Synthesis of 5-(fluorophenyl)tocopherols as novel dioxin receptor antagonists

Article abstract of DOI:10.1002/ejoc.201100178

γ-Tocopherol, a component of the essential nutrient mixture commonly designated as vitamin E, was chemically combined with differently substituted monofluoro- and difluorophenyl moieties to produce potential antagonists for the human aryl hydrocarbon rece

Full text of DOI:10.1002/ejoc.201100178

FULL PAPER
DOI: 10.1002/ejoc.201100178
Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists
Elisabeth Kloser,[a] Stefan Böhmdorfer,[a] Lothar Brecker,[b] Hanspeter Kählig,[b]
Thomas Netscher,[c] Kurt Mereiter,[d] and Thomas Rosenau*[a]
Keywords: Vitamins / Receptors / Cross-coupling / Fluorine / Palladium
γ-Tocopherol, a component of the essential nutrient mixture
commonly designated as vitamin E, was chemically com-
bined with differently substituted monofluoro- and difluoro-
phenyl moieties to produce potential antagonists for the hu-
man aryl hydrocarbon receptor (AhR). 5-Iodo-γ-tocopherol
was a very reliable starting material for the Pd-catalyzed re-
action with (fluorophenyl)boronic acids (Suzuki coupling).
The ortho- and meta-fluoro-substituted derivatives showed
conformational isomerism due to restricted rotation around
the interaromatic bond. This effect was investigated by NMR
spectroscopy. Three of the derivatives showed very high po-
tency in assays and are promising candidates for further test-
ing.
compounds that feature a methyl group instead of the iso-
prenoid C16 side chain are frequently employed. This sub-
stitution does not alter the in vitro chemical behavior, yet
it simplifies handling, crystallization, and analytics of the
products (Figure 1).
Introduction
Vitamin E, containing compounds from the tocopherol and
tocotrienol family,[1,2] is commonly known as a highly po-
tent natural antioxidant that protects the integrity of tissues
against reactive oxygen species.[3–7] Even nowadays, novel
The quest for novel tocopherol derivatives has intensified
non-antioxidant functions of α-tocopherol (1), the main within the last decades and was either aimed at achieving
constituent of vitamin E, such as gene regulatory proper- special properties such as altered lipophilicity or oxidative
ties, cell signaling, and immunological actions, are being lability or at combining the advantages of the vitamin (high
discovered.[8–10] The tocopherols are either produced syn- oxidative efficiency, physiological compatibility, zero toxic-
thetically on an industrial scale,[11–13] or are obtained by ity) with the properties of other chemical systems. Up to
extraction of plant oils.[14] In research, tocopherol model date, most alterations of the tocopherol moiety were
Figure 1. Structures of the four main tocopherol derivatives found in vitamin E (1, 2, 3a, 4) and of γ-tocopherol model compound 3b
with a truncated side chain.
achieved by functionalization of the phenolic hydroxy
group[1] or by modification of the lipophilic side chain,[15,16]
[a] University of Natural Resources and Life Sciences,
Muthgasse 18, 1190 Wien, Austria
but reports on other modifications of the core are scarce.[17]
E-mail: thomas.rosenau@boku.ac.at
[b] University of Vienna, Institute of Organic Chemistry,
Währinger Straße 38, 1090 Wien, Austria
Our research efforts were aimed at combining physiologi-
cally active moieties with the tocopherol system. In such
derivatives, the tocopherol could act either as a lipophilic
carrier or as a substance with an individual physiological
effect. Of special interest was the aryl hydrocarbon receptor
(AhR), also called dioxin receptor. The AhR protein is
[c] DSM Nutritional Products, Research and Development,
P. O. Box 2676, 4002 Basel, Switzerland
[d] Vienna University of Technology, Faculty of Chemistry,
Getreidemarkt 9/164SC, 1060 Vienna, Austria
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100178.
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Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists
present in most cell and tissue types of the body and is pound was readily prepared by the reaction of γ-tocopherol
classified as a member of the basic helix-loop-helix/Per- with elemental bromine,[28] but showed no conversion under
Arnt-Sim (bHLH/PAS) family of ligand-dependent tran- Grignard or Pd-catalyzed coupling reactions. To improve
scription factors.[18–20] Normally inactive and bound to co- reactivity, the bromine substituent was replaced by the more
chaperones, AhR is activated by binding to ligands, such reactive iodine: γ-tocopheryl acetate (4a) was iodinated
as environmental pollutants, carcinogens, and drugs. This with elemental iodine in the presence of silver trifluoroacet-
action makes the chaperones dissociate and allows AhR to ate according to a modified protocol of the Kumadaki
translocate into the nucleus.[21,22] Attachment of the recep- group.[17] The novel O-acetyl-5-iodo-γ-tocopherol (5a) was
tor to ARNT (AhR nuclear translocator) forms a complex recovered in 67% yield besides 4% of 3,4-dehydro-γ-to-
(AhR–ARNT) that binds to dioxin-responsive elements copheryl acetate and 3% of unchanged starting material.
(DRE) and increases their gene transcription rate.[23–25]
The iodination reaction was also applied to model com-
Especially polycyclic aromatic hydrocarbons (PAHs) and pound 4b, which provided crystalline iodide derivative 5b,
halogenated aromatic carbons (PACs) have been identified the X-ray structure of which is shown in Figure 3.
as effective ligands (Figure 2) and their toxic nature, hepa-
totoxicity, immunotoxicity, and tumor promotion has been
shown to be in direct correlation with their ability to bind
to AhR.[26] All ligands identified so far comprise planar
elements (aromatic systems) and possess some lipophilic
character.[27]
Figure 3. Molecular structure of 5-iodo-2,2,7,8-tetramethylchro-
man-6-yl acetate (5b).
Out of several preliminarily tested coupling procedures,
Suzuki reactions – the Pd-catalyzed cross-coupling with
phenylboronic acids – were evidently most promising with
regard to further optimization towards better yields. An-
other practical advantage was that the starting materials re-
quired for the introduction of fluorophenyl residues, that is,
(fluorophenyl)boronic acids, were commercially available.
To boost the yield, various Suzuki coupling protocols were
employed and the conditions varied; the progress of the re-
action between O-acetyl-5-iodo-γ-tocopherol (5a) and
phenylboronic acid was followed by GC–MS. According to
the optimized protocol, 95% of 5-substituted tocopherol
derivative 6a was obtained when Pd(dppf)Cl2·DCM was
used as the catalyst and K2CO3 as auxiliary base, working
in DMF at 80 °C. The addition of some percent of water
to the solvent did not change the outcome of the reaction.
Even when employing 4-hydroxyphenylboronic acid as a
coupling partner, highly labile compound 7 was still ob-
tained in 42%. 4-(Hydroxyphenyl)-γ-tocopherol (7) is a
phenylogous 5-hydroxy-γ-tocopherol that is highly labile
and very readily oxidized to the phenylogous 5,6-chro-
mandione (α-tocored[29]).
