3-Tocopherylisoxazolines by [2+3] cycloaddition

Article abstract of DOI:10.1002/ejoc.200300636

New isoxazoline derivatives of α-tocopherol (1), the main component of vitamin E, were synthesized in a facile, two-step sequence consisting of nitration followed by 1,3-dipolar cycloaddition. 5-Nitromethyl-γ- tocopheryl acetate (3), obtained from the cheap α-tocopheryl acetate (2) by direct nitration in one step, acted as the nitrile oxide precursor in the reaction with various alkenes. The facile conversion proceeded in the presence of equimolar amounts of PhNCO and catalytic amounts of triethylamine. The NMR spectra of the product isoxazolines 5-13, showing strongly temperature-dependent resonances of the 4″-CH, 4-CH₂ and the acetyl group, are discussed, and the crystal structures of model compounds containing a methyl group instead of the isoprenoid side chain are presented. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300636

FULL PAPER
3-Tocopherylisoxazolines by [2؉3] Cycloaddition[‡]
Thomas Rosenau,*[a] Christian Adelwöhrer,[a] Andreas Hofinger,[a] Kurt Mereiter,[b] and
Paul Kosma[a]
Keywords: Tocopherol / Vitamin E / Cycloaddition / Nitration / Nitrile oxide / Vitamins
New isoxazoline derivatives of α-tocopherol (1), the main
component of vitamin E, were synthesized in a facile, two-
step sequence consisting of nitration followed by 1,3-dipolar
cycloaddition. 5-Nitromethyl-γ-tocopheryl acetate (3), ob-
tained from the cheap α-tocopheryl acetate (2) by direct ni-
tration in one step, acted as the nitrile oxide precursor in the
catalytic amounts of triethylamine. The NMR spectra of the
product isoxazolines 5−13, showing strongly temperature-de-
pendent resonances of the 4ЈЈ-CH, 4-CH2 and the acetyl
group, are discussed, and the crystal structures of model
compounds containing a methyl group instead of the iso-
prenoid side chain are presented.
reaction with various alkenes. The facile conversion pro- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ceeded in the presence of equimolar amounts of PhNCO and
Germany, 2004)
Introduction
of tocopheryl derivatives with stable, non-hydrolyzable link-
ages to other moieties, which should, moreover, offer
α-Tocopherol (1), the component of vitamin E with the further positions for chemical modification or anchoring.
highest biological activity, acts mainly in lipidic mammalian These studies are aimed at developing novel multifunctional
tissues. It is known to be one of the most effective chain- antioxidants and at providing model compounds for studies
breaking phenolic antioxidants, and is used in countless for- of the physiologically important tocopherol system.
mulations, cosmetics, food additives and medications, but
In the present work, the synthesis of 4,5-substituted 3-
also as a stabilizer for polymers.[1Ϫ3] Both substituent tocopherylisoxazolines, starting from readily available toco-
effects,[4Ϫ6] and stereoelectronic influences[7] have been in- pheryl acetate (2), is described. The approach is the first
voked as possible reasons for the exceptionally high effec- example of a chemical modification starting from OH-pro-
tiveness of vitamin E as a phenolic antioxidant. Due to its tected tocopherol with retention of the protection, i.e., with-
lability and sensitivity towards air, tocopherol is mainly out involvement of deprotection-reprotection steps. The
used in the form of simple, readily hydrolyzable esters, such new vitamin E derivatives have a stable, non-hydrolyzable
as tocopheryl benzoate, succinate, or, most frequently, the carbonϪcarbon bond extending from C-5a of the toco-
acetate (2), from which the active free phenol is regenerated pheryl part to the attached isoxazoline moiety, and they
in vivo or in vitro.
offer ample opportunities for further modification, for ex-
A current topic in the field of vitamin E chemistry is ample by the choice of isoxazoline substituents or by re-
the synthesis of novel tocopherol derivatives with changed ductive cleavage of the NϪO bond.
properties, as, for instance, the presence of anchor groups
or altered lipophilicity. However, α-tocopheryl acetate com-
pletely lacks functionalities that can readily be used for
modification as the phenolic OH group needs to remain
protected as a readily cleavable ester function in order to
assure higher long-term efficiency as an antioxidant. Our
current synthetic efforts are directed towards the generation
[‡]
Novel Tocopheryl Compounds, XVII. Part XVI: Ref.[11]
[a]
Institute of Chemistry, University of Agricultural Sciences,
Muthgasse 18, 1190 Vienna, Austria
Fax: (internat.) ϩ 43-1-36006-6059
Results and Discussion
E-mail: thomas.rosenau@boku.ac.at
[b]
Department of Chemistry, Vienna University of Technology,
Getreidemarkt 9, 1060 Wien, Austria
Reaction of α-tocopheryl acetate (2) with concentrated
Fax: (internat.) ϩ 43-1-58801-17199
E-mail: Kurt.Mereiter@tuwien.ac.at
nitric acid produced 5-nitro-α-tocopheryl acetate (3)[8,9] in
Eur. J. Org. Chem. 2004, 1323Ϫ1329
DOI: 10.1002/ejoc.200300636
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T. Rosenau, C. Adelwöhrer, A. Hofinger, K. Mereiter, P. Kosma
FULL PAPER
good yields (Scheme 1 and Table 1). With the α-tocopherol being applied in equimolar amounts, but not in excess, and
model compound 6-acetoxy-2,2,5,7,8-pentamethylchroman with TEA in only catalytic amounts. The use of DMF as
(2a),[10] which possesses a methyl group instead of the iso- solvent had the expected, positive effect on the yield, which
prenoid side chain, the nitration proceeded analogously to increased to 41%, as compared to 30% and 21% in the case
give the nitro derivative 3a in similar yields (Table 1, Entry of the less-polar solvents CH2Cl2 and n-hexane, respectively
4). In previous work, the unusual one-step formation of the (see Table 2, Entry 3).[14]
nitration products has been shown to proceed according to
Formation of the isoxazoline derivatives 5Ϫ13 proceeded
a heterolytic, two-step mechanism involving a resonance- according to the mechanism in Scheme 2, giving moderate
stabilized cationic intermediate.[11] This reaction converts yields. TEA catalyzed the formation of the aci-nitro form
the 5a-methyl group into a reactive nitromethyl function. It of 3 (or 3a), from which water was eliminated, which in
is remarkable insofar as it represents the only reaction turn was bound by the PhNCO present. The resulting ni-
known so far to effect a high-yield modification directly at trile oxide intermediate 4 reacted with excess alkene[15] in a
the OH-protected tocopherol skeleton.
