Practical synthesis of FEt-penta-cyclofenil and its derivatives for potential PET imaging

Article abstract of DOI:10.1080/00397910903419829

Generally, FEt-penta-cyclofenil and its derivatives have greater relative binding affinity to estradiol receptors than estradiol. (4-Fluoroethoxyphenyl)- (4'-hydroxyphenyl) methylenecyclopentane and its derivatives were synthesized for potential radioactive image agents, and their structures were characterized by ultraviolet, infrared, ¹H NMR, ¹⁹F NMR, and high-resolution mass spectrometry. Copyright

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Practical Synthesis of FEt-penta-
cyclofenil and Its Derivatives for
Potential PET Imaging
Hua Zhu a b , Liliang Huang a b , Xiaoping Xu a b & Yu-Mei Shen a c
a Radiopharmaceuticals Center, Shanghai Institute of Applied
Physics, Chinese Academy of Sciences , Shanghai, China
b Graduate School of the Chinese Academy of Sciences , Beijing,
China
c Shanghai Center for Systems Biomedicine, Ministry of Education
Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong
University , Shanghai, China
Published online: 15 Oct 2010.
To cite this article: Hua Zhu , Liliang Huang , Xiaoping Xu & Yu-Mei Shen (2010) Practical Synthesis
of FEt-penta-cyclofenil and Its Derivatives for Potential PET Imaging, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:22, 3322-3331,
DOI: 10.1080/00397910903419829
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Synthetic Communications1, 40: 3322–3331, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903419829
PRACTICAL SYNTHESIS OF FEt-PENTA-CYCLOFENIL
AND ITS DERIVATIVES FOR POTENTIAL PET IMAGING
Hua Zhu,1,2 Liliang Huang,1,2 Xiaoping Xu,1,2
and Yu-Mei Shen1,3
1Radiopharmaceuticals Center, Shanghai Institute of Applied Physics,
Chinese Academy of Sciences, Shanghai, China
2Graduate School of the Chinese Academy of Sciences, Beijing, China
3Shanghai Center for Systems Biomedicine, Ministry of Education Key
Laboratory of Systems Biomedicine, Shanghai Jiao Tong University,
Shanghai, China
Generally, FEt-penta-cyclofenil and its derivatives have greater relative binding affinity
to estradiol receptors than estradiol. (4-Fluoroethoxyphenyl)–(40-hydroxyphenyl)
methylenecyclopentane and its derivatives were synthesized for potential radioactive image
agents, and their structures were characterized by ultraviolet, infrared, 1H NMR, 19F
NMR, and high-resolution mass spectrometry.
Keywords: Cyclofenil; PET imaging agent; radiolabeling
INTRODUCTION
Early detection and accurate staging is very important for cancer treatment.
For breast cancer, proper staging includes the determination of estradiol receptor
(ER) status, which is overexpressed in many cases.[1] A number of estradiol (E2)
derivatives labeled with fluorine,[2,3] bromine,[4,5] and iodine[6] have been developed
as positron emission tomography (PET) imaging agents. Selective ER modulators
have been investigated more for steroidal estrogens, and only a few for nonsteroidal
estrogens or antiestrogens.[7–10]
The ER displays a remarkable capacity for binding nonsteroidal ligands with
high affinity.[11] There are two structurally similar subtypes, ERa and ERb, and they
have different biological properties.[12,13] It is notable that in breast cancer the level
of ERb relative to ERa declines with cancer progression.[14–16] Seo et al. proposed
the structure model with greater relative binding affinity (RBA) to ER.[17] Cyclofenil
derivatives, distinguished greatly in RBA value, generally have greater binding
Received April 1, 2009.
