Intramolecular homolytic substitution at selenium: Synthesis of novel selenium-containing vitamin E analogues

Article abstract of DOI:10.1021/jo010274k

Treatment of 1-(benzylselenenyl)-5-butyl-5-nonanol (10) with oxalyl chloride followed by the sodium salt of N-hydroxypyridine-2-thione afforded the corresponding pyridine-2-thione-N-oxycarbonyl (PTOC) oxalate ester which was not isolated but immediately heated to provide 2,2-dibutylselenane (7). This transformation presumably involves a tertiary alkyl radical that undergoes intramolecular homolytic substitution at selenium with loss of the benzyl radical to provide the selenium-containing ring system (7). A similar protocol, when applied to 1-(2-benzylselenenyl-5-methoxyphenyl)-3-methyl3-heptanol (18) and 1-(2-benzylselenenyl-5-methoxyphenyl)-3,7,11,15-tetramethyl-3-hexadecanol (19), followed by deprotection, afforded the selenium-containing α-tocopherol analogues 4 and 1f, respectively, in moderate yields. To the best of our knowledge, these transformations represent the first examples of tertiary radicals involved in homolytic substitution chemistry at selenium.

Full text of DOI:10.1021/jo010274k

6286
J . Org. Chem. 2001, 66, 6286-6290
In tr a m olecu la r Hom olytic Su bstitu tion a t Selen iu m : Syn th esis of
Novel Selen iu m -Con ta in in g Vita m in E An a logu es
Nawaf Al-Maharik,† Lars Engman,*,† J onas Malmstro¨m,† and Carl H. Schiesser*,‡
Institute of Chemistry, Department of Organic Chemistry, Uppsala University, Box 531,
S-751 21 Uppsala, Sweden, and School of Chemistry, The University of Melbourne,
Victoria 3010, Australia
Lars.Engman@kemi.uu.se
Received March 12, 2001
Treatment of 1-(benzylselenenyl)-5-butyl-5-nonanol (10) with oxalyl chloride followed by the sodium
salt of N-hydroxypyridine-2-thione afforded the corresponding pyridine-2-thione-N-oxycarbonyl
(PTOC) oxalate ester which was not isolated but immediately heated to provide 2,2-dibutylselenane
(7). This transformation presumably involves a tertiary alkyl radical that undergoes intramolecular
homolytic substitution at selenium with loss of the benzyl radical to provide the selenium-containing
ring system (7). A similar protocol, when applied to 1-(2-benzylselenenyl-5-methoxyphenyl)-3-methyl-
3-heptanol (18) and 1-(2-benzylselenenyl-5-methoxyphenyl)-3,7,11,15-tetramethyl-3-hexadecanol
(19), followed by deprotection, afforded the selenium-containing R-tocopherol analogues 4 and 1f,
respectively, in moderate yields. To the best of our knowledge, these transformations represent
the first examples of tertiary radicals involved in homolytic substitution chemistry at selenium.
In tr od u ction
Antioxidants are of great interest in biological and
polymeric systems. In biological systems, they protect cell
components from oxidative damage, whereas in polymeric
systems, they act as stabilizers to prevent oxidative,
photochemical, and thermal degradation of the material.
Vitamin E is a well-known lipid-soluble antioxidant in
biological systems.1 It protects cell membranes from
oxidative degradation by acting as a chain-breaking
donating antioxidant. The term vitamin E refers to one
or more structurally related phenolic compounds called
tocopherols (compounds 1a -d ), among which R-toco-
pherol is the most active.
inhibition rate 1.8 times higher than that of R-tocopherol.
Water-soluble R-tocopherol analogues have also been
prepared to increase bioavailability.3 The most notable
example is Trolox (3). However, not so much attention
has been paid to the heteroatom in the fused heterocyclic
ring. Ingold and co-workers prepared the sulfur analogue
(1e) of R-tocopherol,4 but it turned out to be slightly less
efficient as an antioxidant than the parent.5
We have demonstrated that various sulfur-, selenium-,
and tellurium-containing compounds show promising
antioxidative properties in different models6 and poly-
meric systems.7 Divalent organoselenides and tellurides
react readily with many types of oxidants, and the
resulting tetravalent compounds can be reduced by mild
reducing agents. Thus, in the presence of a stoichiometric
reductant, the Se/Te-containing materials can act as
catalytic antioxidants. Because of this facile redox cycling,
we believe selenium- and tellurium-containing R-toco-
Several efforts have been made to develop antioxidants
with better antioxidative properties than vitamin E. For
example, Ingold and co-workers prepared the analogue
2, which has a five-membered fused heterocyclic ring
instead of a six-membered one.2 They reported that this
compound, because of stereoelectronic effects, had an
(3) Bolkenius, F. N.; Grisar, J . M.; De J ong, W. Free Radical Res.
