Synthesis of 4,4-difluoro-α-tocopherol using a cross-coupling reaction of bromodifluoroacetate with aryl iodide in the presence of copper powder

Article abstract of DOI:10.3987/com-01-s(k)61

Using our new methodology for introduction of a CF₂ moiety, 4,4-difluoro-α-tocopherol (2) was synthesized. Thus, 1-iodo-2,5-bis(methoxy-methoxy)-3,4,6-trimethylbenzene (4) was treated with ethyl bromodifluoroacetate (1) in the presence of Cu po

Full text of DOI:10.3987/com-01-s(k)61

HETEROCYCLES, Vol. 56, 2002, pp. 403 - 412, Received, 27th August, 2001
SYNTHESIS
OF
4,4-DIFLUORO-α-TOCOPHEROL
USING
A
CROSS-COUPLING REACTION OF BROMODIFLUOROACETATE
WITH ARYL IODIDE IN THE PRESENCE OF COPPER POWDER
Kazuyuki Sato, Takashi Nishimoto, Kei Tamoto, Masaaki Omote, Akira Ando
and Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University
45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
This is dedicated to 70th birthday of Professor James P. Kutney.
Abstract – Using our new methodology for introduction of a CF2 moiety,
4,4-difluoro-α-tocopherol (2) was synthesized. Thus, 1-iodo-2,5-bis(methoxy-
methoxy)-3,4,6-trimethylbenzene (4) was treated with ethyl bromodifluoroacetate
(1) in the presence of Cu powder to give a substituted phenyldifluoroacetate (5).
Compound (5) was converted to 4,4-difluorochromanol derivative (12).
Elongation of the side chain of 12 gave 2.
Introduction
Nowadays, organofluorine compounds have been attracting much attention in biomedicinal fields, since
they have various biological activities.1 Among them, difluoromethylene (CF2) compounds are very
important, and their syntheses have been reported by many workers.2 Reformatsky reaction3 of
halodifluoroacetate and aldol reaction4 using enolate or ketene acetal from halodifluoroacetate are the
most common methodologies to introduce a CF2 moiety. However, these methods give products with
one hydroxyl group adjacent to the CF2 group. This hydroxyl group is very stable and difficult to be
removed, although deoxygenation of β-fluoro alcohol through xanthates has been reported.5 Therefore,
it is very difficult to introduce a CF2 functional group without hydroxyl group using an appropriate
synthon.6
bromodifluoroacetate (1) with alkenyl or aryl iodides (Scheme 1).7
To solve this difficulty, we have developed a cross-coupling reaction of ethyl

Scheme 1
Cu
R CF2COOEt
+
R I
BrCF2COOEt
DMSO
1
Now, we would like to report the synthesis of the 4,4-difluoro-α-tocopherol (2) using our cross-coupling
reaction of an organocopper reagent derived from ethyl bromodifluoroacetate (1). α-Tocopherol is one
of the most important biologically active compounds and has been used in various fields.8 The main
effect of α-tocopherol has been believed to be anti-oxidizing effect but the clinical effect and the
biological behavior are not clearly solved.9 So, we have synthesized α-tocopherols with one or two CF3
groups (F3- or F6-α-tocopherols) in place of the methyl groups. Study of biological behavior of these
fluorine analogs of α-tocopherols using 19F-NMR gave interesting results.10 This prompted us to
synthesize α-tocopherol with CF2 group in chromane ring (F2-α-tocopherol, 2) using our new
methodology (Figure 1). F2-α-Tocopherol was expected to be useful for elucidation of biological
behavior and effective for the clinical use based on the electronic effect of CF2.
R
F F
HO
R
HO
R
R
R
O
O
2
R
F3-α-Tocopherol: One of R = CF3
F6-α-Tocopherol: Two of R = CF3
Figure 1. F - or F - -Tocopherols and 4,4-difluoro- -tocopherol (2)
α
α
3
6
Cross-coupling reaction of 1 with 1-iodo-2,5-bis(methoxymethoxy)-3,4,6-trimethylbenzene (4).
