A novel tandem [4++2] cycloaddition-elimination reaction: 2-alkenyl-4,4-dimethyl-1,3-oxathianes as synthetic equivalents for α,β-unsaturated thioaldehydes

Article abstract of DOI:10.1016/S0040-4020(03)00179-0

The first tandem cationic [4⁺+2] polar cycloaddition-elimination reaction of 1-thia-1,3-butadienyl cations B with olefins to afford directly 3,4-dihydro-2H-thiopyrans D is described. The cations B were easily accessible by treatment of monothioacetals A, particularly the 2-alkenyl-4,4-dimethyl-1,3-oxathianes 1, with a hard Lewis acid. In this novel reaction, 2-alkenyl-4,4-dimethyl-1,3-oxathianes were utilized as synthetic equivalents for highly reactive α,β-unsaturated thioaldehydes. The effect of geminal dimethyl substituents on the oxathianes 1 and the mechanistic aspect of the reaction are considered. The reaction's asymmetric version was also investigated using a chiral oxathiane 4 derived from (-)-(1R,2R,5R)-2-(1-mercapto-1-methylethyl)-5-methylcyclohexanol. Although the enantioselectivities were moderate, the whole process can be done under odorless conditions.

Full text of DOI:10.1016/S0040-4020(03)00179-0

Tetrahedron 59 (2003) 1859–1871
A novel tandem [4112] cycloaddition–elimination reaction:
2-alkenyl-4,4-dimethyl-1,3-oxathianes as synthetic equivalents for
a,b-unsaturated thioaldehydes
*
Shin-ichi Ohsugi, Kiyoharu Nishide and Manabu Node
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 18 January 2003; revised 30 January 2003; accepted 31 January 2003
Abstract—The first tandem cationic [4þþ2] polar cycloaddition–elimination reaction of 1-thia-1,3-butadienyl cations B with olefins to
afford directly 3,4-dihydro-2H-thiopyrans D is described. The cations B were easily accessible by treatment of monothioacetals A,
particularly the 2-alkenyl-4,4-dimethyl-1,3-oxathianes 1, with a hard Lewis acid. In this novel reaction, 2-alkenyl-4,4-dimethyl-1,3-
oxathianes were utilized as synthetic equivalents for highly reactive a,b-unsaturated thioaldehydes. The effect of geminal dimethyl
substituents on the oxathianes 1 and the mechanistic aspect of the reaction are considered. The reaction’s asymmetric version was also
investigated using a chiral oxathiane 4 derived from (2)-(1R,2R,5R)-2-(1-mercapto-1-methylethyl)-5-methylcyclohexanol. Although the
enantioselectivities were moderate, the whole process can be done under odorless conditions. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
thienium cations can be subjected to cationic [2þþ4] polar
cycloadditions as hetero dienophiles6 or to cationic [4þþ2]
polar cycloadditions as 2-thia-1,3-butadienes,7 there is no
precedent for cationic [4þþ2] polar cycloadditions as
1-thia-1,3-butadienes (i.e. a,b-unsaturated thioaldehydes).
Consequently, we have developed a novel tandem [4þþ2]
cycloaddition–elimination reaction8 of 2-alkenyl-4,4-
dimethyl-1,3-oxathianes A with olefins to give 3,4-dihydro-
2H-thiopyrans D, as shown in Scheme 1. Recently, a similar
reaction was developed using a,b-unsaturated oxathiolanes
and styrene derivatives.9 These reactions can be formally
categorized as hetero Diels–Alder reactions of a,b-
unsaturated thioaldehydes with olefins to afford
heterocyclic adducts containing a sulfur atom.10 We report
herein a full account of the novel tandem [4þþ2]
cycloaddition–elimination reaction as well as its asym-
metric version.
It is usually difficult to control the abnormally high
reactivity of a,b-unsaturated thioaldehydes and aliphatic
thioketones because they easily polymerize or dimerize
even at low temperature. For example, thioacrolein,
generated by pyrolysis of diallyl sulfide, polymerizes at
low temperature1 and methyl vinyl thioketone readily
dimerizes through a hetero Diels–Alder reaction.2 How-
ever, the a,b-unsaturated thioketones used in this cyclo-
addition3 and its asymmetric versions4are limited in most
cases to relatively stable phenyl thioketone derivatives
(such as thiochalcone). For all of this, little attention has
been directed toward the Diels–Alder trapping of a,b-
unsaturated thioaldehydes.5 Synthetic equivalents of these
highly reactive thioaldehydes or ketones are therefore
needed for use in new types of organic reactions. Although
Scheme 1. A strategy for a novel tandem cationic [4þþ2] polar cycloaddition–elimination reaction.
Keywords: a,b-unsaturated thioaldehydes; stereochemistry; cycloaddition.
*
Corresponding author. Tel.: þ81-75-595-4939; fax: þ81-75-595-4775; e-mail: node@mb.kyoto-phu.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00179-0

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S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
During the course of our studies on the development of new
organic reactions utilizing 1,3-mercapto alcohols,11 we
envisioned the elimination of the exocyclic substituent on
the sulfur atom of the cationic cycloadduct C prepared
through [4þþ2] cycloaddition of the a,b-unsaturated
thienium cation B with an olefin that would constitute a
novel cycloaddition reaction to give 3,4-dihydro-2H-
thiopyrans D. It is usually difficult to synthesize this type
of 3,4-dihydro-2H-thiopyran via cycloaddition of an a,b-
unsaturated thioaldehyde because of its high reactivity.
The 1,3-oxathiane A must have gem-dimethyl groups at the
position adjacent to the sulfur atom to facilitate the
elimination of the exocyclic substituent on the sulfur
atom. Therefore, we selected 2-alkenyl-4,4-dimethyl-1,3-
oxathianes (A) as the starting monothioacetals for the
generation of the a,b-unsaturated thienium cation B
promoted by a selective coordination of a hard Lewis acid
to the oxygen of the monothioacetal A. The gem-dimethyl
groups would also retard the coordination of the Lewis acid
to the sulfur atom because of steric hindrance and would
direct the reaction toward formation of the thienium cation
intermediate B.
dichloromethane at 2788C gave the desired 3,4-dihydro-
2H-thiopyran 3aa in 88% yield (entry 1). The reaction of 1a
with a-methylstyrene 2b afforded 3ab in lower yield than
the reaction with 2a (entry 2). Titanium tetraisopropoxide
resulted in no reaction. The other Lewis acids (dimethyl-
aluminum chloride, stannic tetrachloride, and boron tri-
fluoride etherate) gave poor yields (,10%). The reaction of
1a with other a-alkylstyrenes 2c–e also afforded 3ac–3ae
in moderate yields (entries 3–5).
Although the reaction of 40-bromo-a-methylstyrene 2f gave
the 3,4-dihydro-2H-thiopyran 3af (entry 6), the o-bromo-
and o-methoxy substituents on the phenyl group of
a-methylstyrene resulted in unreacted recovered starting
material. The reactions of 1b having the 4-methoxyphenyl
substituent as R1 proceeded slowly to give the correspond-
ing dihydrothiopyrans 3ba, 3bb and 3bd, but the yields
were higher than those of 3ab and 3ad (entries 7–9). The
electron donating effect of the p-methoxy group on
the phenyl substituent obviously affected the stability of
the thienium cation intermediate (B). On the other hand, the
electron withdrawing (4-bromo and 3-trifluoromethyl)
groups on the phenyl ring resulted in low yields of 3,4-
dihydro-2H-thiopyran 3ca and 3da (entries 10 and 11). In
these cases, g-vinylated alcohols (see Scheme 3) were
formed in 37 and 17% yield, respectively. 1,3-Oxathianes
having an alkyl substituent at R1 also afforded 3,4-dihydro-
2H-thiopyrans 3ea and 3fa in moderate yields (entries 12
and 13). All these reactions showed cis diastereoselectivity
varying from 10:1 to 1.2:1. The stereochemistry was
determined by NOE experiments between the methyl proton
and the methine proton adjacent to the phenyl ring of the
diastereomer cis-3ab (Table 1, entry 2) isolated by silica gel
chromatography. The cis and trans stereochemistry of the
2. Results and discussion
2.1. Tandem [4112] cycloaddition–elimination
reactions of 2-alkenyl-4,4-dimethyl-1,3-oxathianes (1)
with olefins
The results of tandem [4þþ2] cycloaddition–elimination
reactions of 2-alkenyl-4,4-dimethyl-1,3-oxathianes 1 with
olefins 2 are summarized in Table 1. Treatment of 1a and
1,1-diphenylethylene (2a) with titanium tetrachloride in
Table 1. A tandem [4þþ2] cycloaddition–elimination reaction of oxathiane 1 with olefin 2
Entry
Oxathiane 1
Olefin 2
R3
TiCl4 (equiv.)