Commun. 1991, 14, 363. Grisar, J . M.; Petty, M. A.; Bolkenius, F. N.;
Dow, J .; Wagner, J .; Wagner, E. R.; Haegele, K. D.; De J ong, W. J .
Med. Chem. 1991, 34, 257.
(4) Robillard, B.; Ingold, K. U. Tetrahedron Lett. 1986, 27, 2817.
(5) Robillard, B.; Hughes, L.; Slaby, M.; Lindsay, D. A.; Ingold, K.
U. J . Org. Chem. 1986, 51, 1700. Zahalka, H. A.; Robillard, B.; Hughes,
L.; Lusztyk, J .; Burton, G. W.; J anzen, E. G.; Kotake, Y.; Ingold, K. U.
J . Org. Chem. 1988, 53, 3739.
* Correspondence may be addressed to either author.
† Uppsala University.
‡ The University of Melbourne.
(1) Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194.
(2) 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.
10.1021/jo010274k CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/24/2001

Synthesis of Vitamin E Analogues
J . Org. Chem., Vol. 66, No. 19, 2001 6287
Sch em e 1
Sch em e 2a
a
pherols will be more efficient than the corresponding
oxygen and sulfur analogues. As model compounds of
increasing complexity, we decided to synthesize the
selenium-containing analogues 4 and 1f.
Key: (a) Bn2Se2, NaBH4, EtOH, 95%. (b) Mg, n-BuBr, Et2O,
76%. (c) Oxalyl chloride, C6H6. (d) Sodium salt of 2-mercaptopy-
ridine N-oxide, DMAP, C6H6, 40% from 10.
Resu lts a n d Discu ssion
Syn t h esis of 2,2-Dib u t ylselen a n e (7), a Mod el
Com p ou n d . To explore methods for the preparation of
the required selenium-containing ring systems (e.g., 1f),
we first turned our attention to the preparation of 2,2-
dibutylselanane (7), a model compound. Barton, Crich,
and co-workers reported some time ago a convenient way
to generate radicals from tertiary alcohols by the use of
PTOC oxalates (anhydrides of an oxalic acid monoester
and N-hydroxypyridine-2-thione).12 It was envisaged that
free-radical homolytic substitution chemistry involving
an appropriately substituted tertiary radical would pro-
duce the desired selenacycle. Model compound 7 was
prepared from commercially available methyl 5-bromo-
valerate (8) as indicated in Scheme 2. Thus, treatment
of bromide 8 with sodium benzylselenolate afforded
selenide 9 in 95% isolated yield. The required tertiary
alcohol 10 was prepared in 76% isolated yield by treat-
ment of ester 9 with 2.1 equiv of n-butylmagnesium
bromide. The alcohol was then treated with oxalyl
chloride, followed by the sodium salt of 2-mercaptopyri-
dine N-oxide and DMAP, to afford the desired selenide 7
in 40% yield from compound 10.
Intramolecular homolytic substitution is now a proven
synthetic method for the preparation of various hetero-
cycles.8 Intramolecular homolytic substitution at sulfur
has been used in the preparation of sulfur-containing
heterocycles.9 We have recently demonstrated that in-
tramolecular homolytic substitution at selenium or tel-
lurium is a convenient method for the preparation of
selenium or tellurium heterocycles.10 For example, ir-
radiation of radical precursor 5 (Scheme 1) leads to rapid
and efficient intramolecular homolytic substitution at
selenium to give substituted and saturated selenium-
containing heterocycles 6 in good yield.11
We now describe, to the best of our knowledge, the first
examples of tertiary radicals undergoing intramolecular
homolytic substitution reactions at selenium to afford
selenium-containing heterocycles.
(6) Cotgreave, I. A.; Molde´us, P.; Engman, L.; Hallberg, A. Biochem.
Pharmacol. 1991, 42, 1481. Cotgreave, I. A.; Molde´us, P.; Brattsand,
R.; Hallberg, A.; Andersson, C.-M.; Engman, L. Biochem. Pharmacol.
1992, 43, 793. Engman, L.; Stern, D.; Cotgreave, I. A.; Andersson, C.-
M. J . Am. Chem. Soc. 1992, 114, 9737. Andersson, C.-M.; Hallberg,
A.; Brattsand, R.; Cotgreave, I. A.; Engman, L.; Persson, J . Bioorg.