First, we synthesized 2-iodo-3,5,6-trimethylhydroquinone (3) according to literature11 for the cross-
coupling reaction.7 The hydroxyl groups of 3 were protected with MOM-Cl to give 1-iodo-2,5-
bis(methoxymethoxy)-3,4,6-trimethylbenzene (4) in 88% yield (Scheme 2). Compound (4) was treated
with 1 in the presence of active Cu powder to give ethyl [2,5-bis(methoxymethoxy)-3,4,6-
trimethylphenyl]difluoroacetate (5) in 96% yield. This result shows that our cross-coupling reaction is
not disturbed by large ortho substituents and proceeds in an excellent yield. On the other hand, the
cross-coupling reactions of the hydroquinone (3) or the corresponding quinone themselves did not
produce the coupling products at all (Scheme 2).
Scheme 2
OH
OMOM
I
OMOM
CF2COOEt
N
Et
I
Cu
BrCF2COOEt (1)
DMSO
MOM-Cl
CH2Cl2
88 %
OH
OMOM
OMOM
3
4
5
96%

Synthesis of the chromane ring. Compound (5) was treated with DIBAL-H, followed by Horner-
Wadsworth-Emmons (HWE) reaction with triethyl 2-phosphonopropionate to give a 4,4-difluoro-
2-butenoate (6) in 60% yield as an E/Z mixture (Scheme 3). Several bases, such as BuLi, were
examined for the HWE reaction. Among them, LDA gave the best yield and stereoselectivity was
moderate in all cases. Compound (6) was reduced by H2 in the presence of 10% Pd-C, followed by a
treatment with LAH to give a saturated alcohol (8). On the other hand, the allyl alcohol (9) obtained by
reduction of 6 with LAH was too unstable to proceed for further synthesis. Since dehydration of 8
through the mesylate was not effective, we adopted Grieco’s o-nitorophenylselenylation method.12
Thus, 8 was treated with o-nitrophenyl selenocyanate and tributylphosphine, followed by a treatment
with 30% H2O2 to give the corresponding methylene compound (10). Compound (10) was epoxidized
by mCPBA, followed by ring closure with CF3COOH to give the corresponding chromanol (12).
Further, 12 was oxidized by Swern reaction to give the aldehyde (13) in 18% overall yield from 6.
(Scheme 3)
Scheme 3
OMOM
CF2COOEt
OMOM
CF2
OMOM
CF2
c
a, b
COOEt
COOEt
OMOM
OMOM
6: 60 % (E/Z mixture)
OMOM
d
7
5
d
OMOM
OMOM
CF2
CF2
OH
c
CH2OH
8
e, f
47%
OMOM
9: unstable
OMOM
8: 84% from 6
OMOM
OMOM
CF2
F F
CF2
MOMO
g
O
12: R = CH2OH
h
i
87%
64%
O
R
82%
13: R = CHO
OMOM
OMOM
11
10
a) 1: DIBAL-H, THF; 2: MeOH, 5% HCl; b) LDA, (EtO)2P(O)CHMeCOOEt, THF; c) 10% Pd-C,
H2, THF; d) LiAlH4, THF; e) o-nitrophenyl selenocyanate, Bu3P, THF; f) 30% H2O2, THF; g)
mCPBA, CH2Cl2; h) CF3COOH, THF, H2O; i) (COCl)2, DMSO, Et3N, CH2Cl2
Synthesis of 4,4-difluoro-α-tocopherol (2) by Wittig reaction.13 For the construction of the side
chain, we attempted to join 13 with the Wittig reagent derived from farnesol (14), followed by reduction
of the double bonds. Unfortunately, catalytic hydrogenation of the Wittig reaction product did not give

the fully saturated side-chain, but a mixture of partially reduced ones. To solve this difficulty, farnesol
(14) was hydrogenated first in the presence of 10% Pd-C to give 3,7,11-trimethyldodecanol (15) in 85%
