Novel tocopheryl compounds. Part 15: One-pot formation of furotocopheryl derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00426-5

Reaction of tocopheryl bromide 2a or chromanyl bromide 2b with triphenyl phosphine produced phosphomium salt intermediates (3a-b), which further reacted with acyl chlorides to novel furotocopherol compounds 4-11 in good yields. The cyclization proceeded according to a two step esterification-Wittig mechanism. Similarly, furotocopheryl dimer 12 was prepared starting from oxalyl chloride. The coupling of tocopheryl phosphonium salt 3a onto modified polystyrene provided a new, vitamin E-loaded resin.

Full text of DOI:10.1016/S0040-4020(03)00426-5

Tetrahedron 59 (2003) 3231–3235
Novel tocopheryl compounds. Part 15: One-pot formation
q
of furotocopheryl derivatives
a
Christian Adelw o¨ hrer, Thomas Rosenau, Wolfgang H. Binder and Paul Kosma
a,*
b
a
a
Institute of Chemistry, University of Agricultural Sciences, Muthgasse 18, A-1190 Vienna, Austria
Institute of Applied Synthetic Chemistry, University of Technology Vienna/163/MC, A-1040 Vienna, Austria
b
Received 17 December 2002; revised 24 February 2003; accepted 17 March 2003
Abstract—Reaction of tocopheryl bromide 2a or chromanyl bromide 2b with triphenyl phosphine produced phosphomium salt
intermediates (3a–b), which further reacted with acyl chlorides to novel furotocopherol compounds 4–11 in good yields. The cyclization
proceeded according to a two step esterification–Wittig mechanism. Similarly, furotocopheryl dimer 12 was prepared starting from oxalyl
chloride. The coupling of tocopheryl phosphonium salt 3a onto modified polystyrene provided a new, vitamin E-loaded resin. q 2003
Elsevier Science Ltd. All rights reserved.
1
. Introduction
difficulties stimulated the search for novel tocopherol-
based antioxidants, which are covalently linked to poly-
meric structures and possess phenolic hydroxyls protected
by more stable structures than the labile ester linkages.
Such derivatives would remain intimately mixed in the
polymer matrix during processing, would be more resistant
towards thermal stress, and release the antioxidatively
acting free phenol much slower, thus increasing the long-
term efficiency of the stabilizer.
a-Tocopherol (1), the component of vitamin E with the
highest biological activity, is known to be one of the most
effective chain breaking phenolic antioxidants. It reacts
rapidly with a variety of radicals to form the relatively stable
a-tocopheroxyl radical, which is either reduced back to
a-tocopherol, or further oxidized to quinoid structures. The
exceptional high efficiency of vitamin E as phenolic
antioxidant has been attributed to substituent effects, and
3
to stereoelectronic influences as well.
1
2
In this work, the synthesis and comprehensive analytical
characterization of novel functional antioxidants—furo-
tocopherol derivates, a furotocopheryl dimer and furotoco-
pherols linked to a polystyrene matrix—is described, which
represent a first step toward this goal.
2. Results and discussion
Especially for packaging in the food industry, esters of
a-tocopherol are used as stabilizers for plastics and other
synthetic polymers. These vitamin E derivatives are
advantageous because of their full physiological compati-
bility, but a wider application is hampered by three major
drawbacks. First, some fabrication steps, such as extrusion,
pressing or melt processing, cause severe problems with
phase-separation of the oily stabilizer and demixing,
second, their thermostability is low, and third, the action
time is rather short, as the esters are readily cleaved
releasing the phenol as the active antioxidant. These
The well known formation of 5a-bromo-a-tocopherol (2a)
by reaction of a-tocopherol (1) with elemental bromine
proceeds quantitatively according to a two-step mechanism:
oxidation and subsequent addition of hydrogen bromide to
4
the intermediate ortho-quinone methide. The tocopheryl
bromide was readily converted into the triphenyl phos-
phonium salt 3a, which started to precipitate within 10 min
from n-hexane, giving complete conversion after about 2 h.
Similar to other 5a-substituted tocopherols, the phos-
phonium salt is rather labile, so that heating above 408C
should be avoided. Best results were obtained if 3 was not
isolated, but prepared in situ and immediately employed in
further reactions.
q
See ref. 9.
Keywords: furotocopheryl derivatives; cyclization; vitamin E; tocopherol.