Med. Chem. Lett. 1993, 3, 2553. Engman, L.; Stern, D.; Pelcman, M.;
Andersson, C.-M. J . Org. Chem. 1994, 59, 1973. Andersson, C. M.;
Brattsand, R.; Hallberg, A.; Engman, L.; Persson, J .; Molde´us, P.;
Cotgreave, I. A. Free Radical Res. 1994, 20, 401. Engman, L.;
Andersson, C.; Morgenstern, R.; Cotgreave, I. A.; Andersson, C.-M.;
Hallberg, A. Tetrahedron 1994, 50, 2929. Engman, L.; Persson, J .;
Vessman, K.; Ekstro¨m, M.; Berglund, M.; Andersson, C.-M. Free
Radical Biol. Med. 1995, 19, 441. Vessman, K.; Ekstro¨m, M.; Berglund,
M.; Andersson, C.-M.; Engman, L. J . Org. Chem. 1995, 60, 4461.
Wieslander, E.; Engman, L.; Svensjo¨, E.; Erlansson, M.; J ohansson,
U.; Linden, M.; Andersson, C.-M.; Brattsand, R. Biochem. Pharmacol.
1998, 55, 573. Kanda, T.; Engman, L.; Cotgreave, I. A.; Powis, G. J .
Org. Chem. 1999, 64, 8161.
Interestingly, attempted intramolecular homolytic sub-
stitution using the tertiary iodide 11 as a starting
material under standard free-radical conditions [(tris-
(trimethylsilyl)silane (TTMSS) and AIBN, n-Bu3SnH and
AIBN, (n-Bu3Sn)2 and hν] gave only low yields of the
desired selenacycle 7. Elimination seems to be the
predominant competing reaction in these cases.
Syn th esis of th e Selen iu m -Con ta in in g Vita m in E
An a logu es 4 a n d 1f. The selenochromane 4 was pre-
pared as outlined in Scheme 3. Bromination of 3-meth-
oxybenzyl bromide, 12,13 gave the dibromide 13 in 97%
yield. Subsequent treatment of compound 13 with the
enolate of tert-butyl acetoacetate, followed by hydrolysis
and decarboxylation, furnished the desired ketone 15
quantitatively. Further protection as the 1,3-dioxolane
(7) Engman, L.; Stern, D.; Stenberg, B. J . Appl. Polym. Sci. 1996,
59, 1365. Malmstro¨m, J .; Engman, L.; Bellander, M.; J acobsson, K.;
Stenberg, B. J . Appl. Polym. Sci. 1998, 70, 449.
(8) Schiesser, C. H.; Wild, L. M. Tetrahedron 1996, 52, 13265.
(9) See, for example: Kampmeier, J . A.; Evans, T. R. J . Am. Chem.
Soc. 1966, 88, 4096. Benati, L.; Montevecchi, P. C.; Tundo, A.; Zanardi,
G. J . Chem. Soc., Perkin Trans. 1 1974, 1272. Beckwith, A. L. J .; Boate,
D. R. J . Chem. Soc., Chem. Commun. 1986, 189. Beckwith, A. L. J .;
Boate, D. R. J . Org. Chem. 1988, 53, 4339. Beckwith, A. L. J . Chem.
Soc. Rev. 1993, 143. Crich, D.; Yao, Q. J . Org. Chem. 1996, 61, 3566.
(10) Schiesser, C. H.; Sutej, K. Tetrahedron Lett. 1992, 33, 5137.
Lyons, J . E.; Schiesser, C. H.; Sutej, K. J . Org. Chem. 1993, 58, 5632.
Fong, M. C.; Schiesser, C. H. Tetrahedron Lett. 1995, 36, 7329. Fong,
M. C.; Schiesser, C. H. J . Org. Chem. 1997, 62, 3103. Lucas, M. A.;
Schiesser, C. H. J . Org. Chem. 1998, 63, 3032. Laws, M. J .; Schiesser,
C. H. Tetrahedron Lett. 1997, 38, 8429. Schiesser, C. H.; Zheng, S.-L.
Tetrahedron Lett. 1999, 40, 5095. Engman, L.; Laws, M. J .; Malmstro¨m,
J .; Schiesser, C. H.; Zugaro, L. M. J . Org. Chem. 1999, 64, 6764. Lucas,
M. A.; Nguyen, O. T. K.; Schiesser, C. H.; Zheng, S.-L. Tetrahedron
2000, 56, 3995.
(11) Schiesser, C. H.; Sutej, K. J . Chem. Soc., Chem. Commun. 1992,
57. Benjamin, L. J .; Schiesser, C. H.; Sutej, K. Tetrahedron 1993, 49,
2557.
(12) Barton, D. H. R.; Crich, D. J . Chem. Soc., Chem. Commun. 1984,
774. Barton, D. H. R.; Crich, D. J . Chem. Soc., Perkin Trans. 1 1986,
1603. Barton, D. H. R.; Crich, D.; Tetrahedron Lett. 1985, 26, 757.
Crich, D.; Fortt, S. M. Synthesis 1987, 35.