stereospecific 1,3-dipolar cycloaddition to give the desired
isoxazolines.
Scheme 1
Table 1. Synthesis of 5a-nitrochromanol derivatives 3 and 3a
Entry
Product
R
Conditions
Yield (%)[a]
1
2
3
4
3
C16H33
C16H33
C16H33
CH3
AcOH/room temp.
CH2Cl2/room temp.
CH2Cl2/Ϫ70 °C
75
0
37
71
3
3
3a
Scheme 2
AcOH/room temp.
[a]
Isolated yields in %.
The products obtained from the truncated model 3a were
crystallized from n-hexane or ethanol, and their crystal
Nitromethyl compounds can be employed as nitrile oxide structures were determined by X-ray diffraction.[16] Fig-
precursors in [2ϩ3] cycloadditions with alkenes. The estab- ures 1 and 2 show the crystal structures of 6 and 9 as ex-
lished one-pot procedure for this reaction,[12] which uses amples, the trans and cis arrangement of the two phenyl
phenyl isocyanate and triethylamine to effect nitrile oxide substituents reflecting the geometry of the starting alkenes,
formation and subsequent cyclization, was modified, as 3 trans- and cis-stilbene, respectively. In all crystal structures
and 3a are unstable in basic media and at temperatures obtained, the pyrano ring adopts the expected twisted-chair
above 40 °C.[13] The best results were obtained with PhNCO conformation. The isoxazoline rings in 6, with a trans con-
Table 2. Synthesis of 3-tocopherylisoxazolines 5Ϫ13
Entry
Product
Co-reactants
R1 [a]
R2 [a]
R3 [a]
Yield (%)[b]
1
2
3
4
5
6
7
8
9
5
6
3, trans-stilbene
C16H33
CH3
C16H33
CH3
CH3
C16H33
CH3
Ph
Ph
Ph
Ph
32
39
41
40
35
16
18
31
41
3a, trans-stilbene
7
3, maleic acid
COOEt
COOEt
Ph
CH2OBz
CH2OBz
OEt
COOEt
COOEt
Ph
CH2OBz
CH2OBz
H
8
9
10
11
12
13
3a, maleic acid
3a, cis-stilbene
3, cis-1,4-dibenzoyloxybut-2-ene
3a, cis-1,4-dibenzoyloxybut-2-ene
3, ethyl vinyl ether
3, 3,4-dihydro-2H-pyran
C16H33
C16H33
OCH2[CH2]2
[a]
[b]
See Scheme 2. Isolated yields in %.
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Eur. J. Org. Chem. 2004, 1323Ϫ1329

3-Tocopherylisoxazolines by [2ϩ3] Cycloaddition
FULL PAPER
figuration of the diphenyl substituents, are planar, whereas more stable trans product,[17] due to isomerization of the
in 9, with a cis configuration of the diphenyl substituents, primarily formed cis product. The basicity of the TEA pre-
they show envelope conformations with C14 lying out of sent is evidently sufficient to induce isomerization accord-
˚
the plane of the other four ring atoms by 0.21 and 0.50 A, ing to a deprotonationϪreprotonation mechanism at C-4ЈЈ.
respectively, for the two independent molecules, one of Reaction of the isolated nitrile oxide 4a[18] with maleic acid
which is shown in Figure 2. The torsion angles between the under neutral conditions gave exclusively the cis product,
mean planes of the isoxazoline and the aromatic rings vary which, upon treatment with TEA, was isomerized into the
between 42 and 88°, depending on the substituent.
trans-configured 8 (Scheme 3).
Scheme 3
The crystal structure of the isomerized product 8 is
shown in Figure 3. One of the ethyl ester groups is placed
in close to the aromatic ring, so that the resulting magnetic
anisotropy is able to explain the comparatively large differ-
ences between the 1H NMR shifts of the two ethoxy groups,
being δ ϭ 4.07 vs. 4.30 (OCH2) and 1.04 vs. 1.36 ppm
(CH3), respectively.
