Synthesis of 5a-α-tocopheryl azide and its reaction to 1-(5a-α-tocopheryl)-1,2,3-triazols by [2+3]-cycloaddition

Article abstract of DOI:10.1002/ejoc.200500898

1,2,3-Triazoles with 1-position substituents, derived from α-tocopherol (vitamin E), were synthesized by 1,3-dipolar cycloaddition reactions of 5a-azido-α-tocopheryl acetate with alkynes, and were fully analytically characterized. NMR spectra of the compounds and crystal structures of derivatives with a truncated isoprenoid side chain are presented. The tocopheryl moiety is readily cleaved in basic media, as a prerequisite for the use in delivery systems showing pH-dependent drug release. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500898

FULL PAPER
DOI: 10.1002/ejoc.200500898
Synthesis of 5a-α-Tocopheryl Azide and Its Reaction to 1-(5a-α-Tocopheryl)-
1,2,3-triazols by [2+3]-Cycloaddition
Christian Adelwöhrer,[a] Thomas Rosenau,*[a] Elisabeth Kloser,[a] Kurt Mereiter,[b] and
Thomas Netscher[c]
Keywords: 1,2,3-Triazole / Tocopherol / Vitamin E / 1,3-Dipolar cycloaddition / Drug release
1,2,3-Triazoles with 1-position substituents, derived from α-
The tocopheryl moiety is readily cleaved in basic media, as
tocopherol (vitamin E), were synthesized by 1,3-dipolar cy- a prerequisite for the use in delivery systems showing pH-
cloaddition reactions of 5a-azido-α-tocopheryl acetate with
alkynes, and were fully analytically characterized. NMR
spectra of the compounds and crystal structures of deriva-
tives with a truncated isoprenoid side chain are presented.
dependent drug release.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Results and Discussion
1,2,3-Triazoles having a wide range of biological activi-
ties are found in bioactive compounds such as anti-HIV
agents,[1] antimicrobial compounds,[2] and β3-selective ad-
renergic receptor agonists.[3] Indeed, the 1,2,3-triazole moi-
ety is present in a number of drugs, for example, the β-
lactam antibiotic tazobactam and the cephalosporine cefa-
trizine. In addition, 1,2,3-triazoles have found ample usage
as agrochemicals, dyes, photographic materials, and cor-
rosion inhibitors.[4]
Within our current project on directed drug delivery sys-
tems, we were interested in 1,2,3-triazoles with lipophilic,
cleavable carriers. For that purpose, we chose the 5a-toco-
pheryl residue, which was supposed to serve three functions.
First, it renders the moderately hydrophilic triazoles much
more lipophilic; second, it acts as a drug carrier anchoring
the compound in lipid membranes in a way similar to toc-
opherols themselves; and third, it undergoes pH-dependent
cleavage. In this study, we communicate the synthesis and
analytical properties of 1-(5a-tocopheryl)-1,2,3-triazoles,
along with example crystal structures of short-chain ana-
logues.
Several methods have been described for the synthesis of
1,2,3-triazoles; the most prominent approach is the cycload-
dition reaction of organic azides with alkynes.[5] This con-
version usually needs elevated temperatures and forms mix-
tures of 1,4- and 1,5-regioisomers in the case of non-sym-
metric alkynes. Studies on the regioselective course were re-
ported by Sharpless,[6] who used CuI salts as catalysts[7] to
obtain 1,4-substituted products with high regioselectivity
from terminal alkynes, and by Meldal,[8] who regioselec-
tively synthesized 1,4-substituted 1,2,3-triazoles by em-
ploying polymer-supported terminal alkynes. Usually, the
1-position of the 1,2,3-triazoles is substituted, since prepa-
ration started from an organic (alkyl or aryl) azide.
α-Tocopherol (1), the main component of vitamin E
which mainly acts in lipidic mammalian tissues, is known
to be one of the most effective chain-breaking phenolic an-
tioxidants.[9] It finds the most widespread uses in medi-
cations, healthcare products, cosmetic formulations, and as
a stabilizer for food, synthetic polymers, and plastics
(Scheme 1).[10]
Room-temperature bromination of α-tocopherol, which
proceeds according to
a two-step oxidation-addition
mechanism, provides 5a-bromo-α-tocopherol, which can be
neatly converted into a variety of 5a-substituted tocoph-
erols. In the case of electronegative 5a-substituents, such as
OR, NR2, or SR, the derivatives readily eliminate the 5a-
substituent in basic media (pH Ͼ 8), whereas they are com-
pletely stable in neutral and acidic media.[11] Upon elimi-
nation, the tocopherol part forms an ortho-quinone methide
intermediate 3,[12] which immediately undergoes spiro-di-
merization to 4, a natural vitamin E metabolite (Scheme 1).
