Novel Antioxidants: Unexpected Rearrangements in the Radical Cyclization Approach to 2,3-Dihydrobenzo[b]thiophene-5-ol Derivatives

Article abstract of DOI:10.1021/jo972087l

The novel α-tocopherol analogue 3,3,4,6,7-pentamethyl-2,3-dihydrobenzo[b]thiophene-5-ol (4a) was prepared by cyclodehydration of the aryl 2-hydroxyalkyl sulfide 6 in concentrated sulfuric acid. Aromatic bromination and dehydration of alcohol 6 furnished the 2-bromoaryl methallyl sulfide 10a as the kinetic product and the 2-bromoaryl 2-methyl-2-propenyl sulfide 11a as the thermodynamic one. Radical cyclization of these compounds afforded the desired 2,3-dihydrobenzo[b]-thiophene derivative 12 in addition to a rearranged isomer 13 thereof. It is proposed that the transformation of compound 10a to 13 occurs via 6-endo cyclization, β-scission, and subsequent 5-exo cyclization. The radical cyclization of the 2-bromoaryl allyl sulfide 16, unsubstituted in the allylic moiety, furnished only 2,3-dihydrobenzo[b]thiophene-5-ol derivative 17.

Full text of DOI:10.1021/jo972087l

3318
J . Org. Chem. 1998, 63, 3318-3323
Novel An tioxid a n ts: Un exp ected Rea r r a n gem en ts in th e Ra d ica l
Cycliza tion Ap p r oa ch to 2,3-Dih yd r oben zo[b]th iop h en e-5-ol
Der iva tives
J onas Malmstro¨m, Vijay Gupta, and Lars Engman*
Uppsala University, Institute of Chemistry, Department of Organic Chemistry,
Box 531, S-751 21 Uppsala, Sweden
Received November 13, 1997
The novel R-tocopherol analogue 3,3,4,6,7-pentamethyl-2,3-dihydrobenzo[b]thiophene-5-ol (4a ) was
prepared by cyclodehydration of the aryl 2-hydroxyalkyl sulfide 6 in concentrated sulfuric acid.
Aromatic bromination and dehydration of alcohol 6 furnished the 2-bromoaryl methallyl sulfide
10a as the kinetic product and the 2-bromoaryl 2-methyl-2-propenyl sulfide 11a as the thermo-
dynamic one. Radical cyclization of these compounds afforded the desired 2,3-dihydrobenzo[b]-
thiophene derivative 12 in addition to a rearranged isomer 13 thereof. It is proposed that the
transformation of compound 10a to 13 occurs via 6-endo cyclization, â-scission, and subsequent
5-exo cyclization. The radical cyclization of the 2-bromoaryl allyl sulfide 16, unsubstituted in the
allylic moiety, furnished only 2,3-dihydrobenzo[b]thiophene-5-ol derivative 17.
In tr od u ction
π-system in the 2,3-dihydrobenzofuran derivative 1, as
compared to R-tocopherol, seems to explain the 1.8-fold
R-Tocopherol, a component of vitamin E, is the major
lipid-soluble antioxidant present in human blood.1 The
antioxidant properties of the tocopherols have been
ascribed to their capacity to rapidly transfer a hydrogen
atom to peroxyl radicals. The tocopheryl radicals formed
in this process are then known to combine with another
peroxyl radical. Thus, tocopherols scavange peroxyl
radicals and act as chain-breaking antioxidants.2 Since
the pioneering work on vitamin E analogues by Ingold
and co-workers in the 1980s,3-7 there has been a continu-
ous search8 for structures with improved or modified
antioxidative properties. Some of the modifications were
introduced to increase hydrophilicity and bioavailability
of the parent chromanol system.9,10 The most notable
improvments in antioxidant efficiency emerged from the
idea that the antioxidant capacity critically depends on
the steric and stereoelectronic effects stabilizing the
aryloxy radical (ArO•) formed in the hydrogen atom
transfer step.5 Thus, the better overlap between the
nonphenolic oxygen 2p-type lone pair and the aromatic
increase in the kinhibition in the inhibited autoxidation of
styrene method. Barclay has recently prepared a 2,3-
dihydronaphthofuran derivative 2 that shows a kinhibition
value 10 times that of R-tocopherol.11,12 The higher
antioxidant activity in this case was attributed to ad-
ditional delocalization of the phenoxyl radical into the
fused aromatic ring.
Sulfur is generally considered to be more effective than
oxygen at stabilizing a neighboring radical center.13
However, 1-thio-R-tocopherol and related 6-hydroxythio-
chromans turned out to be slightly less reactive toward
peroxyl radicals than structurally related 6-hydroxychro-
mans.6,7 To the best of our knowledge, the corresponding
1-seleno- and 1-tellurochromanols were never prepared.
Nishiyama and co-workers14,15 observed the high anti-
oxidant capacity of phenolic compounds carrying a sulfur
atom para to the hydroxyl group. We recently reported
that bis(4-hydroxyphenyl) telluride (3) was a better
inhibitor of azo-initiated peroxidation of linoleic acid than
the corresponding organosulfur compound.16
(1) Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194-
201.
(2) Scott, G. In Free Radicals: Chemistry, Pathology and Medicine;
Rice-Evans, C., Dormandy, T., Eds; Richelieu Press: London, 1988; p
103-130.