Address correspondence to Yu-Mei Shen, Radiopharmaceuticals Center, Shanghai Institute of
Applied Physics, Chinese Academy of Sciences, 2019 Baojia Road, Shanghai 201800, China. E-mail:
shenyumei@sinap.ac.cn
3322

FEt-PENTA-CYCLOFENIL AND ITS DERIVATIVES
3323
affinity than E2.[18] Introducing fluorine in the structure of cyclofenil derivatives
greatly improved the RBA to ER.[19] 18F-labeled fluoro-cyclofenils’ analog
4-[18F] fluoro [bis (4-hydoroxyphenyl) methylene] cyclohexane ([18F]-FCF) and
11C-labeled cyclofenil-ester [11C]methyl-2-{4-[bis(4-hydroxyphenyl) methylene]
cyclohexyl}-acetate ([11C]-CCFE) have been synthesized and investigated as poten-
tial PET agents. Unfortunately, these ligands with high affinity for the ER failed
to show receptor-mediated uptake into the uterus.[20,21] In the structure’s modifica-
tions for cyclofenil derivatives, at least one phenol hydroxyl must be kept free.[22,23]
Herein we report our preliminary result for the synthesis of these compounds
for evaluation as potential radioactive PET imaging agents.
RESULTS AND DISCUSSION
Synthesis of Cyclofenil 2–4
The synthetic procedure for cyclofenil and its analogs 2–4 is shown in Table 1.
The cyclofenil and its analogs were prepared via a McMurry coupling reaction
between 4,40-dihydroxybenzophenone 1 and ketone.[24,25] The low-valent titanium
was formed by reaction of TiCl4 with zinc power in absolute tetrahydrofuran
(THF) at 100 ꢀC. A mixture of 1 and ketone dissolved in absolute THF was injected
into the flask by syringe, followed by refluxing for 2 h. Under the optimized con-
ditions, all of the reactions gave reasonable yields of 78–85%, which is much greater
than that literature reported.
Table 1. Synthesis of cyclofenil 2–4

3324
H. ZHU ET AL.
Scheme 1. Three-step synthesis of 7a.
Rapid and Separation-Free Synthesis of FEt-Cyclofenil
The synthetic procedure of FEt-penta-cyclofenil 7a is for developing a poten-
tial radioactive fluorine-labeling method (Scheme 1).
Compound 2a was dissolved in acetone, and potassium carbonate was added
under an N2 atmosphere. The mixture was cooled to ꢁ5 ꢀC, and methoxymethyl
chloride (MOMCl) was added dropwise. The mixture was stirred about 2 h to give
mono-substituted product MOM-penta-cyclofenil 5. This experiment must be per-
formed below 0 ꢀC because MOMCl is very active.
The synthesis of FEt-MOM-penta-cyclofenil 6 started from fluoroethyltosylate
(FEtOTs), followed by adding compound 5 in acetone under basic conditions. The
mixture was stirred at 65 ꢀC for 50 min. The reaction time was controlled within
1 h with yield of more than 95%.
The general method to remove the MOM group is to overnight at room
temperature. For radioactive labeling synthesis, the reaction temperature was
kept at 60 ꢀC, and compound 7a was formed quantitatively from 6 within
10 min. The high yield and short reaction time make it a potential radioactive
labeling method.
One-Step Synthesis of FEt-Cyclofenil
In this method, although the reaction time was controlled within 1 h, the
two-step procedure is still not convenient for radiolabeling, so a one-step syn-
thetic procedure for fluorinated cyclofenil (7–9) was developed as shown in
Table 2.
Take FEt-penta-cyclofenil 7a as an example: compound 2a was dissolved in
acetone, and then FEtOTs, potassium carbonate (K2CO3), and potassium iodide
(KI) were added to the flask separately under a nitrogen atmosphere. The tempera-
ture was controlled at 60 ꢀC and stirred for 1 h. After purification by flash chroma-
tography, the pure compound 7a was given with up to 85% yield. It is notable that
this reaction’s temperature is extremely important and should be controlled between
59 and 61 ꢀC.

FEt-PENTA-CYCLOFENIL AND ITS DERIVATIVES
3325
Table 2. One-step synthesis of FEt-cyclofenil 7–9
CONCLUSION
Cyclofenil and its analogs were synthesized for evaluation as potential radio-
active PET image agents. Under controlled conditions, the reaction time for both
of them is 1 h. The three-step method for the reaction is very clear and can be used
directly without further purification in animal experiments. For the one-step
method, a little by-product was formed in the reaction; however, in a radioactive
labeling reaction, if the labeling yield can be kept at 85%, the method will be more
practical.