We intended to employ this chemistry in the synthesis of
[a] Department of Chemistry, University of Natural Resources and
Applied Life Sciences Vienna,
Muthgasse 18, 1190 Vienna, Austria
Fax: +43-1-36006-6059
E-mail: thomas.rosenau@boku.ac.at
[b] Department of Chemistry, Vienna University of Technology,
Getreidemarkt 9,
1060 Vienna, Austria
[c] DSM Nutritional Products, Research and Development,
P.O. Box 3255, 4002 Basel, Switzerland
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C. Adelwöhrer, T. Rosenau, E. Kloser, K. Mereiter, T. Netscher
FULL PAPER
Scheme 1. Chemical behavior of 5a-substituted α-tocopherols.
Scheme 2. Preparation of 1-(5a-tocopheryl)-1,2,3-triazoles from α-
tocopherol.
5a-tocopheryl-substituted 1,2,3-triazoles, which would re-
lease the tocopherol carrier upon contact with basic media,
so that a pH-dependent drug release in response to changes
in tissue pH would be feasible. As this elimination principle which has the isoprenoid side chain replaced by a methyl
fails with carbon substituents at C-5a, the tocopheryl sub- group, are white solids with a pronounced tendency to crys-
stituent must be bound to either of the nitrogen atoms of tallize in fine, long needles. For two examples, crystal struc-
the triazole moiety. As the most obvious choice, 5a-toco- tures are reported here. The preliminary room-temperature
pheryl azide had to be reacted with alkynes in a [3+2]-cyclo- X-ray structure of diphenyltriazole 9a was later comple-
addition reaction (Scheme 2).
mented by a low-temperature structure (173 K) of crystals
Reaction of α-tocopherol (1) with bromine in dry hexane obtained from DMF, which provided better parameters
produced 5a-bromo-α-tocopherol (5) quantitatively.[13] The (Figure 1). Diester derivative 11 was crystallized from ethyl-
reaction of the truncated α-tocopherol model compound ene glycol after several unsuccessful attempts with more
2,2,5,7,8-pentamethylchroman-6-ol (1a) proceeded analo- common solvents due to acicular growth (Figure 2). Both
gously. After acetylation of the bromo derivatives, which triazole derivatives crystallized in the monoclinic system,
had to be performed in the absence of basic auxiliaries to although in different unit cells. Both showed the same rod-
avoid elimination of HBr, reaction with sodium azide pro- like stacking with a translation period of 5.6 Å along the
vided the novel 5a-azidotocopheryl acetate 7 and the 5a- needle axis, which is the b-axis of a C2/c cell for 9, and the
azidochromanyl acetate 7a in good yields (Scheme 2). Con- a-axis of a P21/c cell in the case of 11. The arrangement of
version of the free phenols into the acetates considerably the chroman moieties and the triazole units along the rod
increased the temperature stability, which allowed us to axis was similar for both structures.
conduct subsequent reactions of 7 at temperatures above
In all crystal structures obtained, the pyran ring of the
100 °C without losses due to decomposition. The [3+2]-cy- tocopheryl substituent adopted a twisted chair conforma-
cloaddition of the tocopheryl azide with alkynes in re- tion. The 1,2,3-triazole rings exhibited a nearly perfect
fluxing toluene provided the 1-(5a-tocopheryl)-1,2,3-tri- planarity. The torsion angles between the mean planes of
azoles 8–17 in excellent to fair yields. The time until com- the triazole and the aromatic rings of the tocopherol moiety
plete conversion was dependent on the alkyne used; elec- varied between 35° and 84°, depending on the substituent.
tron-withdrawing substituents favored fast reactions. A re-
An interesting feature common to all the tocopheryltria-
giospecific reaction was not attempted in our case, as syn- zoles we studied is the broad shape of the 13C resonances
thesis and characterization of both isomers were of interest, of C-3, C-4, C-2a, and C-1Ј, which indicates reduced flexi-
cf. the pairs 13/14 and 15/16 in Table 1. For these pairs, the bility of the pyran ring in the tocopheryl moiety. At tem-
overall yields of the cycloaddition reactions are the sums of peratures above 60 °C, these resonances change into the
the individual yields of the two regioisomers.
common sharp singlets, reflecting largely unrestricted high-
All tocopheryl-1,2,3-triazoles were purified by flash temperature mobility. The 1,4- and 1,5-regioisomers (the
chromatography (EtOAc/n-hexane, v/v = 1:5) to provide pairs 13/14, 15/16, 17/18) can be readily distinguished by
colorless, waxy products. The products obtained from 7a, their 13C NMR spectroscopic data. While the C-4 and C-
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Tocopheryl Azide and Reaction with Alkynes
FULL PAPER
Table 1. 1-(5a-Tocopheryl)-1,2,3-triazoles.