Figure 1. Thermal ellipsoid plot (20% ellipsoids) and crystallo-
graphic atom labeling of tocopherylisoxazoline 6 (4,5-diphenyl sub-
stituents in trans configuration)
Figure 2. Thermal ellipsoid plot (40% ellipsoids) and crystallo-
graphic atom labeling of tocopherylisoxazoline 9 (4,5-diphenyl sub-
stituents in cis configuration) showing only one of the two confor-
mationally different independent molecules
Figure 3. Thermal ellipsoid plot (25% ellipsoids) and crystallo-
graphic atom labeling of tocopherylisoxazoline 8
1
Interestingly, under the cycloaddition conditions used,
In all the H NMR spectra of the isoxazolines, the meth-
maleic acid afforded exclusively the thermodynamically ylene groups of the substituents R2 and R3 adjacent to the
Eur. J. Org. Chem. 2004, 1323Ϫ1329
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T. Rosenau, C. Adelwöhrer, A. Hofinger, K. Mereiter, P. Kosma
FULL PAPER
1
Figure 4. Stacked plots of H NMR spectra (region between δ ϭ 1.5 and 5.0 ppm) of isoxazoline 6, recorded at different temperatures
in [D6]DMSO; note the temperature-dependent line shape and chemical-shift changes of the resonances of 4ЈЈ-CH (δ ഠ 4.5 ppm), 4-CH2
(δ ഠ 2.6Ϫ2.8 ppm) and the acetyl group (δ ഠ 1.6Ϫ1.8 ppm)
starting materials. TLC was performed on silica gel 60 plates (5
ϫ 10 cm, 0.25 mm) with fluorescence detection under UV light at
254 nm. Column chromatography was performed on silica gel G60
(40Ϫ63 µm). Melting points, determined with a Kofler-type micro
hot stage apparatus with a ReichertϪBiovar microscope, are uncor-
rected. H NMR spectra were recorded at 300 MHz for H and at
75.47 MHz for 13C NMR in CDCl3, unless stated otherwise.
Chemical shifts, relative to TMS as internal standard, are given in
δ values. 13C peaks were assigned by means of APT, HMQC and
HMBC spectra. The resonances of the isoprenoid side chain of
stereogenic centers show a pronounced diastereotopic split-
ting. In addition, an altered signal of the C-4 methylene
group is observed. This peak, which in almost all toco-
pherol derivatives known so far appears as a sharp triplet at
δ ഠ 2.60 ppm, now shows two broad, largely temperature-
independent multiplets at δ ഠ 2.50 and 2.80 ppm. The ace-
tyl group is found as a sharp singlet at δ ϭ 2.25Ϫ2.30 ppm,
with the exception of 5 and 6 (see below).
1
1
The room-temperature spectrum of isoxazoline deriva-
tives 5 and 6, with their relatively bulky, trans-configured tocopherols are not influenced by modifications of the chroman
ring, and are therefore not listed; ‘‘d.i.’’ denotes peaks with double
intensity. Computations, as implemented through Spartan Pro 02
by Wavefunction, Inc., Irvine, CA, USA, were carried out on geo-
metries pre-optimized by the semi-empirical PM3 method. For full
geometry optimization the widely employed B3LYP hybrid
method, which includes a mixture of HF and DFT exchange terms
and the gradient-corrected correlation functional of Lee, Yang and
Parr[19,20] parametrized by Becke,[21,22] was used, along with the
double-zeta split valence basis set 6-31ϩG*,[23,24] which includes
diffuse functions.
phenyl substituents, shows an interesting feature: three
broad peaks originating from 4ЈЈ-H in the isoxazoline moi-
ety, from the 4-CH2 methylene group and, surprisingly,
from the acetyl group, indicating restricted mobility of these
protons (see Figure 4). The crystal structure of 6, as shown
in Figure 1, suggests that this behavior is due to the proxim-
ity of the bulky phenyl substituents. With increasing tem-
perature, the broad resonances sharpen into a triplet, mul-
tiplet and singlet, respectively. In addition, the acetyl CH3
group in 5 and 6 experiences a pronounced high-field shift
to δ ϭ 1.6 ppm (at 298 K; δ ϭ 1.8 ppm at 383 K), as com-
pared to the ‘‘usual’’ appearance in the other isoxazolines
at δ ഠ 2.2Ϫ2.3 ppm.
Acetoxychroman 2a: Compound 2a was obtained by acetylation of
the vitamin E model compound 2,2,5,7,8-pentamethylchroman-6-
ol (PMC, 0.10 g, 0.45 mmol) by acetyl chloride (0.32 mL,
0.50 mmol) in CH2Cl2 in the presence of TEA (55 mg, 0.50 mmol).
After addition of water (100 mL) and extraction with EtOAc, 2a
was isolated quantitatively. Analytical data are consistent with
those given in the literature.[25]
Further experiments will focus on the reaction of 5-nitro-
α-tocopheryl acetate (3) with alkenes to link the tocopheryl
moiety to a polymer support, and on further modifications
starting from the isoxazoline moiety.