*
Reaction of the phosphonium salt with acyl chlorides in dry,
5
refluxing toluene containing a threefold excess of auxiliary
Corresponding author. Tel.: þ43-1-36006-6071; fax: þ43-1-36006-6059;
e-mail: trosenau@edv2.boku.ac.at
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00426-5

3232
C. Adelw o¨ hrer et al. / Tetrahedron 59 (2003) 3231–3235
13
Figure 1. Gel C NMR of furotocopherol loaded polystyrene resin 13.
Stars mark resonances of the resin.
Scheme 1. Formation reaction of furotocopherols 4–11.
base (TEA or NaH) provided furotocopheryl derivatives
4
–11 in fair to good yields (Scheme 1). The reaction
proceeded according to a two-step process consisting of
esterification of the phenolic hydroxyl group followed by an
intramolecular Wittig-type reaction. The auxiliary base
facilitates both the acylation reaction and the intramolecular
cyclization. By employing different acyl chlorides, the
NMR, see Figure 1. This method has been found to be useful
in monitoring reactions conducted directly on the resin
7
material without cleavage from the resin. Critical is the use
of a solvent, which allows a good swelling of the resin
8
2-substituents of the stable 5-membered furan ring can be
6
varied (Scheme 1).
material. In this work, CDCl as the swelling solvent and
3
spinning rates of 4000 Hz to minimize resonances from the
1
3
resin material were used. The observed
C NMR
This one-pot conversion is equally feasible with chroman-6-
ols—compounds lacking the isoprenoid side chain, which
are frequently used as tocopherol model compounds. The
yields are generally comparable to those in the tocopherol
group; one example, 2-phenyl-furochroman 6, is given in
Table 1. Also the reaction with oxalyl chloride as a
bifunctional acid chloride proceeded smoothly providing
the furotocopheryl dimer 12.
resonances of the isoprenoid side chain in polymer-bound
furotocopherol 13 are identical to those of monomeric
furotocopherols. Due to signal overlap with the resonances
from the Kel-F spacer and reduced mobility an assignment
in the aromatic region was not possible. All other relevant
resonances in the aliphatic region, however, are in strong
accordance with the corresponding solution spectrum of 12.
Even though quantitation of the load cannot be achieved by
this method, chemical identity of the vitamin E moiety and
the fixation to the resin could be unambiguously proven.
To test the furotocopherol formation on a polymeric
support, polymer-bound carboxyl groups, in the form of a
polystyrene Merrifield resin containing 0.88 mmol/g carb-
oxyl groups, were converted into acid chloride groups by
All furotocopheryl derivatives were purified by column
chromatography (cf. Section 3) at least two times to obtain
analytically pure products. In contrast to tocopheryl esters,
which release the free tocopherol quite readily, the
furotocopherols represent derivatives with a much more
stable form of protection for the hydroxyl group. Future
tests must reveal whether this property makes them efficient
stabilizers with long-term antioxidative action. Furotoco-
pherol derivatives with conjugated double bonds at
2-position are strongly fluorescent and light sensitive.
They are even unstable when stored for prolonged times
at 2788C in the dark. It will be tested if vinyl compound 8
and styrene derivative 9 can be co-polymerized, which
would provide novel functional polymers with chemically
attached, ‘on-line’ stabilizer functions.
treatment with SOCl . Further reaction with phosphonium
2
salt 3a provided a novel tocopherol-loaded resin with
possible applications as thermostable, extrudable polymer
stabilizer. The presence of tocopheryl moieties on the
polymer beads was confirmed by high resolution MAS
Table 1. Synthesis and yields of furotocopherols 4–13
a
Compound
R1
R2
Yield (%)
4
5
6
7
8
9
C
C
CH
16
H
H
33
Methyl
Phenyl
Phenyl
2-Nitrophenyl
Vinyl
1-Phenylethenyl
Methoxymethyl
tert-Butyl
Furotocopheryl
Polystyrene resin
61
55
55
57
45
67
62
51
16
33
3
C
16
C
16
C
16
C
16
C
16
C
16
C
16
H
33
33
33
33
33
33
33
H
H
H
H
H
H
1
1
1
1
0
1
2
3
In summary, the synthesized furotocopherols represent
vitamin E derivatives, in which the tocopherol structure is
linked to other moieties by stable, non-hydrolyzable
carbon–carbon bonds extending from C-5a. In addition,
the protection of the phenolic hydroxyl group in the
46
See text
a
Isolated yields.