Co-reactants
R[a]
RЈ[a]
RЈЈ[a]
Yield[b]
8
7, diphenylacetylene
C16H33
CH3
C16H33
CH3
C16H33
C16H33
C16H33
C16H33
C16H33
C16H33
C16H33
Ph
Ph
Ph
Ph
COOEt
COOEt
COOtBu
COOEt
H
61
58
91
90
81
55
28
52
18
84
11
9
7a, diphenylacetylene
10
11
12
13
14
15
16
17
18
7, diethyl acetylenedicarboxylate
7a, diethyl acetylenedicarboxylate
7, di-tert-butyl butynedicarboxylate
7, ethyl propiolate
COOEt
COOEt
COOtBu
H
COOEt
H
7, ethyl propiolate
7, phenylacetylene
Ph
7, phenylacetylene
Ph
H
7, 2-amino-5-ethynyl-1,3,4-oxadiazole
7, 2-amino-5-ethynyl-1,3,4-oxadiazole
H
Oxa[c]
H
Oxa[c]
[a] See Scheme 2. [b] Isolated yields in %. [c] Oxa = 2-amino-1,3,4-oxadiazol-5-yl.
Figure 2. Thermal ellipsoid plot (20% ellipsoids), crystallographic
atom labeling (top) and stacking plot along the a-axis (bottom) of
tocopheryl-triazole 11 (4,5-diester substituents).
and the 4,5-disubstituted tocopheryl triazoles (approx.
46 ppm).
1
The room-temperature H NMR spectrum of the 1-(5a-
tocopheryl)-1,2,3-triazole derivatives 8 and 9, with their rel-
atively bulky phenyl substituents, showed an interesting fea-
ture: a broad peak originating from the 4-CH2 group indi-
cated restricted mobility of these protons. A similar behav-
Figure 1. Thermal ellipsoid plot (40% ellipsoids), crystallographic
atom labeling (top) and stacking plot along the b-axis (bottom) of
tocopheryl-triazole 9 (4,5-diphenyl substituents).
5 resonances of the triazole appeared quite close at about ior was observed for the recently described tocopherylisox-
130 ppm in the 1,5-isomers, there was a significant chemical azolines.[14] The crystal structure of 9, as shown in Figure 1,
shift difference in the 1,4-counterpart: 119 ppm for C-5 and makes plausible that this behavior is due to the proximity
150 ppm for C-4. In addition, C-5a in the 1,5-isomer experi- and reduced rotational ability of the bulky diphenyltriazole
enced a 4 ppm downfield shift relative to the 1,4-isomers substituents. With increasing temperature, the broad reso-
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FULL PAPER
nance sharpened into a triplet, as usually observed for toco-
pherols. In addition, the C-4 methylenes in 8 and 9 experi-
enced a pronounced high-field shift (to 2.3 ppm at 298 K
and to 2.55 ppm at 333 K) compared to their “usual” ap-
pearance in the other tocopheryltriazoles (and α-tocopherol
derivatives in general) around 2.6–2.7 ppm. In compound
11 one of the ethyl ester groups is placed into closer proxim-
ity to the aromatic ring, as also indicated by the crystal
structure of 11 in Figure 2, 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:
4.38 vs. 4.08 (OCH2) and 0.92 vs. 1.24 ppm (CH3).
Finally, the base-induced cleavage of the tocopheryl moi-
ety was verified for compounds 9 and 15. Treatment with
base both in organic media, i.e. with the equivalent amount
of NaOH in MeOH, and in aqueous media, i.e. in phos-
phate buffer pH 9 containing sodium dodecyl sulfate as a
micelle formation agent, caused cleavage of the tocopheryl
carrier and quantitative release of the respective 1-dealkyl-
ated triazole moieties (Scheme 3). Thus the requirements
mentioned in the introduction section are fully met. Prelim-
inary experiments showed that removal of the lipophilic
carrier can even be performed under near-neutral (slightly
basic) conditions in the presence of deacetylating enzymes,
which liberated the phenolic hydroxy of the tocopheryl moi-
ety, thus rendering it much more prone to base-induced eli-
mination of the 1,2,3-triazole substituent.