(13) Beard, W. Q., J r.; van Eenam, D. N.; Hauser, C. R. J . Org.
Chem. 1961, 26, 2310.

6288 J . Org. Chem., Vol. 66, No. 19, 2001
Al-Maharik et al.
Sch em e 3a
In summary, we have demonstrated the first examples
of intramolecular homolytic substitution of tertiary radi-
cals at selenium by employing the Barton/Crich protocol
for the preparation of 2,2-dibutylselenane and two sele-
nochromane tocopherol analogues. Currently, we are
exploring this chemistry for the preparation of the
selenium-containing R-tocopherol analogue 1g.
Exp er im en ta l Section
3-(Bromomethyl)-1-methoxybenzene13 and 4,8,12-trimeth-
yltridecyl bromide14 were prepared according to literature
procedures. Melting points are uncorrected. 1H NMR (400
MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3
on a Varian unity 400 spectrometer. For proton spectra, the
residual peak of CHCl3 was used as the internal reference (7.26
ppm), while the central peak of CDCl3 (77.0 ppm) was used as
the reference for carbon spectra. 77Se NMR chemical shifts are
given in ppm relative to externally referenced diphenyl dis-
elenide (δ 464). EI mass spectra were recorded at 70 eV. M+
ions are given for 80Se. Unless otherwise stated, the mass
spectra were recorded via direct inlet. Merck 60 or MATREX
LC 60A/35-70MY 80/25 85040 (GRACE Davison) silica gel was
used for flash column chromatography. Tetrahydrofuran and
diethyl ether were distilled under nitrogen from sodium/
benzophenone. Benzene and pyridine were distilled under
nitrogen from calcium hydride. Elemental analyses were
performed by Chemical and Micro Analytical services Pty. Ltd,
Geelong, Victoria, Australia, or by Analytical Laboratories,
Lindlar, Germany.
Meth yl 5-Ben zylselen en ylva ler a te (9). Sodium borohy-
dride was added, in portions under nitrogen, to a suspension
of dibenzyl diselenide (1.81 g, 5.32 mmol) in absolute ethanol
(150 mL) until the characteristic yellow color of the diselenide
had disappeared. Methyl 5-bromovalerate (8) (2.00 g, 10.3
mmol) was added, and the reaction mixture was stirred at
ambient temperature for 18 h. Water and diethyl ether were
added, and the phases were separated. The aqueous phase was
extracted with diethyl ether (3×). The combined organic
phases were washed with water and brine, dried (MgSO4),
filtered, and evaporated. Chromatography on silica gel (pen-
tane/EtOAc 97.5:2.5) gave the title compound (2.79 g, 95%) as
a colorless oil. 1H NMR: δ 1.66 (4H, m), 2.29 (2H, m), 2.47
(2H, m), 3.66 (3H, s), 3.77 (2H, s), 7.16-7.30 (5H, m). 13C
NMR: δ 23.2, 25.1, 26.9, 29.6, 33.4, 51.5, 126.6, 128.4, 128.7,
139.4, 173.7. 77Se NMR: δ 255. Anal. Calcd for C13H18O2Se:
C, 54.74; H, 6.36. Found: C, 54.37; H, 5.97.
1-Ben zylselen en yl-5-bu tyl-5-n on a n ol (10). To a suspen-
sion of magnesium (442 mg, 18.2 mmol) in dry diethyl ether
(50 mL), under nitrogen, was added n-butyl bromide (2.0 mL,
18.2 mmol) under reflux. The reaction mixture was then
stirred at reflux for 3 h. Compound 9 (2.47 g, 8.66 mmol)
dissolved in diethyl ether (15 mL) was added dropwise at 0
°C, and the reaction mixture was stirred at ambient temper-
ature for 18 h. NH4Cl was added, and the layers were
separated. The aqueous phase was extracted with diethyl ether
(3×), and the combined organic phases were washed with
water and brine, dried (MgSO4), filtered, and evaporated.
Chromatography on silica gel (pentane and then pentane/
EtOAc 95:5) gave the title compound (2.43 g, 76%) as a pale
yellow oil. 1H NMR: δ 0.91 (6H, t, J ) 6.7 Hz), 1.12 (1H, br s),
1.19-1.42 (16H, m), 1.60 (2H, t, J ) 7.4 Hz), 2.50 (2H, m),
3.77 (2H, s), 7.16-7.30 (5H, m). 13C NMR: δ 14.1, 23.3, 23.8,
23.9, 25.7, 26.9, 30.8, 38.7, 38.9, 74.2, 126.6, 128.4, 128.8, 139.5.