C. Adelw o¨ hrer et al. / Tetrahedron 59 (2003) 3231–3235
3233
tocopherol moiety is much more stable than in convention-
ally used tocopheryl esters. These properties render the
novel furo-derivatives promising as stabilizers with long-
term efficiency, possibly applicable either as additives or in
co-polymerized form.
and bromine (0.16 g, 1.10 mmol) as a brown oil (0.27 g,
1
100%). H NMR (CDCl ): d 4.66 (s, 2H, H-5a), 3.98 (s, b,
3
3
1H, OH), 2.78 (t, 2H, H-4, J¼6.8 Hz), 2.15 and 2.12 (2£s,
3
2£3H, H-8b, H-7a), 1.82 (t, 2H, H-3, J¼6.8 Hz), 1.29 (2£s,
1
3
2£3H, H-2a, H-2b). C NMR (CDCl ): d 146.1 (C-6),
3
1
45.5 (C-8a). 127.2 (C-5), 122.2 (C-8), 119.2 (C-7), 117.2
(
C-4a), 75.1 (C-2), 32.6 (C-3), 26.6 (d.i., C-2a), 21.2 (C-4),
12.4 and 12.2 (H-7a, H-8b). IR (film): 3402, 2927, 2864,
442, 1272, 1166, 1122, 1088.
3
. Experimental
1
All chemicals were commercially available. The Merryfield
resin used was obtained from Rapp-Polymer, Germany
3.2. General procedures for the cyclization reaction
(
0
particle size 200–400 mesh, 1% DVB cross-linked,
.88 mmol/g carboxyl groups). Thin layer chromatography
5a-Bromo-a-tocopherol (2a) or 5-bromomethyl-2,2,7,8-
tetramethyl-chroman-6-ol (2b) was stirred with PPh
3
(
0
2
TLC) was performed on silica gel 60 plates (5£10 cm,
.25 mm) with fluorescence detection under UV light at
54 nm. Flash column chromatography was performed on
(1 equiv.) in n-hexane (20 mL) for 2 h at rt. The solvent
was removed in vacuo (water bath temperature lower than
408C!) and dry toluene (20 mL) was added. The carboxylic
acid chloride (1.1 equiv.) and TEA (3.3 equiv.) were added,
and the mixture was refluxed for 16 h. The solvent was
removed in vacuo, the remainder was dissolved in n-hexane
(20 mL), and was washed sequentially with water and brine.
silica gel G60 (40–63 mm). Melting points, determined on a
Kofler-type micro hot stage with Reichert-Biovar micro-
1
scope, are uncorrected. H NMR spectra were recorded at
1
3
3
DMSO-d as the solvents and TMS as the internal standard.
00 MHz, C NMR spectra at 75.47 MHz with CDCl or
3
6
1
3
Data are given in ppm. C peaks were assigned by means of
APT, HMQC and HMBC spectra. Resonances of the
isoprenoid side chain of tocopherols are not influenced by
modifications of the chroman ring, and are therefore not
listed; ‘d.i.’ denotes peaks with double intensity. High
resolution MAS NMR measurements were carried out on a
Bruker DRX-400 with a 4 mm gel-phase probe-head.
Samples were prepared by weighing 100 mg of resin into
a small vial and adding approximately 1 mL of CDCl3.
After equilibration (about 1 h), excess CDCl was removed
3
and the swollen resin was filled into 4 mm zirconia rotors.
After adding a small drop of CDCl in excess the rotor was
closed with a Kel-F screw to avoid liquid leaking out during
spinning, and subsequently closed with the rotor cap. The
rotors were spun at 4000 Hz and C spectra were recorded
in the direct mode with CDCl as lock and internal standard.
The organic layer was dried over MgSO , and the solvent
4
was removed in vacuo. The crude product was purified by
flash chromatography (EtOAc/n-hexane, v/v¼1:50).
3.2.1. 2,4,5,7-Tetramethyl-7-(4,8,12-trimethyltridecyl)-
8,9-dihydro-7H-furo[3,2-f]chromene (4). Methyl-furoto-
copherol 4 was prepared according to the general procedure
from 5-bromomethyl-g-tocopherol (2a) (0.18 g, 0.32 mmol),
PPh
After chromatographic purification 4 (0.09 g, 62%) was
(0.08 g), TEA (0.13 g) and acetyl chloride (0.03 g).