(3) Burton, G. W.; Ingold, K. U. J . Am. Chem. Soc. 1981, 103, 6472-
6477.
(4) Barclay, L. R. C.; Ingold, K. U. J . Am. Chem. Soc. 1981, 103,
6478-6485.
(5) 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.
(6) Robillard, B.; Hughes, L.; Slaby, M.; Lindsay, D. A.; Ingold, K.
U. J . Org. Chem. 1986, 51, 1700-1704.
(11) Barclay, L. R. C.; Vinqvist, M. R.; Mukai, K.; Itoh, S.; Morimoto,
H. J . Org. Chem. 1993, 58, 7416-7420.
(7) 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, 3739-3745.
(12) Barclay, L. R. C.; Edwards, C. D.; Mukai, K.; Egawa, Y.; Nishi,
T. J . Org. Chem. 1995, 60, 2739-2744.
(8) See, for example: Mukai, K.; Okabe, K.; Hosose, H. J . Org. Chem.
1989, 54, 557-560. Gilbert, J . C.; Pinto, M. J . Org. Chem. 1992, 57,
5271-5276.
(13) Luedtke, A. E.; Timberlake, J . W. J . Org. Chem. 1985, 50, 268-
270.
(14) Nishiyama, T.; Kagimasa, T.; Yamada, F. Can. J . Chem. 1994,
72, 1412-1414.
(15) Yamamura, T.; Tanaka, K.; Tomiyama, S.; Sai, S.; Yamada, F.;
Nishiyama, T. J . Am. Oil Chem. Soc. 1995, 72, 1047-1052.
(16) Vessman, K.; Ekstro¨m, M.; Berglund, M.; Andersson, C.-M.;
Engman, L. J . Org. Chem. 1995, 60, 4461-4467.
(9) Bolkenius, F. N.; Grisar, J . M.; De J ong, W. Free Radical Res.
Commun. 1991, 14, 363-372.
(10) 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, 257-260.
S0022-3263(97)02087-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

2,3-Dihydrobenzo[b]thiophene-5-ol Derivatives
J . Org. Chem., Vol. 63, No. 10, 1998 3319
In view of the above structure-activity relationships,
we thought it would be interesting to synthesize a series
of tocopherol analogues 4, where the heteroatom X could
be sulfur, selenium, or tellurium. In this paper, we
describe a radical cyclization approach to the sulfur
analogue 4a and some closely related compounds.
compound 4a . Bromination in acetic acid not only
introduced an aromatic bromide but also caused substi-
tution of the very labile tertiary alcohol. However, on
chromatographic purification, the dibromide 8 was partly
hydrolyzed to the tertiary alcohol 9. In the most practical
Resu lts
There is evidence that the 2,3-dihydrobenzothiophene
as well as the 2H-1-benzothiopyran systems can be
assembled by cyclodehydration of the corresponding aryl
hydroxyalkyl sulfides.17 It occurred to us that the
tertiary alcohol required for such an approach toward
compound 4a can be obtained in few steps from the
commercialy available 2,3,6-trimethylphenol. As shown
in Scheme 1, bromination of the phenol occurred re-
giospecifically18 in the 4-position (97% yield). Protection
of the phenol as a TBDMS ether 5 (95% yield) was
performed to increase the yield in the following one-pot
sequence involving lithiation, sulfur insertion, and thi-
olate ring opening of isobutylene oxide. The epoxide was
selectively attacked from the terminus, affording the
tertiary alcohol 6 as an oil in 74% isolated yield.
approach, the crude dibromide 8 was therefore treated
in aqueous tetrahydrofuran with triethylamine to afford
pure alcohol 9 in 67% overall yield from compound 6.
p-Toluenesulfonic acid-catalyzed dehydration of alcohol
9 in refluxing toluene afforded the terminal olefin 10a
as the kinetic product (1 h reflux; 68% isolated yield) and
the vinylic sulfide 11a as the thermodynamic product (24
h reflux; 74% isolated yield).
5-Endo-trig-cyclization of compound 11a was at-
tempted by syringe pump addition of tris(trimethylsilyl)-
silane and AIBN initiation. In addition to reduced
starting material 11b (50%), a 1:1 mixture of the desired
2,3-dihydrobenzo[b]thiophene 12 and an isomer 13 thereof
was isolated (41% yield). As indicated, the structural
assignments of these materials were supported by NOE-
difference experiments and further corroborated by selec-
tive INEPT experiments. In the case of compound 13,
the experiments were done on the corresponding sulfox-
ide 14. The sulfoxide produced on desilylation and
m-CPBA oxidation of compound 12 was identical to the
sulfoxide of product 4a obtained in the above cyclodehy-
dration approach.
Cyclodehydration of compound 6 was unsuccessful in
polyphosphoric, perchloric, and formic acid. Various
Lewis acids also failed to cause cyclization in ni-
tromethane or toluene. However, when compound 6 was
kept in concentrated sulfuric acid for 30 min at 0 °C, the
desired compound 4a was formed together with the
benzo[b]thiophene derivative 7 (27% isolated yield of a
1/1 mixture; eq 1). The separation of these materials by
flash chromatography was conveniently performed after
m-CPBA oxidation to the respective sulfoxides.