Time
Product 3
Yielda (%)
R1
R2
Ph
Ph
Ph
Equiv.
Ratiob (cis/trans)
1
2
3
4
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2a
2b
2d
2a
2a
2a
2a
Ph
Me
Et
4
4
4
4
5
5
4
4
5
4
4
4
4
1.2
1.0
1.0
1.0
1.0
1.2
1.2
1.2
1.2
1.0
1.0
1.0
1.0
15 h
1 h
1 h
1 h
26 h
3 h
3 d
3 d
4 d
1 d
1.5 h
1 h
0.5 h
3aa
3ab
3ac
3ad
3ae
3af
3ba
3bb
3bd
3ca
3da
3ea
3fa
88
38
37
42
48
31
76
77
65
24e
34f
54
37
–
2:1
2:1
2:1
3.3:1
2.5:1
–
10:1
1.2:1
–
Ph
Ph
Pr
5
Bn
Me
Ph
Me
Pr
6
4-BrPh
Ph
Ph
7c
8
4-MeOPh
4-MeOPh
4-MeOPh
4-BrPh
3-CF3Ph
PhCH2
Me
9d
10
11
12
13
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
–
–
–
Ph
a
Isolated yield.
Determined by 1H NMR.
The reaction was conducted at 2308C.
The reaction was conducted at 2508C.
g-Vinylated alcohol (37%) was obtained.
g-Vinylated alcohol (17%) was obtained.
b
c
d
e
f

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1861
other compounds was determined by comparison of the
chemical shifts of the olefinic protons of 3,4-dihydro-2H-
thiopyran 3.
reaction, the use of dichloropyrocatecholatotitanium13
resulted in recovery of the starting material 4 in 86%
yield. The reaction of the chiral oxathiane 4 and
2-phenylpropene (2b) with titanium tetrachloride was tested
at 2788C. The enantiomeric excess of the cis-thiopyrans
was also low and trans-thiopyrans were almost racemic
(entry 2). Changing the Lewis acid to methylaluminum
dichloride in the reaction with 2a resulted in lower ee (entry
3). Modification of methylaluminum dichloride with bulky
phenols improved the ee to 43% from 14% of the desired
3,4-dihydro-2H-thiopyran 3aa (entries 4 and 5). The
reaction using aluminum Lewis acids afforded the g-viny-
lated alcohols in considerable yields along with 3,4-
dihydro-2H-thiopyrans (entries 3–5). Consequently,
titanium tetrachloride was the best among the Lewis acids
tested. The entire reaction was odorless, even though the
enantioselectivity was moderate.
2.2. Asymmetric version of tandem [4112]
cycloaddition–elimination reactions
Although 3-mercapto-3-methylbutanol, used in the prep-
aration of the oxathiane 1, is a malodorous mercapto
alcohol, (2)-(1R,2R,5R)-2-(1-mercapto-1-methylethyl)-5-
methylcyclohexanol12 does not have the common thiol-
like foul smell. It was therefore suitable as a chiral and
odorless 1,3-mercapto alcohol having geminal dimethyl
groups to prepare the oxathiane in order to test the
asymmetric version of the reaction. The chiral oxathiane 4
derived from (2)-(1R,2R,5R)-2-(1-mercapto-1-methyl-
ethyl)-5-methylcyclohexanol was subjected to the tandem
[4þþ2] cycloaddition–elimination reaction with olefin 2,
and the results are summarized in Table 2.
2.3. The effect of geminal dimethyl substituents
Treatment of 4 and 1,1-diphenylethylene (2a) with titanium
tetrachloride in dichloromethane at 2788C then at 2408C
gave the desired 3,4-dihydro-2H-thiopyran 3aa in 82%
yield (entry 1). The optical purity (51% ee) of (þ)-3aa was
determined by HPLC analysis using a chiral stationary
column (Daicel CHIRALCEL OJ). The absolute configur-
ation of (þ)-3aa was determined to be S by X-ray
crystallographic analysis (see Experimental). 5-Methyl-2-
(1-methylethenyl)cyclohexanol [isopulegol] was isolated in
29% as the fragment from the chiral auxiliary. In the above
In order to prove the significance of geminal dimethyl
substituents on the 1,3-oxathianes 1, we carried out the
reactions of 2-styryl-1,3-oxathiane (5) with a-substituted
styrenes 2a,b or allyltrimethylsilane (2g), as shown in
Scheme 2. The tandem reaction of 5 with 2a or 2b (4 equiv.)
promoted by titanium tetrachloride (1 equiv.) in dichloro-
methane at 2788C did not proceed, and the reaction of 5
with 2g (4 equiv.) afforded only the a-allylated alcohol 6 in
25% yield (see Section 4 for identification of 6). On the
other hand, the reaction of oxathiane 1a having geminal
Table 2. A tandem [4þþ2] cycloaddition–elimination reaction of a chiral oxathiane 4 with olefin 2
Entry
Olefin 2
Lewis acid (equiv.)
Time (h)
Product 3
R2
R3
Yielda (%)
Ratiob (cis/trans)
E.e. (%)c (cis/trans)
1d
2
3
4
2a
2b
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
A (1.0)
A (1.0)
B (4.0)
C (2.0)
D (2.0)
17
17
17
17
18
3aa
3ab
3aa
3aa
3aa
82
21
45e
33f
37g
–
4:1
–
–
–
51
26:0
14
41
43
5
a
Isolated yield.
Determined by 1H NMR.
b
c
d
e
f
Enantiomeric excesses were determined by chiral HPLC analyses using Daicel CHIRALCEL OJ (hexane/isopropanol¼99/1).
The reaction was conducted at 2788C, then temperature was raised to 2408C.
g-Vinylated alcohol (49%) was obtained.
g-Vinylated alcohol (58%) was obtained.
g-Vinylated alcohol (43%) was obtained.
g

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S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
Scheme 2.
dimethyl substituents with 2g gave the g-allylated alcohol 7
(37%) regioselectively, along with 3,4-dihydro-2H-thio-
pyran 3ag (32%). Undoubtedly, geminal dimethyl
substituents at the 4-position of 1,3-oxathianes 1 play
important roles in the novel tandem [4þþ2] cycloaddition–
elimination reaction, i.e. promotion of the reaction and
regioselectivity of the products.
into F via reversion to E or would give g-vinylated alcohols
by the elimination of a proton in some cases (Ar¼electron
deficient phenyl substituent or using aluminum Lewis acid).
The cleavage of the carbon–sulfur bond of the sulfonium
intermediates H and I via path b would result in the cationic
[4þþ2] polar cycloaddition reaction to give 3,4-dihydro-
2H-thiopyrans 3, while the cleavage of the other carbon–
sulfur bond, via path a, would lead back to the intermediate
F. The cis selectivity might be attributed to the stability of
the sulfonium intermediates H and I. The sulfonium
intermediate H should be more stable than I because the
two phenyl substituents assume the equatorial position in
the half chair conformation. The enantioselectivity of the
asymmetric version of this novel tandem reaction using
chiral oxathiane 4 was moderate (up to 51%). The resulting
thienium cation J would reach equilibrium with the cation K
through C–S bond rotation. The cation K would be more
stable than the cation J due to the eclipsed conformation of
J0, as shown in the Newman projection. Presence of this
equilibrium must be a reason of the low enantioselectivity.
Nucleophilic attacks of the olefin to the cations J and K give
the cations L and M, respectively. The major enantiomer
(S)-3aa should be formed through the sulfonium cation
intermediate O with the elimination of isopulegol.