3
1
obtained as a yellow oil. H NMR (CDCl ): d 6.22 (s, 1H,
3
3
H-1), 2.77 (t, 2H, H-9, J¼6.8 Hz), 2.41 (s, 3H, H-2a), 2.37
3
and 2.17 (2£s, 2£3H, H-5b, H-4a), 1.92–1.72 (m, 2H, H-8).
1
3
C NMR (CDCl ): d 154.0 (C-2), 148.0 (C-5a), 147.1
3
1
3
(C-3a), 124.7 (C-9a), 120.6 (C-4), 117.7 (C-5), 108.2 (C-3b),
100.8 (C-1), 75.4 (C-7), 31.0 (C-8), 23.9 (C-7a), 21.1 (C-9),
12.0 (C-4a), 11.6 (C-5b). IR (film): 2916, 2869, 1462, 1397,
3
FT-IR spectra were recorded on a Bruker Equinox-55
2
1
spectrometer; data are given in cm . All new compounds
exhibited satisfactory elemental analysis data.
1377, 1248, 1164, 1119, 1091. Anal. Calcd for C31
H O
50 2
(454.74): C, 81.88; H, 11.08. Found: C, 81.89; H, 10.99.
3
.1. General procedure for the bromination reaction
3.2.2. 2-Phenyl-4,5,7-trimethyl-7-(4,8,12-trimethyltri-
decyl)-8,9-dihydro-7H-furo[3,2-f]chromene (5). Phenyl-
furotocopherol 5 was prepared according to the general
procedure from 2a (1.53 g, 3.00 mmol), PPh (0.79 g), TEA
3
(1.01 g) and benzoyl chloride (0.42 g). After chromato-
graphic purification 5 (0.70 g, 45%) was obtained as
To a solution of a-tocopherol (1) or the model compound
,2,5,7,8-pentamethylchromanol chromanol in dry n-hex-
ane (50 mL) a solution of bromine (1.1 equiv.) in n-hexane
20 mL) was added at once at room temperature. The
2
(
1
3
mixture was stirred for 2 h. Solvent, remaining bromine and
physically dissolved HBr were removed in vacuo at room
temperature with the water bath temperature not exceeding
408C. The products, 2a and 2b, respectively, were obtained
in quantitative yield.
colorless oil. H NMR (CDCl
Ar
3
): d 7.84 (d, 2H, J¼7.7 Hz,
3
Ar
Ar
H-2), 7.42 (t, 2H, J¼7.7 Hz, H-3), 7.30 (m, 1H, H-4),
3
6.84 (s, 1H, H-1), 2.87 (t, 2H, J¼6.6 Hz, H-9), 2.46 and
2.21 (2£s, 2£3H, H-5b, H-4a), 1.92–1.78 (m, 2H, H-8),
1
3
1.29 (s, 3H, H-7a). C NMR (CDCl
(
): d 154.6 (C-2), 148.3
C-5a), 147.5 (C-3a), 131.2 (Bn, C-1), 128.7 (d.i., Bn, C-2),
3
3
.1.1. 5-Bromomethyl-3,4-dihydro-2,7,8-trimethyl-2-
4,8,12-trimethyltridecyl)-2H-chroman-6-ol (2a). 2a was
127.8 (d.i., Bn, C-3), 125.0 (C-9a), 124.5 (Bn, C-4), 122.4
(C-5), 118.2 (C-4), 108.8 (C-9b), 99.8 (C-1), 75.6 (C-7),
32.8 (C-8), 28.0 (C-7a), 19.7 (C-9), 12.1 (C-5b), 11.8
(C-4a). IR (film): 3039, 2860, 1605, 1460, 1396, 1377,
(
prepared according to the general procedure from a-toco-
pherol (0.50 g, 1.16 mmol) and bromine (0.19 g,
1.20 mmol) as a dark-brown oil (0.59 g, 100%). Analytical
4
data are consistent with those given in the literature.
1203, 1118, 1085, 760, 689. Anal. Calcd for C36
(516.81): C, 83.67; H, 10.14. Found: C, 83.81; H, 10.29.
