. B.; Singh, S.; Meyer, K. L. Curr. Med. Chem. 1994, 1,
61.
phenyl (Z)-11a stereoisomer with
[
18F]TsOCH2CH2F in the
2. Jordan, V. C. Annu. Rev. Pharmacol. Toxicol. 1995, 35, 195.
3. Jordan, V. C. Lancet Oncol. 2000, 1, 43.
4. Robertson, D. W.; Katzenellenbogen, J. A.; Hayes, J. R.; Katzenellenbogen, B. S. J.
Med. Chem. 1982, 25, 167.
5. Agouridas, V.; Laios, I.; Cleeren, A.; Kizilian, E.; Magnier, E.; Blazejewski, J.-C.;
Leclercq, G. Bioorg. Med. Chem. 2006, 14, 7531.
6. Yang, D. J.; Wallace, S.; Tansey, W.; Wright, K. C.; Kuang, L.-R.; Tilbury, R. S.;
Diego, I.; Lim, J.-L.; Emran, A. M.; Kim, E. E. Pharm. Res. 1991, 8, 174.
7. Abdellatif, K. R. A.; Velázquez, C. A.; Huang, Z.; Chowdhury, M. A.; Knaus, E. E.
Bioorg. Med. Chem. Lett. 2010, 20, 5245.
presence of K2CO3 and Kryptofix 222 with CH3CN as solvent at
reflux with a reaction time of 10 min will provide a suitable
method to synthesize [18F] labeled (Z)-8.
In conclusion, (i) synthetic methodologies17 suitable for the
synthesis of the putative [124I] and [18F]labeled radiotracers illus-
trated in Figure 2 have been developed, and (ii) these potential
radiopharmaceuticals warrant investigation as PET imaging agents
to detect estrogen positive breast tumors.
8. Foster, A. B.; Jarman, M.; Leung, O.-T.; McCague, R.; Leclercq, G.;
Devleeschouwer, N. J. Med. Chem. 1985, 28, 1491.
9. McCague, R. Iodotamoxifen derivatives and use for estrogen receptor-positive
breast cancer detection and therapy. U. S. Patent 1989, 4839,155, June 13.
10. Shima, I.; Sano, Y.; Nakata, K.; Suzuki, M.; Yokoyama, T.; Sasaki, A.; Orikasa, T.;
Miyamoto, T.; Ikekita, M.; Nagahara, Y.; Hasome, Y. Bioorg. Med. Chem. 2007, 15,
7599.
Acknowledgment
We are grateful to the Canadian Institutes of Health Research
(CIHR) (MOP-14712) for financial support of this research.

1198
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1195–1198
11. Ram, S.; Spicer, L. D. J. Labelled Compd. Radiopharm. 1988, 6, 661.
12. McCague, R.; Leclercq, G.; Jordan, V. C. J. Med. Chem. 1988, 31, 1285.
13. McCague, R.; Leclercq, G.; Legros, N.; Goodman, J.; Blackburn, M.; Jarman, M.;
Foster, A. B. J. Med. Chem. 1989, 32, 2527.
14. Fauq, A. H.; Maharvi, G. M.; Sinha, D. Bioorg. Med. Chem. Lett. 2010, 20, 3036.
15. Stahlschmidt, A.; Machulla, H.-J.; Reischl, G.; Knaus, E. E.; Wiebe, L. I. Appl.
Radiat. Isot. 2008, 66, 1221.
(ES+) 553.1, C29H34IN2O (M+H) requires 553.49. Anal. Calcd for C29H33IN2OÁ1/
2H2O: C, 62.04; H, 6.10; N, 4.99. Found: C, 62.12; H, 5.98; N, 5.02.