EXPERIMENTAL
General Experimental Procedures
Melting points (mp) were determined on a WRS-1A melting-point apparatus
and were uncorrected. 1H and 19F NMR spectra were recorded on a Bruker
AC-300 (300-MHz) instrument with Me4Si and CFCl3 as internal standards in the
indicated solution. Chemical shifts were reported in d values in parts per million
(ppm) downfield from Me4Si (d ¼ 0) for proton and upfield from CFCl3 (d ¼ 0) for
fluorine NMR. Electrospray ionization high-resolution mass spectra electron
(ESI-HRMS) were obtained on a Micromass GCTTM. Infrared spectra (IR) were
recorded on an Avatar 370 Fourier transform FT–IR (Thermo Nicolet) as KBr disc.
Ultraviolet spectra (UV) were recorded on a Shimadzu UV-240 spectrophotometer.

3326
H. ZHU ET AL.
Synthesis of Cyclofenil and Its Analogs 2–4
A two-necked flask containing zinc powder (2.4 g, 37.0 mmol) was fitted with a
reflux condenser, and charged with N2. After THF (15 mL) was added, the reaction
mixture was cooled in an ice bath (0 ꢀC), and then titanium(IV) chloride (3.28 g,
17.24 mmol) was slowly added. The reaction was refluxed for 1 h at 100 ꢀC and then
cooled to room temperature. A solution of 1 (1.00 g, 4.66 mmol) and each ketone
(aldehyde) (5.3 mmol) dissolved in THF (15 mL) was injected by syringe and refluxed
for 2 h. The cooled reaction mixture was slowly poured into a NaHCO3 solution
(50 mL) and then filtered through celite. After the organic layer was decanted and
saved, the aqueous layer was extracted with additional CH2Cl2 (100 mL). The
combined organic layer was dried over MgSO4 and concentrated. Flash-column
chromatography or recrystallization from hexane=dichloromethane (DCM) gave a
white solid.
Selected Data
Bis(4-hydroxyphenyl)methylenecyclopentane (2a). Yield 81.0%, white
solid, mp 193–194 ꢀC; IR (KBr): n 3280, 2949, 1613, 1592, 1429, 1332, 840,
562 cmꢁ1 1H NMR (DMSO-d6) d: 9.25 (s, 2H, -OH), 6.91 (d, 4H, aromatic,
;
J ¼ 8.6 Hz), 6.66 (d, 4H, aromatic, J ¼ 8.6 Hz), 2.28 (t, 4H, C2-H, J ¼ 6.8 Hz), 1.61
2
3
(dt, 4H, C3-H, JH-H ¼ 6.6 Hz, JH-H ¼ 2.7 Hz).
Bis(4-hydroxyphenyl)methylenecyclohexane (2b). Yield 78.0%, white
solid, mp 235.1–237.0 ꢀC; IR (KBr): n 3276, 2929, 1605, 1507, 1429, 1225, 1168,
1
833, 563 cmꢁ1; H NMR (DMSO-d6) d: 9.25 (2H, s, -OH), 6.81 (4H, d, J ¼ 8.6 Hz,
aromatic), 6.64 (4H, d, J ¼ 7.6 Hz, aromatic), 2.14 (4H, s, C2-H), 1.49–1.60 (6H,
m, C3,4-H).
Bis(4-hydroxyphenyl)methylenecycloheptane (2c). Yield 83.0%, white
solid, mp 195–198 ꢀC; IR (KBr): n 3248, 2933, 1609, 1503, 1230, 829, 567 cmꢁ1
;
1H NMR (acetone-d6) d: 6.95 (4H, d, J ¼ 7.3 Hz, aromatic), 6.74 (4H, d, J ¼ 7.3 Hz,
aromatic), 2.26 (4H, t, J ¼ 6.0 Hz, C2-H), 1.50–1.70 (m, 8H, C3,4-H).