Experimental Section
All-racemic α-tocopherol and α-tocopheryl acetate were used as the
starting materials. Thin layer chromatography (TLC) was per-
formed on silica gel 60 plates (5×10 cm, 0.25 mm) with fluores-
cence detection under UV light at 254 nm. Column chromatog-
raphy was performed on silica gel G60 (40-63 µm). Melting points,
determined on a Kofler-type micro hot stage with Reichert-Biovar
microscope, are uncorrected. NMR spectra were recorded at
300.13 MHz for 1H and at 75.47 MHz for 13C in CDCl3 if not
otherwise stated. Chemical shifts, relative to TMS as internal stan-
dard, are given in δ values; coupling constants are reported in Hz.
13C peaks were assigned by means of APT, HMQC and HMBC
spectra. The influence of modifications at the chroman ring on the
resonances of the isoprenoid side chain of tocopherols is negligible
(Ͻ 0.1 ppm for 13C and Ͻ 0.01 ppm for H). The 13C resonances
1
are therefore listed only for one example, the starting material 5a-
tocopheryl azide (7). “d.i.” denotes peaks with double intensity, E
stands for the ethoxycarbonyl (“ester”) group. High-resolution MS
data were obtained with a Waters ESI Q-TOF spectrometer. All
new compounds exhibited satisfactory purity data.
Preparation of Tocopheryl Azide 7 and Chromanyl Azide 7a: To a
solution of α-tocopherol or pentamethylchromanol in dry n-hexane
(1% solution), a solution of bromine (1.1 equiv.) in a tenfold vol-
ume of n-hexane was added at once at room temperature. The mix-
ture was stirred for 2 h. The initial dark red color of the solution
changed to dark yellow within seconds, and the evolution of HBr
started. The solvent and the small excess of bromine, along with
dissolved HBr, were removed in vacuo at room temperaure. 5a-
Bromo-tocopherol (5) was obtained in quantitative yield, and no
further purification was required. The product was dissolved in
dichloromethane (1% solution), and acetic anhydride (1.1 equiv.)
and concentrated sulfuric acid (2 drops) were added. The mixture
was stirred overnight at room temperature, quenched with water
under ice-cooling, and stirred for an additional 2 hours. After re-
peated extraction with n-hexane, the organic layer was neutralized
with a saturated NaHCO3 solution, washed with water, and dried
with MgSO4. After filtration, the solvent was removed in vacuo.
The product, 5a-bromo-tocopheryl acetate (6), was dissolved in
acetonitrile (1% solution). After addition of sodium azide
(1.3 equiv.), the mixture was refluxed for two hours. After cooling
to room temperature, the solids were filtered off and the solvent
was removed in vacuo. The crude product was purified by column
chromatography on silica gel (EtOAc/n-hexane, v/v = 1:20) to pro-
vide 5a-tocopheryl azide as a yellow wax in 84% overall yield. Prep-
aration of the corresponding model azide, containing a methyl
group instead of the isoprenoid side chain, proceeded analogously
with 2,2,5,7,8-pentamethylchroman-6-ol (1a) as the starting mate-
rial, providing 7a (84%) as colorless solid.
Scheme 3. Base-induced cleavage of the lipophilic 5a-tocopheryl
moiety.
Conclusion
The facile preparation of 5a-azido-α-tocopheryl acetate
from commercially available α-tocopherol, and its further
reaction with alkynes in a [3+2]-cycloaddition reaction
opens the way to 1-(5a-tocopheryl)-substituted 1,2,3-tri-
azoles, which were fully analytically characterized. The
structure of the compounds was supported by crystal struc-
ture analysis of derivatives with truncated isoprenoid side
chains. NMR spectra indicated a reduced mobility of the
pyran ring in the tocopherol moiety due to the bulky tri-
azole substituent, with especially strong influences on the
C-4 methylene group. The target tocopheryltriazole exhib-
ited the desired property of base-induced cleavage of the
lipophilic tocopheryl moiety to be used in drug delivery sys-
tems.