(Z)-1-(4-Iodophenyl)-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-2-phe-
nylbut-1-ene [(Z)-8b]: The title compound (Z)-8b was synthesized from the
chloroethoxy compound (Z)-7b using the same procedure described for the
preparation of (Z)-8a as white crystals in 59% yield; mp 119–120 °C (from ether);
IR (film): 2961 (C–H aromatic), 2933 (C–H aliphatic) cmÀ1 1H NMR (CDCl3): d
;
16. Nanda, D.; de Jong, M.; Vogels, R.; Havenga, M.; Driesse, M.; Bakker, W.; Bijster,
M.; Avezaat, C.; Cox, P.; Morin, K.; Naimi, E.; Knaus, E.; Wiebe, L.; Sillevis Smitt,
P. Eur. J. Nucl. Med. Mol. Imag. 2002, 29, 939.
0.91 (t, J = 7.4 Hz, 3H, CH2CH3), 2.44 (q, J = 7.4 Hz, 2H, CH2CH3), 2.47 (s, 3H, NCH3),
2.65–2.88 (m, 10H, piperazinyl hydrogens and OCH2CH2N), 3.98 (t, J = 5.5 Hz, 2H,
OCH2CH2N), 6.58 (d, J = 9.2 Hz, 2H, ethoxyphenyl H-3, H-5), 6.80 (d, J = 9.2 Hz,
2H, ethoxyphenyl H-2, H-6), 7.02 (dd, J = 8.5, 1.8 Hz, 2H, iodophenyl H-2, H-6),
7.06–7.12 (m, 5H, phenyl hydrogens), 7.67 (dd, J = 8.5, 1.8 Hz, 2H, iodophenyl H-
3, H-5); 13C NMR (CDCl3): d 13.5, 29.0, 45.7, 53.1, 54.8, 57.0, 65.7, 92.0, 113.6,
126.2, 127.9, 129.4, 129.6, 131.5 131.8, 135.1, 137.1, 137.2, 142.0, 142.1, 156.8;
MS m/z (ES+) 553.1, C29H34IN2O (M+H) requires 553.49. Anal. Calcd for
17. Experimental procedures and spectral data for compounds (Z)-7a–b, (Z)-8a–b,
(Z)-11a, (Z)-12. General: Melting points were determined on a Thomas–Hoover
capillary apparatus and are uncorrected. Infrared (IR) spectra were recorded as
films on NaCl plates using a Nicolet 550 Series II Magna FT-IR spectrometer. 1
H
NMR and 13C NMR spectra were measured on a Bruker AM-300 spectrometer
in CDCl3, CD3OD, or CDCl3 + CD3OD with TMS as the internal standard, where J
(coupling constant) values are estimated in Hertz (Hz). Mass spectra (MS) were
C
29H33IN2O: C, 63.04; H, 6.02; N, 5.07. Found: C, 62.97; H, 5.94; N, 5.07.
(Z)-2-(4-Hydroxylphenyl)-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-1-
phenylbut-1-ene [(Z)-11a]: Titanium tetrachloride (1.97 mL, 18 mmol) was
added drop wise to a stirred suspension of Zn powder (2.35 g, 36 mmol) in dry
THF (30 mL) under an argon atmosphere at À10 °C, and this mixture was heated
at reflux for 1.5 h to produce the titanium reagent. A cooled suspension of this
titanium reagent was added to a solution of 4-(2-chloroethoxy)benzophenone
(5a, 1.56 g, 6.0 mmol) and 4-hydroxypropiophenone (9, 0.9 g, 6.0 mmol) in THF
(40 mL) at 0 °C, and the reaction was allowed to proceed at reflux for 2 h. After
cooling to 25 °C, the reaction mixture was poured into a 10% aqueous K2CO3
solution (90 mL), this mixture was stirred vigorously for 5 min, and the dispersed
insoluble material was removed by vacuum filtration. The organic fraction was
separated, the aqueous layer was extracted with EtOAc (3 Â 50 mL), and the
combined organic fractions were dried (Na2SO4). Removal of the solvent in vacuo
gave a residue which was purified by silica gel column chromatography using
EtOAc–hexane (1:4, v/v) as eluent to furnish a mixture of the (Z)-10a and (E)-10b
stereoisomers in a ratio of 1:1 (1H NMR integrals) in 44% yield (1.0 g); mp 136–
138 °C. All attempts to separate these (Z)-10a and (E)-10b stereoisomers by
fractional crystallization from solvents of different polarity (diethyl ether, ethyl
acetate, isopropanol and ethanol) were unsuccessful. Therefore, this mixture of
recorded on
a Water’s Micromass ZQ 4000 mass spectrometer using the
electrospray (ES) ionization mode. Microanalyses were performed for C, H, N
by the Microanalytical Service Laboratory, Department of Chemistry,
University of Alberta. Silica gel column chromatography was performed
using Merck silica gel 60 ASTM (70–230 mesh). All other reagents, purchased
from the Aldrich Chemical Company (Milwaukee, WI), were used without
further purification. The 4-(2-chloroethoxy)benzophenone (5a),18 1-[4-(2-
chloroethoxy)phenyl](4-iodophenyl)methanone (5b)19 and p-iodopropio-
phenone (6a)20 were prepared according to the literature procedures. The
chemical name for K222 (Kryptofix 222) is 1,10-diaza-4,7,13,16,21,24-
hexaoxabicyclo[8.8.8]hexacosane.