H O
52 2
3
2
.1.2. 5-Bromomethyl-3,4-dihydro-2,2,7,8-tetramethyl-
H-chroman-6-ol (2b). 2b was prepared according to the
3.2.3. 2-Phenyl-4,5,7-trimethyl-8,9-dihydro-7H-furo[3,2-f]-
chromene (6). Phenyl-furochroman 6 was prepared
according to the general procedure from 2b (0.27 g,
general procedure from chroman-6-ol (0.20 g, 0.91 mmol)

3234
C. Adelw o¨ hrer et al. / Tetrahedron 59 (2003) 3231–3235
0.91 mmol), PPh3 (0.25 g), TEA (0.27 g) and benzoyl
chloride (0.13 g). After chromatographic purification 6
After chromatographic purification 9 (0.14 g, 67%) were
1
obtained as a yellow oil. H NMR (CDCl ): d 7.52 (d, 2H,
3
3
Ar
3
Ar
(
0.15 g, 55%) was obtained as white crystals, mp¼135–
J¼7.4 Hz, H-2), 7.39 (t, 2H, J¼7.3 Hz, H-3,), 7.39 (d,
1
3
Ar
3
Ar
3
1
7
1
2
6
1
378C. H NMR (CDCl ): d 7.83 (d, 2H, J¼8.4 Hz, H-2),
2H, J¼16.2 Hz, H-4, CHvCHPh), 7.00 (d, 1H, J¼
3
Ar
3
Ar
3
.39 (t, 2H, J¼7.8 Hz, H-3), 7.28 (m, 1H, H-4), 6.84 (s,
16.2 Hz, CHvCHPh), 6.58 (s, 1H, H-1), 2.83 (t, 2H, J¼
13
3
H, H-1), 2.86 (t, 2H, J¼6.8 Hz, H-9), 2.46 and 2.21 (2£s,
6.7 Hz, H-9), 2.45 (s, 3H, H-4a), 2.21 (s, 3H, H-5b), 1.91–
1.75 (m, 2H, H-8), 1.28 (s, 3H, H-7a). C NMR (CDCl ): d
3
£3H, H-4a, H-5b), 1.84 (t, 2H, J¼6.8 Hz, H-8). 1.34 (s,
3
1
3
H, H-7a; H-7b). C NMR: d 154.7 (C-2), 148.4 (C-5a),
47.7 (C-3a), 131.1 (Bn, C-1), 128.6 (d.i., Bn, C-2), 127.8
153.9 (C-2), 148.3 (C-5a), 147.5 (C-3a), 136.0 (Ph, C-1),
128.7 (d.i., Ph, C-3), 128.5 (CHvCHPh), 127.7 (d.i., Ph,
C-2), 126.5 (Ph, C-4), 124.9 (C-9a), 122.9 (C-5), 117.9
(C-4), 117.9 (CHvCHPh), 108.7 (C-9b), 103.9 (C-1), 75.5
(C-7), 30.9 (C-8), 23.9 (C-7a), 21.0 (C-9), 12.1 and 11.9
(C-4a, C-5b). IR (film): 3040, 2860, 1597, 1460, 1394,
1377, 1315, 1201, 1116, 1083, 950, 792. Anal. Calcd for
C H O (542.85): C, 84.08; H, 10.03. Found: C, 83.98; H,
(
1
d.i., Bn, C-3), 125.0 (C-9a), 124.5 (Bn, C-4), 122.4 (C-5),
18.2 (C-4), 108.2 (C-9b), 99.8 (C-1), 75.6 (C-7), 32.5
(
(
C-8), 26.8 (C-7a, C-7b), 20.1 (C-9), 12.0 (C-5b), 11.8
C-4a). IR (KBr): 3023, 2882, 1604, 1458, 1400, 1377,
1
204, 1120, 760. Anal. Calcd for C H O (306.41): C,
21 22 2
8
2.32; H, 7.24. Found: C, 82.38; H, 7.32.
3
8 54 2
10.29.