Various radical routes to the 2,3-dihydrobenzothiophene
system were also considered. Crich19 recently reported
the efficient formation of the sulfur-aryl bond of 3,3-
dimethyl-2,3-dihydrobenzo[b]thiophene by intramolecu-
lar homolytic substitution at sulfur.20 With some func-
tional group modification (aromatic halogenation,
elimination), compound 6 could be transformed into a
precursor for a radical cyclization approach to the target
Compound 10a was also subjected to radical cycliza-
tion. In this case, slow addition of hydride donor and
the use of tris(trimethylsilyl)silane instead of tributyl-
stannane were not necessary to avoid formation of a
reduction product (10b). Heating of compound 10a with
Sch em e 1
(17) See, for example: El-Khawaga, A. M.; El-Zohry, M. F.; Ismail,
M. T.; Abdel- Wahab, A. A.; Khalaf, A. A. Phosphorus Sulfur 1987,
29, 265-270. Spruce, L. W.; Gale, J . B.; Berlin, K. D.; Verma, A. K.;
Breitman, T. R.; J i, X.; van der Helm, D. J . Med. Chem. 1991, 34, 430-
439.
(18) Mikhailov, V. A.; Savelova, V. A.; Rodygin, M. Yu. Russ. J . Org.
Chem. 1993, 29, 1868-1870.
(19) Crich, D.; Yao, Q. J . Org. Chem. 1996, 61, 3566-3570.
(20) Beckwith, A. L. J . Chem. Soc. Rev. 1993, 143-151.

3320 J . Org. Chem., Vol. 63, No. 10, 1998
Malmstro¨m et al.
Sch em e 2
1.2 equiv of tributylstannane and a trace of AIBN in
benzene for 3 h resulted in the formation of a 3/1 mixture
of compounds 12 and 13 (40% isolated yield). The
reaction was also tried using an excess of the hydride
donor. With a 5-fold excess, compound 12 was isolated
as the only cyclized product in low (17%) yield.
Sch em e 3
The radical cyclization approach to the 2,3-dihydroben-
zo[b]thiophene-5-ol system was also tried using a 2-bro-
moaryl allyl sulfide unsubstituted in the allyl moiety.
Unfortunately, propylene oxide was ring-opened with
poor yield and regioselectivity using the procedure de-
scribed in Scheme 1. Therefore, the lithium arenethiolate
derived from compound 5 was alkylated with allyl
bromide (43% overall yield) and the resulting sulfide 15
treated with 3 equiv of bromine in acetic acid (Scheme
2). The double bond was regenerated by treatment of
the crude reaction mixture with sodium borohydride/bis-
(2-thienyl) ditelluride according to a literature method21
to give radical precursor 16 in 50% yield. Heating of
compound 16 with tributyltin hydride and AIBN initia-
tion afforded 2,3-dihydrobenzo[b]thiophene 17 in 55%
yield, uncontaminated by any isomer thereof.
Compound 12 results from 5-exo cyclization of radical 18,
followed by hydrogen atom abstraction (Scheme 4). The
formation of “rearranged” product 13 can be accounted
for by assuming 6-endo cyclization of the initially formed
aryl radical, followed by â-scission and 5-exo cyclization.
In fact, it is well established that a methyl substituent
at the 5-position in a hexenyl radical makes the 6-endo
mode of cyclization more competitive.23 An alternative
mechanism, involving a neophyl rearrangement of com-
pound 19 to 20, appears unlikely. Unless electron-
withdrawing substituents are present in the aromatic,
such processes are usually slow.24 Also, in contrast to
cases where the neophyl rearrangment is likely to be
operative,25 the ratio 12/13 ratio was invariant of the
concentration of the radical precursor (0.35 or 0.05 M).
In the presence of an excess of the hydrogen atom donor,
isomer-free compound 12 was isolated in much lower
yields than those obtained in the stoichiometric reaction.
We hypothesize that this selectivity is due to suppression
of the 6-endo route to product. Compound 16, lacking
substituents in the allylic moiety, failed to give a “rear-
ranged” radical cyclization product. In this case, the endo
Discu ssion
The cyclodehydration route to 2,3-dihydrobenzo[b]-
thiophenes (eq 1) has previously been high yielding with
tertiary alcohols and unsubstituted aryl groups.17 The
low yield of compound 4a obtained in the attempted
cyclization of compound 6 can probably be ascribed to
unfavorable steric interactions between the gem-dimethyl
groups and the methyl substituent in the 4-position.
Recently, an analogue of vinylic sulfide 11b, lacking
substituents in the aryl ring, was induced to rearrange
to 3,3-dimethyl-2,3-dihydrobenzo[b]thiophene in meth-
ylene chloride in the presence of an excess of aluminum
chloride.22 The similar treatment of compound 11b
induced desilylation but essentially no cyclization.
The transformation of sulfide 6 to dibenzo[b]thiophene
derivative 7 probably occurs via carbocation and episul-
fonium ion intermediates. It also has to involve methyl
and hydride shifts and finally oxidation (Scheme 3). The
aromaticity of the heterocyclic ring formed provides a
driving force for this kind of reorganization.
The formation of isomeric mixtures of 2,3-dihydroben-
zo[b]thiophenes 12 and 13 in the radical cyclization of
compounds 10a and 11a is mechanistically intriguing.