4-Methyl[bis(4-hydroxyphenyl)methylene]cyclohexane (3a). Yield 82.7ꢁ%1,
white solid, mp 183–184 ꢀC; IR (KBr): n 3249, 2924, 1608, 1509, 1235, 827, 569 cm
;
1H NMR (CDCl3) d: 6.80 (4H, d, J ¼ 8.4 Hz, aromatic), 6.74 (4H, d, J ¼ 8.1 Hz,
aromatic), 4.67 (2H, s, -OH), 2.57 (2H, bd, J ¼ 13.2 Hz, C2-H), 1.94 (2H, td,
J ¼ 13 Hz, C2-H), 1.70–1.80 (2H, m, C3-H), 1.55–1.65 (1H, m, C4-H), 0.93–1.1
(2H, m, C3-H), 0.92 (3H, d, J ¼ 8.0 Hz, -CH3).
3-Methyl[bis(4-hydroxyphenyl)methylene]cyclohexane (3b). Yield 78.0%,
white solid, mp 172.2–172.7 ꢀC; IR (KBr): n 3238, 2930, 1612, 1506, 1231, 831,
2
3
565 cmꢁ1; 1H NMR (CDCl3) d: 6.80 (4H, dd, JH-H ¼ 6.39 Hz, JH-H ¼ 2.24 Hz, aro-
matic), 6.72 (4H, dd, 2JH-H ¼ 5.93 Hz, 3JH-H ¼ 2.96 Hz, aromatic), 4.67 (2H, s, -OH),
0
2.51 (2H, bd, J ¼ 12.3 Hz, C2-H), 1.77 (2H, td, C2 ꢁH, J ¼ 11.6 Hz), 1.50–1.70 (4H,
m, C3’,4-H), 1.30–1.40 (1H, m, C3-H), 0.87 (3H, d, J ¼ 6.19 Hz, -CH3).
Iso-[bis(4-hydroxyphenyl)methylene]butane (4). Yield 85.0%, white solid,
mp 168.4–170.4 ꢀC; IR (KBr): n 3314, 2958, 1607, 1513, 1223, 835, 595 cmꢁ1; 1H NMR

FEt-PENTA-CYCLOFENIL AND ITS DERIVATIVES
3327
(CDCl3) d: 7.09 (2H, d, J¼ 8.7 Hz, aromatic), 7.04 (2H, d, J¼ 8.7 Hz, aromatic), 6.82 (2H,
d, J¼ 8.7 Hz, aromatic), 6.71 (2H, d, J¼ 8.7 Hz, aromatic), 5.72 (1H, d, J¼ 10.3 Hz,
alkene-H), 4.88 (2H, s, -OH), 2.42 (1H, m, C-H), 1.00 (6H, d, J¼ 6.9 Hz, -CH3).
Synthesis of (4-Methoxymethylphenyl)-(4’-hydroxyphenyl)
methylenecycloheptane (5)
Two-necked flask containing 2a (800 mg, 3.0 mmol) and K2CO3 (960 mg,
6.9 mmol) was charged with N2. After acetone (10 mL) was added, it was stirred
and cooled to ꢁ5 ꢀC, and MOMCl (0.27 ml, 3.3 mmol) dissolved in another 10 mL
acetone was dropped into the mixture and then reacted for 2 h below zero. The reac-
tion stopped, the solvent was filtered, and the filtrate was evaporated under reduced
pressure and purified by column chromatography. The desired product, straw yellow
oil, was obtained in 37.3% yield (350 mg). IR (KBr): n 3320, 2941, 1610, 1585, 1214,
1
1165, 1018, 916, 766 cmꢁ1; H NMR (CDCl3) d: 7.09 (2H, d, J ¼ 8.7 Hz, aromatic),
7.04 (2H, d, J ¼ 7.8 Hz, aromatic), 6.94 (2H, d, J ¼ 8.7 Hz, aromatic), 6.84 (2H, d,
J ¼ 8.6 Hz, aromatic), 5.18 (2H, s, -OCH2O-), 3.49 (3H, s, -OCH3), 2.37–2.38 (4H,
m, C2-H), 1.60–1.70 (4H, m, C3-H).