yield. Treatment of 15 with CBr4 and PPh3 gave the bromide (16) in 80% yield. Compound (16) was
converted to the phosphonium salt (17) by treatment with PPh3. In this case, the presence of solvent
interfered production of the objective phosphonium salt. This salt was an oil and unstable, and used for
the Wittig reaction without purification. The ylide obtained from 17 and BuLi was treated with 13 to
give 4,4-difluoro-6-methoxymethoxy-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-1-tridecenyl)chromane (18)
in 52% yield. Finally, hydrogenation of 18 in the presence of 10% Pd-C afforded 19, which was
hydrolyzed with PTSA to give 4,4-difluoro-α-tocopherol (2) in 75% yield from 18. (Scheme 4)
Scheme 4
a, b
c
HO
Br
: 68% from
16
14
14
F F
MOMO
d
Ph3P
Br
O
18: 52% based on 13
17
F F
HO
e, f
a) Pd-C, H2, MeOH; b) CBr4, PPh3,
CH2Cl2; c) PPh3; d) nBuLi, 13, THF; e)
10% Pd-C, H2, MeOH; f) TsOH, MeOH
O
: 75% from
2
18
Concluding Remark Our cross-coupling reaction of bromodifluoroacetate with an aryl iodide was
successfully applied for the synthesis of 4,4-difluoro-α-tocopherol (2). This result showed that our
method is widely applicable for the syntheses of aryldifluoromethylene compounds even in the presence
of large substituents in ortho positions. Compound (2) is a new fluorine derivative of α-tocopherol, and
it is expected to have new effect different from those of F3- or F6-α-tocopherols.
Experimental
General Procedures
1H-NMR spectra were recorded on JEOL-FX90Q and JNM-GX400 Spectrometer using tetramethylsilane
as an internal standard. 19F-NMR spectra were recorded on Hitachi FT-NMR R-1500, JEOL-FX90Q
and GE-Omega 600 Spectrometers using benzotrifluoride as an internal standard. MS spectra were
obtained by JEOL JMS-DX-300 and JEOL JMS-700T. Gas-liquid chromatography (GLC) was carried
out on a Hitachi 263-50 gas chromatograph (column: 5% SE-30 3 mm x 2 m, carrier: N2 at 30 mL/min).
Peak areas were calculated on a Shimadzu C-R5A Chromatopac. The melting point was measured on

an Ishii Shoten Melting Point Apparatus. After the purities of samples were confirmed by TLC or GLC,
elemental analyses were obtained by high resolution mass spectra.
1-Iodo-2,5-bis(methoxymethoxy)-3,4,6-trimethylbenzene (4)
Under an atmosphere of Ar, chloromethyl methyl ether (0.52 mL, 6.8 mmol) in CH2Cl2 (2.5 mL) was
added to a solution of 2-iodo-3,5,6-trimethylhydroquinone (3, 480 mg, 1.7 mmol) and
N,N-diisopropylethylamine (2.37 mL, 13.6 mmol) in CH2Cl2 (2.5 mL) at rt for 1 h. The mixture was
poured into a mixture of ice and 3% HCl, and extracted with CH2Cl2. The CH2Cl2 layer was washed
with saturated aq. NaHCO3 and saturated aq. NaCl, and dried over MgSO4. After evaporation of the
solvent, the residue was purified by column chromatography (SiO2, AcOEt:hexane=1:9) to give 4 (548
mg, 88%). 4: Colorless crystals. mp 82.8-83.8 °C. MS m/z: 366 (M+). HRMS Calcd C13H19O4I:
366.033 (M+) Found: 366.033. 1H-NMR (CDCl3) δ: 4.98 (s, 2H), 4.88 (s, 2H), 3.67 (s, 3H), 3.60 (s, 3H),
2.44 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H).