(Z)-1-[4-(2-Chloroethoxy)phenyl]-2-(4-iodophenyl)-1-phenylbut-1-ene [(Z)-7a]:
Titanium tetrachloride (0.99 mL, 9 mmol) was added drop wise to a stirred
suspension of Zn powder (1.18 g, 18 mmol) in dry THF (15 mL) under an argon
atmosphere at À10 °C, and this mixture was heated at reflux for 1.5 h to
produce the titanium reagent. A cooled suspension of this titanium reagent
was added to
a solution of 4-(2-chloroethoxy)benzophenone (5a, 0.78 g,
3.0 mmol) and p-iodopropiophenone (6a, 0.78 g, 3.0 mmol) in THF (20 mL) at
0 °C, and the reaction was allowed to proceed at reflux for 2 h. After cooling to
25 °C, the reaction mixture was poured into a 10% aqueous K2CO3 solution
(45 mL), this mixture was stirred vigorously for 5 min, and the dispersed
insoluble material was removed by vacuum filtration. The organic fraction was
separated, the aqueous layer was extracted with EtOAc (3 Â 25 mL), and the
combined organic fractions were dried (Na2SO4). Removal of the solvent in
(Z)-10a and (E)-10b, without separation, was added to
a solution of N-
methylpiperazine (26.4 g, 264 mmol) in ethanol (50 mL). The mixture was
heated under reflux for 24 h, the solvent was evaporated in vacuo, and the
residue obtained was purified by silica gel column chromatography using
methanol-chloroform (1:9, v/v) as eluent to give a 1:1 (1H NMR integrals) of the
(Z)-11a and (E)-11b stereoisomers in 90% yield (1.05 g). Repeated fractional
crystallization of this mixture from methanol furnished 170 mg of (Z)-11a as a
white solid; mp 181–183 °C; IR (film): 3505–3097 (O–H), 2967 (C–H aromatic),
vacuo afforded
a residue which was purified by silica gel column
chromatography using EtOAc–hexane (1:4, v/v) as eluent followed by
recrystallization of the product from ethanol to give (Z)-7a as a white solid
(0.5 g, 35%); mp 117–118 °C; IR (film): 2966 (C–H aromatic), 2931 (C–H
2930 (C–H aliphatic) cmÀ1 1H NMR (CDCl3): d 0.95 (t, J = 7.4 Hz, 3H, CH2CH3),
;
2.35 (s, 3H, NCH3), 2.44 (q, J = 7.4 Hz, 2H, CH2CH3), 2.60–2.77 (m, 8H, piperazinyl
hydrogens), 2.75 (t, J = 5.5 Hz, 2H, OCH2CH2N), 4.01 (t, J = 5.5 Hz, 2H, OCH2CH2N),
6.53 (d, J = 8.6 Hz, 2H, ethoxyphenyl H-3, H-5), 6.63 (d, J =8.6 Hz, 2H,
hydroxyphenyl H-3, H-5), 6.78 (d, J = 8.6 Hz, 2H, ethoxyphenyl H-2, H-6), 7.01
(d, J =8.6 Hz, 2H, hydroxyphenylH-2, H-6), 7.23–7.38 (m, 5H, phenylhydrogens);
MS m/z (ES+) 443.2, C29H35N2O2 (M+H) requires 443.59.