Synthesis of (4-Fluoroethoxyphenyl)-(4’-methoxymethylphenyl)
methylenecycloheptane (6)
A flask containing 5 (300 mg, 0.97 mmol) and K2CO3 (200 mg, 1.45 mmol) was
fitted with a reflux condenser and charged with nitrogen gas. After acetone (15 mL)
was added, stirred, and heated to 60 ꢀC, FEtOTs (400 mg, 1.83 mmol) dissolved in
another 10 mL acetone was dropped into the mixture and then reacted for 1 h at
65 ꢀC. The reaction stopped, the solvent was filtered while hot, the filtrate was eva-
porated under reduced pressure, and water was added to remove the inorganic salt.
Then the residue was filtered, rinsed with water, extracted with additional CH2Cl2
(10 mL), and concentrated without further purification. The desired product, yellow
oil, was obtained in 93.3% yield (317 mg). UV (EtOH): k 205, 232 nm; IR (KBr): n
1
2954, 1607, 1508, 1241, 1175, 1008, 924, 775 cmꢁ1; H NMR (CDCl3) d: 7.05–7.15
(4H, m, aromatic), 6.94 (2H, d, J ¼ 8.7 Hz, aromatic), 6.84 (2H, d, J ¼ 8.6 Hz,
2
2
aromatic), 5.16 (2H, s, -OCH2O-), 4.74 (2H, dt, JH-F ¼ 47.36 Hz, JH-H ¼ 4.18 Hz,
3
2
-CH2F), 4.20 (2H, dt, JH-F ¼ 27.65 Hz, JH-H ¼ 4.17 Hz, -OCH2-), 3.49 (3H, s,
-OCH3), 2.36–2.38 (4H, m, C2-H), 1.62–1.72 (4H, m, C3-H); 19F NMR (CDCl3) d:
2
3
ꢁ223.09 (1 F, tt, JF-H ¼ 50.10 Hz, JF-H ¼ 23.08 Hz).
Synthesis of (4-Fluoroethoxyphenyl)-(4’-hydroxyphenyl)
methylenecycloheptane (7a)
Two-necked flask containing 6 (100 mg, 0.28 mmol) was fitted with a reflux
condenser and charged with N2. Concentrated HCl (0.4 mL) dissolved in 10 ml
CH3OH was injected by syringe. The reaction mixture was stirred at room
temperature for 12 h, rinsed with saturation NaHCO3, then extracted with additional
CH2Cl2, and concentrated without further purification. Desired product, straw
yellow oil, was obtained in about 99% yield (86.7 mg). It also can be obtained by

3328
H. ZHU ET AL.
stirring at 60 ꢀC for 10 min to get about 95% yield. UV (EtOH): k 208, 225, 265 nm;
1
IR (KBr): n 3350, 2953, 2864, 1605, 1164, 829, 575 cmꢁ1; H NMR (CDCl3) d: 7.09
(2H, d, J ¼ 8.3 Hz, aromatic), 7.03 (2H, d, J ¼ 8.2 Hz, aromatic), 6.84 (2H, d,
2
J ¼ 8.3 Hz, aromatic), 6.74 (2H, d, J ¼ 8.4 Hz, aromatic), 4.7 (2H, dt, JH-F
¼
2
3
2
47.44 Hz, JH-H ¼ 3.88 Hz, -CH2F), 4.39 (2H, dt, JH-F ¼ 27.79 Hz, JH-H ¼ 5.98 Hz,
-OCH2-), 2.40–2.45 (4H, m, C2-H), 1.60–1.70 (4H, m, C3-H); 19F NMR (CDCl3)
2
3
d: ꢁ223.83 (1 F, tt, JF-H ¼ 50.55 Hz, JF-H ¼ 24.45 Hz); ESI-HRMS calcd. for
C20H22O2F [M þ 1]þ 313.1604; found 313.1604.