(23) Abeywickrema, A. N.; Beckwith, A. L. J . J . Chem. Soc., Chem.
Commun. 1986, 464-465.
(21) Engman, L. Tetrahedron Lett. 1982, 23, 3601-3602.
(22) Derouane, D.; Harvey, J . N.; Viehe, H. G. J . Chem. Soc., Chem.
Commun. 1995, 993-994.
(24) Abeywickrema, A. N.; Beckwith, A. L. J .; Gerba, S. J . Org.
Chem. 1987, 52, 4072-4078.
(25) Crich, D.; Yao, Q. J . Org. Chem. 1995, 60, 84-88.

2,3-Dihydrobenzo[b]thiophene-5-ol Derivatives
J . Org. Chem., Vol. 63, No. 10, 1998 3321
Sch em e 4
Sch em e 5
mode of cyclization is too slow to become an effective
competing reaction.26
from sodium/benzophenone. Benzene and dichloromethane
were distilled under nitrogen from calcium hydride. Elemental
analyses were performed by Analytical Laboratories, Lindlar,
Germany.
The analogous mechanism (Scheme 5) for formation
of compounds 12 and 13 from compound 11b is more
speculative. Synthetically useful 4-exo and 5-endo pen-
tenyl radical cyclizations are rarely seen.26 However,
since radical 21 is an aryl radical, it could be expected
to undergo cyclization 2-3 orders of magnitude faster
than a corresponding alkyl radical. Furthermore, the
products of 4-exo and 5-endo cyclization are both stabi-
lized, the latter (radical 22) by interaction with sulfur,
the former (radical 23) by being tertiary. In combination,
these factors may serve to make radical cyclization
become competitive to hydrogen atom abstraction.
In conclusion, we have prepared new 2,3-dihydrobenzo-
[b]thiophene-5-ol derivatives in few steps from 2,3,6-
trimethylphenol by using a radical cyclization approach.
The antioxidative properties of the novel R-tocopherol
analogues are presently being evaluated.
4-Br om o-2,3,6-tr im eth ylp h en ol.18 A solution of bromine
(3.80 mL, 73.4 mmol) in acetic acid (40 mL) was added
dropwise to a magnetically stirred solution of 2,3,6-trimeth-
ylphenol (10.0 g, 73.4 mmol) in acetic acid (70 mL) maintained
at 15 °C. After addition, the cooling bath was removed, and
the reaction mixture was stirred at room temperature for 1 h.
Water was added, and the mixture was neutralized with
NaOH (2 M (aq)). The aqueous phase was extracted with
diethyl ether (3 × 100 mL), and the combined organic phases
were washed with water and saturated sodium chloride. The
organic phase was then dried (Na2SO4), filtered, and concen-
trated under reduced pressure to give the title compound (15.3
g, 97%) as light yellow crystals, which were used in the next
step without further purification. Recrystallized material
melted at 83-85 °C (lit.18 mp 85-86 °C).
ter t-Bu tyld im eth ylsilyl 4-Br om o-2,3,6-tr im eth ylp h en yl
Eth er (5). To a solution of tert-butylchlorodimethylsilane
(12.2 g, 80.9 mmol) in DMF (35 mL) at ambient temperature
were added imidazole (11.5 g, 169 mmol) and 4-bromo-2,3,6-
trimethylphenol (14.5 g, 67.4 mmol). The resulting mixture
was then stirred at ambient temperature for 66 h. Water (50
mL) was added, and the solution was extracted with pentane
(4 × 80 mL). The combined organic phases were washed with
water and saturated sodium chloride. The organic phase was
then dried (Na2SO4), filtered, and concentrated under reduced
pressure to give the title compound (21.1 g, 95%) as white
crystals, mp 48-49 °C, which were used in the next step
without further purification: 1H NMR δ 0.15 (s, 6H), 1.04 (s,
9H), 2.16 (s, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 7.19 (s, 1H); 13C
NMR δ -3.2, 15.3, 17.4, 18.7, 20.0, 26.0, 116.9, 127.9, 129.2,
131.3, 134.5, 151.1. Anal. Calcd for C15H25BrOSi: C, 54.70;
H, 7.65. Found: C, 54.83; H, 7.54.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR (300 or 400 MHz)
and 13C NMR (75 or 100 MHz) spectra were recorded in CDCl3
on Varian XL-300 or VXR unity 400 spectrometers. 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. Merck 60
silica gel was used for flash column chromatography. Bis(2-
thienyl) ditelluride was prepared according to a literature
procedure.27 Tetrahydrofuran was distilled under nitrogen
(26) Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in Organic
Chemistry; Wiley: New York, 1995.
(27) Engman, L.; Cava, M. P. Organometallics 1982, 1, 470-473.

3322 J . Org. Chem., Vol. 63, No. 10, 1998
Malmstro¨m et al.
2-Meth yl-2-h yd r oxyp r op yl 4-[(ter t-Bu tyld im eth ylsily-
l)oxy]-2,3,5-tr im eth ylp h en yl Su lfid e (6). tert-Butyllithium
(19.6 mL, 1.7 M, 32.2 mmol) was added, dropwise, to a stirred
solution of compound 5 (5.31 g, 16.1 mmol) in dry THF (100
mL) maintained at -78 °C under an atmosphere of dry
nitrogen. After 0.5 h, the cooling bath was removed, and the
reaction mixture was allowed to warm to room temperature.