Ethyl [2,5-bis(methoxymethoxy)-3,4,6-trimethylphenyl]difluoroacetate (5)
Under an atmosphere of Ar, ethyl bromodifluoroacetate (1, 1.49 mL, 11.7 mmol) was added to a
suspension of activated Cu powder (1.62 g, 25.8 mmol) and 4 (1.42 g, 3.9 mmol) in DMSO (19.5 mL).
After the mixture was stirred at 55 °C for 7 h, it was poured into a mixture of ice and saturated aq. NH4Cl,
and extracted with Et2O. The Et2O layer was washed with saturated aq. NH4Cl and saturated aq. NaCl,
and dried over MgSO4. After evaporation of the solvent, the residue was purified by column
chromatography (SiO2, AcOEt:hexane=1:4) to give 5 (1.36 g, 96%). 5: A pale yellow oil. bp
113-115 °C / 0.017 mmHg. MS m/z: 362 (M+). HRMS Calcd C17H24O6F2: 362.154 (M+) Found: 362.154.
1H-NMR (CDCl3) δ: 4.90 (s, 2H), 4.79 (s, 2H), 4.33 (q, 2H, J= 7.3 Hz), 3.62 (s, 3H), 3.55 (s, 3H), 2.42 (t,
19
3H, J= 4.4 Hz), 2.24 (s, 3H), 2.20 (s, 3H), 1.31 (t, 3H, J= 7.3 Hz). F-NMR (CDCl3) ppm: –29.7 (m,
2F).
Ethyl 4-[2,5-bis(methoxymethoxy)-3,4,6-trimethylphenyl]-4,4-difluoro-2-methyl-2-butenoate (6)
Under an atmosphere of Ar, DIBAL-H (7.6 mL: 0.94 M in hexane, 7.1 mmol) was added to a solution of
5 (1.08 g, 3.0 mmol) in Et2O (9.0 mL) at –78 °C and stirred at this temperature for 2 h, then MeOH (1.5
mL) and 5% HCl (3.0 mL) were added to the solution. After the mixture was stirred at rt for 10 min, it
was poured into saturated aq. NaCl, and extracted with Et2O. The Et2O layer was dried over MgSO4.
After evaporation of the solvent, the residue was used for next step without purification. Triethyl
n
phosphonopropionate (0.77 mL, 3.6 mmol) was added at –78 °C to a solution of LDA from BuLi (2.3
mL: 1.56 M in hexane, 3.6 mmol) and diisopropylamine (0.5 mL, 3.6 mmol) in THF (12 mL), and then
the above residue dissolved in THF (6 mL) was added. After 10 min, the mixture was gradually
warmed to rt and stirred for 15 min. The mixture was poured into 10% HCl, and extracted with Et2O.
The Et2O layer was washed with saturated aq. NaHCO3 and saturated aq. NaCl, and dried over MgSO4.

After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=1:9) to give (E)-6 (531 mg, 44%) and (Z)-6 (193 mg, 16%). (E)-6: A pale yellow oil.
1
MS m/z: 402 (M+). HRMS Calcd C20H28O6F2: 402.185 (M+) Found: 402.185. H-NMR (CDCl3) δ: 6.06
(tq, 1H, J= 12.7, 2.0 Hz), 4.87 (s, 2H), 4.84 (s, 2H), 4.11 (q, 2H, J= 7.3 Hz), 3.61 (s, 3H), 3.59 (s, 3H),
2.36 (dd, 3H, J= 4.9, 4.3 Hz), 2.23 (s, 3H), 2.22 (s, 3H), 2.01 (td, 3H, J= 2.9, 2.0 Hz), 1.30 (t, 3H, J= 7.3
Hz). 19F-NMR (CDCl3) ppm: –15.6 (m, 2F). (Z)-6: A pale yellow oil. MS m/z: 402 (M+). HRMS Calcd
1
C20H28O6F2: 402.185 (M+) Found: 402.185. H-NMR (CDCl3) δ: 7.13 (tq, 1H, J= 12.0, 1.5 Hz), 4.88 (s,
2H), 4.85 (s, 2H), 4.22 (q, 2H, J= 7.3 Hz), 3.61 (s, 3H), 3.58 (s, 3H), 2.40 (dd, 3H, J= 4.8, 4.4 Hz), 2.24
(s, 3H), 2.21 (s, 3H), 1.85 (td, 3H, J= 2.9, 1.5 Hz), 1.30 (t, 3H, J= 7.3 Hz). 19F-NMR (CDCl3) ppm: –17.3
(m, 2F).