aliphatic) cmÀ1 1H NMR (CDCl3): d 0.92 (t, J = 7.4 Hz, 3H, CH2CH3), 2.43 (q,
;
J = 7.4 Hz, 2H, CH2CH3), 3.73 (t, J = 5.5 Hz, 2H, OCH2CH2Cl), 4.13 (t, J = 5.5 Hz,
2H, OCH2CH2Cl), 6.59 (dd, J = 6.7, 1.8 Hz, 2H, chloroethoxyphenyl H-3, H-5),
6.78 (dd, J = 6.7, 1.8 Hz, 2H, chloroethoxyphenyl H-2, H-6), 6.88 (d, J = 8.3 Hz,
2H, iodophenyl H-2, H-6), 7.20–7.37 (m, 5H, phenyl hydrogens), 7.50 (d,
J = 8.3 Hz, 2H, iodophenyl H-3, H-5); 13C NMR (CDCl3): d 13.5, 28.8, 41.8, 67.8,
91.5, 113.8, 126.7, 128.2, 129.3, 131.7, 131.9, 135.8, 137.0, 138.9, 140.4, 142.0,
143.4, 156.3; MS m/z (ES+) 489.0, C24H23ClIO (M+H) requires 489.79.
(Z)-1-[4-(2-Chloroethoxy)phenyl]-1-(4-iodophenyl)-2-phenylbut-1-ene (7b): The
title compound 7b was synthesized using the same procedure described for the
preparation of 7a, by reaction of (4-chloroethoxyphenyl)(4-iodophenyl)-
methanone (5b) with the propiophenone (6b). The product obtained after
columnchromatography is a1:1 mixture(NMR)of the(Z)-and(E)-stereoisomers
from which the target (Z)-7b stereoisomer could be recrystallized from ethanol
as white crystals in 20% yield; mp 94–96 °C (Lit.13 mp 96–97 °C). The 1H NMR
spectral data for (Z)-7b was the same as previously reported data.13
(Z)-2-[4-(2-Fluoroethoxy)phenyl]-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]
phenyl]-1-phenylbut-1-ene [(Z)-12]: A mixture of the phenol [(Z)-11a, 111 mg,
0.25 mmol], Kryptofix 222 (94 mg, 0.25 mmol) and anhydrous potassium
carbonate (38 mg, 0.28 mmol) in acetonitrile (3 mL) was heated at 50 °C for
15 min. 2-Fluoroethyl p-toluenesulfonate (55 mg, 0.25 mmol) was added and
the mixture was heated under reflux for 10 min. After cooling to 25 °C, the solid
was separated by filtration, the filtrate was concentrated in vacuo, and the
residue was purified by silica gel column chromatography using EtOAc–hexane
(9:1, v/v) as eluent to give (Z)-12 as a pale yellow gum (79 mg, 35%); IR (film):
2962 (C–H aromatic), 2933 (C–H aliphatic) cmÀ1 1H NMR (CDCl3): d 0.93 (t,
;
J = 7.4 Hz, 3H, CH2CH3), 2.31 (s, 3H, NCH3), 2.44 (q, J = 7.4 Hz, 2H, CH2CH3), 2.49–
2.76 (m, 8H, piperazinyl hydrogens), 2.77 (t, J = 5.5 Hz, 2H, OCH2CH2N), 4.00 (t,
J = 5.5 Hz, 2H, OCH2CH2N), 4.20 (ddd, J = 28.0, J = 4.2, 4.2 Hz, 2H, OCH2CH2F), 4.74