Figure 2. Typical ligands for AhR: 2,3,7,8-tetrachlorodibenzo-p-di-
oxin (TCDD), methylcholanthrene (MC), and β-naphthoflavone
(β-NF).
Based on recent studies that identified ortho-(fluo-
rophenyl)phenols as lead structures for AhR antagonists,
we reasoned that by combining the antioxidative properties,
the lipophilicity (effecting directed transport to the lipo-
philic action site), and the planar aromatic ring of tocoph-
erol compounds with an additional fluorinated aromatic
moiety attached to the chromanol unit would produce very
suitable ligands for the AhR target. To test this hypothesis
and to provide compounds for assay testing, we synthesized
a small library of 5-substituted tocopherols, carrying mono-
or difluorinated aromatic substituents. The synthetic ap-
proach and the interesting analytical properties of the prod-
ucts are communicated in the present report.
Results and Discussion
Previous studies on the synthesis of novel tocopherol de-
With the optimized protocol in hand, a small library of
rivatives and on comparative oxidation chemistry of to- monofluorophenyl and difluorophenyl tocopherol deriva-
copherols showed us an almost complete lack of reports on tives was established (Table 1), with all possible substitution
transition-metal-catalyzed coupling reactions with the aro- patterns being included. The monofluoro derivatives (2-
matic ring of non-α tocopherols (α-tocopherol itself pos- fluorophenyl: 8, 3-fluorophenyl: 9, 4-fluorophenyl: 10a with
sesses no free aromatic position for such couplings). At first isoprenoid side chain, 10b with truncation of that chain)
this was surprising, but it became understandable when we were produced smoothly, and only the low yield of the or-
realized that 5-bromo-γ-tocopherol, the most obvious start- tho-fluoro derivative was remarkable. It is plausible to
ing material, failed in all attempts in our hands. The com- evoke steric or electronic reasons for the limited success of
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T. Rosenau et al.
FULL PAPER
the coupling, although possible effects were not studied in
For a detailed analysis and discussion of proton and car-
detail. With two ortho-fluorinated substituents the effect bon assignments refer to the Supporting Information. As-
was even more drastic, and no coupling reaction was ob- signment of the proton signals of the aromatic region of 9
served; the 2,6-difluorophenyl derivative was the only of the was achieved with the help of 19F decoupled NMR and
1
six bisfluorinated compounds that could not be produced. noncoupled H NMR spectroscopy. Proton 5-HЈ appears
1
The isolated yields of bisfluorinated compounds 11–15 were as a triplet in the 19F decoupled H NMR spectrum at δ =
satisfying (39 to 70% yield).
7.34 ppm with a coupling constant of 7.8 Hz (upper trace
in Figure 5), and as a broad multiplet in the 19F coupled
spectrum (middle trace in Figure 5) because of the meta-
coupling to the fluorine atom. The 4-HЈ proton shows a
homonuclear ortho-coupling JH,H to the 5-HЈ proton, as a
well as two homonuclear meta-couplings JH,H to 6-HЈ and
2-HЈ, the former being similar to the heteronuclear ortho-
JH,F coupling that becomes visible in the decoupled spec-
trum by the triplet-type splitting. The 6-HЈ proton appears
as a doublet and shows no detectable coupling to the fluor-
ine atom in the 19F coupled proton experiment. The 2-HЈ
proton appears as a broad singlet in the 19F decoupled spec-
trum, and shows ortho-JH,F = 9.7 Hz in the nondecoupled
spectrum. Carbon resonance assignment of the fluo-
rophenyl substituent was supported by the HSQC spectrum
(Figure 5, bottom trace) and crosschecked by HMBC ex-
periments.
Table 1. Preparation of iodide derivatives 5a and 5b, followed by
Suzuki coupling with F-substituted phenylboronic acids.[a]
Entry
(a)
(b)
(c)
(d)
(e)
R
Yield [%]
1
2
3
4
5
6
7
8
6a
6b
7
8
9
10a
10b
11
12
13
14
15
16
H
H
H
F
H
H
H
H
H
F
H
H
H
H
F
H
H
F
F
H
F
H
H
H
H
OH
H
H
F
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
F
C16H33
CH3
95
83
42
20
33
95
75
54
60
40
43
39
C16H33
C16H33
C16H33
C16H33
CH3
C16H33
C16H33
C16H33
C16H33
C16H33
F
F
9
H
F
H
H
H
10
11
12
13
H
H
F
F
F
F
H
C16H33 no reaction
[a] Reaction conditions: (i) CF3COOAg, I2; (ii) Suzuki coupling.
Besides the expected complication of the nuclear mag-
netic resonance spectral assignment of the tocopherol deriv-
atives due to the additional couplings with 19F, we observed
the existence of two conformational isomers (Figure 4) for
all compounds that had ortho- and/or meta-substituents,
that is, for all compounds except 10a and 10b, which have
a para-F substituent. In these rotamers the rotation around
the C5–C1Ј bond that links the two phenyl units is restric-
ted. Compound 12, having a 3,5-difluorophenyl unit and
thus two meta-F, is a special case. Due to the symmetric
substitution pattern, the two conformers are identical and
cannot be distinguished, but the compounds certainly ex-
perience rotational barriers similar to those of the other
ortho- and meta-substituted derivatives. In the following,
this behavior and the spectral implications are exemplified
for tocopherol derivative 9.
Figure 5. 1H NMR spectrum with 19F coupling (middle trace,
600 MHz) and 19F decoupled (upper trace, 600 MHz) and HSQC
spectrum of 9.
While the carbon signals of the tocopherol moiety were
easily identified on the basis of previous work, the assign-
ment of the carbon resonances in the fluorophenyl substitu-
ents was quite interesting: all aromatic signals should ap-
pear as doublets in the monofluoro derivatives and as reso-
nances of higher multiplicity in the difluoro derivatives be-
cause of the different JC,F couplings. Some of the carbon
signals in 9 showed a further line broadening or splitting.
Figure 4. Two possible conformational isomers of 5-(3-fluoro-
phenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl
acetate (9).