Nitrotocopherol 3 and Nitrochromanol 3a: Concentrated nitric acid
(16 mL) was added dropwise at ambient temperature to a solution
of 2 or 2a (6.70 mmol) in glacial acetic acid (50 mL). After stirring
for 30 min, the solution was diluted with water (100 mL) and ex-
tracted repeatedly with n-hexane. The combined organic layers were
neutralized with saturated NaHCO3 solution, washed with water
and brine, dried with MgSO4, and filtered. The solvent was re-
Experimental Section
General Remarks: All chemicals were commercially available. All-
racemic α-tocopherol and α-tocopheryl acetate were used as the
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Eur. J. Org. Chem. 2004, 1323Ϫ1329

3-Tocopherylisoxazolines by [2ϩ3] Cycloaddition
moved in vacuo and the crude product was purified by column Chromanylisoxazoline trans-Diester 8: Diethyl 3-[6-acetoxy-2,2,7,8-
FULL PAPER
chromatography (EtOAc/n-hexane, 1:20, v/v). 3,4-Dihydro-5-nitro-
tetramethyl-2-chroman-5-yl]-4,5-dihydroisoxazole-trans-4,5-dicarb-
methyl-2,2,7,8-tetramethyl-2H-chroman-6-yl acetate (3a). White oxylate, white solid, m.p. 191Ϫ193 °C. 1H NMR: δ ϭ 5.48 (d, 3J ϭ
solid, m.p. 122Ϫ124 °C. 1H NMR: δ ϭ 5.38 (s, 2 H, 5a-H), 2.76 6.3 Hz, 1 H, 5Ј-H), 4.81 (m, 1 H, 4Ј-H), 4.30 (q, J ϭ 7.2 Hz, 2 H,
3
3
(t, J ϭ 6.8 Hz, 2 H, 4-H), 2.34 (s, 3 H, acetyl CH3), 2.13 (s, 3 H,
OCH2), 4.07 (m, 2 H, OCH2O), 2.95Ϫ2.75 (m, 1 H, 4-H),
3
8b-H), 2.03 (s, 3 H, 7a-H), 1.82 (t, J ϭ 6.8 Hz, 2 H, 3H-), 1.31 (s, 2.57Ϫ2.44 (m, 1 H, 4-H), 2.25 (s, 3 H, acetyl CH3), 2.14 (s, 3 H,
6 H, 2a-H) ppm. 13C NMR: δ ϭ 169.3 (CO), 150.1 (C-8b), 141.7 7a-H), 2.01 (s, 3 H, 8b-H), 1.82Ϫ1.62 (m, 2 H, 3-H), 1.36 (m, 12
3
(C-6), 129.0 (C-8), 128.2 (C-7), 118.6 (C-4a), 117.9 (C-5), 73.7 (C-
H, ethyl CH3, 2a-H, 2b-H), 1.04 (t, J ϭ 7.2 Hz, 3 H, ethyl CH3)
2), 71.5 (C-5a), 32.3 (C-3), 26.8 (C-2a), 20.4 (acetyl CH3), 20.3 (C- ppm. 13C NMR: δ ϭ 169.0 (acetyl CO and COOEt), 167.2 (CO-
4), 13.2 (C-8b), 12.4 (C-7a) ppm. IR (KBr): ν˜ ϭ 2978, 2939, 1749, OEt), 150.7 (CϭN), 149.8 (C-8a), 140.5 (C-6), 128.2 (C-8), 128.1
1560, 1427, 1373, 1218, 1170, 1014 cmϪ1. C16H21NO5 (307.34):
calcd. C 62.53, H 6.89, N 4.56; found C 62.44, H 6.79, N 4.46.
(C-7), 118.1 (C-5), 117.2 (C-4a), 81.0 (C-5Ј), 73.8 (C-2), 62.4 and
62.2 (2 ϫ OCH2), 59.1 (C-4Ј), 32.4 (C-3), 27.8 and 26.0 (C-2a, C-
2b), 20.9 (C-4), 14.1 and 13.7 (ethoxy CH3), 13.0 (C-8b), 12.3 (C-
7a) ppm. IR (film): ν˜ ϭ 2950, 2865, 1769, 1740, 1450, 1364, 1189,
1079, 1076 cmϪ1. C24H31NO8 (461.51): calcd. C 62.46, H 6.77, N
3.03; found C 62.18, H 6.48, N 2.95.
Tocopherylisoxazolines 5؊13: Phenyl isocyanate (0.050 g,
0.43 mmol), a catalytic amount of triethylamine (5 drops) and al-
kene component (5 equiv., 2 mmol) were added to 3 or 3a
(0.40 mmol) in dry DMF (50 mL). The mixture was stirred for 48
h under argon (nitrogen) at room temp., quenched with water, ex-
tracted repeatedly with n-hexane, dried with MgSO4, and filtered.
The solvent was removed in vacuo, and the crude product was puri-
fied by column chromatography (EtOAc/n-hexane, 1:10, v:v) at le-
ast twice.
cis-Diphenyl-chromanylisoxazoline 9: 5-(cis-4,5-Diphenyl-4,5-di-
hydroisoxazol-3-yl)-2,2,7,8-tetramethylchroman-6-yl acetate,
white crystals, m.p. 181Ϫ183 °C. 1H NMR (room temp.): δ ϭ 7.13
(m, 5 H, Ar-H), 6.99 (m, 3 H, Ar-H), 6.88 (m, 2 H, Ar-H), 5.95
3
3
(d, J ϭ 9.8 Hz, 1 H, 5Ј-H), 4.93 (br. d, J ϭ 9.8 Hz, 1 H, 4Ј-H),
2.92 (br. s, 1 H, 4-H), 2.38 (s, 3 H, acetyl), 2.35 (br. m, 1 H, 4-H),
2.05 (s, 3 H, 8b-H), 1.98 (s, 3 H, 7a-H), 1.76Ϫ1.48 (m, 2 H, 3-H),
1.17 (s, 6 H, 2a-H) ppm. 13C NMR: δ ϭ 168.4 (CO), 158.0 (Cϭ
N), 149.8 (C-8a), 140.4 (C-6), 135.6, 133.4, 129.3, 128.0 (ArC), 128.0
(C-8), 127.9 (C-7), 127.8, 127.3, 127.2, 126.6 (ArC), 118.9 (C-5),
117.7 (C-4a), 86.2 (C-5Ј), 73.6 (C-2), 61.4 (C-4Ј), 32.3 (C-3), 27.5
(C-2a), 26.1 (C-2aЈ), 21.2 (C-4), 20.8 (acetyl CH3), 12.9 (C-8b), 12.3
(C-7a) ppm. IR: ν˜ ϭ 3057, 2972, 2925, 1759, 1452, 1359, 1205,
1080, 698 cmϪ1. C30H31NO4 (469.6): calcd. C 76.74, H 6.65, N
2.98; found. C 76.66, H 6.76, N 2.90.