77Se NMR: δ 254. Anal. Calcd for C20H34OSe: C, 65.02; H,
9.28. Found: C, 64.98; H, 9.09.
2,2-Dibu tyl Selen a n e (7). The alcohol 10 (199 mg, 0.538
mmol) was treated with oxalyl chloride (1 mL) in benzene (3
mL) for 18 h at ambient temperature under an atmosphere of
dry nitrogen. After the reaction mixture was evaporated to
dryness under reduced pressure, the residue was taken up in
benzene (2 mL) and added over 10 min to a stirred suspension
of the sodium salt of 2-mercaptopyridine N-oxide (88 mg, 0.65
mmol) and DMAP (7 mg, 0.057 mmol) in benzene (4 mL) at
a
Key: (a) Br2, CHCl3, 97%. (b) tert-Butyl acetoacetate, NaH,
THF, 71%. (c) 6 M HCl. (d) heat, quantitative from 14. (e) Ethylene
glycol, p-TsOH‚H2O, C6H6, 97%. (f) t-BuLi, THF. (g) Elemental
Se. (h) Benzyl bromide. (i) 3 M HCl, 78% from 16. (j) Mg, n-BuBr,
Et2O, 74% of 18; Mg, 4,8,12-trimethyltridecyl bromide, Et2O, 54%
of 19. (k) Oxalyl chloride, C6H6. (l) Sodium salt of 2-mercaptopy-
ridine N-oxide, DMAP, C6H6. (m) BBr3, CH2Cl2, 48 % of 4 from
18; 62% of 1f from 19.
16 proceeded in excellent yield (97%). Compound 16 was
lithiated, selenium was inserted into the carbon-lithium
bond, and the lithium selenolate was benzylated in situ.
After workup, the crude material was subjected to
deprotection with hydrochloric acid to furnish selenide
17 in 78% isolated yield from compound 16. The desired
tertiary alcohol 18 was conveniently prepared in 74%
yield by treatment of ketone 17 with n-butylmagnesium
bromide under standard Grignard conditions. Ring clo-
sure was achieved as described previously for compound
10. Accordingly, the alcohol 18 was treated with oxalyl
chloride in benzene, followed by the sodium salt of
2-mercaptopyridine N-oxide and DMAP, to obtain the
desired cyclized selenide in moderate yield. The crude
product was subjected to treatment with boron tribromide
in CH2Cl2 to furnish the desired selenochromane 4 in 48%
isolated yield from compound 18. The selenium-contain-
ing analogue 1f was prepared as outlined in Scheme 3.
To introduce the racemic vitamin E side chain, bromide
20 was first prepared following a modified literature
procedure from commercially available farnesol.14 Sub-
sequent conversion of 20 into the corresponding Grignard
reagent and treatment with ketone 17 afforded the
tertiary alcohol 19 in 54% isolated yield. This compound
was then subjected to the Barton/Crich procedure as
described previously; selenide 1f was isolated in 62%
yield from compound 19 as a mixture of diastereomers.
(14) Aldrich, J . R.; Oliver, J . E.; Lusby, W. R.; Kochansky, J . P.;
Borges, M. J . Chem. Ecol. 1994, 20, 1103. Cohen, N.; Schaer, B. J .
Org. Chem. 1992, 57, 5783.

Synthesis of Vitamin E Analogues
J . Org. Chem., Vol. 66, No. 19, 2001 6289
reflux, under nitrogen. The reaction mixture was then stirred
at reflux for 2 h. After the reaction mixture was filtered
through a plug of Celite, the crude material was purified by
flash chromatography (hexane) to give the title compound (56
mg, 40%) as a pale yellow oil. 1H NMR: δ 0.93 (6H, m), 1.18-
1.38 (8H, m), 1.54-1.72 (6H, m), 1.81 (2H, m), 1.88 (2H, m),
2.66 (2H, m). 13C NMR: δ 14.1, 18.3, 22.6, 23.2, 26.2, 27.9,
38.5(3), 38.5(6), 44.7. 77Se NMR: δ 303. GC-MS m/z (relative
intensity): 262 (M+, 85.1). HRMS: calcd for C13H26Se, 262.1199;
found, 262.1168.