Sulfur (0.52 g, 16.3 mmol) was added, in one portion, and the
reaction was stirred at room temperature for 20 min. Finally,
isobutylene oxide (1.45 mL, 16.1 mmol) was added, and the
mixture was stirred at room temperature for 1 h. The reaction
mixture was then quenched with a saturated NH4Cl solution,
and the phases were separated. The aqueous phase was
extracted with dichloromethane (3 × 100 mL), and the
combined organic phases were washed with water and brine
and then dried over Na2SO4. The solvent was removed in
vacuo, and the residue was purified by flash chromatography
(EtOAc/pentane 15/85) to afford 4.22 g (74%) of the title
compound as a light yellow oil: 1H NMR δ 0.15 (s, 6H), 1.03
(s, 9H), 1.28 (s, 6H), 2.13 (s, 3H), 2.16 (s, 3H), 2.32 (s, 1H),
2.38 (s, 3H), 2.96 (s, 2H), 7.15 (s, 1H); 13C NMR δ -3.1, 14.9,
17.6, 17.7, 18.7, 26.0, 28.7, 50.2, 70.8, 126.7, 127.0, 128.4, 132.3,
137.1, 151.5. Anal. Calcd for C19H34O2SSi: C, 64.35; H, 9.66.
Found: C, 64.16; H, 9.61.
SO4), filtration, removal of the solvent in vacuo, and chroma-
tography (EtOAc/pentane 10/90), the title compound (2.05 g,
66%) was obtained as a light yellow oil: 1H NMR δ 0.14 (s,
6H), 1.04 (s, 9H), 1.28 (s, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 2.56
(s, 1H), 2.58 (s, 3H), 2.90 (s, 2H); 13C NMR δ -3.3, 15.4, 18.6,
20.0, 20.5, 25.9, 28.5, 51.2, 70.5, 127.7, 128.2, 128.4, 132.0,
140.7, 152.5.
1H NMR data for crude 2-bromo-2-methylpropyl 4-[(tert-
butyldimethylsilyl)oxy]-6-bromo-2,3,5-trimethylphenyl sulfide
(8): δ 0.15 (s, 6H), 1.04 (s, 9H), 1.88 (s, 6H), 2.12 (s, 3H), 2.31
(s, 3H), 2.59 (s, 3H), 3.24 (s, 2H); MS m/z (relative intensity)
496 (M+, 46.7).
2-Meth yl-2-p r op en yl 6-Br om o-4-[(ter t-bu tyld im eth yl-
silyl)oxy]-2,3,5-tr im eth ylp h en yl Su lfid e (10a ). p-Toluene-
sulfonic acid (0.019 g, 98.8 µmol) was added to a solution of
alcohol 6 (0.57 g, 1.32 mmol) in toluene (20 mL). The reaction
mixture was then stirred under reflux for 1 h, water was
added, and the phases were separated. The aqueous phase
was extracted with diethyl ether (3 × 80 mL). The combined
organic phases were washed with NaHCO3 (5% (aq)), water,
and then brine. After drying (Na2SO4), filtration, and removal
of the solvent in vacuo, the residue was purified by flash
chromatography (pentane) to give 0.37 g (68%) of the title
1
compound as white crystals: mp 37-39 °C; H NMR δ 0.13
3,3,4,6,7-P en ta m eth yl-2,3-d ih yd r oben zo[b]th iop h en e-
5-ol (4a ) a n d 2,3,4,6,7-P en ta m eth ylben zo[b]th iop h en e-5-
ol (7). Neat concentrated sulfuric acid (12 mL) was added to
compound 6 (1.00 g, 2.82 mmol), and the reaction was stirred
at ambient temperature for 35 min. The reaction mixture was
poured onto ice and neutralized with potassium hydroxide. The
residue was then extracted with diethyl ether (3 × 50 mL),
and the combined organic phases were washed with water and
saturated sodium chloride. The organic phase was dried (Na2-
SO4), filtered, and concentrated under reduced pressure and
the residue purified by flash chromatography (EtOAc/pentane
5/95) to afford an inseparable 1:1 mixture of the title com-
pounds 4a and 7 (0.172 g, 27%). To a stirred solution of the
mixture in dichloromethane (40 mL) was added m-chloroper-
benzoic acid (0.18 g, 0.808 mmol) at 0 °C under nitrogen.
Stirring was then continued at 0 °C for 35 min, whereupon
water was added and the phases were separated. The aqueous
phase was extracted with dichloromethane (3 × 50 mL), and
the combined organic phases were washed with NaHCO3 (5%
(aq)), water, and brine. After drying (Na2SO4), evaporation
of the solvent, and flash chromatography (EtOAc/pentane 80/
20), the pure sulfoxides (0.164 g, 85%) were obtained.