2.4. Mechanistic aspects
The generation of 3,4-dihydro-2H-thiopyrans 3 can be
formally interpreted as being the result of a hetero Diels–
Alder reaction of an a,b-unsaturated thioaldehyde with an
olefin. However, we could rule out the mechanism of the
concerted process (hetero Diels–Alder reaction) and
concluded that this novel cationic [4þþ2] polar cyclo-
addition proceeded via a stepwise process for the
following reasons: (1) using normal olefins such as 1-
hexene, 3-phenyl-1-propene, 2-hexyl-1-octene, and methyl
acrylate did not give 3,4-dihydro-2H-thiopyrans in this
reaction, (2) the reactive olefins were limited to
a-substituted styrenes and allylsilane, which generate stable
cations through attack of an electrophile, (3) the ee’s of cis-
and trans-3ab were not equal (Table 2, entry 2), and (4) in
some cases g-vinylated alcohols were formed via a stepwise
mechanism. In addition, the generation of free thiocin-
namaldehyde from the thienium cation E can probably be
excluded, because the starting 1,3-oxathiane 1a was
recovered in 87% yield when 1a was treated with titanium
tetrachloride (1.0 equiv.) in dichloromethane at 2788C for
1 h. A plausible reaction mechanism for oxathianes 1 and 4
with the olefin 2 is illustrated in Scheme 3.
3. Conclusion
We have exploited a novel tandem [4þþ2] cycloaddition–
elimination reaction using 1,3-oxathianes 1 as synthetic
equivalents of a,b-unsaturated thioaldehydes to give 3,4-
dihydro-2H-thiopyrans 3. This is the first reaction of
cationic [4þþ2] polar cycloaddition utilizing a 1-thia-1,3-
butadienyl cation derived from 2-alkenyl-4,4-dimethyl-1,3-
oxathianes. An asymmetric version of this reaction with a
chiral 1,3-oxathiane 4 resulted in moderate enantiomeric
excesses. It can be concluded that this novel tandem
cycloaddition–elimination reaction probably proceeds via a
stepwise mechanism due to our experimental evidence. In
these reactions, g-vinylated alcohols or g-allylated alcohols
accompanied the 3,4-dihydro-2H-thiopyrans 3 in some
cases. This chemistry will be reported elsewhere. It is
worth noting that, because of their high reactivity, it is
difficult to synthesize a,b-unsaturated thioaldehydes;
The selective coordination of titanium tetrachloride with the
oxygen of 1,3-oxathiane 1 would initially generate the a,b-
unsaturated thienium cation E. After rotation to the s-cis
conformation of E, electrophilic attack on a styrene
derivative would give the carbocation intermediate F,
whereas the intermediate G would be formed from E
without the rotation to its s-cis conformation. The
subsequent cyclization by sulfur in the (Z)-vinyl sulfide F
would form the sulfonium intermediates H and I, but the
(E)-vinyl sulfide G could not cyclize because of the strong
strain in the 6-membered ring and would be transformed

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1863
Scheme 3. A plausible reaction mechanism.
however, a,b-unsaturated 1,3-oxathianes, as substrates in
this reaction, can be easily prepared from the corresponding
aldehydes by monothioacetalization using 1,3-mercapto
alcohols. This tandem reaction therefore offers a new
method of controlling the high reactivity toward
polymerization of a,b-unsaturated thioaldehydes.
internal standard. Infrared spectra were measured with a
Shimazu FTIR-8300 spectrometer. Low and high-resolution
mass spectra were determined on either a JEOL JMS GC-
mate (EI) or a JEOL JMX SX 102A QQ (FAB) mass
spectrometers. Preparative high performance liquid chro-
matography was performed on a Japan Analytical Industry
Co.LTD., LC 908 series, silica gel column (JAIGEL SIL-
043-15) or a GPC column (JAIGEL 1H and 2H). Silica gel
60 (230–400 mesh Merck) was used for column chroma-
tography. Silica gel F254 plates (Merck) were used for thin
layer chromatography and preparative thin layer chroma-
tography (ptlc). Visualization was performed using UV
light, iodine, and 12-molybdo(VI) phosphoric acid
n-hydrate in EtOH. Melting points were taken on a micro
hot-stage apparatus (Yanagimoto) and are uncorrected.
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained with a VARIAN
GEMINI 2000/200, XL-300, INOVA-400NB or JEOL
JNM-AL300 spectrometer with tetramethylsilane as

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S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
4.2. Materials
J¼6.6 Hz, 2H), 1.81 (s, 1H, SH), 1.43 (s, 6H) (OH proton
was not observed); IR (CHCl3): 3730–3160 (br), 3620,
3011, 2968, 2928, 2895, 1458, 1369, 1126, 1070,
1022 cm21; EI-MS (20 eV) m/z: 120 (Mþ, 12), 87 (28),
86 (70), 75 (21), 71 (44), 69 (100), 41 (28); HRMS calcd for
C5H12OS (Mþ): 120.0609, found 120.0599.
Dichloromethane was distilled from CaH2, after washing
with water. Most of the reagents were obtained from Wako
Pure Chemical Industries, Ltd, Nacalai Tesque, Inc., Tokyo
Chemical Industries, Ltd, or Aldrich Chemical Inc. trans-4-
Phenyl-2-butenal was prepared by the reported procedure.14
4.4. General procedure for the preparation of 4,4-
dimethyl-1,3-oxathianes (1a–d)
4.3. General methods for the synthesis of 3-mercapto-3-
methyl-1-butanol
To a dichloromethane solution of 3-mercapto-3-methyl-1-
butanol was added the a,b-unsaturated aldehydes followed
by addition of boron trifluoride etherate at 08C, and the
reaction mixture was stirred at room temperature. The
reaction mixture was neutralized with a saturated NaHCO3
solution, and the aqueous layer was extracted with CHCl3,
washed with brine, dried (MgSO4), filtered, and concen-
trated in vacuo. Purification of the residue by silica gel
column chromatography gave the 4,4-dimethyl-1,3-
oxathianes (1a–d).
To an ethanol solution (80 mL) of ethyl 3,3-dimethylacryl-
ate (14.7 g, 115.1 mmol) was added benzyl mercaptan
(21.4 g, 172.6 mmol) followed by addition of an ethanol
(2 mL) solution of sodium ethoxide (4.3 mmol) at room
temperature. The resultant mixture was stirred for 1 d.
Additional benzyl mercaptan (10.7 g, 86.3 mmol) was
added, and the reaction solution was heated and stirred at
508C for 12 h. The reaction solution was poured into 1N
HCl, and concentrated in vacuo. The aqueous layer was
extracted with AcOEt, dried (Na2SO4), filtered, and
concentrated in vacuo. The crude mixture was purified by
silica gel column chromatography to give ethyl 3-methyl-3-
benzylthiobutanoate (29.1 g, 100%). To a tetrahydrofuran
suspension (150 mL) of lithium aluminum hydride (9.62 g,
253.6 mmol) was added dropwise a tetrahydrofuran
(50 mL) solution of ethyl 3-methyl-3-benzylthiobutanoate
(29.1 g, 115.3 mmol) at 08C, and the mixture was refluxed
for 1.5 h. The reaction mixture was quenched with a
saturated Na2SO4 solution, dried (Mg2SO4), filtered, and
concentrated in vacuo. An ether (100 mL) solution of the
crude residue was added to a solution of liq. NH3 (300 mL)
and ether (150 mL) solution of sodium (11.9 g, 518.7 mmol)
at 2788C. The reaction mixture was stirred for 1.5 h. The
reaction mixture was quenched with solid NH4Cl until its
purple color disappeared, then liq. NH3 was evaporated.
After neutralization with conc. HCl, the aqueous layer was
extracted with AcOEt, dried (Mg2SO4), filtered, and
concentrated in vacuo. The crude residue was purified by
silica gel column chromatography to give 3-mercapto-3-
methyl-1-butanol (12.1 g, 2 steps 87%).
4.4.1. trans-4,4-Dimethyl-2-styryl-1,3-oxathiane (1a).
According to the general procedure, the reaction was
carried out using 3-mercapto-3-methyl-1-butanol (1.5 g,
12.5 mmol), trans-cinnamaldehyde (2.5 g, 18.7 mmol),
boron trifluoride etherate (0.46 mL, 3.7 mmol), and
CH2Cl2 (15 mL). Reaction time; 40 min. 1a (2.9 g, 99%).