One-Step Synthesis of FEt-Cyclofenil and Its Analogs 7–9
A flask containing cyclofenil (1.0 mmol), 2-fluoroethyl tosylate (305 mg,
1.4 mmol), K2CO3 (205 mg, 1.5 mmol), and KI (17 mg, 0.2 mmol) was fitted with a
reflux condenser and charged with nitrogen gas. After acetone (10 mL) was added,
the mixture was stirred and heated to 60 ꢀC for 6 h. The reaction stopped, the solvent
was filtered while hot, the filtrate was evaporated under reduced pressure, and water
was added to remove the inorganic salt. Then the residue was filtered, rinsed with
water, and purified by column chromatography.
Selected Data
(4-Fluoroethoxyphenyl)-(4’-hydroxyphenyl)methylenecyclopentane (7a).
Yield 85.0%, characterized previously.
(4-Fluoroethoxyphenl)-(4’-hydroxyphenyl)methylenecyclohexane
(7b). Yield 61.0%, white solid, mp 73.5–75.5 a; UV (EtOH): k 207, 253 nm; IR
1
(KBr): n 3259, 2921, 1707, 1609, 1169, 833, 575 cmꢁ1; H NMR (CDCl3) d: 7.01
(2H, d, J ¼ 8.9 Hz, aromatic), 6.92 (2H, d, J ¼ 8.9 Hz, aromatic), 6.83 (2H, d,
2
J ¼ 7.4 Hz, aromatic), 6.73 (2H, d, J ¼ 7.3 Hz, aromatic), 4.7 (2H, dt, JH-F
¼
2
3
2
47.46 Hz, JH-H ¼ 2.66 Hz, -CH2F), 4.18 (2H, dt, JH-F ¼ 27.72 Hz, JH-H ¼ 2.84 Hz,
-OCH2-), 2.10–2.25 (4H, m, C2-H), 1.50–1.70 (6H, m, C3,4-H); 19F NMR (CDCl3)
2
3
d: ꢁ223.03 (tt, 1F, JF-H ¼ 49.35 Hz, JF-H ¼ 24.55 Hz); ESI-HRMS calcd. for
C21H24O2F [M þ 1]þ 327.1760; found 327.1765.
(4-Fluoroethoxyphenyl)-(4’-hydroxyphenyl)methylenecyclopentane
(7c). Yield 66.4%, yellow oil; UV (EtOH): k 209, 225 nm; IR (KBr): n 3293, 2913,
1605, 1507, 1180, 608 cmꢁ1; 1H NMR (CDCl3) d: 7.06 (2H, d, J ¼ 8.6 Hz, aromatic),
7.00 (2H, d, J ¼ 8.4 Hz, aromatic), 6.83 (2H, d, J ¼ 8.5 Hz, aromatic), 6.72 (2H, d,
2
2
J ¼ 8.4 Hz, aromatic), 4.72 (2H, dt, JH-F ¼ 47.37 Hz, JH-H ¼ 4.13 Hz, -CH2F),
3
2
4.18 (2H, dt, JH-F ¼ 27.65 Hz, JH-H ¼ 4.1 Hz, -OCH2-), 2.30–2.45 (4H, m, C2-H),
2
1.50–1.70 (8H, m, C3,4-H); 19F NMR (CDCl3) d: ꢁ223.16 (1F, tt, JF-H ¼ 50.55 Hz,
3JF-H ¼ 23.03 Hz); ESI-HRMS calcd. for C22H26O2F [M þ 1]þ 341.1917; found
341.1928.