4-[2,5-Bis(methoxymethoxy)-3,4,6-trimethylphenyl]-4,4-difluoro-2-methylbutanol (8)
A THF (10 mL) solution of 6 (525 mg, 1.3 mmol) was vigorously stirred in the presence of 10% Pd-C
(13 mg) under an atmosphere of H2 at rt for 6.5 h. After the catalyst was filtered off, the solvent was
evaporated to give the crude 7, which was added to a solution of LiAlH4 (7.4 mg, 1.95 mmol) in THF
(3.7 mL) at 0 °C under an atmosphere of Ar. After 30 min, the mixture was poured into 10% HCl, and
extracted with Et2O. The Et2O layer was washed with saturated aq. NaHCO3 and saturated aq. NaCl,
and dried over MgSO4. After evaporation of the solvent, the residue was purified by column
chromatography (SiO2, AcOEt:hexane=2:3) to give 8 (395 mg, 84% from 6). 8: A pale yellow oil. MS
1
m/z: 362 (M+). HRMS Calcd C18H28O5F2: 362.190 (M+); Found: 362.190. H-NMR (CDCl3) δ: 4.86 (s,
4H), 3.62 (s, 3H), 3.61 (s, 3H), 3.52 (t, 2H, J= 5.3 Hz), 2.38-2.52 (m, 1H), 2.34 (dd, 3H, J= 5.2, 4.8 Hz),
2.23 (s, 3H), 2.22 (s, 3H), 2.08 (m, 2H), 1.59 (bs, 1H), 1.03 (d, 3H, J= 6.8 Hz). 19F-NMR (CDCl3) ppm:
–21.6 (m, 2F).
4-[2,5-Bis(methoxymethoxy)-3,4,6-trimethylphenyl]-4,4-difluoro-2-methyl-1-butene (10)
Under an atmosphere of Ar, Bu3P (0.09 mL, 0.38 mmol) was slowly added at 0 °C to a stirred solution of
8 (100 mg, 0.27 mmol) and o-nitrophenyl selenocyanate (74 mg, 0.32 mmol) in THF (1 mL), and the
mixture was stirred at rt for 24 h. After THF was evaporated from the mixture, the residue was passed
through an SiO2 column (AcOEt:hexane=2:3) to give the corresponding selenide. 30% H2O2 (0.31 mL,
2.7 mmol) was slowly added at 0 °C to a solution of the selenide in THF (2 mL), and the mixture was
stirred at 0 °C for 1 h and then at rt for 2 h. The mixture was poured into H2O and was extracted with
Et2O. The Et2O layer was washed with 10% aq. Na2CO3 and saturated aq. NaCl, and dried over MgSO4.
After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=2:3) to give 10 (44 mg, 47% from 8). 10: A pale yellow oil. MS m/z: 344 (M+). HRMS
Calcd C18H26O4F2: 344.179 (M+); Found: 344.179. 1H-NMR (CDCl3) δ: 4.93 (m, 1H), 4.87 (s, 2H), 4.86
(s, 2H), 4.79 (m, 1H), 3.63 (s, 3H), 3.60 (s, 3H), 2.98 (t, 2H, J= 17.7 Hz), 2.33 (t, 3H, J= 5.2 Hz), 2.23 (s,

6H), 1.77 (s, 3H). 19F-NMR (CDCl3) ppm: –21.0 (m, 2F).