2,3,4,6,7-P en t a m et h ylb en zo[b]t h iop h en e-5-ol 1-ox-
id e: mp 193-196 °C; 1H NMR δ 2.07 (s, 3H), 2.23 (s, 3H),
2.25 (s, 3H), 2.28 (s, 3H), 2.46 (s, 3H), 6.80 (s, 1H); 13C NMR
δ 10.8, 12.3, 12.7, 16.8, 16.9, 121.3, 124.7, 132.8, 134.4, 135.7,
139.1, 139.4, 156.4. Anal. Calcd for C13H16O2S: C, 66.07; H,
6.82. Found: C, 65.35; H, 6.41.
(s, 6H), 1.03 (s, 9H), 1.88 (s, 3H), 2.10 (s, 3H), 2.32 (s, 3H),
2.53 (s, 3H), 3.32 (s, 2H), 4.48 (m, 1H), 4.62 (m, 1H); 13C NMR
δ -3.3, 15.4, 18.6, 20.0, 20.4, 21.6, 26.0, 43.7, 113.5, 127.2,
127.5, 128.0, 132.8, 141.3, 141.9, 152.4. Anal. Calcd for
C
19H31BrOSSi: C, 54.92; H, 7.52. Found: C, 55.00; H, 7.55.
2-Meth yl-1-p r op en yl 6-Br om o-4-[(ter t-bu tyld im eth yl-
silyl)oxy]-2,3,5-tr im eth ylp h en yl Su lfid e (11a ). p-Toluene-
sulfonic acid (0.066 g, 0.35 mmol) was added to a solution of
alcohol 9 (1.00 g, 2.31 mmol) in toluene (55 mL). The reaction
mixture was then heated under reflux for 22 h, water was
added, and the phases were separated. The aqueous phase
was extracted with diethyl ether (3 × 80 mL). The combined
organic phases were washed with NaHCO3 (5% (aq)), water,
and then brine. After drying (Na2SO4), filtration, and removal
of the solvent in vacuo, the residue was purified by flash
chromatography (pentane) to give 0.71 g (74%) of the title
1
compound as white crystals: mp 53-55 °C; H NMR δ 0.14
(s, 6H), 1.05 (s, 9H), 1.76 (s, 3H), 1.87 (s, 3H), 2.11 (s, 3H),
2.32 (s, 3H), 2.49 (s, 3H), 5.46 (m, 1H); 13C NMR δ -3.3, 15.3,
18.6, 19.4, 19.9, 20.3, 25.1, 26.0, 118.9, 127.6, 127.8, 128.0,
131,7, 133.6, 140.8, 152.4. Anal. Calcd for C19H31BrOSSi: C,
54.92; H, 7.52. Found: C, 54.86; H, 7.39.
5-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,3,4,6,7-p en ta m eth yl-
2,3-d ih yd r oben zo[b]th iop h en e (12) a n d 5-[(ter t-Bu tyld i-
m et h ylsilyl)oxy]-2,2,4,6,7-p en t a m et h yl-2,3-d ih yd r ob en -
zo[b]th iop h en e (13). A. F r om Com p ou n d 11a . A solution
of AIBN (0.045 g, 0.27 mmol) and tris(trimethylsilyl)silane (670
µL, 2.17 mmol) in dry benzene (8 mL) was injected by syringe
pump over 8 h into a stirred refluxing solution of olefin 11a
(0.75 g, 1.81 mmol) in dry benzene (35 mL) kept under an
atmosphere of dry nitrogen. After being heated at reflux for
another 15 h, the reaction mixture was cooled and the solvent
removed in vacuo. Flash chromatography (pentane) afforded
a 1:1 mixture (0.25 g, 41%) of compound 12, mp 111-113 °C,
and its constitutional isomer 13. Compound 11b (0.30 g, 50%)
was also isolated from this reaction. The use of tributyltin
hydride instead of tris(trimethylsilyl)silane resulted in lower
yields of cyclized products. Compound 13 could only be
isolated in pure form from the mixture after conversion of the
products to sulfoxides. 1H NMR compound 11b: δ 0.16 (s, 6Η),
1.04 (s, 9Η), 1.85 (s, 3Η), 1.86 (s, 3Η), 2.13 (s, 3H), 2.17 (s,
3H), 2.29 (s, 3H), 5.74 (s, 1H), 6.99 (s, 1H). 1H NMR compound
12: δ 0.12 (s, 6H), 1.04 (s, 9H), 1.44 (s, 6H), 2.08 (s, 3H), 2.14
(s, 3H), 2.20 (s, 3H), 3.06 (s, 2H); 13C NMR δ -3.3, 13.8, 14.4,
18.5, 18.6, 26.0, 26.2, 47.3, 49.7, 122.9, 126.4, 128.3, 132.9,
142.0, 149.5.
3,3,4,6,7-P en ta m eth yl-2,3-d ih yd r oben zo[b]th iop h en e-
1
5-ol 1-oxid e: mp 164-167 °C; H NMR δ 1.51 (s, 3H), 1.73
(s, 3H), 2.16 (s, 3H), 2.31 (s, 3H), 2.56 (s, 3H), 2.98 (d, 1H, J )
14.0 Hz), 3.13 (d, 1H, J ) 14.1 Hz), 5.54 (s, 1H); 13C NMR δ
11.9, 12.1, 17.2, 28.8, 30.0, 48.9, 64.7, 118.2, 122.6, 134.8, 136.0,
147.6, 156.5.