5a-Azido-tocopheryl Acetate (7): 1H NMR: δ = 4.19 (s, 2 H, 5a-H),
2.73 (t, J = 6.7 Hz, 4-H), 2.36 (s, 3 H, CH3CO), 2.12 (s, 3 H, 8b-
3
H), 2.03 (s, 3 H, 7a-H), 1.90–1.72 (m, 2 H, 3-H) ppm. 13C NMR:
δ = 169.7 (COO), 149.8 (C-8a), 141.1 (C-6), 127.8 (C-7), 127.0 (C-
8), 122.0 (C-5), 117.9 (C-4a), 75.5 (C-2), 46.3 (C-5a), 40.2 (C-1Ј),
39.4 (C-11Ј), 37.2, 37.3, 37.4, 37.5 (C-3Ј, C-5Ј, C-7Ј, C-9Ј), 32.6,
32.7 (C-4Ј, C-8Ј), 30.8 (C-3), 28.0 (C-12Ј), 24.8, 24.4 (C-6Ј, C-10Ј),
23.9 (C-2a), 22.6, 22.7 (C-12aЈ, C-13Ј), 21.0 (C-4), 20.6 (CH3CO),
19.9 (C-2Ј), 19.6, 19.7 (C-4aЈ, C-8aЈ), 13.1 (C-7a), 12.2 (C-8b) ppm.
C31H51N3O3 (513.77): calcd. C 72.47, H 10.01, N 8.18; found C
72.63, H 10.23, N 7.98.
6-Acetoxy-5-azidomethyl-2,2,7,8-tetramethylchroman (7a): M.p.
73 °C (dec.), 1H NMR: δ = 4.19 (s, 2 H, 5a-H), 2.75 (t, 3J = 6.8 Hz,
4-H), 2.36 (s, 3 H, CH3CO), 2.12 (s, 3 H, 8b-H), 2.03 (s, 3 H, 7a-
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Tocopheryl Azide and Reaction with Alkynes
FULL PAPER
H), 1.80 (t, J = 6.8 Hz, 2 H, 3-H), 1.31 (s, 6 H, 2a-H, 2b-H) ppm.
13C NMR: δ = 169.7 (COO), 149.9 (C-8a), 141.1 (C-6), 127.8 (C-
Di-tert-butyl 1-{[6-Acetoxy-2,7,8-trimethyl-2-(4,8,12-trimethyltride-
cyl)chroman-5-yl]methyl}-1H-1,2,3-triazole-4,5-dicarboxylate (12):
7), 127.0 (C-8), 122.0 (C-5), 117.7 (C-4a), 73.4 (C-2), 46.3 (C-5a), 1H NMR: δ = 5.54 (s, 2 H, 5a-H), 2.65 (m, 2 H, 4-H), 2.26 (s, 3
32.4 (C-3), 26.9 (C-2a, C-2b), 20.6 (CH3CO), 20.4 (C-4), 13.1 (C- H, CH3CO), 2.10 (s, 3 H, 8b-H), 1.97 (s, 3 H, 7a-H), 1.82 (m, 2 H,
7a), 12.2 (C-8b) ppm. C16H21N3O3 (303.36): calcd. C 63.35, H 6.98,
N 13.85; found C 63.16, H 7.12, N 13.78.
3-H), 1.60 (s, 9 H, tBu), 1.44 (s, 9 H, tBu) ppm. 13C NMR: δ =
170.1 (COOCH3), 160.0 (COOtBu), 158.4 (COOtBu), 150.3 (C-8a),
141.7 (C-5ЈЈ), 141.3 (C-6), 131.8 (C-4ЈЈ), 128.2, 127.8 (C-7, C-8),
121.1 (C-5), 119.0 (C-4a), 85.0 (tBu), 83.0 (tBu), 75.9 (C-2), 46.8
(C-5a), 31.2 (C-3), 28.5 (tBu), 28.1 (tBu), 21.8 (C-4), 20.4
(CH3CO), 13.4 (C-7a), 12.6 (C-8b) ppm. HRMS for C43H69N3O7
(740.05): calcd. 741.05 [M + H+]; found 740.54.
General Procedure for the 1,3-Dipolar Cycloaddition Leading to 1-
(5a-Tocopheryl)-1,2,3-triazols: To 7 or 7a (1.0 mmol) in dry toluene
(5 mL), the alkyne component (1–2.2 equiv.) was added. The mix-
ture was refluxed for 1–3 d under argon or nitrogen (TLC control),
and cooled to room temp. The solvent was removed in vacuo and
the crude product was purified by column chromatography
(EtOAc/n-hexane, v/v = 1:5).