trans-Diphenyl-tocopherylisoxazoline 5: 5-(trans-4,5-Diphenyl-4,5-
dihydroisoxazol-3-yl)-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
1
chroman-6-yl acetate, colorless oil. H NMR: δ ϭ 7.59Ϫ7.49 (m,
3
10 H, Ar-H), 5.90 (d, J ϭ 4.4 Hz, 1 H, 5Ј-H), 4.50 (br. s, 1 H, 4Ј-
H), 2.75 (br. s, 2 H, 4-H), 2.04 (s, 3 H, 8b-H), 1.91 (s, 3 H, 7a-H),
1.62 (br. s, 3 H, acetyl), 1.60Ϫ1.45 (m, 2 H, 3-H) ppm. 13C NMR:
δ ϭ 168.9 (CO), 155.6 (CϭN), 149.6 (C-8a), 141.7 (C-6), 128.9,
127.9, 127.8, 127. 6, 124.9 (CAr), 127.7 (C-8), 127.5 (C-7), 118.9 (C-
5), 118.0 (C-4a), 88.1 (C-5Ј), 75.8 (C-2), 66.2 (C-4Ј), 30.7 (C-3),
21.0 (C-4), 22.6 (acetyl CH3), 12.9 (C-8b), 12.3 (C-7a) ppm. IR
(film): ν˜ ϭ 2971, 1768, 1755, 1452, 1367, 1195, 1101, 1076, 752,
700 cmϪ1. HRMS for [C45H61NO4 ϩ Na]ϩ: calcd. 702.48, found
702.46.
[Bis(benzoyloxymethyl)tocopheryl]isoxazoline 10: 3-[6-Acetoxy-
2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-5-yl]-4,5-cis-
bis(phenylcarbonyloxymethyl)-4,5-dihydroisoxazole, colorless oil.
1H NMR: δ ϭ 8.06 (d, 3J ϭ 7.3 Hz, 2 H, Ar-H), 7.77 (d, 3J ϭ
7.3 Hz, 2 H, Ar-H), 7.59Ϫ7.49 (m, 2 H, Ar-H), 7.43 (t, 3J ϭ 7.8 Hz,
trans-Diphenyl-chromanylisoxazoline 6: 5-(trans-4,5-Diphenyl-4,5-
dihydroisoxazol-3-yl)-2,2,7,8-tetramethylchroman-6-yl acetate,
white crystals, m.p. 171Ϫ171 °C. 1H NMR (room temp.): δ ϭ
3
2 H, Ar-H), 7.34 (t, J ϭ 7.8 Hz, 2 H, Ar-H), 5.15Ϫ5.07 (m, 1 H,
2
3
3
5Ј-H), 4.80 (dd, J ϭ 11.9, J ϭ 4.7 Hz, 1 H, 5Ј-CHCH2O), 4.69
7.45Ϫ7.20 (m, 10 H, Ar-H), 5.90 (d, J ϭ 3.9 Hz, 1 H, 5Ј-H), 4.48
2
3
(dd, J ϭ 11.9, J ϭ 7.2 Hz, 1 H, 5Ј-CHCH2O), 4.32Ϫ4.41 (m, 2
H, 4Ј-CHCH2O), 4.25Ϫ4.13 (m, 1 H, 4Ј-H), 2.95Ϫ2.80 (m, 1 H, 4-
H), 2.60Ϫ2.41 (m, 1 H, 4-H), 2.25 (s, 3 H, acetyl CH3), 2.10 (s, 3
H, 7a-H), 1.96 (s, 3 H, 8b-H), 1.76Ϫ1.66 (m, 2 H, 3-H) ppm. 13C
NMR: δ ϭ 168.9 (acetyl CO), 166.2 (benzoyl CO), 165.8 (benzoyl
CO), 155.2 (CϭN), 150.1 (C-8a), 140.2 (C-6), 133.3, 129.8, 129.4
(br. s, 1 H, 4Ј-H), 2.83 (br. s, 2 H, 4-H), 2.04 (s, 3 H, 8b-H), 1.91
(s, 3 H, 7a-H), 1.60 (br. s, 3 H, acetyl), 1.60Ϫ1.45 (m, 2 H, 3-H)
ppm. 13C NMR: δ ϭ 168.9 (CO), 155.6 (CϭN), 149.6 (C-8a), 141.7
(C-6), 128.9, 127.9, 127.8, 127. 6, 124.9 (ArC), 127.7 (C-8), 127.5
(C-7), 118.9 (C-5), 118.0 (C-4a), 88.1 (C-5Ј), 75.8 (C-2), 66.2 (C-
4Ј), 30.7 (C-3), 22.6 (acetyl CH3), 21.0 (C-4), 12.9 (C-8b), 12.3 (C-
7a) ppm. IR: ν˜ ϭ 3030, 2972, 2920, 1770, 1452, 1369, 1193, 1068,
1074, 700 cmϪ1. C30H31NO4 (469.6): calcd. C 76.73, H 6.65, N
2.98; found C 76.66, H 6.76, N 2.90.