4-Br om o-3-(br om om eth yl)-1-m eth oxyben zen e (13). To
a solution of compound 12 (2.02 g, 10.1 mmol) in chloroform
(40 mL) was added bromine (525 µL, 10.1 mmol), dissolved in
chloroform (20 mL), dropwise at ambient temperature. The
reaction mixture was then stirred at ambient temperature for
18 h. Sodium thiosulfate (aqueous) was added, and the phases
were separated. The aqueous phase was extracted with dichlo-
romethane (3×). The combined organic phases were washed
with water and brine, dried (MgSO4), filtered, and evaporated
to give the product (2.73 g, 97%) as white crystals, which were
used in the next step without further purification. The NMR
data were in good agreement with the literature.15
ter t-Bu tyl-2-(2-br om o-5-m eth oxyben zyl) Acetoa ceta te
(14). To a suspension of NaH (80% in mineral oil) (161 mg,
5.36 mmol) in dry THF, under nitrogen, was added tert-butyl
acetoacetate (890 µL, 5.36 mmol) at 0 °C, and the mixture was
stirred for 2.5 h at ambient temperature before compound 13
(500 mg, 1.79 mmol) was added. The reaction mixture was then
stirred overnight at ambient temperature. Water and diethyl
ether were added, and the phases were separated. The aqueous
phase was extracted with diethyl ether (3×). The combined
organic phases were washed with water and brine, dried
(MgSO4), filtered, and evaporated to give the crude material.
The excess of tert-butyl acetoacetate was then removed by
Kugelrohr distillation. Chromatography on silica gel (hexane/
EtOAc 95:5) gave the product (454 mg, 71%) as a colorless oil.
1H NMR: δ 1.40 (9H, s), 2.22 (3H, s), 3.14 (1H, dd, J ) 14.0,
8.3 Hz), 3.22 (1H, dd, J ) 14.0, 6.6 Hz), 3.75 (3H, s), 3.84 (1H,
dd, J ) 8.4, 6.5 Hz), 6.65 (1H, dd, J ) 8.8, 3.1 Hz), 6.80 (1H,
d, J ) 3.1 Hz), 7.40 (1H, d, J ) 8.8 Hz). 13C NMR: δ 27.9,
29.6, 34.3, 55.4, 59.8, 82.1, 114.3, 114.8, 117.1, 133.3, 138.6,
158.8, 168.0, 202.5. Anal. Calcd for C16H21BrO4: C, 53.79; H,
5.93. Found: C, 53.96; H, 6.08.
compound (1.648 g, 97%) as a colorless oil, which was used in
the next step without further purification. 1H NMR: δ 1.41
(3H, s), 1.94 (2H, m), 2.79 (2H, m), 3.77 (3H, s), 4.00 (4H, m),
6.62 (1H, dd, J ) 8.7, 3.1 Hz), 6.79 (1H, d, J ) 3.1 Hz), 7.39
(1H, d, J ) 8.7 Hz). 13C NMR: δ 23.9, 31.1, 39.0, 55.4, 64.8,
109.5, 113.2, 114.8, 115.8, 133.2, 142.4, 159.0.
2-(2-Ben zylselen en yl-5-m et h oxyp h en yl)et h yl Met h yl
Keton e (17). To a solution of compound 16 (750 mg, 2.49
mmol) in dry THF (30 mL), under nitrogen, was added t-BuLi
(3.8 mL, 1.38 M) at 0 °C. The reaction mixture was stirred for
30 min at 0 °C, and then elemental selenium (200 mg, 2.49
mmol) was added in one portion. The reaction mixture was
then stirred at ambient temperature for 30 min. Finally, benzyl
bromide (325 µL, 2.74 mmol) was added, and the reaction
mixture was stirred overnight at ambient temperature.
NH4Cl(aq) was added, and the aqueous phase was extracted
with diethyl ether (3×). The combined organic phases were
washed with water and brine, dried (MgSO4), filtered, and
evaporated. To a solution of crude selenide (497 mg, 1.27 mmol)
in THF (6 mL) was added HCl (3 M, 5 mL). The reaction
mixture was stirred at ambient temperature for 18 h. Water
and diethyl ether were added, and the layers were separated.
The aqueous phase was extracted with diethyl ether (3×). The
combined organic phases were washed with water and brine,
dried (MgSO4), filtered, and evaporated. Chromatography on
silica gel (pentane/EtOAc 90:10) gave the title compound (674
1
mg, 78% from 16) as white crystals: mp 47-48 °C. H NMR:
δ 2.07 (3H, s), 2.49 (2H, m), 2.87 (2H, m), 3.78 (3H, s), 3.95
(2H, s), 6.66 (1H, dd, J ) 8.5, 2.9 Hz), 6.73 (1H, d, J ) 2.9
Hz), 7.06 (2H, m), 7.20 (3H, m), 7.42 (1H, d, J ) 8.5 Hz). 13C
NMR: δ 29.8, 30.6, 33.2, 44.8, 55.2, 112.6, 114.9, 120.5, 126.7,
128.3, 128.7, 138.0, 139.0, 146.0, 159.9, 207.8. 77Se NMR: δ
319. Anal. Calcd for C18H20O2Se: C, 62.25; H, 5.80. Found: C,
61.98; H, 5.65.