2-[2-{2,5-Bis(methoxymethoxy)-3,4,6-trimethylphenyl}-2,2-difluoroethyl]-2-methyloxirane (11)
Under an atmosphere of Ar, to a stirred solution of mCPBA (100 mg, 0.58 mmol) in CH2Cl2 (4 mL) was
slowly added a solution of 10 (200 mg, 0.58 mmol) in CH2Cl2 (6 mL), and the mixture was stirred at rt
for 24 h. Further, mCPBA (75%, 130 mg, 0.58 mmol) was added to the mixture and stirred for 24 h.
After 10 was not detected by TLC, the mixture was poured into saturated aq. NaHCO3 and extracted with
CH2Cl2. The CH2Cl2 layer was washed with saturated aq. NaCl, and dried over MgSO4. After
evaporation of the solvent, the residue was purified by column chromatography (SiO2, AcOEt:hexane
=1:4) to give 11 (181 mg, 87%). 11: A pale yellow oil. MS m/z: 360 (M+). HRMS Calcd C18H26O5F2:
360.175 (M+) Found: 360.175. 1H-NMR(CDCl3) δ: 4.86 (s, 2H), 4.86 (s, 2H), 3.62 (s, 3H), 3.61 (s, 3H),
2.77 (m, 1H), 2.70 (d, 1H, J= 4.8 Hz), 2.62 (dd, 1H, J= 4.8, 1.2 Hz), 2.33 (dd, 3H, J= 5.2, 4.8 Hz), 2.29
(m, 1H), 2.23 (s, 3H), 2.22 (s, 3H), 1.42 (s, 3H). 19F-NMR (CDCl3) ppm: –21.0 (m, 2F).
(4,4-Difluoro-6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-yl)methanol (12)
Under an atmosphere of Ar, 50 %(v/v) CF3COOH-H2O (0.08 mL) was added dropwise at 0 °C to a
solution of 11 (40 mg, 0.11 mmol) in THF (0.22 mL), and the mixture was stirred for 1 h at 0 °C. The
mixture was warmed up to rt and stirred for 14 h. The mixture was poured into saturated aq. NaHCO3
and extracted with Et2O. The Et2O layer was washed with saturated aq. NaCl, and dried over MgSO4.
After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=2:3) to give 12 (22 mg, 64%). 12: A pale yellow oil. MS m/z: 316 (M+). HRMS Calcd
C16H22O4F2: 316.149 (M+) Found: 316.149. 1H-NMR (CDCl3) δ: 4.88 (d, 1H, J= 7.7 Hz), 4.87 (d, 1H, J=
7.7 Hz), 3.72 (m, 1H), 3.62 (s, 3H), 3.59 (m, 1H), 2.72 (ddd, 1H, J= 21.6, 14.7, 14.4 Hz), 2.44 (s, 3H),
2.30 (ddd, 1H, J= 17.5, 14.7, 8.5 Hz), 2.22 (s, 3H), 2.08 (s, 3H), 1.95 (bs, 1H), 1.32 (d, 3H, J= 1.7 Hz).
19F-NMR (CDCl3) ppm: –16.80 (m, 1F), –18.80 (m, 1F).
4,4-Difluoro-6-methoxymethoxy-2,5,7,8-tetramethyl-2-chromancarbaldehyde (13)
Under an atmosphere of Ar, a solution of DMSO (0.037 mL, 0.52 mmol) in CH2Cl2 (0.065 mL) was
added dropwise at –78 °C to a solution of (COCl)2 (0.023 mL, 0.26 mmol) in CH2Cl2 (0.32 mL), and the
mixture was stirred for 30 min at that temperature. A solution of 12 (67 mg, 0.21 mmol) in CH2Cl2 (0.4
mL) was added to the mixture at –78 °C, and the mixture was stirred for 30 min, followed by slow
addition of Et3N (0.148 mL, 1.06 mmol) at –78 °C. The mixture was gradually warmed up to rt, and
was poured into saturated aq. NaCl and extracted with CH2Cl2. The CH2Cl2 layer was dried over
MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=1:4) to give 13 (54 mg, 82%). 13: A pale yellow oil. MS m/z: 314 (M+). HRMS Calcd
1
C16H20O4F2: 314.133 (M+) Found: 314.133. H-NMR (CDCl3) δ: 9.64 (dd, 1H, J= 1.4, 0.8 Hz), 4.89 (d,
1H, J= 6.6 Hz), 4.87 (d, 1H, J= 6.6 Hz), 3.62 (s, 3H), 2.81 (ddd, 1H, J= 16.1, 14.7, 9.2 Hz), 2.49 (ddd,

19
1H, J= 19.8, 14.7, 12.1 Hz), 2.40 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H), 1.48 (d, 3H, J= 1.0 Hz). F-NMR
(CDCl3) ppm: –14.82 (ddd, 1F, J= 263.7, 19.8, 16.1 Hz), –23.54 (ddd, 1F, J= 263.7, 12.1, 9.2 Hz).