Colorless powder; mp 32.8–33.08C (hexane); 1H NMR
(300 MHz, CDCl3) d 7.39–7.23 (m, 5H), 6.77 (dd, J¼16.0,
1.2 Hz, 1H), 6.23 (dd, J¼16.0, 5.7 Hz, 1H), 5.52 (dd, J¼5.7,
1.2 Hz, 1H), 4.16 (ddd, A part of AB, J¼12.4, 4.4, 2.2 Hz,
1H), 3.88 (dt, B part of AB, J¼12.4, 2.2 Hz, 1H), 1.97 (dt, A
part of AB, J¼12.4, 4.4 Hz, 1H), 1.55 (s, 3H), 1.49 (dt, B
part of AB, J¼12.4, 2.2 Hz, 1H), 1.32 (s, 3H); IR (CHCl3):
3009, 2968, 2939, 2928, 2901, 2870, 1497, 1460, 1448,
1387, 1367, 1279, 1140, 1103, 1074, 1038, 1007, 986, 964,
691 cm21; EI-MS (70 eV) m/z: 234 (Mþ, 100), 201 (4), 165
(12), 147 (27), 133 (38), 131 (59), 115 (36), 104 (54), 102
(37), 91 (13), 87 (36), 70 (79), 69 (71); HRMS calcd for
C14H18OS (Mþ): 234.1078, found 234.1075; Anal. calcd
for C14H18OS: C, 71.75; H, 7.74. Found: C, 71.96; H,
7.71.
4.3.1. Ethyl 3-methyl-3-benzylthiobutanoate. Colorless
oil; 1H NMR (300 MHz, CDCl3) d 7.35–7.19 (m, 5H), 4.15
(q, J¼7.1 Hz, 2H), 3.80 (s, 2H), 2.61 (s, 2H), 1.47 (s, 6H),
1.28 (t, J¼7.1 Hz, 3H); IR (CHCl3): 3034, 3011, 2981,
2931, 1724, 1494, 1454, 1369, 1317, 1194, 1107,
1032 cm21; FAB-MS m/z: 253 (MþþH, 17), 252 (Mþ, 8),
154 (100); HRMS calcd for C14H21O2S (MþþH): 253.1262,
found 253.1267.
4.4.2. trans-2-(p-Methoxystyryl)-4,4-dimethyl-1,3-
oxathiane (1b). According to the general procedure, the
reaction was performed using 3-mercapto-3-methyl-1-
butanol (1.0 g, 8.3 mmol) trans-p-methoxycinnamaldehyde
(1.3 g, 7.9 mmol), boron trifluoride etherate (0.2 mL,
1.7 mmol), and CH2Cl2 (10 mL). Reaction time; 50 min.
1b (1.7 g, 78%). Colorless powder; mp 41.1–41.88C
(hexane); 1H NMR (400 MHz, CDCl3) d 7.31 (d,
J¼8.8 Hz, 2H), 6.83 (d, J¼8.8 Hz, 2H), 6.70 (dd, J¼15.9,
0.7 Hz, 1H), 6.09 (dd, J¼15.9, 5.8 Hz, 1H), 4.15 (ddd, A
part of AB, J¼12.0, 4.3, 2.4 Hz, 1H), 3.87 (dt, B part of AB,
J¼12.0, 2.0 Hz, 1H), 3.80 (s, 3H), 1.96 (dt, A part of AB,
J¼13.4, 4.4 Hz, 1H), 1.54 (s, 3H), 1.48 (dt, B part of AB,
J¼16.1, 2.4 Hz, 1H), 1.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 159.5, 131.5, 128.9, 127.9, 123.6, 113.9, 79.3,
65.8, 55.2, 40.9, 39.3, 32.3, 26.8; IR (CHCl3): 3032, 3024,
3011, 2964, 2937, 2901, 2868, 2839, 1607, 1512, 1460,
1248, 1175, 1138, 1036, 966 cm21; EI-MS (20 eV) m/z: 264
(Mþ, 60), 231 (5), 162 (25), 161 (24), 147 (22), 134 (100),
131 (19), 121 (12), 70 (14), 69 (14); HRMS calcd for
1
4.3.2. 3-Benzylthio-3-methyl-1-butanol. Colorless oil; H
NMR (300 MHz, CDCl3) d 7.35–7.23 (m, 5H), 3.83 (t,
J¼6.4 Hz, 2H), 3.78 (s, 2H), 2.30 (br, 1H, OH), 1.86 (t,
J¼6.4 Hz, 2H), 1.37 (s, 6H); IR (CHCl3): 3730–2940 (br),
3620, 3086, 3065, 3034, 3007, 2964, 2932, 2897, 1603,
1494, 1454, 1387, 1367, 1261, 1126, 1069, 1028, 1016, 982,
968 cm21; FAB-MS m/z: 211 (MþþH, 75), 210 (Mþ, 38),
154 (100); HRMS calcd for C12H19O2S (MþþH): 211.1157,
found 211.1151.
1
4.3.3. 3-Mercapto-3-methyl-1-butanol. Colorless oil; H
NMR (300 MHz, CDCl3) d 3.87 (t, J¼6.6 Hz, 2H), 1.89 (t,

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1865
C15H20O2S (Mþ): 264.1184, found 264.1191. Anal. calcd
for C15H20O2S: C, 68.14; H, 7.62. Found: C, 68.27; H, 7.75.
1069, 972 cm21; EI-MS (70 eV) m/z: 248 (Mþ, 21), 157
(13), 146 (100), 129 (25), 117 (23), 115 (23), 102 (28), 91
(22), 87 (25), 74 (20), 69 (65), 56 (26); HRMS calcd for
C15H20OS (Mþ): 248.1235, found 248.1232.
4.4.3. trans-2-(p-Bromostyryl)-4,4-dimethyl-1,3-
oxathiane (1c). According to the general procedure, the
reaction was carried out using 3-mercapto-3-methyl-1-
butanol (42 mg, 0.35 mmol), trans-p-bromocinnamalde-
hyde (73 mg, 0.35 mmol), boron trifluoride etherate (4 mL,
0.04 mmol), and CH2Cl2 (4 mL). Reaction time; 20 min. 1c
(61 mg, 56%). Colorless powder; 1H NMR (300 MHz,
CDCl3) d 7.42 (d, J¼8.3 Hz, 2H), 7.23 (d, J¼8.3 Hz, 2H),
6.70 (br d, J¼16.0 Hz, 1H), 6.23 (dd, J¼16.0, 5.3 Hz, 1H),
5.50 (dd, J¼5.3, 1.4 Hz, 1H), 4.16 (ddd, A part of AB,
J¼12.2, 4.2, 2.0 Hz, 1H), 3.87 (dt, B part of AB, J¼12.2,
2.0 Hz, 1H), 1.98 (dt, A part of AB, J¼12.2, 4.2 Hz, 1H),
1.55 (s, 3H), 1.49 (dt, B part of AB, J¼12.2, 2.0 Hz, 1H),
1.31 (s, 3H); IR (CHCl3): 3013, 2963, 2939, 3870, 1601,
1489, 1462, 1138, 1072, 1011 cm21; EI-MS (70 eV) m/z:
314 (Mþþ2, 16), 312 (Mþ, 15), 211 (12), 184 (16), 182
(16), 147 (11), 131 (67), 116 (23), 103 (46), 102 (77), 87 (3),
77 (26), 74 (34), 70 (100), 69 (91), 56 (51), 55 (45); HRMS
calcd for C14H17BrOS (Mþ): 312.0183, found 312.0181.
4.4.6. 4,4-Dimethyl-2-(1-propenyl)-1,3-oxathiane (1f). To
an ethereal (20 mL) solution of 3-mercapto-3-methyl-1-
butanol (875 mg, 7.28 mmol) was added crotonaldehyde
(510 mg, 7.28 mmol) followed by addition of anhydrous
lithium perchlorate (774 mg, 7.28 mmol) at 08C. The
reaction mixture was stirred at room temperature for 3 d.
The reaction mixture was then neutralized with a saturated
NaHCO3 solution, the aqueous layer was extracted with
AcOEt, washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by silica
gel column chromatography gave 1f (982 mg, 78%).
1
Colorless oil; H NMR (400 MHz, CDCl3) d 5.88 (dqm,
J¼15.4, 6.6 Hz, 1H), 5.54 (ddm, J¼15.4, 6.3 Hz, 1H), 5.26
(br d, J¼6.3 Hz, 1H), 4.07 (ddd, A part of AB, J¼12.4, 4.2,
2.4 Hz, 1H), 3.80 (dt, B part of AB, J¼12.4, 2.4 Hz, 1H),
1.89 (dtm, A part of AB, J¼13.5, 4.2 Hz, 1H), 1.71 (dm,
J¼6.6 Hz, 1H), 1.49 (s, 3H), 1.42 (br dt, B part of AB,
J¼13.5, 2.4 Hz, 1H), 1.27 (s, 3H); IR (CHCl3): 3005, 2966,
2939, 2901, 2870, 1674, 1458, 1368, 1254, 1142, 1092,
1069, 1003, 964, 941 cm21; EI-MS (70 eV) m/z: 172 (Mþ,
28), 157 (6), 130 (15), 102 (100), 87 (54), 74 (41), 70 (82),
69 (86), 58 (80); HRMS calcd for C9H16OS (Mþ):
172.0922, found 172.0919.
