Bromination of Tocopherols
probehead operating at 400.13 MHz (1H) or 100.61 MHz (13C) and
a Bruker DPX 300 spectrometer with QNP probehead operating at
300.13 MHz (1H) or 75.47 MHz (13C) using standard Bruker soft-
ware with CDCl3 as the solvent if not otherwise stated. Chemical
shifts, relative to TMS as internal standard, are given as δ values,
coupling constants in Hz. 13C peaks were assigned by means of
APT, HMQC and HMBC spectra. The abbreviation “d.i.” denotes
13C NMR resonances originating from two magnetically equivalent
cedure as described above for the preparation of 11a was used with
the γ-tocopherol model (3a, 41.2 mg, 0.20 mmol) as the starting
material, affording 18a as a slightly yellow solid. M.p. 41–42 °C
(46.9 mg, 78 %). Rf = 0.23 (n-hexane/diethyl ether, 5:1, v/v).
C13H17BrO3 (301.18): calcd. C 51.84, H 5.69; found C 51.78, H
5.89.
(3) From δ-Tocopherol: 2,6-Dibromo-δ-tocopherylquinone [2,6-di-
bromo-3-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-5-methyl-
[1,4]benzoquinone, 24]. The same procedure as described above for
the preparation of 11 was used, with δ-tocopherol (4, 40.3 mg,
0.10 mmol) and the Br2 solution (0.1 m, 3.5 mL, corresponding to
0.35 mmol Br2) as the starting materials, affording 24 as a yellow
wax. M.p. 27–28 °C (53.6 mg, 93%). Rf = 0.33 (n-hexane/diethyl
ether, 5:1, v/v). C27H44Br2O3 (576.46): calcd. C 56.26, H 7.69;
found C 56.37, H 8.01.
carbon atoms. GC–MS was performed with
a GC 6890N/
MSD 5973B instrument with fused silica HP-5ms (30 m,
a
0.25 mm, 25 μm) column and helium as carrier gas. Total flow was
27.5 mLmin–1 at 46.9 kPa carrier gas pressure, and the resulting
column flow was 0.9 mLmin–1. The temperature programs were as
follows: 100 °C (5 min), 10 °Cmin–1 to 280 °C (20 min). Aliquots
(0.2 μL) of the dissolved samples were injected at 230 °C inlet tem-
perature in split mode (25:1). Ionization was performed in EI mode
at 70 eV.
2,6-Dibromo-δ-tocopherylquinone Model [2,6-Dibromo-3-(3-hy-
droxy-3-methylbutyl)-5-methyl-[1,4]benzoquinone, 24a]: The same
procedure as described above for the preparation of 11a was used,
with the δ-tocopherol model (4a, 38.4 mg, 0.20 mmol) and the Br2
solution (0.1 m, 6.5 mL, corresponding to 0.65 mmol Br2) as the
starting materials, affording 24a as a yellow solid. M.p. 55–56 °C
(54.0 mg, 74 %). Rf = 0.29 (n-hexane/diethyl ether, 5:1, v/v).
C12H14Br2O3 (366.05): calcd. C 39.38, H 3.86; found C 39.28, H
4.14.
Synthesis of Brominated p-Tocopherylquinones
(1) From β-Tocopherol: 2-Bromo-β-tocopherylquinone [2-bromo-5-
(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,6-dimethyl-[1,4]benzo-
quinone, 11]. A solution (0.1 m) of Br2 (1.60 g, 0.51 mL) in ethanol
(50 mL) and phosphate buffer (pH = 6, 2 m, 50 mL) was prepared.
Part of this solution (2.5 mL, corresponding to 0.25 mmol Br2) was
added in one portion at 0 °C to a stirred solution of β-tocopherol
(2, 41.7 mg, 0.10 mmol) in the same solvent (20 mL). The solution
was stirred for 1 h, allowed to warm to room temp., stirred for
another 10 min, and then concentrated in vacuo at room temp. to
about two thirds of its volume. The remaining solution was ex-
tracted with n-hexane (3 times 10 mL), and the combined extracts
were dried with MgSO4. After removal of the solids, the solvent
was evaporated and the residue was purified by flash chromatog-
raphy on silica gel (n-hexane/diethyl ether, 20:1, v/v) to afford 11
as a colorless oil (47.1 mg, 91%). Rf = 0.27 (n-hexane/diethyl ether
5:1, v/v). C28H47BrO3 (511.59): calcd. C 65.74, H 9.26; found C
65.84, H 9.52.
2-Bromo-δ-tocopherylquinone [2-Bromo-3-(3-hydroxy-3,7,11,15-tet-
ramethylhexadecyl)-5-methyl-[1,4]benzoquinone, 28]: FeCl3·6H2O
(3 equiv.) was added in one portion at 0 °C to a solution of 5-
bromo-δ-tocopherol (27, 24.1 mg, 0.05 mmol) in the ternary sol-
vent system methanol/water/diethyl ether (19:1:20, v/v/v, 40 mL).