2-Meth yl-2-h yd r oxyp r op yl 6-Br om o-4-[(ter t-bu tyld im -
eth ylsilyl)oxy]-2,3,5-tr im eth ylp h en yl Su lfid e (9). A solu-
tion of bromine (0.745 mL, 14.4 mmol) in acetic acid (30 mL)
was added dropwise to a magnetically stirred solution of
compound 6 (2.55 g, 7.19 mmol) in acetic acid (55 mL) at 15
°C. After addition, the cooling bath was removed, and the
reaction mixture was stirred at ambient temperature for 3 h.
Sodium thiosulfate (10% (aq)) was added, and the aqueous
phase was extracted with diethyl ether (3 × 80 mL). The
combined organic phases were washed with NaHCO3 (5% (aq);
5 × 100 mL), water, and brine. The organic phase was dried
over Na2SO4, and filtered and the solvent removed in vacuo.
The residue was then dissolved in THF (120 mL) and stirred
with triethylamine (1.25 mL) and water (60 mL) at room
temperature for 2.5 h. The reaction mixture was extracted
with diethyl ether (3 × 150 mL), and the combined organic
phases were washed with water and brine. After drying (Na2-
B. F r om Com p ou n d 10a . To a solution of olefin 10a (0.25
g, 0.61 mmol) in dry benzene (15 mL) under nitrogen was
added AIBN (0.025 g, 0.15 mmol). The reaction mixture was
then heated to reflux, and tributyltin hydride (203 µL, 0.76
mmol) was added dropwise. Heating was then continued at

2,3-Dihydrobenzo[b]thiophene-5-ol Derivatives
J . Org. Chem., Vol. 63, No. 10, 1998 3323
reflux for 3.5 h and the solvent removed in vacuo after cooling
of the flask. Flash chromatography (pentane) afforded a 3:1
mixture of compound 12 and 13. The mixture (0.081 g, 40%)
was oxidized with m-CPBA as described above (compounds 4a /
7), and the corresponding sulfoxides were separated by flash
chromatography (EtOAc/pentane 70/30). A similar result was
also obtained by using significantly less (10 mol %) AIBN. Also,
the 12/13 ratio was invariant to the initial concentration (0.05
or 0.35 M) of the radical precursor.
2-P r op en yl 6-Br om o-4-[(ter t-bu tyld im eth ylsilyl)oxy]-
2,3,5-tr im eth ylp h en yl Su lfid e (16). To a solution of com-
pound 15 (0.19 g, 0.59 mmol) in acetic acid (10 mL) maintained
at 15 °C was added bromine (92 µL, 1.8 mmol) dropwise. The
cooling bath was then removed, and the reaction mixture was
stirred at room temperature for 6 h. Sodium thiosulfate (10%
(aq)) was added, and the aqueous phase was extracted with
diethyl ether (3 × 25 mL). The combined organic phases were
washed with NaHCO3 (5% (aq); 5 × 80 mL), water, and brine.
The organic phase was dried over Na2SO4 and filtered and the
solvent removed in vacuo. The residue was then dissolved in
ethanol (8 mL), and bis(2-thienyl) ditelluride (0.086 g, 50 mol
%) was added under an atmosphere of dry nitrogen (the use
of less ditelluride21 resulted in very poor conversion of starting
material). NaBH4 (5% in 5% aqueous NaOH) was then added,
dropwise, until the red color of the ditelluride disappeared.
The aqueous phase was then extracted with pentane (4 × 10
mL) under an atmosphere of dry nitrogen to remove most of
the remaining ditelluride. The combined organic phases were
dried (Na2SO4) and filtered, and the solvent was removed in
vacuo. Chromatography (pentane) afforded 0.12 g (50% from
compound 15) of the title compound as a colorless oil: 1H NMR
δ 0.14 (s, 6H), 1.04 (s, 9H), 2.11 (s, 3H), 2.32 (s, 3H), 2.54 (s,
3H), 3.37-3.40 (m, 2H), 4.83-4.91 (m, 2H), 5.79-5.91 (m, 1H);
13C NMR δ -3.3, 15.4, 18.6, 20.0, 20.6, 26.0, 39.2, 117.0, 126.8,
127.3, 128.0, 132.0, 133.7, 141.9, 152.5.
5-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,2,4,6,7-p en ta m eth yl-
2,3-d ih yd r oben zo[b]th iop h en e 1-oxid e (14): mp 129-131
1
°C; H NMR δ 0.14 (s, 6H), 1.04 (s, 9H), 1.22 (s, 3H), 1.56 (s,
3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.52 (s, 3H), 2.89 (d, 1H, J )
16.3 Hz), 3.44 (d, 1H, J ) 16.3 Hz); 13C NMR δ -3.1 (4), -3.0
(6), 14.1, 14.8, 17.6, 18.6, 21.1, 23.8, 26.0, 45.2, 60.9, 123.7,
127.5, 135.7, 136.8, 142.3, 155.0. Anal. Calcd for C19H32O2-
SSi: C, 64.72; H, 9.15. Found: C, 64.60; H, 9.08.