1-(2-Ben zylselen en yl-5-m et h oxyp h en yl)-3-m et h yl-3-
h ep ta n ol (18). To a suspension of magnesium (92 mg, 3.74
mmol) in dry diethyl ether (10 mL), under nitrogen, was added
n-butyl bromide (405 µL, 3.74 mmol) under reflux. The reaction
mixture was then stirred at reflux for 5 h. Compound 17 (1.005
g, 2.89 mmol) dissolved in diethyl ether (5 mL) was added
dropwise at 0 °C, and the reaction mixture was stirred at
ambient temperature for 18 h. NH4Cl(aq) was added, and the
layers were separated. The aqueous phase was extracted with
diethyl ether (3×), and the combined organic phases were
washed with water and brine, dried (MgSO4), filtered, and
evaporated. Chromatography on silica gel (hexane/EtOAc 90:
10) gave the title compound (0.873 g, 74%) as a pale yellow
4-(2-Br om o-5-m eth oxyp h en yl)-2-bu ta n on e (15). To com-
pound 14 (1.98 g, 5.55 mmol) was added 6 M hydrochloric acid
(40 mL), and the reaction mixture was stirred overnight at
ambient temperature. Then, another 10 mL of concentrated
HCl was added, and the reaction mixture was stirred for 24
h. Because hydrolysis was not complete, another 10 mL of
concentrated HCl was added, and the reaction mixture was
stirred for another 24 h. During the reaction, the carboxylic
acid was partly decarboxylated. Diethyl ether was added, and
the phases were separated. The solvent was evaporated, and
the crude material was heated neat at 130 °C for 3 h. Diethyl
ether was added, and the organic phase was dried (MgSO4),
filtered, and evaporated to give the title compound (1.42 g,
1
oil. H NMR: δ 0.92 (3H, m), 1.17 (3H, s), 1.31 (4H, m), 1.45
(2H, m), 1.55 (2H, m), 2.64 (2H, m), 3.79 (3H, s), 3.95 (2H, s),
6.65 (1H, dd, J ) 8.5, 2.9 Hz), 6.75 (1H, d, J ) 2.9 Hz), 7.08
(2H, m), 7.20 (3H, m), 7.42 (1H, d, J ) 8.5 Hz). 13C NMR: δ
14.1, 23.3, 26.2, 26.7, 31.1, 33.2, 41.6, 43.5, 55.2, 72.7, 112.2,
114.8, 120.7, 126.6, 128.3, 128.7, 137.9, 139.1, 147.7, 159.9.
77Se NMR: δ 316. Anal. Calcd for C22H30O2Se: C, 65.17; H,
7.46. Found: C, 65.05; H, 7.42.
2-Bu tyl-2-m eth ylselen och r om a n -6-ol (4). The selenide
18 (0.18 g, 0.443 mmol) was treated with oxalyl chloride (0.5
mL) in benzene (3 mL) for 18 h at ambient temperature under
an atmosphere of dry nitrogen. After the reaction mixture was
evaporated to dryness under reduced pressure, the residue was
taken into benzene (3 mL) and added over 15 min to a well-
stirred suspension of the sodium salt of 2-mercaptopyridine
N-oxide (79 mg, 0.532 mmol) and DMAP (5.4 mg, 0.044 mmol)
in benzene (3 mL) at reflux, under nitrogen. The reaction
mixture was stirred at reflux for 2.5 h. After the reaction
mixture was filtered through a plug of Celite, the crude
material was purified by flash chromatography (hexane/EtOAc
97.5:2.5) to give almost pure 2-butyl-6-methoxy-2-methylse-
lenochromane (70 mg, 53%). To a solution of this material (45
mg, 0.15 mmol) dissolved in dry CH2Cl2 (2 mL) was added BBr3
(290 µL, 0.29 mmol), under nitrogen at -78 °C. The reaction
was then allowed to reach ambient temperature, and the
mixture was stirred for 22 h. Water and diethyl ether were
added, and the phases were separated. The aqueous phase was
extracted with diethyl ether (3×), and the combined organic
1
100%) as white crystals: mp 34.0-34.5 °C. H NMR: δ 2.16
(3H, s), 2.76 (2H, m), 2.96 (2H, m), 3.77 (3H, s), 6.63 (1H, dd,
J ) 8.8, 3.1 Hz), 6.79 (1H, d, J ) 3.1 Hz), 7.39 (1H, d, J ) 8.8
Hz). 13C NMR: δ 30.0, 30.5, 43.4, 55.4, 113.6, 114.6, 116.2,
133.3, 141.2, 159.0, 207.4. Anal. Calcd for C11H13BrO2: C,
51.38; H, 5.10. Found: C, 51.25; H, 4.97.