The mixture was stirred at this temperature for 1.5 h. A gradual
color change to yellow indicated progressing formation of the para-
quinone. Water (50 mL) was added, and the mixture was extracted
with diethyl ether (30 mL). The organic phase was washed with
brine and water, dried with MgSO4, and concentrated in vacuo.
The oily residue was purified by flash chromatography on silica gel
(n-hexane/diethyl ether, 20:1, v/v) to afford 28 as a colorless oil
(23.4 mg, 94 %). Rf = 0.27 (n-hexane/diethyl ether, 5:1, v/v).
C27H45BrO3 (497.56): calcd. C 65.18, H 9.12; found C 65.22, H
9.03.
2-Bromo-β-tocopherylquinone Model [2-Bromo-5-(3-hydroxy-3-
methylbutyl)-3,6-dimethyl-[1,4]benzoquinone, 11a]:
A
solution
(0.1 m) of Br2 (1.60 g, 0.51 mL) in aqueous ethanol (1:1, v/v, total
volume 100 mL) was prepared. Part of this solution (5.0 mL, corre-
sponding to 0.50 mmol Br2) was added in one portion at 0 °C to
a stirred solution of the 6-hydroxy-2,2,5,8-tetramethylchroman β-
tocopherol model 2a (41.2 mg, 0.20 mmol) in the same solvent
(20 mL). The solution was stirred for 1 h, allowed to warm to room
temp., stirred for another 10 min, and then concentrated in vacuo
at room temp. to about one third of its volume. The remaining
solution was extracted with dichloromethane (3 times 10 mL), and
the combined extracts were dried with MgSO4. After removal of
the solids, the solvent was evaporated, and the residue was purified
by flash chromatography on silica gel (n-hexane/diethyl ether, 5:1,
v/v) to afford 11a as a white, waxy solid. M.p. 27–29 °C (48.2 mg,
80%). Rf = 0.32 (n-hexane/diethyl ether, 1:1, v/v). C13H17BrO3
(301.18): calcd. C 51.84, H 5.69; found C 52.00, H 5.62.
2-Bromo-δ-tocopherylquinone Model [2-Bromo-3-(3-hydroxy-3-
methylbutyl)-5-methyl-[1,4]benzoquinone, 28a]: FeCl3·6H2O
(3 equiv.) was added in one portion at 0 °C to a solution of 5-
bromo-δ-tocopherol model (27a, 27.1 mg, 0.10 mmol) in the ter-
nary solvent system methanol/water/diethyl ether (19:1:20, v/v/v,
40 mL). The mixture was stirred at this temperature for 1.5 h. A
gradual color change to yellow indicated progressing formation of
the para-quinone. Water (50 mL) was added, and the mixture was
extracted with diethyl ether (3 times 20 mL). The combined organic
phases were washed with water, dried with MgSO4, and concen-
trated in vacuo. The waxy residue was purified by flash chromatog-
raphy on silica gel (n-hexane/diethyl ether, 5:1, v/v) to afford 28a
as a colorless solid (19.5 mg, 68%). Rf = 0.39 (n-hexane/diethyl
ether, 1:1, v/v). C12H15BrO3 (287.16): calcd. C 50.19, H 5.27; found
C 50.42, H 28.12.
(2) From γ-Tocopherol: 2-Bromo-γ-tocopherylquinone [2-bromo-3-
(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-5,6-dimethyl-[1,4]-
benzoquinone, 18]. The same procedure as described above for the
preparation of 11 was used with γ-tocopherol (3, 41.7 mg,
0.10 mmol) as the starting material, affording 18 as a colorless oil
(45.0 mg, 88 %). Rf = 0.24 (n-hexane/diethyl ether, 5:1, v/v).
C28H47BrO3 (511.59): calcd. C 65.74, H 9.26; found C 65.72, H
9.29.
2-Bromo-5-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3-methyl-
[1,4]benzoquinone (26): The same procedure as above was used for
the preparation of 28. The starting material was 7-bromo-δ-tocoph-
erol (25, 24.1 mg, 0.05 mmol); the product was obtained as a yel-
lowish oil (21.9 mg, 88%). C27H45BrO3 (497.56): calcd. C 65.18, H
9.12; found C 65.32, H 9.11.
2-Bromo-γ-tocopherylquinone Model [2-Bromo-3-(3-hydroxy-3-
methylbutyl)-5,6-dimethyl-[1,4]benzoquinone, 18a]: The same pro-
2-Bromo-5-(3-hydroxy-3-methylbutyl)-3-methyl-[1,4]benzoquinone
(26a): The same procedure as above was used for the preparation of
Eur. J. Org. Chem. 2011, 3036–3049
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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