5-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,3,4,6,7-p en ta m eth yl-
2,3-d ih yd r oben zo[b]th iop h en e 1-oxid e: 1H NMR δ 0.15 (s,
3H), 0.16 (s, 3H), 1.04 (s, 9H), 1.49 (s, 3H), 1.70 (s, 3H), 2.13
(s, 3H), 2.27 (s, 3H), 2.54 (s, 3H), 3.00-3.14 (m, 2H); 13C NMR
δ -3.1, -3.0, 13.7, 14.3, 17.3, 18.7, 26.0, 28.5, 29.7, 48.8, 64.9,
123.6, 128.3, 135.1, 136.9, 147.3, 156.2.
3,3,4,6,7-P en ta m eth yl-2,3-d ih yd r oben zo[b]th iop h en e-
5-ol (4a ) fr om Com p ou n d 12. To a solution of compound
12 (0.027 g, 0.079 mmol) in dry THF (5 mL) was added tetra-
n-butylammonium fluoride (80 µL, 1.0 M, 0.079 mmol) under
an atmosphere of dry nitrogen. The reaction mixture was then
stirred at ambient temperature for 1 h. Water was added, and
the phases were separated. The aqueous phase was extracted
with diethyl ether (3 × 20 mL). The combined organic phases
were washed with water and brine and dried over Na2SO4,
and the solvent was removed in vacuo. Chromatography
(EtOAc/pentane 5/95) afforded the title compound (0.014 g,
79%) as white crystals: mp 84-86 °C; 1H NMR δ 1.47 (s, 6H),
2.14 (s, 3H), 2.19 (s, 3H), 2.27 (s, 3H), 3.07 (s, 2H), 4.43 (s,
1H); 13C NMR δ 11.8, 12.3, 18.4, 26.6, 47.2, 49.6, 117.9, 121.0,
128.1, 132.0, 142.1, 149.9. Anal. Calcd for C13H18OS: C, 70.23;
H, 8.16. Found: C, 70.40; H, 7.99.
2-P r op en yl 4-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,3,5-tr i-
m eth ylp h en yl Su lfid e (15). tert-Butyllithium (12.5 mL, 1.5
M, 18.3 mmol) was added, dropwise, to a stirred solution of
compound 5 (3.01 g, 9.14 mmol) in dry THF (55 mL) main-
tained at -78 °C under an atmosphere of dry nitrogen. After
0.5 h, sulfur (0.29 g, 9.14 mmol) was added in one portion,
and the reaction mixture was stirred at -78 °C for 1 h.
Finally, allyl bromide (795 µL, 9.14 mmol) was added, and the
mixture was allowed to slowly reach room-temperature over-
night. A saturated NH4Cl solution was then added, and the
phases were separated. The aqueous phase was extracted with
dichloromethane (3 × 80 mL), and the combined organic
phases were washed with water and brine and then dried over
Na2SO4. The solvent was removed in vacuo and the residue
was purified by flash chromatography (pentane) to afford 1.27
g (43%) of the title compound as a colorless oil: 1H NMR δ
0.16 (s, 6H), 1.03 (s, 9H), 2.13 (s, 3H), 2.16 (s, 3H), 2.35 (s,
3H), 3.36-3.40 (m, 2H), 4.97-5.03 (m, 2H), 5.79-5.91 (m, 1H),
7.08 (s, 1H); 13C NMR δ -3.1, 14.9, 17.5 (6), 17.6 (1), 18.7,
26.0, 38.6, 117.0, 126.0, 126.2, 128.1, 132.7, 133.9, 137.4, 151.4;
MS m/z (relative intensity) 322 (M+, 100).
5-[(ter t-Bu t yld im et h ylsilyl)oxy]-3,4,6,7-t et r a m et h yl-
2,3-d ih yd r oben zo[b]th iop h en e (17). To a solution of olefin
16 (0.118 g, 0.294 mmol) in dry benzene (10 mL) under
nitrogen was added AIBN (0.012 g, 0.073 mmol). The reaction
mixture was then heated to reflux, and tributyltin hydride (103
µL, 0.38 mmol) was added dropwise. The reaction mixture
was then heated at reflux for 2.5 h and the solvent removed
in vacuo after cooling of the flask. Flash chromatography
(pentane) afforded 0.052 g (55%) of the title compound as white
1
crystals: mp 69-71 °C; H NMR δ 0.13 (s, 3H), 0.14 (s, 3H),
1.03 (s, 9H), 1.21 (d, 3H), 2.09 (s, 3H), 2.13 (s, 3H), 2.14 (s,
3H), 2.81-2.87 (m, 1H), 3.50-3.61 (m, 2H); 13C NMR δ -3.2,
-3.1, 14.3, 17.6, 18.6, 18.9, 26.1, 30.3, 40.0, 41.8, 122.1, 126.3,
128.2, 131.7, 141.4, 149.3. Anal. Calcd for C18H30OSSi: C,
67.02; H, 9.37. Found: C, 66.85; H, 9.55.
Ack n ow led gm en t. Financial support by the Swed-
ish Research Council for Engineering Sciences and the
Swedish Natural Science Research Council is gratefully
acknowledged. We also thank professor Carl Schiesser,
University of Melbourne, for valuable suggestions con-
cerning the mechanistic discussion.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 9, 12, 15, 16, 2,3,4,6,7-pentamethylbenzo[b]-
thiophene-5-ol 1-oxide, and 3,3,4,6,7-pentamethyl-2,3-dihy-
drobenzo[b]thiophene-5-ol 1-oxide (6 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O972087L