4.4.4. trans-4,4-Dimethyl-2-(m-trifluoromethylstyryl)-
1,3-oxathiane (1d). According to the general procedure,
the reaction was done using 3-mercapto-3-methyl-1-butanol
(60 mg, 0.50 mmol), trans-m-trifluoromethylcinnamalde-
hyde (100 mg, 0.50 mmol), boron trifluoride etherate
(6 mL, 0.05 mmol), and CH2Cl2 (6 mL). Reaction time;
70 min. 1d (128 mg, 85%). Colorless oil; 1H NMR
(400 MHz, CDCl3) d 7.61 (br s, 1H), 7.54 (d, J¼7.7 Hz,
1H), 7.48 (d, J¼7.7 Hz, 1H), 7.42 (t, J¼7.7 Hz, 1H), 6.80
(dd, J¼16.1, 1.3 Hz, 1H), 6.30 (dd, J¼16.1, 5.5 Hz, 1H),
5.53 (dd, J¼5.5, 1.3 Hz, 1H), 4.17 (ddd, A part of AB,
J¼12.5, 4.4, 2.4 Hz, 1H), 3.89 (dt, B part of AB, J¼12.5,
2.4 Hz, 1H), 1.95 (br dt, A part of AB, J¼14.2, 4.4 Hz, 1H),
1.56 (s, 3H), 1.50 (dt, B part of AB, J¼14.2, 2.4 Hz, 1H),
1.32 (s, 3H); IR (CHCl3): 2970, 2939, 2901, 2870, 1458,
1443, 1335, 1272, 1254, 1169, 1134, 1072, 964 cm21; EI-
MS (70 eV) m/z: 302 (Mþ, 60), 283 (8), 215 (11), 199 (12),
183 (10), 172 (16), 151 (17), 131 (20), 102 (43), 87 (38), 74
(30), 70 (97), 69(100), 56 (44); HRMS calcd for
C15H17OF3S (Mþ): 302.0952, found 302.0949.
4.5. General procedure for the preparation of a-
substituted styrene derivatives (2c–2f)
To a THF solution of methyltriphenylphosphonium bromide
was added n-butyllithium (hexane solution) at 08C. After the
mixture stirred for 5 min, a THF solution of a carbonyl
compound (propiophenone, butyrophenone, benzyl phenyl
ketone or p-bromoacetophenone) was added at 08C.
Hydrochloric acid (1N) was added to the reaction mixture,
and the aqueous layer (pH 5) was extracted with AcOEt,
washed with brine, dried (MgSO4), filtered, and concen-
trated in vacuo. The crude residue was purified by silica gel
column chromatography (hexane) to give the a-substituted
styrene derivatives 2c–2f.
4.4.5. trans-4,4-Dimethyl-2-(3-phenyl-1-propenyl)-1,3-
oxathiane (1e). To an ethereal (10 mL) solution of
3-mercapto-3-methyl-1-butanol (53 mg, 0.44 mmol) was
added trans-4-phenyl-2-butenal (64 mg, 0.44 mmol) fol-
lowed by addition of anhydrous lithium perchlorate (47 mg,
0.44 mmol) at room temperature. The reaction mixture was
stirred for 3 d. The reaction mixture was then neutralized
with a saturated NaHCO3 solution, and the aqueous layer
was extracted with AcOEt, washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification
of the residue by silica gel column chromatography gave 1e
(62 mg, 57%). Colorless oil; 1H NMR (200 MHz, CDCl3) d
7.33–7.11 (m, 5H), 6.03 (ddt, J¼16.0, 6.6, 1.0 Hz, 1H),
5.56 (ddt, J¼16.0, 6.8, 1.5 Hz, 1H), 5.31 (dd, J¼6.8, 1.0 Hz,
1H), 4.08 (ddd, A part of AB, J¼12.5, 4.2, 2.2 Hz, 1H), 3.79
(dt, B part of AB, J¼12.5, 2.2 Hz, 1H), 3.38 (br d,
J¼6.6 Hz, 2H), 1.90 (br dt, J¼12.7, 4.2 Hz, 1H), 1.49 (s,
3H), 1.44 (dt, J¼12.7, 2.2 Hz, 1H), 1.39 (s, 3H); IR
(CHCl3): 3005, 2966, 2928, 2901, 2870, 1458, 1250, 1138,
4.5.1. 2-Phenyl-1-butene (2c). According to the general
procedure, the reaction was performed using methyltri-
phenylphosphonium bromide (13.5 g, 38 mmol), propio-
phenone (5.0 g, 38 mmol), and n-butyllithium (14.9 mL,
2.53 M in hexane, 38 mmol), and THF (50 mL). Reaction
time; 14 h. 2c (3.2 g, 64%). Colorless oil; 1H NMR
(300 MHz, CDCl3) d 7.43–7.23 (m, 5H), 5.27 (s, 1H),
5.06 (dd, J¼2.9, 1.5 Hz, 1H), 2.51 (dm, J¼7.4 Hz, 2H), 1.10
(t, J¼7.4 Hz, 3H); IR (CHCl3): 3082, 3059, 3032, 2970,
2934, 2875, 1628, 1599, 1574, 1495, 1463, 1443, 1375,
1234, 1082, 1028 cm21; EI-MS (20 eV) m/z: 132 (Mþ,
100), 117 (94), 97 (34), 85 (55), 71 (74), 57 (73); HRMS
calcd for C10H12 (Mþ):132.0939, found 132.0941.
4.5.2. 2-Phenyl-1-pentene (2d). According to the general
procedure, the reaction was carried out using methyltri-
phenylphosphonium bromide (4.8 g, 13.5 mmol), butyro-
phenone (1.0 g, 6.7 mmol), n-butyllithium (8.4 mL, 1.6 M
in hexane, 13.5 mmol), and THF (40 mL). Reaction time;

1866
S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
29 h. 2d (789 mg, 80%). Colorless oil; 1H NMR (300 MHz,
CDCl3) d 7.46–7.38 (m, 2H), 7.37–7.23 (m, 3H), 5.26 (d,
J¼1.7 Hz, 1H), 5.05 (dd, J¼2.9, 1.4 Hz, 1H), 2.46 (br t,
J¼7.4 Hz, 2H), 1.48 (sextet, J¼7.4 Hz, 2H), 0.92 (t,
J¼7.4 Hz, 3H); IR (CHCl3): 3082, 3059, 3030, 2961,
EI-MS (20 eV) m/z: 146 (Mþ, 28), 131 (47), 118 (100), 71
(12), 57 (11); HRMS calcd for C11H14 (Mþ):146.1096,
found 146.1081.
(dd, J¼10.0, 2.2 Hz, 1H), 5.75 (dd, J¼10.0, 2.0 Hz, 1H),
2.92–2.81 (m, 3H); 13C NMR (75 MHz, CDCl3) d 146.1,
144.9, 144.4, 128.6, 128.5, 128.3, 128.1, 127.7, 127.1,
126.9, 126.7, 126.6, 124.8, 121.7, 56.0, 44.1, 39.6; IR
(CHCl3): 3060, 2900, 1601, 1491, 1445, 1300, 1013,
934 cm21; EI-MS (70 eV) m/z: 328 (Mþ, 33), 295 (40),
217 (21), 198 (41), 180 (100), 165 (68), 147 (85), 115 (25),
103 (13), 91 (53), 77 (17); HRMS calcd for C23H20S (Mþ):
328.1286, found 328.1291. Anal. calcd for C23H20S: C,
84.10; H, 6.14. Found: C, 83.77; H, 6.00.
2934, 2872, 1626, 1495, 1456, 1379, 1028, 901 cm21
;
4.5.3. 2,3-Diphenyl-1-propene (2e). According to the
general procedure, the reaction was carried out using
methyltriphenylphosphonium bromide (18.2 g, 50.6
mmol), benzyl phenyl ketone (10 g, 50.6 mmol), n-butyl-
lithium (20.1 mL, 2.53 M in hexane, 50.6 mmol), and THF
(300 mL). Reaction time; 24 h. 2e (1.4 g, 8%). Colorless oil;
1H NMR (400 MHz, CDCl3) d 7.46–7.43 (m, 2H), 7.32–
7.17 (m, 8H), 5.51 (t, J¼0.8 Hz, 1H), 5.04–5.02 (m, 1H),
3.85 (br s, 2H); IR (CHCl3): 3086, 3063, 2924, 2855, 1628,
1601, 1493, 1450, 1072, 1030, 903 cm21; EI-MS (20 eV)
m/z: 194 (Mþ, 39), 179 (49), 145 (31), 129 (33), 116 (100),
103 (42), 91 (21), 58 (18); HRMS calcd for C15H14
(Mþ):194.1096, found 194.1097.