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Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists
In particular, the signal of C-2Ј at ca. 116.5 ppm appears
twice. Measurements at different field strengths (150 and
100 MHz) indicate the splitting not to be induced by cou-
pling. It is rather caused by a doubled set of signals with
very similar shifts as well as by far equal intensity and 2JC,F
coupling (see Figure 6, top). This phenomenon is explained
by the existence of two conformational isomers as shown
in Figure 4. Four carbon spectra were recorded at different
temperatures (298, 312, 322, and 332 K) to facilitate the
rotation of the aryl substituent (Figure 6, stack plot at bot-
Figure 7. 19F NMR spectrum of 9 recorded at various tempera-
tom). In this process the two doublets suffer distinct line
broadening by converging near the coalescence tempera-
ture. Further heating (Ͼ332 K) of the sample was not pos-
sible because of the low boiling point of the solvent CDCl3.
tures, 565 MHz.
values of 1.8ϫ10–8, 0.9ϫ10–9, and 8.4ϫ10–8 mol/L,
respectively. These compounds are two to three orders of
magnitude more effective than 3-hydroxymethylindole and
bis(indol-3-yl)methane (5.8ϫ10–6 and 1.1ϫ10–6 mol/L,
respectively), which are known from the literature[31,32] to
be potent AhR antagonists and were comparable to some
of the strongest antagonists hitherto known, such as
indolo[3,2-b]carbazole (EC50
=
1.9ϫ10–9) and form-
ylindolo[3,2-b]carbazole (EC50 = 3.5ϫ10–9). The para-
fluorinated compound – the only one of the test candidates
not showing rotational isomerism – showed a much more
deficient behavior with an EC50 value of 3.3ϫ10–4, and the
values of the other compounds tested were in the range be-
tween 10–5 and 10–6. A detailed description of the com-
pound screening in different activity assays will follow.
Conclusions
Figure 6. Top: section of the carbon NMR APT spectrum of 9
showing the C-2Ј resonance, recorded at 100 MHz (left) and
150 MHz (right). Bottom: stack plot of sections of carbon NMR
spectra of 9 recorded at various temperatures, 100 MHz.
O-Acetyl-5-iodo-γ-tocopherol (5) was shown to be an ex-
cellent starting material for the functionalization of γ-to-
copherol by Suzuki coupling with phenylboronic acids,
demonstrated with fluorophenyl- and difluorophenyl-
boronic acids in the present case. The products, novel 5-
substituted tocopherols, are physiologically relevant as AhR
antagonists with promising assay results especially for the
3-fluorophenyl, 3,4-difluorophenyl, and 3,5-difluorophenyl
derivatives (i.e., 9, 11 and 12, respectively). All compounds
besides para-F derivatives 10a and 10b show conformation
isomerism at room temperature with restricted rotation
around the C-5–C1Ј bond. The Suzuki protocol allowed in-
troduction of a non-hydrolyzable linkage between the to-
copherol residue and the attached moiety. At present, the
tocopherol hybrid compounds synthesized are screened in
receptor binding and expression studies and used as a pre-
liminary basis for establishing quantitative structure–ac-
tivity relationship (QSAR) models, especially with regard to
the possible role of the conformational isomerism as the
reason for the observed increased activity.
To further disprove a coupling-derived phenomenon, the
1H NMR spectrum of compound 9 was additionally re-
corded on a different spectrometer (600 and 400 MHz). In
this case, the coalescence temperature is approx. 288 K
leading to significant broadening of the proton signals. An
increase in the measurement temperature leads to distinct
improvements in the signal resolution caused by faster
isomerization of the two different conformational isomers
(see Figure 4 and Supporting Information, Figure S1). 19F
NMR experiments at various temperatures furnished the
unambiguous proof of the existence of at least two confor-
mational isomers. With increasing temperature the rotation
barrier is minimized and the two signals unify to a single
one, indicating the coalescent point to be between 308 and
318 K. The 19F NMR spectrum clearly shows two signals
at room temperature and proves the existence of two con-
formational isomers at room temperature (Figure 7).
In a preliminary yeast AhR screening following the
Miller protocol,[30] we found that compounds 5-(3-fluo-
rophenyl)-γ-tocopherol (9), 5-(3,4-difluorophenyl)-γ-to-
copherol (11), and 5-(3,5-difluorophenyl)-γ-tocopherol (12)
Experimental Section
General: (all-R)-Derivatives prepared from (2R,4ЈR,8ЈR)-tocoph-
erols were used as starting materials. All other chemicals were ob-
are quite potent AhR antagonists in vitro, having EC50 tained from commercial suppliers (Sigma–Aldrich) and used with-
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T. Rosenau et al.
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3
out further purification. Et2O was dried with sodium with benzo-
phenone (0.2% w/v) as indicator. Dried ether was stored over acti-
vated 4 Å molecular sieves. Similarly, CH2Cl2 was heated at reflux
over calcium hydride (5% w/v) and stored over activated 4 Å mo-
lecular sieves. Reagent-grade solvents were used for all extractions
and workup procedures. Distilled water was used for all aqueous
extractions and for all aqueous solutions. n-Hexane, Et2O, and
EtOAc used in chromatography were distilled before use. Yields
refer to isolated pure products. All non-aqueous reactions were
conducted in oven-dried (140 °C, overnight) or flame-dried glass-
ware under an argon or nitrogen atmosphere; room temperature
was 22 °C. Air- or moisture-sensitive liquids were transferred by
oven-dried syringes and were introduced into the reaction flasks
through rubber septa or through a stopcock under argon or nitro-
gen positive pressure. Column chromatography was performed on
silica gel G60 (40–63 μm). Melting points were determined with a
Kofler-type micro hot stage with Reichert-Biovar microscope. If
not otherwise stated, NMR spectra were measured in CDCl3 and
recorded with a Bruker DPX300 or DPX400 spectrometer (300 or
(s, 3 H, CH3CO), 2.64 (t, J = 6.9 Hz, 2 H, 4-H), 5.29 (s, 1 H, 5-
H) ppm.
2,2,7,8-Tetramethylchroman-6-ol: 2,3-Dimethyl-1,4-hydroquinone
(3.00 g, 21.70 mmol) was dissolved in a mixture of formic acid
(28.00 mL) and THF (4.00 mL), and the mixture was heated to
reflux followed by the dropwise addition of 2-methyl-3-buten-2-ol
(1.54 mL, 14.80 mmol) dissolved in THF (1.00 mL). The reaction
was heated at reflux for 3 h, poured onto crushed ice, then diluted
with H2O and extracted repeatedly with Et2O. The Et2O layers were
combined, diluted with n-hexane (40 mL), and repeatedly washed
with H2O. The organic extracts were dried with Na2SO4, filtered,
and concentrated. The residue was dissolved in MeOH (40 mL),
conc. HCl (0.5 mL) was added, and the mixture was heated at re-
flux for 20 min to hydrolyze any formate ester that might have been
formed in the reaction. The solvent was removed under reduced
pressure. The residue was dissolved in Et2O (100 mL) and washed
with H2O, a saturated aqueous solution of NaHCO3, and then
H2O, dried with Na2SO4, and concentrated in vacuo. The residue
was extracted by heating at reflux in n-hexane (50 mL) for 20 min.