(ddd, J = 48.0, J = 4.2, 4.2 Hz, 2H, OCH2CH2F), 6.57 (d, J = 8.6 Hz, 2H, ethoxyphenyl
H-3, H-5), 6.76 (d, J =8.6 Hz, 2H, fluoroethoxyphenyl H-3, H-5), 6.79 (d, J = 8.6 Hz,
2H, ethoxyphenylH-2, H-6), 7.06 (d, J =8.6 Hz, 2H, fluoroethoxyphenyl H-2, H-6),
7.22-7.38 (m, 5H, phenyl hydrogens); 13C NMR (CDCl3): d 13.6, 28.9, 45.8, 53.2,
54.9, 57.1, 65.6, 66.95 (d, 2JCCF = 19.7 Hz), 81.4 (d, 1JCF = 169.2 Hz), 113.5, 114.1,
127.3, 128.1, 129.4, 130.8, 131.8 135.2, 136.3, 138.0, 140.7, 143.5, 143.9, 156.6;
MS m/z (ES+) 489.2, C31H42FN2O4 (M+H) requires 489.64. Anal. Calcd for
(Z)-2-(4-Iodophenyl)-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-1-phe-
nylbut-1-ene [(Z)-8a]: (Z)-1-[4-(2-Chloroethoxy)phenyl]-2-(4-iodophenyl)-1-
phenylbut-1-ene [(Z)-7a, 245 mg, 0.5 mmol] and N-methylpiperazine (5.0 g,
50 mmol) in ethanol (10 mL) was heated under reflux for 24 h. The solvent was
evaporated under vacuum and the residue purified by silica gel column
chromatography using methanol–chloroform (1:9, v/v) as eluent followed by
recrystallizationof the productfrom petroleum ether(35–60 °C)to give(Z)-8aas
a white solid (149 mg, 54%); mp 93–95 °C; IR (film): 2966 (C–H aromatic), 2932
(C–H aliphatic) cmÀ1 1H NMR (CDCl3): d 0.91 (t, J = 7.4 Hz, 3H, CH2CH3), 2.42 (q,
;
J = 7.4 Hz, 2H, CH2CH3), 2.44 (s, 3H, NCH3), 2.55–2.70 (m, 8H, piperazinyl
hydrogens), 2.79 (t, J = 5.5 Hz, 2H, OCH2CH2N), 4.00 (t, J = 5.5 Hz, 2H, OCH2CH2N),
6.57 (dd, J = 6.7, 2.4 Hz, 2H, ethoxyphenyl H-3, H-5), 6.76 (dd, J = 6.7, 2.4 Hz, 2H,
ethoxyphenyl H-2, H-6), 6.87 (dd, J = 6.1, 1.8 Hz, 2H, iodophenyl H-2, H-6), 7.19–
7.37 (m, 5H, phenyl hydrogens), 7.49 (dd, J = 6.1, 1.8 Hz, 2H, iodophenyl H-3, H-
5); 13C NMR (CDCl3): d 13.6, 28.8, 45.7, 53.1, 54.8, 57.1, 65.7, 91.4, 113.6, 126.7,
128.1, 129.3, 130.7, 131.8 135.2, 137.0, 139.0, 140.1, 142.0, 143.4, 156.8; MS m/z
C
31H41FN2O4Á1.7H2O: C, 71.46; H, 7.85; N, 5.38. Found: C, 71.22; H, 7.32; N, 5.13.
18. Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans. 1 1986, 475.
19. Ace, K. W.; Armitage, M. A.; Bellingham, R. K.; Blacker, P. D.; Ennis, D. S.;
Hussain, N.; Lathbury, D. C.; Morgan, D. O.; O’Connor, N.; Oakes, G. H.; Passey,
S. C.; Powling, L. C. Org. Process Res. Dev. 2001, 5, 479.
20. Yuan, Y.; Jin, D.; Qu, Y. Chinese Patent, CN1733676A, 2006.