4.6.2. 2-Methyl-2,4-diphenyl-3,4-dihydro-2H-thiopyran
(3ab). According to the general procedure, the reaction
was conducted using trans-4,4-dimethyl-2-styryl-1,3-
oxathiane (1a) (30 mg, 0.13 mmol), a-methylstyrene (2b)
(61 mg, 0.51 mmol), titanium tetrachloride (0.13 mL, 1.0 M
in a dichloromethane solution, 0.13 mmol), and dichloro-
methane (4 mL). Reaction time; 1 h. 3ab (13 mg, 38%). The
resulting diastereomeric mixture was separated by prepara-
tive high performance liquid chromatography (Japan
Analytical Industry Co.LTD., LC 908 series, silica gel
column; JAIGEL SIL-043-15, hexane). cis-3ab: colorless
oil; 1H NMR (300 MHz, CDCl3) d 7.55 (d, J¼7.2 Hz, 2H),
7.38–7.20 (m, 8H), 6.37 (dd, J¼10.2, 2.2 Hz, 1H), 5.86 (dd,
J¼10.2, 2.2 Hz, 1H), 3.71–3.64 (m, 1H), 2.25 (t, A part of
AB, J¼13.4 Hz, 1H), 2.15 (dd, B part of AB, J¼13.4,
6.3 Hz, 1H), 1.92 (s, 3H); IR (CHCl3): 3065, 2970, 2926,
2862, 1599, 1493, 1452, 1443, 1063, 1028 cm21; EI-MS
(70 eV) m/z: 266 (Mþ, 29), 233 (31), 147 (100), 136 (22),
115 (33), 91 (38), 77 (21); HRMS calcd for C18H18S (Mþ):
226.1129, found 226.1126. Relative configuration was
determined by nOe between the methyl signal (1.92 ppm)
and the benzylic methine signal (3.71–3.64 ppm). trans-
4.5.4. p-Bromo-a-methylstyrene (2f). According to the
general procedure, the reaction was effected using methyl-
triphenylphosphonium bromide (4.3 g, 12.0 mmol),
p-bromoacetophenone (2 g, 10.0 mmol), n-butyllithium
(7.5 mL, 1.6 M in hexane, 12.1 mmol), and THF (40 mL).
Reaction time; 48 h. 2f (1.9 g, 94%). Colorless oil; 1H NMR
(400 MHz, CDCl3) d 7.44 (d, J¼8.6 Hz, 2H), 7.32 (d,
J¼8.6 Hz, 2H), 5.37 (br s, 1H), 5.10 (m, 1H), 2.12 (br s,
3H); IR (CHCl3): 3090, 3032, 3009, 2976, 2949, 2922,
1628, 1589, 1558, 1490, 1456, 1392, 1375, 1307, 1296,
1250, 1115, 1072, 1045, 1009, 899, 833, 806 cm21; EI-
MS (70 eV) m/z: 198 (Mþþ2, 99), 196 (Mþ, 100), 183 (31),
181 (26), 117 (82), 115 (66), 102 (64), 85 (13), 71 (50), 57
(62); HRMS calcd for C9H9Br (Mþ):195.9887, found
195.9881.
1
3ab: colorless oil; H NMR (300 MHz, CDCl3) d 7.63 (d,
J¼8.0 Hz, 2H), 7.42–7.12 (m, 8H), 6.29 (dd, J¼10.1,
2.2 Hz, 1H), 5.68 (dd, J¼10.1, 2.2 Hz, 1H), 2.94 (ddt,
J¼12.3, 5.0, 2.2 Hz, 1H), 2.51 (dd, A part of AB, J¼13.4,
5.0 Hz, 1H), 2.21 (dd, B part of AB, J¼13.4, 12.3 Hz, 1H),
1.66 (s, 3H); IR (CHCl3): 3065, 2926, 2868, 1601, 1491,
1452, 1377, 1302, 1065, 1030 cm21; EI-MS (70 eV) m/z:
266 (Mþ, 24), 233 (29), 148 (31), 147 (100), 136 (31), 115
(33), 103 (20), 91 (50), 77 (23); HRMS calcd for C18H18S
(Mþ): 266.1129, found 266.1124. The nOe was not
observed between the methyl signal (1.66 ppm) and the
benzylic methine signal (2.94 ppm).
4.6. General procedure for the tandem [4112]
cycloaddition–elimination reaction of 4,4-dimethyl-1,3-
oxathianes 1 with styrene derivatives. (Table 1)
To a dichloromethane solution of a 4,4-dimethyl-1,3-
oxathiane 1 was added the styrene derivative 2 followed
by addition of titanium tetrachloride (1.0 M dichloro-
methane solution) at 2788C. The reaction mixture was
quenched with a saturated NaHCO3 solution, the aqueous
layer was extracted with CHCl3, washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification
of the residue by silica gel column chromatography gave the
3,4-dihydro-2H-thiopyrans 3.
4.6.3. 2-Ethyl-2,4-diphenyl-3,4-dihydro-2H-thiopyran
(3ac). According to the general procedure, the reaction
was performed using trans-4,4-dimethyl-2-styryl-1,3-
oxathiane (1a) (30 mg, 0.13 mmol), 2-phenyl-1-butene
(2c) (67 mg, 0.51 mmol), titanium tetrachloride (0.13 mL,
1.0 M in a dichloromethane solution, 0.13 mmol), and
dichloromethane (4 mL). Reaction time; 1 h. 3ac (13.5 mg,
37%). Colorless oil; 1H NMR (300 MHz, CDCl3) d 7.61 (d,
J¼8.4 Hz, 0.33H, minor diastereomer), 7.45 (d, J¼8.4 Hz,
0.67H, major diastereomer), 7.41–7.12 (m, 9H), 6.31 (dd,
J¼10.1, 2.3 Hz, 1H), 5.83 (dd, J¼10.1, 2.2 Hz, 0.67H,
major diastereomer), 5.65 (dd, J¼10.1, 1.0 Hz, 0.33H,
minor diastereomer), 3.73–3.62 (m, 0.67H, major diaster-
eomer), 2.98–2.92 (m, 0.33H, minor diastereomer), 2.63–
2.45 (m, 1H), 2.45–1.98 (m, 3H), 0.80 (t, J¼7.2 Hz, 2.11H,
major diastereomer), 0.79 (t, J¼7.5 Hz, 0.99H, minor
diastereomer); IR (CHCl3): 3084, 3063, 2970, 2937, 2878,
4.6.1. 2,2,4-Triphenyl-3,4-dihydro-2H-thiopyran (3aa).
According to the general procedure, the reaction was carried
out using trans-4,4-dimethyl-2-styryl-1,3-oxathiane (1a)
(30 mg, 0.13 mmol), 1,1-diphenylethylene (2a) (92 mg,
0.51 mmol), titanium tetrachloride (0.14 mL, 1.0 M in a
dichloromethane solution, 0.14 mmol), and dichloro-
methane (4 mL). Reaction time; 15 h. 3aa (37 mg, 88%).
1
Prisms; mp 132.5–134.08C (AcOEt); H NMR (400 MHz,
CDCl3) d 7.52 (d, J¼8.1 Hz, 2H), 7.41–7.16 (m, 13H), 6.36

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1867
1601, 1493, 1452, 1379, 1306, 1078, 1032, 1001, 914 cm21
;
0.24H, minor diastereomer), 2.22 (dd, B part of AB, J¼13.0,
12.0 Hz, 0.76H, major diastereomer); IR (CHCl3): 3086,
3063, 3036, 2920, 2855, 1601, 1495, 1452, 1306, 1078,
1032, 864 cm21; EI-MS (20 eV) m/z: 342 (Mþ, 3), 251
(100), 217 (16), 121 (10), 115 (12), 91 (24); HRMS calcd for
C24H22S (Mþ): 342.1442, found 342.1432. Relative con-
figuration was determined by nOe between the benzylic
methylene proton and the benzylic methine proton of the
major cis diastereomer [major diastereomer¼cis, minor
diastereomer¼trans].