6-Acetoxy-2,7,8-trimethyl-5-[(4-phenyl-1,2,3-triazol-1-yl)methyl]-2-
1
3
(4,8,12-trimethyltridecyl)chroman (15): H NMR: δ = 7.76 (d, J =
3
8.7 Hz, 2 H, Ar-H), 7.56 (s, 1 H, CHN), 7.36 (t, J = 7.1 Hz, 2 H,
Ar-H), 7.27 (t, J = 7.3 Hz, 1 H, Ar-H), 5.45 (s, 2 H, 5a-H), 2.54
3
6-Acetoxy-5-[(4,5-diphenyl-1,2,3-triazol-1-yl)methyl]-2,7,8-trimeth-
1
yl-2-(4,8,12-trimethyltridecyl)chroman (8): H NMR: δ = 7.54–7.08
(br. s, 2 H, 4-H), 2.33 (s, 3 H, CH3CO), 2.15 (s, 3 H, 8b-H), 2.06
(s, 3 H, 7a-H), 1.72 (m, 2 H, 3-H) ppm. 13C NMR: δ = 170.2
(COO), 150.6 (C-Ph), 148.3 (C-8a), 141.6 (C-6), 131.0 (Ph, C-1),
129.1 (d.i.), 129.6, 128.4 (C-7, C-8), 128.4 (Ph, C-4), 126.1 (d.i.),
121.5 (C-5), 119.6 (CHN), 118.8 (C-4a), 76.1 (C-2), 46.5 (C-5a),
30.9 (C-3), 21.4 (C-4), 20.2 (CH3CO), 13.6 (C-7a), 12.7 (C-8b) ppm.
HRMS for C39H57N3O3 (615.91): calcd. 616.92 [M + H+]; found
619.90.
3
(m, 10 H, Ar-H), 5.25 (s, 2 H, 5a-H), 2.27 (t, 2 H, J = 6.4 Hz, 4-
H), 2.20 (s, 3 H, CH3CO), 2.08 (s, 3 H, 8b-H), 1.90 (s, 3 H, 7a-H),
1.52 (m, 2 H, 3-H) ppm. 13C NMR: δ = 170.1 (COO), 150.0 (C-
8a), 145.0 (C-6), 141.8 (C-5ЈЈ), 134.1 (C-4ЈЈ), 131.5 (Ph, C-1), 130.7
(d.i.), 129.8 (Ph, C-4), 129.2 (d.i.), 128.7 (d.i.), 128.6 (Ph, C-1),
128.4 (C-7), 128.0 (Ph, C-4), 127.4 (C-8), 127.1 (d.i.), 121.9 (C-5),
118.5 (C-4a), 75.7 (C-2), 45.9 (C-5a), 33.1 (C-3), 20.2 (CH3CO),
20.0 (C-4), 13.3 (C-7a), 12.6 (C-8b) ppm. HRMS for C45H61N3O3
(692.01): calcd. 693.01 [M + H+]; found 693.04.
6-Acetoxy-2,7,8-trimethyl-5-[(5-phenyl-1,2,3-triazol-1-yl)methyl]-2-
1
(4,8,12-trimethyltridecyl)chroman (16): H NMR: δ = 7.75 (s, 1 H,
6-Acetoxy-5-[(4,5-diphenyl-1,2,3-triazol-1-yl)methyl]-2,2,7,8-tetra-
CHN), 7.73 (m, 2 H, Ar-H), 7.36 (m, 3 H, Ar-H), 5.52 (br. s, 2 H,
5a-H), 2.74 (br. s, 2 H, 4-H), 2.35 (s, 3 H, CH3CO), 2.11 (s, 3 H,
8b-H), 2.00 (s, 3 H, 7a-H), 1.82 (m, 2 H, 3-H) ppm. 13C NMR: δ
= 169.6 (COO), 149.8 (C-8a), 141.3 (C-6), 130.9 (CHN), 130.5 (Ph,
C-1), 129.4 (C-Ph), 128.7 (d.i.), 128.1 (Ph, C-4), 127.9, 127.1 (C-7,
C-8), 125.8 (d.i.), 122.0 (C-5), 118.6 (C-4a), 75.5 (C-2), 50.3 (C-5a),
30.6 (C-3), 21.0 (C-4), 20.8 (CH3CO), 13.2 (C-7a), 12.2 (C-8b) ppm.
HRMS for C39H57N3O3 (615.91): calcd. 616.92 [M + H+]; found
619.88.
1
methylchroman (9): M.p. 105–107 °C. H NMR: δ = 7.49–7.10 (m,
3
10 H, Ar-H), 5.29 (br. s, 2 H, 5a-H), 2.31 (t, J = 6.5 Hz, 2 H, 4-
H), 2.14 (s, 3 H, CH3CO), 2.08 (s, 3 H, 8b-H), 1.91 (s, 3 H, 7a-H),
1.56 (m, 2 H, 3-H), 1.21 (s, 6 H, 2a-H, 2b-H) ppm. 13C NMR: δ =
169.6 (COO), 149.6 (C-8a), 144.5 (C-6), 141.4 (C-5ЈЈ), 133.6 (C-
4ЈЈ), 131.0 (Ph, C-1), 130.3 (d.i.), 129.4 (Ph, C-4), 128.8 (d.i.), 128.3
(d.i.), 128.0 (Ph, C-1), 127.7 (C-7), 127.4 (Ph, C-4), 127.0 (C-8),
126.6 (d.i.), 121.5 (C-5), 117.8 (C-4a), 73.1 (C-2), 45.4 (C-5a), 32.4
(C-3), 20.6 (CH3 in acetyl), 20.1 (C-4), 12.9 (C-7a), 12.2 (C-8b)
ppm. HRMS for C30H31N3O3 (481.60): calcd. 482.60 [M + H+];
found 482.55.