4-Methyl-[(4-fluoroethoxyphenyl)-(4’-hydroxyphenyl)methylene]-
cyclohexane (8a). Yield 77.1%, straw yellow oil; UV (EtOH): k 225 nm; IR (KBr):
1
n 3270, 2810, 1599, 1359, 1178, 922, 555 cmꢁ1; H NMR (CDCl3) d: 7.02 (2H, d,
J ¼ 8.7 Hz, aromatic), 6.96 (2H, d, J ¼ 8.4 Hz, aromatic), 6.83 (2H, d, J ¼ 8.7 Hz,

FEt-PENTA-CYCLOFENIL AND ITS DERIVATIVES
3329
2
2
aromatic), 6.72 (2H, d, J ¼ 8.1 Hz, aromatic), 4.81 (2H, dt, JH-F ¼ 47.1 Hz, JH-H
3
2
¼ 4.42 Hz, -CH2F), 4.18 (2H, dt, JH-F ¼ 27.6 Hz, JH-H ¼ 4.1 Hz, -OCH2-), 2.54
(2H, bd, J ¼ 15.2 Hz, C2-H), 1.93 (2H, td, J ¼ 13.0 Hz, C2-H), 1.70–1.80 (2H, m,
C3-H), 1.55–1.65 (1H, m, C4-H), 0.99–1.1 (2H, m, C3-H), 0.93 (3H, d, J ¼ 8.0 Hz,
2
3
-CH3); 19F NMR (CDCl3) d: ꢁ223.09 (1F, tt, JF-H ¼ 50.40 Hz, JF-H ¼ 25.90 Hz);
ESI-HRMS calcd. for C22H26O2F [M þ 1]þ 341.1917; found 341.1911.
3-Methyl-(4-fluoroethoxyphenyl)-(4’-hydroxyphenyl)methylenecyclo-
hexane (8b). Yield 68.9%, colorless oil. UV (EtOH): k 225 nm; IR (KBr): n 3245,
2958, 1598, 1359, 1177, 921, 554 cmꢁ1;1H NMR (CDCl3) d: 7.02 (2H, d, J ¼ 7.5 Hz,
aromatic), 6.96 (2H, d, J ¼ 8.4 Hz, aromatic), 6.83 (2H, d, J ¼ 7.5 Hz, aromatic), 6.73
2
2
(2H, d, J ¼ 6.9 Hz, aromatic), 4.76 (2H, dt, JH-F ¼ 47.2 Hz, JH-H ¼ 4.1 Hz,
3
2
-CH2F,), 4.20 (2H, dt, JH-F ¼ 27.1 Hz, JH-H ¼ 4.1 Hz, -OCH2), 2.52 (2H, bd,
0
0
J ¼ 11.1 Hz, C2-H), 1.77 (2H, bd, J ¼ 14.4 Hz, C2 -H), 1.40–1.70 (4H, m, C3 ,4-H),
1.20–1.30 (1H, m, C3-H), 0.87 (3H, d, J ¼ 5.7 Hz, -CH3); 19F NMR (CDCl3) d:
2
3
ꢁ223.74 (1F, tt, JF-H ¼ 50.25 Hz, JF-H ¼ 23.50 Hz); ESI-HRMS calcd. for
C22H26O2F [M þ 1]þ 341.1917; found 341.1892.
Iso-(4-fluoroethoxyphenyl)-(4’-hydroxyphenyl)methylenebutane (9). Yield
68.9%, straw yellow oil. UV (EtOH): k 224, 265 nm; IR (KBr): n 3212, 2955,
1519, 1269, 1169, 918, 552 cmꢁ1
;
1H NMR (CDCl3) d: 7.15 (2H, d, J ¼ 8.7 Hz,
aromatic), 7.04 (2H, d, J ¼ 8.4 Hz, aromatic), 6.93 (2H, d, J ¼ 8.7 Hz, aromatic),
6.72 (2H, d, J ¼ 8.4 Hz aromatic), 5.76 (1H, d, J ¼ 10.2 Hz, alkene-H), 4.73 (2H,
2
2
3
2
dt, JH-F ¼ 47.1 Hz, JH-H ¼ 2.1 Hz, -CH2F), 4.20 (2H, dt, JH-F ¼ 28.2 Hz, JH-H
¼ 3.45 Hz, -OCH2-), 2.42 (1H, m, C-H), 1.00 (6H, d, J ¼ 6.9 Hz, -CH3); 19F NMR
2
3
(CDCl3) d: ꢁ223.03 (1F, tt, JF-H ¼ 50.55 Hz, JF-H ¼ 23.65 Hz); ESI-HRMS calcd.
for C19H22O2F [M þ 1]þ 301.1604; found 301.1616.
ACKNOWLEDGMENT
This project was supported by the Hundred Talent Program of the Chinese
Academy of Sciences (No. 26200601).
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