2-[2-(2-Br om o-5-m et h oxyp h en yl)et h yl]-2-m et h yl-1,3-
d ioxola n e (16). To a solution of compound 15 (1.456 g, 5.66
mmol) in benzene (40 mL) were added p-TsOH hydrate (108
mg, 0.566 mmol) and ethylene glycol (530 mL, 8.49 mmol). The
reaction mixture was refluxed overnight with azeotropic
removal of water. The solvent was evaporated, water and
diethyl ether were added, and the layers were separated. The
aqueous phase was extracted with diethyl ether (3×). The
combined organic phases were washed with water and brine,
dried (MgSO4), filtered, and evaporated to give the title
(15) Hoye, T. R.; Mi, L. J . Org. Chem. 1997, 62, 8586.

6290 J . Org. Chem., Vol. 66, No. 19, 2001
Al-Maharik et al.
phases were washed with water and brine, dried (MgSO4),
filtered, and evaporated. Chromatography on silica gel (hex-
ane/EtOAc 95:5) gave the title compound (39 mg, 91%) as a
colorless oil. 1H NMR: δ 0.91 (3H, t, J ) 7.3 Hz), 1.33 (2H,
m), 1.43 (2H, m), 1.54 (3H, s), 1.66-1.87 (4H, m), 2.79 (2H,
m), 4.61 (1H, s), 6.59 (1H, dd, J ) 8.3, 2.8 Hz), 6.66 (1H, d, J
) 2.8 Hz), 7.10 (1H, d, J ) 8.3 Hz). 13C NMR: δ 14.1, 23.2,
27.3, 29.2, 30.0, 38.4, 44.4, 46.6, 114.2, 116.3, 120.2, 130.3,
138.8, 153.1. 77Se NMR: δ 380. MS m/z (relative intensity):
284 (M+, 100.0). HRMS: calcd for C14H20OSe, 284.0679; found,
284.0636.
dure for compound 4. Treatment of selenide 19 (0.45 g, 0.784
mmol) as described gave after flash chromatography on silica
gel (pentane/EtOAc 97.5:2.5) almost pure 6-methoxy-2-methyl-
2-(4,8,12-trimethyltridecyl)selenochromane (235 mg, 65%).
Demethylation of this material (130 mg, 0.281 mmol) afforded
1
the title compound (121 mg, 96%) as a colorless oil. H NMR:
δ 0.86 (12H, m), 1.02-1.91 (26H, m), 2.79 (2H, m), 4.54 (1H,
br s), 6.59 (1H, dd, J ) 8.3, 2.8 Hz), 6.66 (1H, d, J ) 2.8 Hz),
7.10 (1H, d, J ) 8.3 Hz). 13C NMR: δ (some characteristic
peaks) 46.7, 114.2, 116.3, 120.3, 130.3, 138.8, 153.1. 77Se
NMR: δ 380 (0.5), 381 (0.7), 381 (0.9). MS m/z (relative inten-
sity): 452 (M+, 100.0). HRMS: calcd for C26H44OSe, 452.2557;
found, 452.2522.
1-(2-Ben zylselen en yl-5-m et h oxyp h en yl)-3,7,11,15-t et -
r a m eth yl-3-h exa d eca n ol (19). The title compound was
prepared using the procedure for compound 18. Treatment of
ketone 17 (1.51 g, 4.35 mmol) with the Grignard reagent of
bromide 20 gave after flash chromatography (pentane/EtOAc
Ackn owledgm en t. Financial support from the Swed-
ish Council for Engineering Sciences, the Swedish
Natural Science Research Council, Cancerfonden and
the Australian Research Council is gratefully acknowl-
edged.
1
90:10) compound 19 (1.36 g, 54%) as a colorless oil. H NMR:
δ 0.86 (12H, m), 1.00-1.62 (27H, m), 2.64 (2H, m), 3.79 (3H,
s), 3.95 (2H, s), 6.65 (1H, dd, J ) 8.4, 2.9 Hz), 6.74 (1H, d, J
) 2.9 Hz), 7.08 (2H, m), 7.20 (3H, m), 7.42 (1H, d, J ) 8.4 Hz).
13C NMR: δ (some characteristic peaks) 55.2, 72.7, 112.2,
114.8, 120.7, 126.7, 128.3, 128.7, 137.9, 139.1, 147.7, 159.9.
77Se NMR: δ 316 (0.8), 316 (0.9). MS m/z (relative intensity):
574 (M+, 12.9). HRMS: calcd for C34H54O2Se, 574.3289; found,
574.3276.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of compounds 1f, 4, 7, and 19. This material is available free
of charge via the Internet at http://pubs.acs.org.
2-Met h yl-2-(4,8,12-t r im et h ylt r id ecyl)selen och r om a n -
6-ol (1f). The title compound was prepared using the proce-
J O010274K