3,7,11-Trimethyldodecanol (15)
A MeOH (140 mL) solution of farnesol (14, 1.0 g, 4.50 mmol) was vigorously stirred in the presence of
10% Pd-C (150 mg) under an atmosphere of H2 at rt for 4 h. After removal of the catalyst and
evaporation of the solvent, the residue was purified by column chromatography (SiO2, AcOEt:hexane
=1:1) to give 15 (872 mg, 85%) as a mixture of diastereomers. 15: A colorless oil: MS m/z: 227 (M+–1).
1
HRMS Calcd C15H32O: 227.238 (M+–1) Found: 227.237. H-NMR(CDCl3) δ: 3.68 (m, 2H), 1.47-1.66
(m, 3H), 1.00-1.44 (m, 15H), 0.89 (d, 3H, J= 6.1 Hz), 0.86 (d, 6H, J= 6.7 Hz), 0.84 (dd, 3H, J= 6.6, 0.6
Hz).
1-Bromo-3,7,11-trimethyldodecane (16)
Under an atmosphere of Ar, to CBr4 (1.3 g, 3.4 mmol) was added a solution of 15 (711 mg, 3.1 mmol) in
CH2Cl2 (13 mL) and a solution of PPh3 (892 mg, 3.4 mmol) in CH2Cl2 (3 mL) at 0 °C, and the mixture
was stirred at rt for 1 h. MeOH (3 mL) was added to the mixture, and stirred for 1 h. After
evaporation of the solvent, the residue was purified by column chromatography (SiO2, AcOEt:hexane
=1:1) and vacuum distillation to give 16 (729 mg, 81%) as a mixture of diastereomers. 16: A colorless
oil. bp 110-115 °C / 4 mmHg. MS m/z: 290 (M+), 292 (M++2). HRMS Calcd C15H31Br: 290.161 (M+)
Found: 290.160. 1H-NMR (CDCl3) δ: 3.44 (m, 2H), 1.87 (m, 1H), 1.46-1.72 (m, 3H), 1.01-1.43 (m, 13H),
*
*
*
0.89 (d, 3H, J= 6.2 Hz), 0.87 (d, 6H, J= 6.8 Hz), 0.85 (d, H, J= 6.8 Hz), 0.85 (d, H, J= 7.2 Hz); H is
total 3H.
1-(4,4-Difluoro-6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-yl)-4,8,12-trimethyl-1-tridecene
(18)
Under an atmosphere of Ar, PPh3 (89 mg, 0.34 mmol) and 16 (100 mg, 0.34 mmol) was stirred at 200 °C
for 17 h without a solvent. After the mixture was cooled to rt, THF (3 mL) was added to the mixture.