(
ArC), 129.1 (C-8), 128.4, 128.3, 129.5 (ArC), 128.2 (C-7), 118.2 (C-
5), 117.9 (C-4a), 79.6 (C-5Ј), 75.4 (C-2), 62.3 (CH2O), 60.3 (CH2O),
52.2 (C-4Ј), 30.4 (C-3), 21.1 (C-4), 20.6 (acetyl CH3), 13.0 (C-7a),
12.3 (C-8b) ppm. IR (film): ν˜ ϭ 2935, 2866, 1760, 1724, 1450, 1373,
1269, 1195, 1140, 1109, 709 cmϪ1. HRMS for [C49H65NO8 ϩ H]ϩ:
calcd. 796.48, found 796.50.
Tocopherylisoxazoline trans-Diester 7: Diethyl 3-[6-acetoxy-2,7,8-
trimethyl-2-(4,8,12-trimethyltridecyl)chroman-5-yl]-4,5-dihydro-
isoxazole-trans-4,5-dicarboxylate, colorless oil. 1H NMR: δ ϭ 5.48
(d, 3J ϭ 6.3 Hz, 1 H, 5Ј-H), 4.81 (m, 1 H, 4Ј-H), 4.30 (q, 3J ϭ
7.2 Hz, 2 H, OCH2), 4.07 (m, 2 H, OCH2), 2.95Ϫ2.75 (m, 1 H, 4-
[Bis(benzoyloxymethyl)chromanyl]isoxazoline 11: 3-[6-Acetoxy-
2,2,7,8-tetramethylchroman-5-yl]-4,5-cis-bis(phenylcarbonyloxy-
1
H), 2.57Ϫ2.44 (m, 1 H, 4-H), 2.25 (s, 3 H, acetyl CH3), 2.14 (s, 3 methyl)-4,5-dihydroisoxazole, white crystals, m.p. 131Ϫ133 °C. H
H, 7a-H), 2.01 (s, 3 H, 8b-H), 1.50 (m, 2 H, 3-H), 1.36 (t, 3J ϭ NMR: δ ϭ 8.06 (d, 3J ϭ 7.3 Hz, 2 H, Ar-H), 7.77 (d, 3J ϭ 7.3 Hz,
7.2 Hz, 3 H, ethyl CH3), 1.04 (m, 3 H, ethyl CH3) ppm. 13C NMR:
2 H, Ar-H), 7.59Ϫ7.49 (m, 2 H, Ar-H), 7.42 (t, J ϭ 7.8 Hz, 2 H,
3
δ ϭ 169.0 (acetyl CO and COOEt), 167.2 (COOEt), 150.7 (CϭN), Ar-H), 7.33 (t, 3J ϭ 7.8 Hz, 2 H, Ar-H), 5.16Ϫ5.08 (m, 1 H, 5Ј-
2
3
149.7 (C-8a), 140.4 (C-6), 128.1 (C-8), 128.0 (C-7), 118.3 (C-5),
117.1 (C-4a), 81.0 (C-5Ј), 75.4 (C-2), 62.3 and 62.2 (2 ϫ OCH2), 2J ϭ 11.9, 3J ϭ 7.2 Hz, 1 H, 5Ј-CHCH2O), 4.53Ϫ4.42 (m, 2 H, 4Ј-
59.1 (C-4Ј), 27.9 (C-3), 21.0 (C-4), 14.1 and 13.7 (ethyl CH3), 13.0 CHCH2O), 4.21 (m, 1 H, 4Ј-H), 2.91 (m, 1 H, 4-H), 2.50 (m, 1 H,
H), 4.80 (dd, J ϭ 11.9, J ϭ 4.7 Hz, 1 H, 5Ј-CHCH2O), 4.69 (dd,
(C-8b), 12.3 (C-7a) ppm. IR (film): ν˜ ϭ 2947, 2862, 1768, 1737, 4-H), 2.25 (s, 3 H, acetyl CH3), 2.09 (s, 3 H, 7a-H), 1.96 (s, 3 H,
1452, 1367, 1188, 1080, 1076, 1026, 862 cmϪ1. HRMS for
8b-H), 1.74Ϫ1.44 (m, 2 H, 3-H), 1.24 (s, 6 H, 2a-H) ppm. 13C
NMR: δ ϭ 168.9 (acetyl CO), 166.1 (benzoyl CO), 165.7 (benzoyl
[C39H61NO8 ϩ H]ϩ: calcd. 672.45, found 672.46.
Eur. J. Org. Chem. 2004, 1323Ϫ1329
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1327

T. Rosenau, C. Adelwöhrer, A. Hofinger, K. Mereiter, P. Kosma
Z ϭ 8, Dcalcd. ϭ 1.250 g/cm3, T ϭ 100 K, µ ϭ 0.082 mmϪ1
FULL PAPER
CO), 155.2 (CϭN), 150.0 (C-8a), 140.2 (C-6), 133.21, 133.24, 129.7,
129.5, 129.4 (ArC), 129.0 (C-7), 128.4, 128.2 (ArC), 128.1 (C-8), F(000) ϭ 2000, colorless block, (0.64 ϫ 0.32 ϫ 0.24 mm); total
118.2 (C-4a), 117.5 (C-5), 79.5 (C-5Ј), 73.7 (C-2), 62.1 (CH2O), 60.3 reflections ϭ 26853, unique reflections ϭ 8762, Rint ϭ 0.042, final
(CH2O), 51.1 (C-4Ј), 32.1 (C-3), 27.9, 25.9 (C-2a), 21.2 (C-4), 20.9 refinement: data/restraints/parameters ϭ 8762/0/641, goodness-of-
(acetyl CH3), 12.9 (C-7a), 12.2 (C-8b) ppm. IR (KBr): ν˜ ϭ 3060,
2993, 2972, 1757, 1720, 1600, 1450, 1367, 1271, 1197, 1070, 707
cmϪ1. C34H35NO8 (585.7): calcd. C 69.73, H 6.02, N 2.39; found
C 69.97, H 6.06, N 2.60.