After cooling to room temperature, the unreacted 2,3-dimethyl-1,4-
hydroquinone (33%) was filtered off. The filtrate was concentrated
in vacuo and purified by column chromatography on silica gel
(EtOAc/n-hexane, 1:9) to give 2,2,7,8-tetramethylchroman-6-ol in
28% yield (42% rel. to unreacted and recycled starting material)
and the disubstituted byproduct 3,3,5,6,8,8-hexamethyl-
1,2,3,8,9,10-hexahydro-pyrano[3,2-f]chromene in 19% yield.[34]
Data for 2,2,7,8-tetramethylchroman-6-ol: M.p. 75–77 °C (n-hex-
1
400 MHz for H, 75 or 100 MHz for 13C), 19F NMR spectra were
recorded with a Bruker DPX400 (376 MHz), and for compound 9
the NMR spectrum was additionally recorded with a Bruker
DRX600 spectrometer (600 MHz for 1H, 150 MHz for 13C,
565 MHz for 19F). 13C NMR spectra were measured with complete
proton decoupling. Chemical shifts are reported in ppm downfield
from tetramethylsilane with the solvent reference as the internal
1
standard (CDCl3: δ = 7.26 ppm for H, CDCl3: δ = 77.7 ppm for
13C); chemical shifts for 19F NMR are reported in ppm and tri-
fluoroacetic acid was used as an external standard (–78.51 ppm);
13C resonances were assigned by APT, HMQC, and HMBC spec-
tra. Resonances of the isoprenoid side chain of tocopherols are not
influenced by modifications of the chroman ring and are therefore
not listed. GC–MS ionization was performed in the EI mode at
70 eV, 230 °C, and 1.5ϫ10–5 Torr. For HRMS, a solution of the
sample, dissolved in acetonitrile, was injected by a micro wellplate
autosampler from Agilent technologies and measured by an Ag-
ilent 6210 TOF MS. The MS had been previously tuned with the
Agilent tune mix and further reference masses were added to the
method to provide a mass accuracy below 2 ppm. Data analysis
was performed with Mass Hunter software from Agilent Technol-
ogies. Elemental analyses were performed at the Microanalytical
Laboratory of the University of Vienna and are reported in percent
atomic abundance. X-ray diffraction data were collected with a
Bruker AXS Smart APEX CCD diffractometer. For further details,
see compound 5b in the Experimental Section.
ane/EtOAc). 1H NMR: δ = 1.29 (s, 6 H, 2a-H, 2b-H), 1.74 (t, J =
3
6.8 Hz, 2 H, 3-H), 2.10 (s, 3 H, 7a/8b-H), 2.12 (s, 3 H, 8b/7a-H),
3
2.68 (t, J = 6.8 Hz, 2 H, 4-H), 4.0 (br. s, 1 H, -OH), 6.37 (s, 1 H,
5-H) ppm. 13C NMR: δ = 11.9 (C-7a, C-8b), 22.6 (C-4), 27.0
(C-2a, C-2b), 33.0 (C-3), 73.4 (C-2), 112.1 (C-5), 118.0 (C-4a),
121.6 (C-8), 125.8 (C-7), 145.9 (C-8a), 146.3 (C-6) ppm. Data
for
3,3,5,6,8,8-hexamethyl-1,2,3,8,9,10-hexahydropyrano[3,2-f]-
chromene: M.p. 102–104 °C (n-hexane/EtOAc). 1H NMR: δ = 1.28
3
(s, 12 H, 3a-H, 3b-H, 8a-H, 8b-H), 1.78 (t, J = 6.8 Hz, 4 H, 2-H,
9-H), 2.09 (s, 6 H, 5a-H, 6b-H), 2.54 (t, 3J = 6.8 Hz, 4 H, 1-H, 10-
H) ppm. 13C NMR: δ = 11.8 (C-5a, C-6b), 20.1 (C-1, C-10), 26.8
(C-3a, C-3b, C-8a, C-8b), 32.9 (C-2, C-9), 72.4 (C-3, C-8), 115.6 (C-
10a, C-10b), 123.4 (C-5, C-6), 144.7 (C-4a, C-6a) ppm. C18H26O2
(274.40): calcd. C 78.79, H 9.55; found C 78.88, H 9.56.
2,2,7,8-Tetramethylchroman-6-yl-acetate (4b): 2,2,7,8-Tetrameth-
ylchroman-6-ol (0.50 g, 2.40 mmol) was dissolved in pyridine
(10 mL) and cooled to 0 °C followed by the addition of acetic acid
anhydride (18.5 mL). The mixture was brought to room tempera-
ture and stirred for 18 h. The solvent was evaporated in vacuo and
then co-evaporated with toluene. The crude residue was purified by
column chromatography on silica gel (n-hexane/EtOAc, 20:1) to
afford 4b in 95% yield. Analytical data was in accordance with the
data published in the literature.[35]
O-Acetyl-γ-tocopherol (4a): γ-Tocopherol (3.60 g, 8.294 mmol) was
dissolved in dry CH2Cl2 (200 mL) followed by the addition of ace-
tic acid anhydride (9 mL) and three drops of conc. H2SO4. The
mixture was stirred at room temperature for 18 h, then diluted with
H2O (400 mL) and stirred at pH 5 for an additional 1 h. The neu-
tralized reaction mixture (NaHCO3) was filtered through Celite
and washed with CH2Cl2. The layers were separated, and the or-
ganic layer was washed with brine. The aqueous layer was repeat-
edly extracted with n-hexane. The n-hexane extracts were combined
and washed with brine, then combined with the CH2Cl2 layer, dried
with Na2SO4, and concentrated in vacuo. The crude residue was
purified by column chromatography on silica gel (toluene) to afford
4a (65%). Alternatively, 4a was prepared following the same pro-
cedure as for the preparation of 4b with acetic anhydride in pyr-
idine to give a yield of 93%. The analytical data for compound 4a
matched the previously published data.[33] 1H NMR: δ = 1.23 (s, 3
H, 2-Hb), 1.67–1.87 (m, 2 H, 3-H), 2.08 (s, 6 H, 7-Ha, 8-Hb), 2.37
O-Acetyl-5-iodo-γ-tocopherol (5a):
A solution of I2 (6.23 g,
24.55 mmol) in dry CH2Cl2 (300 mL) was added dropwise to a sus-
pension of 4a (7.60 g, 16.57 mmol) and silver trifluoroacetate
(5.420 g, 24.54 mmol) in CH2Cl2 (300 mL) at room temperature
whilst stirring (color of the reaction mixture changed from cloudy
white to yellow to orange with yellow precipitate during the ad-
dition). The mixture was stirred at room temperature for 2 h and
an aqueous solution of NaHCO3 (4.2 g) and Na2S2O3 (3.9 g) in
H2O (300 mL) was added. The mixture was stirred for 1 h and then
filtered through a Celite layer. The filtrate was extracted with
CH2Cl2. The organic layers were combined, washed with a satu-
rated aqueous solution of NaHCO3 and brine, dried with Na2SO4,
2454
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2450–2457

Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists
filtered, and concentrated in vacuo. The crude residue was purified
by column chromatography on silica gel (toluene/n-hexane, 1:2 Ǟ
1:1) to afford 5a as a yellow oil in 67% yield. Furthermore 3,4-
dehydro-γ-tocopheryl acetate was isolated in a yield of 4% and 3%
of unreacted starting material could be recycled. Data for O-acetyl-
Ph-H), 7.29–7.34 (m, 1 H, Ph-H), 7.34–7.40 (m, 2 H, Ph-H) ppm.