nBuLi (0.25 mL: 1.56 M in hexane, 0.4 mmol) was slowly added at 0 °C to the solution and stirred for 15
min. A solution of 13 (54 mg, 0.17 mmol) in THF (2 mL) was added to the mixture and stirred at rt for
2 h and then at 50 °C for 30 min. The mixture was poured into saturated aq. NH4Cl, and extracted with
Et2O. The Et2O layer was washed with saturated aq. NH4Cl and saturated aq. NaCl, and dried over
MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=1:9) to give 18 (45 mg, 52%) as E-Z and diastereo mixture. 18: A pale yellow oil. MS
1
m/z: 508 (M+). HRMS Calcd C31H50O3F2: 508.371 (M+) Found: 508.372. H-NMR (CDCl3) δ: 5.50 (m,
1H), 5.40 (m, 1H), 4.87 (d, 1.6H, J= 0.6 Hz), 4.86 (s, 0.4H), 3.62 (s, 2.4H), 3.61 (s, 0.6H), 2.42 (s, 3H),
2.22 (s, 3H), 2.13 (s, 3H), 1.70-2.70 (m, 5H), 0.87 (d, *H, J= 6.8 Hz), 0.86 (d, 6H, J= 6.8 Hz), 0.84 (dd,
*H, J= 6.8, 0.4 Hz), 0.83 (d, **H, J= 6.4 Hz), 0.81 (d, **H, J= 6.4 Hz), 0.74 (d, *H, J= 6.8 Hz), 0.71 (d, *H,

J= 6.8 Hz), *H is total 3H, **H is total 3H. 19F-NMR (CDCl3) ppm: –18.6 (t, 2F, J= 14.6 Hz).
1-(4,4-Difluoro-6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-yl)-4,8,12-trimethyltridecane
(19)
A MeOH (3 mL) solution of 18 (45 mg, 0.09 mmol) was vigorously stirred in the presence of 10% Pd-C
(3 mg) under an atmosphere of H2 at rt for 12 h. After removal of the catalyst and the evaporation of
the solvent, the residue was purified by column chromatography (SiO2, AcOEt:hexane=1:9) to give 19
(42 mg, 93%) as a mixture of diastereomers. 19: A pale yellow oil. MS m/z: 510 (M+). HRMS Calcd
C31H52O3F2: 510.388 (M+) Found: 510.376. 1H-NMR (CDCl3) δ: 4.87 (s, 2H), 3.61 (s, 3H), 2.43 (s, 3H),
2.26-2.52 (m, 2H), 2.21 (s, 3H), 2.08 (s, 3H), 1.00-1.75 (m, 24H), 0.87 (d, 6H, J= 6.8 Hz), 0.85 (dd, 3H,
J= 6.8, 0.4 Hz), 0.84 (d, 3H, J= 6.8 Hz). 19F-NMR (CDCl3) ppm: –18.0 (m, 2F).
4,4-Difluoro-α-tocopherol (2)
Under an atmosphere of Ar, a solution of 19 (42 mg, 0.08 mmol) and p-toluenesulfonic acid·H2O (5 mg)
in MeOH (2 mL) was stirred at rt for 24 h. The mixture was poured into saturated aq. NaHCO3 and
extracted with Et2O. The Et2O layer was washed with saturated aq.NaCl, and dried over MgSO4.
After evaporation of the solvent, the residue was purified by column chromatography (SiO2,
AcOEt:hexane=1:19) to give 2 (31 mg, 81%) as a mixture of diastereomers. 2: A pale yellow oil. MS
1
m/z: 466 (M+). HRMS Calcd C29H48O2F2: 466.362 (M+) Found: 466.362. H-NMR (CDCl3) δ: 4.37 (s,
1H), 2.38 (s, 3H), 2.26-2.52 (m, 2H), 2.19 (s, 3H), 2.10 (s, 3H), 0.95-1.75 (m, 24H), 0.87 (d, 6H, J= 6.8
19
Hz), 0.85 (d, 3H, J= 6.8 Hz), 0.84 (d, 3H, J= 6.8 Hz). F-NMR (CDCl3) ppm: –16.7 (dd, 2F, J= 30.8,
15.0 Hz).
ACKNOWLEDGEMENT
This work was partly supported by Grant-in-Aid for Scientific Research (C) from Japan Society for the
Promotion of Science.
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