,
fit on F2 ϭ 1.028, R1 ϭ 0.050 [I Ͼ 2σ(I)], wR2 ϭ 0.124 (all data).
Chromanylisoxazoline trans-Diester 8: C24H31NO8, M ϭ 461.50,
˚
monoclinic, space group Cc (No. 9), a ϭ 17.1462(9) A, b ϭ
3
˚
˚
˚
9.8498(5) A, c ϭ 15.4341(8) A, β ϭ 112.754(2)°, V ϭ 2403.8(2) A ,
Z ϭ 4, Dcalcd. ϭ 1. 275 g/cm3, T ϭ 297 K, µ ϭ 0.096 mmϪ1
,
Ethoxy-tocopherylisoxazoline 12: 2,7,8-Trimethyl-5-(5-ethoxy-4,5-
dihydroisoxazol-3-yl)-2-(4,8,12-trimethyltridecyl)chroman-6-yl
F(000)ϭ 984, colorless block (0.75 ϫ 0.45 ϫ 0.35 mm); total reflec-
tions 17535, unique reflections 6926, Rint ϭ 0.017, final refinement:
1
3
acetate, colorless oil. H NMR: δ ϭ 5.58 (d, J ϭ 6.3 Hz, 1 H, 5Ј-
H), 3.98Ϫ3.88 (m, 1 H, OCH2), 3.65Ϫ3.55 (m, 1 H, OCH2), 3.22
(m, 1 H, 4Ј-H), 3.00 (m, 1 H, 4Ј-H), 2.83Ϫ2.73 (m, 1 H, 4-H),
2.59Ϫ2.48 (m, 1 H, 4-H), 2.26 (s, 3 H, acetyl CH3), 2.13 (s, 3 H,
8b-H), 2.03 (s, 3 H, 7a-H), 1.83Ϫ1.69 (m, 2 H, 3-H) ppm. 13C
NMR: δ ϭ 169.6 (CO), 154.7 (CϭN), 149.7 (C-8a), 140.0 (C-6),
128.0 (C-8), 127.6 (C-7), 119.3 (C-5), 117.6 (C-4a), 102.3 (C-5Ј),
75.7 (C-2), 63.6 (OCH2), 47.8 (C-4Ј), 30.2 (C-3), 20.6 (C-4), 15.1
(ethyl CH3), 12.8 (C-7a), 12.2 (C-8b) ppm. IR (film): ν˜ ϭ 2937,
1776, 1457, 1400, 1377, 1195, 1110, 752, 700 cmϪ1. HRMS for
[C35H57NO5 ϩ H]ϩ: calcd. 572.43, found 572.44.
data/restraints/parameters ϭ 6926/2/301, goodness-of-fit on F2
1.044, R1 ϭ 0.052 [I Ͼ 2σ(I)], wR2 ϭ 0.138 (all data).
ϭ
Acknowledgments
Financial support by the Austrian Fonds zur Förderung der wissen-
schaftlichen Forschung (project P-14687) and by Lenzing AG, Aus-
tria, is gratefully acknowledged. The authors would like to thank
Prof. Dr. H.-U. Reissig, Freie Universität Berlin, for helpful dis-
cussions.
Pyrano-tocopherylisoxazoline 13: 6-Acetoxy-2,7,8-trimethyl-5-
(3a,5,6,7a-tetrahydro-4H-pyrano[3,2-d]isoxazol-3-yl)-2-(4,8,12-tri-
methyltridecyl)chroman, colorless oil. 1H NMR: δ ϭ 5.74 (d, J ϭ
3
6.2 Hz, 1 H, 5Ј-H), 3.90Ϫ3.83 (m, 1 H, OCH2), 3.58Ϫ3.50 (m, 2
H, OCH2, 4Ј-H), 2.88 (br. s, 1 H, 4-H), 2.66Ϫ2.51 (m, 1 H, 4-H),
2.25 (s, 3 H, acetyl CH3), 2.15 (s, 3 H, 8b-H), 2.03 (s, 3 H, 7a-H),
1.89Ϫ1.58 (m, 3 ϫ 2 H, 3-H, H in pyran) ppm. 13C NMR: δ ϭ
168.7 (CO), 158.1 (CϭN), 150.1 (C-8a), 140.4 (C-6), 128.2 (C-8),
128.1 (C-7), 118.0 (C-5), 118.0 (C-4a), 99.9 (C-5Ј), 76.0 (C-2), 61.3
(O-CH2), 47.8 (pyran CH2), 30.7 (C-3), 24.4 (pyran CH2), 20.6 (C-
4), 19.6 (pyran CH2), 13.0 (C-8b), 12.3 (C-7a) ppm. IR (film): ν˜ ϭ
2973, 2937, 1776, 1460, 1409, 1365, 1195, 1107, 1076, 752, 700
cmϪ1. HRMS for [C36H57NO5 ϩ Na]ϩ: calcd. 606.41, found
606.40.
[1]
L. Packer, J. Fuchs, Vitamin E in Health and Disease, Marcel
Dekker Inc., New York, 1993.