Ethyl 1-[6-Acetoxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chro-
man-5-ylmethyl]-1H-1,2,3-triazole-4-carboxylate (13): 1H NMR: δ
3
= 5.52 (s, 2 H, 5a-H), 4.42 (q, J = 7.3 Hz, 2 H, OCH2), 2.58 (m,
2 H, 4-H), 2.22 (s, 3 H, CH3CO), 2.13 (s, 3 H, 8b-H), 2.06 (s, 3 H,
7a-H), 1.73 (m, 2 H, 3-H) ppm. The signal of the methyl group of
E is overlapped by the signals of the isoprenoid side chain. 13C
NMR: δ = 169.6 (COO in Ac), 160.5 (COO in E), 148.6 (C–E),
148.1 (C-8a), 141.6 (C-6), 129.1, 128.8 (C-7, C-8), 123.6 (CHN),
121.0 (C-5), 118.1 (C-4a), 76.0 (C-2), 61.5 (OCH2), 46.3 (C-5a),
30.4 (C-3), 20.9 (C-4), 20.4 (CH3CO), 14.2 (CH3 in E), 13.6 (C-7a),
12.7 (C-8b) ppm. HRMS for C36H57N3O5 (611.87): calcd. 612.87
[M + H+]; found 612.88.
Diethyl 1-[6-Acetoxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
1
chroman-5-ylmethyl]-1H-1,2,3-triazole-4,5-dicarboxylate (10): H
3
NMR: δ = 5.57 (s, 2 H, 5a-H), 4.39 (q, 2 H, J = 7.1 Hz, OCH2),
3
4.16 (q, 2 H, J = 7.1 Hz, OCH2), 2.71 (m, 2 H, 4-H), 2.24 (s, 3 H,
CH3CO), 2.11 (s, 3 H, 8b-H), 1.97 (s, 3 H, 7a-H), 1.78 (m, 2 H, 3-
H) ppm. 13C NMR: δ = 169.6 (COO in Ac), 160.1 (COO in E),
159.3 (COO in E), 150.0 (C-8a), 141.3 (C-6), 139.1 (C-5ЈЈ), 131.4
(C-4ЈЈ), 128.0, 127.9 (C-7, C-8), 120.5 (C-5), 118.7 (C-4a), 75.8 (C-
2), 63.0 (OCH2), 61.7 (OCH2), 46.8 (C-5a), 30.7 (C-3), 21.1 (C-4),
20.6 (CH3CO), 14.3 (CH3 in E), 13.7 (CH3 in E), 13.0 (C-7a), 12.3
(C-8b) ppm. HRMS for C39H61N3O7 (683.45): calcd. 684.45 [M +
H+]; found 684.46.
Ethyl 1-{[6-Acetoxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
chroman-5-yl]methyl}-1H-1,2,3-triazole-5-carboxylate (14): 1H
3
NMR: δ = 5.41 (s, 2 H, 5a-H), 4.30 (q, J = 7.3 Hz, 2 H, OCH2),
2.74 (m, 2 H, H-4), 2.21 (s, 3 H, CH3CO), 2.11 (s, 3 H, 8b-H), 2.03
(s, 3 H, 7a-H), 1.78 (m, 2 H, 3-H) ppm. The signal of the methyl
group of E is overlapped by the signals of the isoprenoid side chain.
13C NMR: δ = 169.6 (COO), 160.1 (COO in E), 149.4 (C-8a), 141.8
(C-6), 131.3 (C-E), 127.9 (CHN), 127.8, 127.7 (C-7, C-8), 122.2 (C-
5), 118.0 (C-4a), 75.5 (C-2), 61.0 (O–CH2), 48.9 (C-5a), 31.2 (C-3),
21.1 (C-4), 20.4 (CH3CO), 14.3 (CH3 in E), 13.2 (C-7a), 12.2 (C-
8b). HRMS for C36H57N3O5 (611.87): calcd. 612.87 [M + H+];
found 612.85.