EI-MS (70 eV) m/z: 280 (Mþ, 62), 251 (64), 147 (100), 115
(44), 91 (76); HRMS calcd for C19H20S (Mþ): 280.1286,
found 280.1282.
4.6.4. 2,4-Diphenyl-2-propyl-3,4-dihydro-2H-thiopyran
(3ad). According to the general procedure, the reaction
was carried out using trans-4,4-dimethyl-2-styryl-1,3-
oxathiane (1a) (30 mg, 0.13 mmol), 2-phenyl-1-pentene
(2d) (74 mg, 0.51 mmol), titanium tetrachloride (0.13 mL,
1.0 M in a dichloromethane solution, 0.13 mmol), and
dichloromethane (4 mL). Reaction time; 1 h. 3ad (16 mg,
42%). The resulting diastereomeric mixture was separated
by preparative high performance liquid chromatography
(Japan Analytical Industry Co.LTD, LC 908 series, silica
gel column; JAIGEL SIL-043-15, hexane). cis-3ad: color-
less oil; 1H NMR (300 MHz, CDCl3) d 7.46–7.42 (m, 2H),
7.38–7.20 (m, 8H), 6.31 (dd, J¼10.0, 2.4 Hz, 1H), 5.83 (dd,
J¼10.0, 2.4 Hz, 1H), 3.66 (ddt, J¼12.0, 5.3, 2.4 Hz, 1H),
2.56 (dd, J¼13.7, 5.3 Hz, 1H), 2.42–2.18 (m, 3H), 1.40–
1.20 (m, 1H), 1.16–0.98 (m, 1H), 0.88 (t, J¼7.2 Hz, 3H); IR
(CHCl3): 3063, 3032, 2961, 2936, 2874, 1601, 1493, 1452,
1309, 1103, 1078, 1032, 862 cm21; EI-MS (20 eV) m/z: 294
(Mþ, 81), 261 (56), 251 (100), 217 (20), 164 (48), 148 (54),
147 (76), 134 (32), 131 (31), 118 (37), 91 (88); HRMS calcd
for C20H22S (Mþ): 294.1442, found 294.1447. trans-3ad:
colorless oil; 1H NMR (300 MHz, CDCl3) d 7.64–7.58 (m,
2H), 7.43–7.35 (m, 2H), 7.32–7.16 (m, 4H), 7.15–7.09 (m,
2H), 6.28 (dd, J¼10.1, 1.5 Hz, 1H), 5.65 (dd, J¼10.1,
1.2 Hz, 1H), 2.95–2.89 (m, 1H), 2.48 (dd, A part of AB,
J¼13.1, 4.8 Hz, 1H), 2.23 (dd, B part of AB, J¼13.1,
12.4 Hz, 1H), 2.00–1.84 (m, 2H), 1.42–1.22 (m, 1H),
1.09–0.90 (m, 1H), 0.79 (t, J¼7.3 Hz, 3H); IR (CHCl3):
3063, 3032, 3020, 2961, 2934, 2874, 1601, 1493, 1452,
1445, 1030, 1000, 858 cm21; EI-MS (70 eV) m/z: 294 (Mþ,
37), 261 (32), 251 (70), 217 (20), 164 (16), 148 (36), 147
(100), 118 (35), 115 (48), 103 (22), 91 (77), 77 (18); HRMS
calcd for C20H22S (Mþ): 294.1442, found 294.1445.
4.6.6. 2-(p-Bromophenyl)-2-methyl-4-phenyl-3,4-di-
hydro-2H-thiopyran (3af). According to the general
procedure, the reaction was conducted using trans-4,4-
dimethyl-2-styryl-1,3-oxathiane (1a) (30 mg, 0.13 mmol),
p-bromo-a-methylstyrene (2f) (126 mg, 0.64 mmol),
titanium tetrachloride (0.15 mL, 1.0 M in a dichloro-
methane solution, 0.15 mmol), and dichloromethane
(4 mL). Reaction time; 3 h. 3af (13 mg, 31%). The resulting
diastereomeric mixture was separated by preparative high
performance liquid chromatography (Japan Analytical
Industry Co.LTD., LC 908 series, silica gel column;
JAIGEL SIL-043-15). cis-3af: colorless oil; 1H NMR
(300 MHz, CDCl3) d 7.44 (d, J¼6.1 Hz, 2H), 7.42 (d,
J¼6.1 Hz, 2H), 7.37–7.21 (m, 5H), 6.35 (dd, J¼10.2,
2.3 Hz, 1H), 5.86 (dd, J¼10.2, 2.3 Hz, 1H), 3.65 (ddt,
J¼11.7, 6.0, 2.3 Hz, 1H), 2.22 (br t, A part of AB,
J¼13.4 Hz, 1H), 2.13 (dd, B part of AB, J¼13.4, 6.0 Hz,
1H), 1.88 (s, 3H); IR (CHCl3): 3100, 3070, 2928, 2862,
1601, 1562, 1474, 1454, 1416, 1296, 1080, 995, 910,
868 cm21; EI-MS (20 eV) m/z: 346 (Mþþ2, 23), 344 (Mþ,
22), 313 (21), 311 (21), 232 (12), 216 (17), 214 (16), 199
(40), 197 (39), 188 (45), 147 (100), 130 (40), 91 (14);
HRMS calcd for C18H17BrS (Mþ): 344.0234, found
344.0230. trans-3af: colorless oil; 1H NMR (300 MHz,
CDCl3) d 7.51 (br s, 4H), 7.32–7.17 (m, 3H), 7.13 (d,
J¼8.5 Hz, 2H), 6.28 (dd, J¼10.0, 2.4 Hz, 1H), 5.68 (dd,
J¼10.0, 2.4 Hz, 1H), 2.90 (ddt, J¼10.0, 5.1, 2.4 Hz, 1H),
2.46 (dd, A part of AB, J¼13.6, 5.1 Hz, 1H), 2.20 (dd, B
part of AB, J¼13.6, 10.0 Hz, 1H), 1.63 (s, 3H); IR (CHCl3):
3090, 3070, 3040, 2920, 2840, 1601, 1562, 1493, 1470,
1300, 1103, 995, 860 cm21; EI-MS (70 eV) m/z: 346
(Mþþ2, 14), 344 (Mþ, 14), 313 (12), 311 (13), 232 (10),
217 (11), 148 (35), 147 (100), 130 (38), 115 (37), 91 (21), 77
(10); HRMS calcd for C18H17BrS (Mþ): 344.0234, found
344.0230.