13C NMR: δ = 12.1 (C-8b), 13.0 (C-7a), 20.2 (CH3CO), 21.7 (C-
4), 27.1 (C-2b), 32.6 (C-3), 73.5 (C-2), 117.0 (C-5), 125.0 (C-7/8),
127.3 (C-7/8), 127.0/128.0/129.5 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-6Ј),
131.7 (C-4a), 136.9 (C-1Ј), 139.5 (C-6), 149.7 (C-8a), 170.0 (CO)
ppm. C21H24O3 (324.42): calcd. C 77.75, H 7.86; found C 77.70, H
1
5-iodo-γ-tocopherol: H NMR: δ = 1.25 (s, 3 H, 2b-H), 1.67–1.89
(m, 2 H, 3-H), 2.09 (s, 6 H, 7a-H, 8b-H), 2.38 (s, 3 H, CH3CO), 7.68.
2.65 (t, J = 6.8 Hz, 2 H, 4-H) ppm. 13C NMR: δ = 12.2/14.1 (C-
3
5-(4-Hydroxyphenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
7a, C-8b), 21.2 (CH3CO), 28.0 (C-2b), 29.6 (C-4), 31.9 (C-3), 76.2
(C-2), 94.7 (C-5), 122.0 (C-4a), 126.3/128.2 (C-7, C-8), 142.4 (C-6),
150.2 (C-8a), 169.1 (CO) ppm. (for full spectra and numeration of
5a see Supporting Information). MS (EI, 70 eV): m/z = 584.4,
542.3, 277.0, 151.1, 57.1. Data for 3,4-dehydro-γ-tocopheryl acet-
chroman-6-yl Acetate (7): Following the general procedure for the
Suzuki coupling, 5a (217 mg, 0.371 mmol) was treated with 4-hy-
droxyphenylboronic acid (77 mg, 0.557 mmol), K2CO3 (104 mg,
0.742 mmol), and PdCl2(dppf)·DCM. The crude residue was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc,
1
ate: H NMR: δ = 2.04 (s, 3 H, 7a/8b-H), 2.13 (s, 3 H, 8b/7a-H),
1
100:1) to afford 7 (42%). H NMR: δ = 1.26 (s, 3 H, 2b-H), 1.90
3
3
2.30 (s, 3 H, CH3-CO), 5.55 (d, J = 9.8 Hz, 1 H, 3-H), 6.25 (d, J
(s, 3 H, CH3CO), 2.07 (s, 3 H, 7a-H), 2.16 (s, 3 H, 8b-H), 2.27–
2.45 (m, 2 H, 4-H), 4.80–5.40 (br. s, 1 H, OH), 6.83 (br. d, 2 H, 2Ј-
H, 4Ј-H), 7.03 (br. d, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR: δ = 12.1
(C-8b), 12.9 (C-7a), 20.3 (CH3CO), 21.4 (C-4), 24.2 (C-2b), 31.0
= 9.8 Hz, 1 H, 4-H), 6.51 (s, 1 H, 5-H) ppm.
5-Iodo-2,2,7,8-tetramethylchroman-6-yl Acetate (5b): Compound 5b
was synthesized in the same manner as compound 5a with I2
(1.87 g, 7.36 mmol), 4b (1.22 g, 4.91 mmol), silver trifluoroacetate (C-3), 75.6 (C-2), 115.0 (C-2Ј, C-6Ј), 117.6 (C-5), 125.0/127.1 (C-7,
(1.63 g, 7.36 mmol), and CH2Cl2 (400 mL). The crude residue was
purified by recrystallization from n-hexane to give 5b in a yield of
52% besides nonreacted starting material. M.p. 130.5–133 °C (n-
hexane). 1H NMR: δ = 1.30 (s, 6 H, 2a-H, 2b-H), 1.78 (t, 3J =
6.8 Hz, 2 H, 3-H), 2.09 (s, 6 H, 7a-H, 8b-H), 2.38 (s, 3 H, CH3CO),
C-8), 129.1 (C-4a), 130.8/130.7 (C-3Ј, C-5Ј), 131.2 (C-1Ј), 139.7 (C-
6), 149.7 (C-8a), 154.6 (C-4Ј), 170.4 (CO) ppm.
5-(2-Fluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (8): Following the general procedure for the
Suzuki coupling, 5a (173 mg, 0.295 mmol) was treated with 2-fluo-
rophenylboronic acid (62 mg, 0.443 mmol), K2CO3 (83 mg,
0.591 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude resi-
due was purified by column chromatography on silica gel (n-hex-
3
2.66 (t, J = 6.8 Hz, 2 H, 4-H) ppm. 13C NMR: δ = 12.2/14.1 (C-
7a, C-8b), 21.2 (CH3CO), 26.6 (C-2a, C-2b), 29.9 (C-4), 33.5 (C-
3), 74.1 (C-2), 94.8 (C-5), 121.8 (C-4a), 126.3/128.3 (C-7, C-8),
142.4 (C-6), 150.3 (C-8a), 169.1 (CO) ppm. C15H19IO3 (374.22):
calcd. C 48.14, H 5.12; found C 48.09, H 5.16.
1
ane/EtOAc, 5:1) to afford 8 (20%). H NMR: δ = 1.27 (s, 6 H, 2a-
H), 1.89 (s, 3 H, CH3CO), 2.08 (s, 3 H, 7a-H), 2.18 (s, 3 H, 8b-H),
2.31–2.43 (m, 2 H, 4-H), 7.10–7.20 (m, 3 H, Ph-H), 7.30–7.37 (m,
General Procedure for Suzuki Coupling: To a solution of aryl iodide
dissolved in predegassed DMF (20 mL per 1 mmol starting mate-
rial) was added K2CO3 (2.0 equiv.) and PdCl2(dppf)·DCM (10 mol-
%). The resulting suspension was degassed with Ar, and the corre-
sponding boronic acid (1.5 equiv.) was added. The mixture was
stirred for 18 h at 80 °C, then diluted with H2O, and extracted with
EtOAc. The organic extracts were combined and washed with
brine, dried with Na2SO4, filtered, and concentrated in vacuo to
afford the crude product.