3
.2.4. 2-(2-Nitrophenyl)-4,5,7-trimethyl-7-(4,8,12-tri-
methyltridecyl)-8,9-dihydro-7H-furo[3,2-f]chromene
7). 2-(2-Nitrophenyl)-furotocopherol 7 was prepared
according to the general procedure from 2a (0.20 g,
.39 mmol), PPh (0.10 g), TEA (0.13 g) and 2-nitroben-
3.2.7. 2-Methoxymethyl-4,5,7-trimethyl-7-(4,8,12-tri-
methyltridecyl)-8,9-dihydro-7H-furo[3,2-f]chromene
(10). 2-Methoxymethyl-furotocopherol 10 was prepared
according to the general procedure from 2a (0.20 g,
(
0
3
zoyl chloride (0.08 g). After chromatographic purification 7
1
0.39 mmol), PPh (0.10 g), TEA (0.13 g) and 2-methoxy-
3
(
0.13 g, 57%) was obtained as a yellow oil. NMR: H NMR
3
acetyl chloride (0.05 g). After chromatographic purification
1
4
Ar
(
7
3
CDCl ): d 7.87 (dd, 1H, J¼7.9 Hz, J¼1.3 Hz, H-3),
10 (0.12 g, 62%) was obtained as yellow oil. H NMR
(CDCl ): d 6.68 (s, 1H, H-1), 4.52 (s, 2H, CH OCH ), 3.41
3
3
4
Ar
.71 (dd, 1H, J¼8.1 Hz, J¼1.2 Hz, H-5), 7.60 (dt, 1H,
3
2
3
4
Ar
3
3
J¼7.7 Hz, J¼1.3 Hz, H-4), 7.43 (dt, 1H, J¼7.7 Hz,
(s, 3H, CH OCH ), 2.81 (t, 2H, J¼6.7 Hz, H-9), 2.40 (s,
2
3
4
Ar
3
J¼1.4 Hz, H-3), 6.92 (s, 1H, H-3), 2.86 (t, 2H, J¼
3H, H-4a), 2.19 (s, 3H, H-5b), 1.92–1.73 (m, 2H, H-8), 1.28
(s, 3H, H-7a). C NMR (CDCl ): d 153.0 (C-2), 148.0 (s,
1
3
7
1
1
1
1
.0 Hz, H-9), 2.39 and 2.20 (2£s, 2£3H, H-5b, H-4a), 1.89–
Ar
3
1
3
.76 (m, 2H, H-8), 1.29 (s, 3H, H-2a). C NMR (CDCl ): d
3
C-5a), 147.3 (C-3a), 123.8 (C-9a), 122.4 (C-5), 118.8 (C-4),
108.8 (C-9b), 104.3 (C-1), 75.5 (C-7), 67.2 (CH OCH ),
49.5, 149.3 (C-2, C5a), 148.4, 148.2 ( C–NO , C-3a),
32.1 (Bn, C-4), 129.6 (Bn, C-3), 128.9 (Bn, C-5), 124.7,
24.4 (C-4, C-3a), 125.0 (Bn, C-1), 118.8 (C-9a), 109.5
2
2
3
58.0 (CH OCH ), 32.8 (C-8), 23.9 (C-7a), 21.9 (C-9), 12.1
2 3
(C-5b), 11.9 (C-4a). IR (film): 2860, 1460, 1400, 1377,
1170, 1116, 950. Anal. Calcd for C H O (484.77): C,
79.29; H, 10.81. Found: C, 78.80; H, 10.51.
(
C-3a), 104.9 (C-3), 76.2 (C-7), 31.2 (C-8), 28.4 (C-7a),
3
2 52 3
2
2
1
1.4 (C-9), 12.1 and 11.8 (C-5b, C-4a). IR (film): 3372,
937, 2850, 1718, 1600, 1533, 1460, 1396, 1377, 1205,
089, 748. Anal. Calcd for C H O N (561.81): C, 76.97;
0
0
3.2.8. 2-(2 ,2 -Dimethyl-propyl)-4,5,7-trimethyl-7-(4,8,
12-trimethyltridecyl)-8,9-dihydro-7H-furo[3,2-f]chro-
mene (11). tert-Butyl-furotocopherol 11 was prepared
according to the general procedure from 2a (0.2 g,
0.39 mmol), PPh3 (0.10 g), TEA (0.13 g) and pivaloyl
chloride (0.03 g). After chromatographic purification 11
3
6 51 4
H, 9.15; N, 2.49. Found: C, 77.21; H, 8.97; N, 2.41.