Diethyl 1-[(6-Acetoxy-2,2,7,8-tetramethylchroman-5-yl)methyl]-1H-
1
1,2,3-triazole-4,5-dicarboxylate (11): M.p. 83–87 °C. H NMR: δ =
3
5.55 (s, 2 H, 5a-H), 4.38 (q, 2 H, J = 7.1 Hz, OCH2), 4.18 (q, 2
3
H, J = 7.1 Hz, OCH2), 2.70 (t, J = 6.8 Hz, 2 H, 4-H), 2.24 (s, 3
H, CH3CO), 2.11 (s, 3 H, 8b-H), 1.98 (s, 3 H, 7a-H), 1.79 (t, J =
6.8 Hz, 2 H, 3-H), 1.26 (s, 6 H, 2a-H, 2b-H), 1.24 (s, 3 H, CH3 in
E), 0.92 (s, 3 H, CH3 in E) ppm. 13C NMR: δ = 170.4 (COO in
Ac), 160.4 (COO in E), 159.8 (COO in E), 149.8 (C-8a), 141.3 (C-
6), 139.1 (C-5ЈЈ), 131.4 (C-4ЈЈ), 128.2, 128.1 (C-7, C-8), 120.7 (C-
5), 118.8 (C-4a), 73.3 (C-2), 62.5 (OCH2), 61.4 (OCH2), 46.1 (C- 6-Acetoxy-5-{[4-(2-amino-1,3,4-oxadiazol-5-yl)-1,2,3-triazol-1-
5a), 32.4 (C-3), 20.6 (CH3CO), 20.4 (C-4), 14.2 (CH3 in E), 13.9 yl]methyl}-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman (17):
(CH3 in E), 13.0 (C-7a), 12.3 (C-8b) ppm. HRMS for C24H31N3O7 1H NMR: δ = 5.47 (s, 2 H, 5a-H), 5.08 (br. s, NH2), 2.58 (br. s, 2
(473.22): calcd. 474.22 [M + H+]; found 474.22.
H, 4-H), 2.30 (s, 3 H, CH3CO), 2.14 (s, 3 H, 8b-H), 2.04 (s, 3 H,
Eur. J. Org. Chem. 2006, 2081–2086
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2085

C. Adelwöhrer, T. Rosenau, E. Kloser, K. Mereiter, T. Netscher
FULL PAPER
7a-H), 1.74 (m, 2 H, 3-H). 13C NMR: δ = 164.2 (C-2 in oxadiazole),
160.4 (C-5 in oxadiazole), 148.1 (C-4 in triazole), 147.9 (C-8a),
140.9 (C-6), 129.2 (C-7), 128.0 (C-8), 121.3 (C-5), 120.5 (CH-5 in
triazole), 118.4 (C-4a), 75.7 (C-2), 45.9 (C-5a), 30.9 (C-3), 22.2 (C-
4), 20.4 (CH3 in acetyl), 13.7 (C-7a), 12.4 (C-8b). HRMS for
C35H54N6O4 (622.86): calcd. 622.87 [M + H+], found: 622.76.
Acknowledgments
The financial support by the Austrian Fonds zur Förderung der
wissenschaftlichen Forschung (project P-17428) is gratefully ac-
knowledged.
6-Acetoxy-5-{[5-(2-Amino-1,3,4-oxadiazol-5-yl)-1,2,3-triazol-1-
yl]methyl}-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman (18):
1H NMR: δ = 6.24 (br. s, NH2), 5.53 (s, 2 H, 5a-H), 2.79 (br. s, 2
H, 4-H), 2.36 (s, 3 H, CH3CO), 2.11 (s, 3 H, 8b-H), 2.02 (s, 3 H,
7a-H), 1.81 (m, 2 H, 3-H). 13C NMR: δ = 163.9 (C-2 in oxadiazole),
163.0 (C-5 in oxadiazole), 149.1 (C-8a), 144.5 (C-6), 132.1 (CH-4
in triazole), 129.1 (C-5 in triazole), 127.4 (C-7), 127.0 (C-8), 122.1
(C-5), 118.3 (C-4a), 75.4 (C-2), 50.5 (C-5a), 30.2 (C-3), 21.4 (C-4),
20.4 (CH3 in acetyl), 13.4 (C-7a), 12.1 (C-8b). HRMS for
C35H54N6O4 (622.86): calcd. 622.87 [M + H+], found: 622.89.
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Diethyl Chromanyl-triazoledicarboxylate 11: C24H31N3O7, M =
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CCDC-289354 and -289355 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: November 16, 2005
Published Online: March 1, 2006
2086
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2081–2086