1 H, Ph-H) ppm. 13C NMR: δ = 12.2 (C-8b), 13.0 (C-7a), 20.2
2
(CH3CO), 21.0 (C-4), 30.9 (C-3), 75.7 (C-2), 115.5 (d, JC,F
=
22.3 Hz, C-3Ј), 117.8 (C-5), 123.8 (d, C-4Ј/C-5Ј/C-6Ј), 124.1 (d,
2JC,F = 17.7 Hz, C-1Ј), 125.2 (C-7/C-8), 126.0 (C-4a), 127.4 (C-7/
C-8), 129.3 (“q”, JC,F = 7.9 Hz, C-4Ј/C-5Ј/C-6Ј), 131.8 (d, C-4Ј/C-
1
5Ј/C-6Ј), 139.6 (C-6), 149.7 (C-8a), 159.7 (d, JC,F = 246.2 Hz, C-
2Ј), 170.1 (CO) ppm. 19F NMR: δ = –116.9 (s), –115.9 (s) ppm.
5-(3-Fluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (9): Following the general procedure for the
Suzuki coupling, 5a (278 mg, 0.478 mmol) was treated with 3-fluo-
rophenylboronic acid (101 mg, 0.718 mmol), K2CO3 (133 mg,
0.957 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude resi-
due was purified by column chromatography on silica gel (n-hex-
ane/EtOAc, 5:1) to afford 9 (33%). 1H NMR: δ = 1.27 (s, 3 H, 2a-
O-Acetyl-5-phenyl-γ-tocopherol (6a): Following the general pro-
cedure for the Suzuki coupling, 5a (160 mg, 0.274 mmol) was
treated with phenylboronic acid (52 mg, 0.411 mmol), K2CO3
(76 mg, 0.548 mmol), and PdCl2(dppf)·DCM (10 mol-%). The
crude residue was purified by column chromatography on silica gel
1
(n-hexane/EtOAc, 50:1) to afford 6a (95%). H NMR: δ = 1.26 (s,
3 H, 2b-H), 1.50–1.70 (m, 2 H, 3-H), 1.85 (s, 3 H, CH3CO), 2.06 H), 1.91 (s, 3 H, CH3CO), 2.07 (s, 3 H, 7a-H), 2.18 (s, 3 H, 8b-H),
(s, 3 H, 7a-H), 2.17 (s, 3 H, 8b-H), 2.29–2.41 (m, 2 H, 4-H), 7.14– 2.25–2.48 (m, 2 H, 4-H), 7.35 (m, 1 H, 5Ј-H), 7.03 (m, 1 H, 4Ј-H),
7.19 (m, 2 H, Ph-H), 7.28–7.33 (m, 1 H, Ph-H), 7.35–7.40 (m, 2 H,
6.97 (m, 1 H, 6Ј-H), 6.92 (m, 1 H, 2Ј-H) ppm. 13C NMR: δ = 12.1
(C-8b), 12.9 (C-7a), 20.2 (CH3CO), 21.3 (C-4), 31.0 (C-3), 75.7 (C-
Ph-H) ppm. 13C NMR: δ = 12.1 (C-8b), 13.0 (C-7a), 20.2
2
2
(CH3CO), 21.4 (C-4), 28.0 (C-2a), 31.0 (C-3), 75.6 (C-2), 117.2 (C- 2), 113.9 (d, JC,F = 20.8 Hz, C-4Ј), 116.5 (d, JC,F = 20.7 Hz, C-
5), 125.0 (C-7/8), 127.3 (C-7/8), 127.0/128.0/129.5 (C-2Ј, C-3Ј, C-
4Ј, C-5Ј, C-6Ј), 131.6 (C-4a), 137.0 (C-1Ј), 139.4 (C-6), 149.7 (C- (C-7/8), 129.5 (d, JC,F = 8.3 Hz, C-5Ј), 130.3 (C-4a), 139.2 (C-6),
8a), 170.0 (CO) ppm. C36H54O3 (534.83): calcd. C 80.85, H 10.18;
found C 80.91, H 10.29.
4
2Ј), 117.0 (C-5), 125.3 (d, JC,F Ͻ 3 Hz, C-6Ј), 125.6 (C-7/8), 127.4
3
3
1
139.2 (d, JC,F = 8.4 Hz, C-1Ј), 149.7 (C-8a), 162.5 (d, JC,F =
246.0 Hz, C-3Ј), 169.8 (CO) ppm. 19F NMR (298 K): δ = –113.6
(s), –114.2 (s) ppm. 19F NMR (308 K): δ = –114.1 (s) ppm.
2,2,7,8-Tetramethyl-5-phenylchroman-6-yl Acetate (6b): Following
the general procedure for the Suzuki coupling, 5b (200 mg,
0.534 mmol) was treated with phenylboronic acid (101 mg,
0.801 mmol), K2CO3 (147 mg, 1.068 mmol), and PdCl2(dppf)·
DCM (10 mol-%). The crude residue was purified by column
chromatography on silica gel (n-hexane/EtOAc, 50:1) to afford 6b
5-(4-Fluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (10a): Following the general procedure for
the Suzuki coupling, 5a (217 mg, 0.371 mmol) was treated with 4-
fluorphenylboronic acid (78 mg, 0.557 mmol), K2CO3 (104 mg,
0.742 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude resi-
due was purified by column chromatography on silica gel (n-hex-
1
(83%). M.p. 108–110 °C. H NMR: δ = 1.31 (s, 6 H, 2a-H, 2b-H),
1.65 (t, 3J = 6.8 Hz, 2 H, 3-H), 1.85 (s, 3 H, CH3CO), 2.06 (s, 3 H,
ane/EtOAc, 5:1) to afford 10a (95%). H NMR: δ = 1.25 (s, 3 H,
1
7a-H), 2.16 (s, 3 H, 8b-H), 2.32–2.41 (m, 4-H), 7.14–7.19 (m, 2 H, 2a-H), 1.88 (s, 3 H, CH3CO), 2.06 (s, 3 H, 7a-H), 2.16 (s, 3 H, 8b-
Eur. J. Org. Chem. 2011, 2450–2457
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2455