3
.2.5. 2-Ethenyl-4,5,7-trimethyl-7-(4,8,12-trimethyltri-
decyl)-8,9-dihydro-7H-furo[3,2-f]chromene (8). Vinyl-
furotocopherol 8 was prepared according to the general
procedure from 2a (0.20 g, 0.39 mmol), PPh (0.10 g), TEA
1
(0.10 g, 51%) was obtained as a yellow oil. NMR: H NMR
3
3
(0.13 g) and acryloyl chloride (0.03 g). After chromato-
graphic purification 7 (0.08 g, 45%) was obtained as yellow
(CDCl ): d 6.22 (s, 1H, H-1), 2.79 (t, 2H, J¼6.9 Hz, H-9),
3
2.34 (s, 3H, H-4a), 2.18 (s, 3H, H-5b), 1.90–1.74 (m, 2H,
H-8), 1.36 (s, 9H, C(CH ) ), 1.27 (s, 3H, H-7a). C NMR
1
3
3
13
oil. H NMR (CDCl ): d 6.60 (dd, 1H, J¼17.4 Hz, J¼
3
3 3
2
1
1.2 Hz, CHvCH ), 6.48 (s, 1H, H-1), 5.87 (dd, 1H, J¼
(CDCl ): d 166.1 (C-2), 147.8 (C-5a), 147.0 (C-3a), 124.3
3
2
3
2
0
3
.8 Hz, J¼17.4 Hz, CHvCH ), 5.28 (dd, 1H, J¼1.0 Hz,
(C-9a), 124.3 (C-5), 117.7 (C-4), 108.5 (C-9b), 97.0 (C-1),
75.7 (C-7), 33.2 (C(CH ) ), 32.8 (C(CH ) ), 31.1 (C-8), 24.0
2
3
J¼11.2 Hz, CHvCH ), 2.80 (t, 2H, J¼6.8 Hz, H-9), 2.40
2
3 2
3 2
and 2.19 (2£s, 2£3H, H-4a, H-5b), 1.91–1.77 (m, 2H, H-8),
(C-7a), 21.0 (C-9), 12.0 and 11.6 (C-4a, C-5b). IR (film):
2916, 2869, 140, 1400, 1377, 1250, 1164, 1119, 1091. Anal.
Calcd for C H O (496.82): C, 82.20; H, 11.36. Found: C,
13
1
.27 (s, 3H, H-7a). C NMR (CDCl ): d 153.8 (C-2), 148.1
3
(
C-5a), 147.3 (C-3a), 125.7 (CHvCH ), 124.5 (C-9a),
2
34 56 2
1
1
1
1
22.8 (C-5), 118.8 (C-4), 113.8 (CHvCH ), 108.8 (C-9b),
2
82.40; H, 11.12.
03.2 (C-1), 75.5 (C-7), 32.8 (C-8), 23.9 (C-7a), 19.7 (C-9),
2.0 and 11.8 (C-4a, C-5b). IR (film): 3037, 2859, 1597,
460, 1397, 1377, 1315, 1201, 1116, 1087. Anal. Calcd for
0
0
0
0
3.2.9. 4,5,7,4 ,5 ,7 -Hexamethyl-7,7 -bis(4,8,12-trimethyl-
0
0
0
0
tridecyl)-8,9,8 ,9 -tetrahydro-7H,7 H-2,2 -bis{furo[3,2-f]-
chromene} (12). The furotocopheryl dimer 12 was prepared
according to the general procedure from 2a (0.10 g,
C H O (466.75): C, 82.35; H, 10.80. Found: C, 82.50; H,
3
2 50 2
1
0.92.
0.20 mmol), PPh3 (0.05 g), TEA (0.07 g) and oxalyl
chloride (0.03 g). After chromatographic purification 12
3
.2.6. 2-Phenylethenyl-4,5,7-trimethyl-7-(4,8,12-tri-
1
methyltridecyl)-8,9-dihydro-7H-furo[3,2-f]chromene
9). 2-Styryl-furotocopherol 9 was prepared according to
the general procedure from 2a (0.20 g, 0.39 mmol), PPh3
0.10 g), TEA (0.13 g) and cinnamoyl chloride (0.07 g).
(0.07 g, 41%) was obtained as a yellow oil. H NMR
3
(
(CDCl ): d 7.01 (s, 1H, H-1), 2.88 (t, 2H, J¼6.7 Hz, H-9),
3
2.49 (s, 3H, H-4a), 2.22 (s, 3H, H-5b), 1.92–1.80 (m, 2H,
H-8), 1.30 (s, 3H, H-7a). C NMR (CDCl ): d 148.5 (C-2),
3
1
3
(

C. Adelw o¨ hrer et al. / Tetrahedron 59 (2003) 3231–3235
3235
1
(
2
3
1
47.7 (C-3a), 147.4 (C-5a), 124.6 (C-9a), 122.9 (C-5), 118.1
C-4), 109.0 (C-9b), 101.2 (C-1), 75.6 (C-7), 30.9 (C-8),
at the University of Agricultural Sciences Vienna, for
recording the NMR spectra, as well as Dr. Barbara
Hinterstoisser for providing access to IR instrumentation.