O. Isler, G. Brubacher, Vitamins I, Georg Thieme Verlag,
Stuttgart, 1982, pp. 126.
For a general review on chromans and tocopherols see: R. M.
[2]
[3]
Parkhurst, W. A. Skinner, Chromans and Tocopherols, in Chem-
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[4]
K. Mukai, K. Fukuda, K. Tajima, K. Ishizu, J. Org. Chem.
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K. Mukai, S. Yokoyama, K. Fukuda, Y. Uemoto, Bull. Chem.
Soc. Jpn. 1987, 60, 2161.
K. Mukai, Y. Kageyama, T. Ishida, K. Fukuda, J. Org. Chem.
[6]
X-ray Crystallographic Study: X-ray data collection was performed
1989, 54, 522.
with a Bruker AXS Smart APEX CCD diffractometer and graph-
ite-monochromated Mo-Kα radiation, λ ϭ 0.71073 A; corrections
[7]
˚
G. W. Burton, T. Doba, E. J. Gabe, L. Hughes, F. L. Lee, L.
Prasad, K. U. Ingold, J. Am. Chem. Soc. 1985, 107, 7053.
for absorption with the program SADABS, structure solution with
direct methods, structure refinement on F2 (Bruker AXS, 2001: pro-
grams SMART, version 5.626; SAINT, version 6.36A; SADABS
version 2.05; XPREP, version 6.12; SHELXTL, version 6.10.
Bruker AXS Inc., Madison, WI, USA). CCDC-220789 to -220791
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (in-
ternat.) ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
[8]
S. Witkowski, A. Markowska, Polish J. Chem. 1996, 70, 656.
[9]
S. Witkowski, A. Markowska, Polish J. Chem. 1997, 71, 1.
[10]
See Exp. Sect.
[11]
C. Adelwöhrer, T. Rosenau, P. Kosma, Tetrahedron 2003, 59,
8177Ϫ8182.
D. P. Curran, J. Am. Chem. Soc. 1983, 18, 5826.
Treatment with base at elevated temperatures causes formation
of the 5-carbaldehydes along with smaller amounts of the re-
duced acetates (2 or 2a) and other unidentified by-products.
Even at room temperature the presence of equimolar amounts
of TEA caused formation of these by-products in small
amounts.
See Exp. Sect. for working procedure and analytical data of
the products
[12]
[13]
trans-Diphenyl-chromanylisoxazoline 6: C30H31NO4, M ϭ 469.56,
[14]
˚
˚
˚
monoclinic, space group P21/c, a ϭ 10.465(2) A, b ϭ 22.554(4) A,
3
˚
c ϭ 10.925(2) A, β ϭ 94.470(4)°, V ϭ 2570.6(8) A , Z ϭ 4, Dcalcd. ϭ
1.213 g/cm3, T ϭ 299 K, µ ϭ 0.080 mmϪ1, F(000) ϭ 1000, colorless
plate (0.66 ϫ 0.45 ϫ 0.08 mm); total reflections ϭ 11812, unique
reflections ϭ 3690, Rint ϭ 0.054, final refinement: data/restraints/
[15]
4-Phenylcarbonyloxy-2-butenyl benzoate (see Table 2, Entries 6
and 7) was obtained by treatment of 2-butene-1,4-diol (0.50 g,
5.67 mmol) with benzoyl chloride (1.38 mL, 11.91 mmol) in
CH2Cl2 (50 mL) and triethylamine (1.20 g, 11.91 mmol).
Recrystallization from ethanol afforded the product as white
crystals (75%), the analytical data are consistent with those
given in the literature: J. A. Marchall, J. Liao, J. Org. Chem.
1998, 63, 5962.
parameters ϭ 3690/0/321, goodness-of-fit on F2 ϭ 1.112, R1
0.078 [I Ͼ 2σ(I)], wR2 ϭ 0.65 (all data).
ϭ
cis-Diphenyl-chromanylisoxazoline 9: The compound contains two
conformationally different molecules, which are distinguished by
the orientation of isoxazole and phenyl rings. C30H31NO4, M ϭ
[16]
Crystal structures not given here will be reported in due course.
DFT computations at the B3LYP-6-31G* level confirmed that
[17]
˚
469.56, monoclinic, space group P21/n, a ϭ 15.020(2) A, b ϭ
the trans compound is more stable than the cis isomer by
3
˚
˚
˚
18.676(3) A, c ϭ 18.438(3) A, β ϭ 105.229(3)°, V ϭ 4990.4(12) A ,
44.6 kJ·molϪ1
.
1328
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1323Ϫ1329

3-Tocopherylisoxazolines by [2ϩ3] Cycloaddition
FULL PAPER
A. Becke, J. Chem. Phys. 1993, 98, 5648.
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G. W. Burton, T. Doba, E. J. Gabe, L. Hughes, F. L. Lee, L.
Prasad, K. U. Ingold, J. Am. Chem. Soc. 1985, 107, 7053.
Received October 8, 2003
[18]
[22]
[23]
[24]
Compound 4a was refined by adsorption to alumina, and used
1
further in crude form. H NMR spectroscopy indicated a pu-
rity of greater than 85%, IR [νCϭN (s) at 2292 cmϪ1] confirmed
the identity of the product.
C. Lee, W. Yang, R. G. Parr, Phys. Rev. 1988, B37, 785.
B. Miehlich, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett.
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1989, 157, 200.
A. Becke, Phys. Rev. 1988, A38, 3098.
[21]
Eur. J. Org. Chem. 2004, 1323Ϫ1329
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1329