T. Rosenau et al.
FULL PAPER
H), 2.26–2.38 (m, 2 H, 4-H), 7.00–7.10 (m, 2 H, 3Ј-H, 5Ј-H), 7.10–
ane/EtOAc, 5:1) to afford 13 (70%). 1H NMR: δ = 1.23 (s, 3 H,
2a-H), 1.94 (s, 3 H, CH3CO), 2.08 (s, 3 H, 7a-H), 2.18 (s, 3 H, 8b-
7.18 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR: δ = 12.1 (C-8b), 12.9
(C-7a), 20.2 (CH3CO), 21.4 (C-4), 31.0 (C-3), 75.6 (C-2), 115.0 (d, H), 2.27–2.43 (m, 2 H, 4-H), 6.86–6.96 (m, 2 H, 5Ј-H, 6Ј-H), 7.15
2JC,F = 21.0 Hz, C-3Ј, C-5Ј), 117.3 (C-5), 125.4 (C-7/8), 127.4 (C-
(m, 1 H, 3Ј-H) ppm. 13C NMR: δ = 12.2 (C-8b), 13.0 (C-7a), 20.2
3
7/8), 130.6 (C-4a), 131.1 (d, JC,F = 8.1 Hz, C-2Ј/C-6Ј), 131.2 (d, (CH3CO), 21.0 (C-4), 30.9 (C-3), 75.8 (C-2), 103.9/111.0/132.5 (m,
4
3JC,F = 8.1 Hz, C-2Ј/C-6Ј), 132.8 (d, JC,F = 3.4 Hz, C-1Ј), 139.6
C-3Ј/5Ј/6Ј), 117.9 (C-5), 120.2 (m, C-1Ј), 126.3 (C-4a), 124.3 (C-7/
1
1
(C-6), 149.7 (C-8a), 161.9 (d, JC,F = 245.5 Hz, C-4Ј), 169.8 (CO) 8), 127.4 (C-7/8), 139.8 (C-6), 149.8 (C-8a), 159.5/162.5 (dd, JC,F
ppm. 19F NMR: δ = –117.54 (s) ppm.
= 249.0 Hz, JC,F = 12.0 Hz, C-2Ј, C-4Ј), 169.7 (CO) ppm. 19F
3
NMR: δ = –110.1 to –112.3 (br. d), –112.96 (d, J = 7.4 Hz) ppm.
5-(4-Fluorophenyl)-2,2,7,8-tetramethylchroman-6-yl Acetate (10b):
Following the general procedure for the Suzuki coupling, 5b
(200 mg, 0.534 mmol) was treated with 4-fluorophenylboronic acid
(112 mg, 0.801 mmol), K2CO3 (147 mg, 1.068 mmol), and
PdCl2(dppf)·DCM (10 mol-%). The crude residue was purified by
column chromatography on silica gel (n-hexane/EtOAc, 5:1) to af-
5-(2,3-Difluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (14): Following the general procedure for the
Suzuki coupling, 5a (150 mg, 0.257 mmol) was treated with 2,3-
difluorphenylboronic acid (61 mg, 0.385 mmol), K2CO3 (71 mg,
513 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude residue
was purified by column chromatography on silica gel (n-hexane/
EtOAc, 5:1) to afford 14 (43%). 1H NMR: δ = 0.82–0.89 (m, 12
H, 4aЈ, 8aЈ, 12aЈ, 13), 0.99–1.81 (m, 23 H, 3, 1Ј, 2Ј, 3Ј, 4Ј, 5Ј, 6Ј,
7Ј, 8Ј, 9Ј, 10Ј, 11Ј, 12Ј-H), 1.27 (s, 3 H, 2a-H), 1.92 (s, 3 H,
CH3CO), 2.07 (s, 3 H, 7a-H), 2.18 (s, 3 H, 8b-H), 2.26–2.45 (m, 2
H, 4-H), 6.92 (t, J = 6.9 Hz, 1 H, 4Ј-H), 7.03–7.21 (m, 5 H, 5Ј-H,
6Ј-H) ppm. 13C NMR: δ = 12.2 (C-8b), 13.0 (C-7a), 19.6 (C-8aЈ),
19.7 (C-4aЈ), 20.2 (CH3CO), 20.9 (C-4), 21.0 (C-2Ј), 22.6 (C-2a),
22.7 (C-12aЈ, C-13), 24.4 (C-10Ј), 24.8 (C-6Ј), 28.0 (C-12Ј), 30.9 (C-
3), 32.6 (C-4Ј), 32.8 (C-8Ј), 37.6 (C-9Ј), 37.7 (C-5Ј), 37.8 (C-7Ј),
37.8 (C-11Ј), 37.8 (C-3Ј), 37.3 (C-9Ј), 37.4 (C-5Ј), 37.4 (C-7Ј), 37.4
(C-11Ј), 37.4 (C-3Ј), 39.6 (C-1Ј)75.8 (C2), 116.4 (d, 2JC,F = 17.1 Hz,
Ph-C4Ј), 117.7 (C4a), 123.7 (Ph-C5Ј), 126.4 (Ph-C6Ј), 126.5 (C5),
126.5 (C8), 126.7 (2JC,F = 14 Hz, Ph-C1Ј), 127.6 (C7), 139.6 (C6),
1
ford 10b (75%). H NMR: δ = 1.32 (s, 6 H, 2a-H, 2b-H), 1.66 (t,
3J = 6.7 Hz, 2 H, 3-H), 1.89 (s, 3 H, CH3CO), 2.06 (s, 3 H, 7a-H),
2.16 (s, 3 H, 8b-H), 2.27–2.40 (m, 2 H, 4-H), 7.03–7.10 (m, 2 H,
3Ј-H, 5Ј-H), 7.10–7.17 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR: δ =
12.1 (C-8b), 13.0 (C-7a), 20.2 (CH3CO), 21.7 (C-4), 27.1 (C-2a, C-
2
2b), 32.6 (C-3), 73.6 (C-2), 115.0 (d, JC,F = 21.2 Hz, C-3Ј, C-5Ј),
117.1 (C-5), 125.4 (C-7/8), 127.4 (C-7/8), 130.6 (C-4a), 131.2 (d,
4
3JC,F = 7.9 Hz, C-2Ј, C-6Ј), 132.8 (d, JC,F = 3.6 Hz, C-1Ј), 139.6
1
(C-6), 149.8 (C-8a), 161.9 (d, JC,F = 245.0 Hz, C-4Ј), 169.9 (CO)
ppm. 19F NMR: δ = –118.11 (s) ppm. C21H23FO3 (342.41): calcd.
C 73.66, H 6.77; found C 73.36, H 7.00.