3.9 (C-7a), 19.8 (C-9), 12.1 (C-5b), 11.9 (C-4a). IR (film):
023, 2860, 1598, 1496, 1460, 1396, 1377, 1317, 1166,
114, 1085, 952, 748, 690. Anal. Calcd for C H O
0 94 4
6
(
879.42): C, 81.95; H, 10.77. Found: C, 82.15; H, 11.01.
References
3
.2.10. 4,5,7-Trimethyl-7-(4,8,12-trimethyltridecyl)-8,9-
dihydro-7H-furo[3,2-f]chromen-2-yl, linked to poly-
styrene (13). Merryfield resin (polystyrene, crosslinked
with 1% divinylbenzene (DVB), containing 0.88 mmol/g
carboxyl groups, 200 mg corresponding to 0.176 mmol
COOH) was refluxed with 2 mL of SOCl for 3 h. The resin
2
was filtered off and was repeatedly washed with EtOAc and
n-hexane. 5-Bromomethyl-g-tocopherol (2a, 450 mg,
1. (a) Packer, L.; Fuchs, J. Vitamin E in Health and Disease;
Marcel Dekker: New York, 1993. (b) Isler, O.; Brubacher, G.
Vitamins I; Georg Thieme: Stuttgart, 1982; pp 126. For a
general review on chromans and tocopherols see: (c)
Parkhurst, R. M.; Skinner, W. A. Chromans and Tocopherols.
In Chemistry of Heterocyclic Compounds; Ellis, G. P., Lock-
hardt, I. M., Eds.; Wiley: New York, 1981; Vol. 36.
2. (a) Mukai, K.; Fukuda, K.; Tajima, K.; Ishizu, K. J. Org.
Chem. 1988, 53, 430. (b) Mukai, K.; Yokoyama, S.; Fukuda,
K.; Uemoto, Y. Bull. Chem. Soc. Jpn 1987, 60, 2161.
(c) Mukai, K.; Kageyama, Y.; Ishida, T.; Fukuda, K. J. Org.
Chem. 1989, 54, 522.
0
.88 mmol) was stirred with PPh (0.25 g, 1.1 equiv.) in
3
n-hexane (50 mL) for 2 h. The modified Merryfield resin
COCl form, 0.2 equiv.) and TEA (0.29 g, 3.3 equiv.) were
(
added, and the mixture was refluxed for 16 h. The
furotocopherol-loaded resin was removed by filtration, and
thoroughly washed with ethyl acetate and n-hexane. IR
3. Burton, G. W.; Doba, T.; Gabe, E. J.; Hughes, L.; Lee, F. L.;
Prasad, L.; Ingold, K. U. J. Am. Chem. Soc. 1985, 107,
7053–7065.
(
1
(
KBr): 3423, 2928, 2675, 1735, 1683, 1600, 1460, 1434,
1
3
394, 1377, 1230, 1169, 1078, 1035, 744, 694. C NMR
CDCl ): d 75.4, 38.9, 36.9, 32.3, 31.1, 27.5, 24.3, 23.9,
4. Rosenau, T.; Habicher, W. D. Tetrahedron 1995, 51, 7919.
5. Both raising and lowering the reaction temperature caused a
significant decrease in yield, as did changes of the solvent, e.g.
3
2
2.3, 22.2, 20.5, 19.3, 8.4.
refluxing in DMF or CH
6. Hercouet, A.; LeCorre, M. Tetrahedron Lett. 1979, 23, 2145.
2 2
Cl .
Acknowledgements
7
. Sarkar, S. K.; Garigipati, R. S.; Adams, J. L.; Keifer, P. A.
J. Am. Chem. Soc. 1996, 118, 2305–2306.
The financial support by the Austrian Fonds zur F o¨ rderung
der wissenschaftlichen Forschung, project P-14687 (T. R.)
and project P-14844 CHE (W. B.), is gratefully acknowl-
edged. The authors would like to thank Dr. Andreas
Hofinger and Dr J u¨ rgen R o¨ hrling, Institute of Chemistry
8. Meissner, A.; Bloch, P.; Humpfer, E.; Spraul, M.; S o¨ rensen,
O. W. J. Am. Chem. Soc. 1997, 119, 1787–1788.
9. Part 14: Rosenau, T.; Potthast, A.; Elder, T.; Kosma, P. Org.
Lett. 2002, 4(24), 4285–4288.