5-(3,4-Difluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (11): Following the general procedure for the
Suzuki coupling, 5a (300 mg, 0.513 mmol) was treated with 3,4-
difluorphenylboronic acid (122 mg, 0.770 mmol), K2CO3 (144 mg,
1.026 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude prod-
uct was purified by column chromatography on silica gel (n-hexane/
EtOAc, 5:1) to afford 11 (54%). 1H NMR: δ = 1.29 (s, 3 H, 2a-H),
1.95 (s, 3 H, CH3CO), 2.08 (s, 3 H, 7a-H), 2.19 (s, 3 H, 8b-H),
2.27–2.44 (m, 2 H, 4-H), 6.89–6.97 (m, 1 H, 6Ј-H), 7.03 (m, 1 H,
2Ј-H), 7.19 (m, 1 H, 5Ј-H) ppm. 13C NMR: δ = 12.2 (C-8b), 13.0
(C-7a), 20.3 (CH3CO), 21.4 (C-4), 31.0 (C-3), 75.7 (C-2), 117.0 (C-
5), 117.0/118.6/125.9 (m, C-2Ј/C-5Ј/C-6Ј), 125.9 (C-7/8), 127.5 (C-
7/8), 129.6 (C-4a), 133.8 (m, C-1Ј), 139.3 (C-6), 149.8 (C-8a), 149.5
1
147.9 (2JC,F = 10 Hz, JC,F = 246 Hz, Ph-C2Ј), 149.5 (C8a), 150.7
(1JC,F = 249 Hz, 2JC,F = 14 Hz, Ph-C3Ј) ppm. 19F NMR: δ = –139.0
(s), –137.9 (s) ppm.
5-(2,5-Difluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (15): Following the general procedure for the
Suzuki coupling, 5a (150 mg, 0.257 mmol) was treated with 2,5-
difluorphenylboronic acid (61 mg, 0.385 mmol), K2CO3 (71 mg,
513 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude residue
was purified by column chromatography on silica gel (n-hexane/
EtOAc, 5:1) to afford 15 (39%). 1H NMR: δ = 0.82–0.93 (m, 12
H, 4aЈ, 8aЈ, 12aЈ, 13-H), 0.98–1.83 (m, 23 H, 3, 1Ј, 2Ј, 3Ј, 4Ј, 5Ј, 6Ј,
7Ј, 8Ј, 9Ј, 10Ј, 11Ј, 12Ј-H), 1.26 (s, 3 H, 2a-H), 1.94 (s, 3 H,
CH3CO), 2.07 (s, 3 H, 7a-H), 2.17 (s, 3 H, 8b-H), 2.25–2.59 (m, 2
H, 4-H), 6.89 (m, 1 H, Ph-6 H), 6.96–7.13 (m, 2 H, Ph-3 H, Ph-4
H) ppm. 13C NMR: δ = 12.5 (C-8b), 13.4 (C-7a), 19.9 (C-8aЈ), 20.1
(C-4aЈ), 20.5 (CH3CO), 21.1 (C-4), 21.3 (C-2Ј), 23.0 (C-2a), 23.1
(C-12aЈ, C-13), 24.8 (C-10Ј), 25.2 (C-6Ј), 28.3 (C-12Ј), 31.2 (C-3),
3
1
(dd, 1JC,F = 248.4 Hz, JC,F = 12.8 Hz, C-3Ј/4Ј), 150.0 (dd, JC,F
=
248.4 Hz, JC,F = 12.8 Hz, C-3Ј/4Ј), 169.7 (CO) ppm. 19F NMR: δ
3
= –140.02 (d, J = 21.2 Hz), –141.97 (br. d) ppm.
5-(3,5-Difluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (12): Following the general procedure for the
Suzuki coupling, 5a (310 mg, 0.530 mmol) was treated with 3,5-
difluorphenylboronic acid (126 mg, 0.800 mmol), K2CO3 (149 mg,
1.060 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude resi-
due was purified by column chromatography on silica gel (n-hex-
ane/EtOAc, 5:1) to afford 12 (60%). 1H NMR: δ = 1.27 (s, 3 H,
2a-H), 1.96 (s, 3 H, CH3CO), 2.07 (s, 3 H, 7a-H), 2.18 (s, 3 H, 8b-
H), 2.27–2.44 (m, 2 H, 4-H), 6.71–6.76 (m, 2 H, 2Ј-H, 6Ј-H), 6.76–
6.83 (m, 1 H, 4Ј-H) ppm. 13C NMR: δ = 12.2 (C-8b), 13.0 (C-7a),
20.2 (CH3CO), 21.2 (C-4), 30.9 (C-3), 75.8 (C-2), 102.6/112.6 (m,
33.0 (C-4Ј), 33.1 (C-8Ј), 37.6 (C-9Ј), 37.7 (C-5Ј), 37.8 (C-7Ј), 37.8
3
(C-11Ј), 37.9 (C-3Ј), 39.7 (C-1Ј), 76.2 (C-2), 116.0 (dd, JC,F
=
=
=
2
7.4 Hz, 2JC,F = 23.2 Hz, Ph-C3), 116.8 (dd, 3JC,F = 9.3 Hz, JC,F
3
2
25.9 Hz, Ph-C4), 117.9 (C-4a), 118.4 (dd, JC,F = 11.1 Hz, JC,F
3
2
24.1 Hz, Ph-C6), 126.0 (dd, JC,F = 7.6 Hz, JC,F = 20.9 Hz, Ph-
C1), 126.8 (C5), 126.8 (C8), 128.0 (C7), 139.8 (C6), 150.1 (C8a)
156.2 (1JC,F = 249 Hz, Ph-C2), 158.6 (1JC,F = 243 Hz, Ph-C5),
169.5 (CH3CO) ppm. 19F NMR: δ = –120.2 (s), –119.1 (s) ppm.
C-2Ј/C-4Ј/C-6Ј), 116.7 (C-5), 126.1 (C-7/8), 127.7 (C-7/8), 129.4 (C-
1
4a), 139.0 (C-6), 140.4 (m, C-1Ј), 149.8 (C-8a), 162.7 (dd, JC,F
=
X-ray Single-Crystal Diffraction: Data were collected with a Bruker
AXS Smart APEX CCD diffractometer and graphite monochro-
mated Mo-Kα. There was only one useful crystal available, which
was bent, gave poor reflection profiles and consequently furnished
modest reflection data. Corrections for absorption was performed
with program SHELXA, The structure was solved and refined with
program SHELXTL (version 6.10. Bruker AXS Inc., Madison, WI,
USA) using anisotropic displacement parameters only for iodine.
Crystal data and information on the structure refinement are given
248.7 Hz, 3JC,F = 12.7 Hz, C-3Ј, C-5Ј), 169.7 (CO) ppm. 19F NMR:
δ = –112.21 (d, J = 231.5 Hz) ppm.
5-(2,4-Difluorophenyl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-6-yl Acetate (13): Following the general procedure for the
Suzuki coupling, 5a (300 mg, 0.513 mmol) was treated with 2,4-
difluorphenylboronic acid (122 mg, 0.770 mmol), K2CO3 (144 mg,
1.026 mmol), and PdCl2(dppf)·DCM (10 mol-%). The crude resi-
due was purified by column chromatography on silica gel (n-hex-
2456
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Eur. J. Org. Chem. 2011, 2450–2457

Synthesis of 5-(Fluorophenyl)tocopherols as Novel Dioxin Receptor Antagonists
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Received: February 8, 2011
Published Online: March 17, 2011
Eur. J. Org. Chem. 2011, 2450–2457
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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