4.6.5. 2-Benzyl-2,4-diphenyl-3,4-dihydro-2H-thiopyran
(3ae). According to the general procedure, the reaction
was carried out using trans-4,4-dimethyl-2-styryl-1,3-
oxathiane (1a) (50 mg, 0.21 mmol), 2,3-diphenyl-1-propene
(2e) (207 mg, 1.67 mmol), titanium tetrachloride (0.21 mL,
1.0 M in a dichloromethane solution, 0.21 mmol), and
dichloromethane (4 mL). Reaction time; 26 h. 3ae (35 mg,
48%). A diastereomer mixture; colorless oil; 1H NMR
(400 MHz, CDCl3) d 7.57–7.53 (m, 0.48H, minor dia-
stereomer), 7.39–7.06 (m, 12.52H), 6.78–6.73 (m, 2H,
major diastereomer), 6.37 (dd, J¼10.0, 2.3 Hz, 0.76H,
major diastereomer), 6.20 (dd, J¼10.0, 2.3 Hz, 0.24H,
minor diastereomer), 5.93 (dd, J¼10.0, 2.3 Hz, 0.76H,
major diastereomer), 5.61 (dd, J¼10.0, 2.3 Hz, 0.24H,
minor diastereomer), 3.95 (ddt, J¼12.0, 5.5, 2.3 Hz, 0.76H,
major diastereomer), 3.65 (d, A part of AB, J¼14.1 Hz,
0.76H, major diastereomer), 3.56 (d, B part of AB,
J¼14.1 Hz, 0.76H, major diastereomer), 3.31 (d, A part of
AB, J¼13.4 Hz, 0.24H, minor diastereomer), 3.13 (d, B part
of AB, J¼13.4 Hz, 0.24H, minor diastereomer), 3.04 (ddt,
J¼12.2, 4.9, 2.3 Hz, 0.24H, minor diastereomer), 2.77 (dd,
A part of AB, J¼14.0, 4.9 Hz, 0.24H, minor diastereomer),
2.48 (dd, A part of AB, J¼13.0, 5.5 Hz, 0.76H, major
diastereomer), 2.33 (dd, B part of AB, J¼14.0, 12.2 Hz,
4.6.7. 4-(p-Methoxyphenyl)-2,2-diphenyl-3,4-dihydro-
2H-thiopyran (3ba). According to the general procedure,
the reaction was performed using trans-2-(p-methoxy-
styryl)-4,4-dimethyl-1,3-oxathiane (1b) (30 mg, 0.11
mmol), 1,1-diphenylethylene (2a) (81 mg, 0.45 mmol),
titanium tetrachloride (0.14 mL, 1.0 M in a dichloro-
methane solution, 0.14 mmol), and dichloromethane
(4 mL). The reaction was conducted at 2308C for 3 d and
1
afforded 3ba (31 mg, 76%). Colorless powder; H NMR
(400 MHz, CDCl3) d 7.51 (d, J¼7.4 Hz, 2H), 7.36 (t,
J¼7.9 Hz, 2H), 7.30–7.16 (m, 6H), 7.07 (d, J¼8.6 Hz, 2H),
6.84 (d, J¼8.6 Hz, 2H), 6.33 (dd, J¼10.0, 2.0 Hz, 1H), 5.72
(dd, J¼10.0, 1.3 Hz, 1H), 3.79 (s, 3H), 2.89–2.75 (m, 3H);
13C NMR (100 MHz, CDCl3): 158.3, 146.2, 144.4, 137.0,
128.6, 128.4, 128.2, 128.0, 127.1, 126.8, 126.7, 125.2, 121.4,
113.9, 56.0, 55.2, 44.2, 38.8; IR (CHCl3): 3063, 3020, 2970,

1868
S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
2950, 2914, 2837, 1609, 1510, 1491, 1443, 1302, 1250, 1177,
1036, 833 cm21; EI-MS (20 eV) m/z: 358 (Mþ, 33), 325 (44),
280 (11), 254 (18), 180 (50), 178 (72), 168 (54), 160 (84), 147
(100), 121 (17), 91 (18); HRMS calcd for C24H22OS (Mþ):
358.1391, found 358.1403. Anal. calcd for C24H22OS: C,
80.41; H, 6.19. Found: C, 79.98; H, 6.16.
1034, 910, 833 cm21; EI-MS (70 eV) m/z: 324 (Mþ, 35),
291 (45), 281 (42), 248 (24), 190 (31), 177 (69), 160 (43),
147 (100), 134 (74), 121 (71), 91 (80), 77 (19); HRMS calcd
for C21H24OS (Mþ): 324.1548, found 324.1550.
4.6.10. 4-(p-Bromophenyl)-2,2-diphenyl-3,4-dihydro-
2H-thiopyran (3ca). According to the general procedure,
the reaction was performed using trans-2-(p-bromostyryl)-
4,4-dimethyl-1,3-oxathiane (1c) (53 mg, 0.17 mmol), 1,1-
diphenylethylene (2a) (122 mg, 0.68 mmol), titanium tetra-
chloride (0.17 mL, 1.0 M in a dichloromethane solution,
0.17 mmol), and dichloromethane (4 mL). Reaction time;
1 d. 3ca (16 mg, 24%). 3ca: Colorless oil; 1H NMR
(400 MHz, CDCl3) d 7.50 (d, J¼8.6 Hz, 2H), 7.41 (d,
J¼8.6 Hz, 1H), 7.36 (t, J¼7.8 Hz, 2H), 7.31–7.16 (m, 6H),
7.03 (d, J¼8.6 Hz, 2H), 6.37 (dd, J¼10.1, 2.2 Hz, 1H), 5.68
(dd, J¼10.1, 2.2 Hz, 1H), 2.92–2.84 (m, 1H), 2.81–2.76
(m, 2H); 13C NMR (100 MHz, CDCl3): 145.9, 144.2, 143.9,
131.6, 129.5, 128.5, 128.4, 128.0, 127.2, 126.8, 124.0,
122.3, 120.3, 55.9, 44.0, 39.2; IR (CHCl3): 3063, 2930,
2910, 1605, 1489, 1443, 1404, 1296, 1072, 1011, 934,
826 cm21; EI-MS (70 eV) m/z: 408 (Mþþ2, 8), 406 (Mþ,
7), 375 (12), 373 (12), 294 (6), 227 (7), 225 (7), 198 (25),
180 (100), 165 (53), 147 (34), 115 (8), 91 (12), 77 (10);
HRMS calcd for C23H19BrS (Mþ): 406.0390, found
406.0393.
4.6.8. 4-(p-Methoxyphenyl)-2-methyl-2-phenyl-3,4-di-
hydro-2H-thiopyran (3bb). According to the general
procedure, the reaction was carried out using trans-2-(p-
methoxystyryl)-4,4-dimethyl-1,3-oxathiane (1b) (30 mg,
0.11 mmol), a-methylstyrene (2b) (53 mg, 0.45 mmol),
titanium tetrachloride (0.14 mL, 1.0 M in a dichloro-
methane solution, 0.14 mmol), dichloromethane (4 mL).
Reaction time; 3 d. 3bb (26 mg, 77%). A diastereomeric
1
mixture; colorless oil; H NMR (300 MHz, CDCl3) d 7.63
(d, J¼7.1 Hz, 0.18H, minor diastereomer), 7.54 (d,
J¼7.7 Hz, 1.82H, major diastereomer), 7.42–7.17 (m,
3H), 7.21 (d, J¼8.6 Hz, 1.82H), 6.86 (d, J¼8.6 Hz, 1.82H,
major diastereomer), 6.82 (d, J¼8.6 Hz, 0.18H, minor
diastereomer), 6.34 (dd, J¼10.2, 2.4 Hz, 0.91H, major
diastereomer), 6.27 (dd, J¼10.2, 2.5 Hz, 0.09H, minor
diastereomer), 5.83 (dd, J¼10.2, 1.5 Hz, 0.91H, major
diastereomer), 5.65 (dd, J¼10.0, 1.5 Hz, 0.09H, minor
diastereomer), 3.79 (s, 2.73H, major diastereomer), 3.77 (s,
0.27H, minor diastereomer), 3.67–3.58 (m, 0.91H, major
diastereomer), 2.92–2.86 (m, 0.09H, minor diastereomer),
2.49 (dd, J¼13.5, 4.9 Hz, 0.09H, minor diastereomer),
2.30–2.13 (m, 1.91H), 1.90 (s, 2.73H, major diastereomer),
1.64 (s, 0.27H, minor diastereomer); IR (CHCl3): 3061,
2961, 2936, 2912, 2866, 2837, 1610, 1601, 1512, 1464,
1445, 1302, 1259, 1240, 1177, 1036, 908, 831 cm21; EI-MS
(20 eV) m/z: 296 (Mþ, 52), 263 (90), 191 (44), 190 (100),
178 (23), 177 (40), 160 (51), 147 (71), 121 (17), 106 (59), 91
(18); HRMS calcd for C19H20OS (Mþ): 296.1235, found
296.1231.
4.6.11. 2,2-Diphenyl-4-(m-trifluoromethylphenyl)-3,4-
dihydro-2H-thiopyran (3da). According to the general
procedure, the reaction was conducted using trans-4,4-
dimethyl-2-(m-trifluoromethylstyryl)-1,3-oxathiane
(1d)
(50 mg, 0.17 mmol), 1,1-diphenylethylene (2a) (119 mg,
0.66 mmol), titanium tetrachloride (0.17 mL, 1.0 M in a
dichloromethane solution, 0.17 mmol), and dichloro-
methane (4 mL). Reaction time; 1.5 h. 3da (22 mg, 34%).
1
3da: Colorless oil; H NMR (400 MHz, CDCl3) d 7.55–
7.46 (m, 3H), 7.44–7.18 (m, 11H), 6.43 (dd, J¼10.1,
2.4 Hz, 1H), 5.73 (dd, J¼10.1, 2.4 Hz, 1H), 3.03–2.94 (m,
1H), 2.88–2.79 (m, 2H); IR (CHCl3): 3060, 2950, 2920,
4.6.9. 4-(p-Methoxyphenyl)-2-phenyl-2-propyl-3,4-di-
hydro-2H-thiopyran (3bd). According to the general
procedure, the reaction was done using trans-2-(p-methoxy-
styryl)-4,4-dimethyl-1,3-oxathiane (1b) (30 mg, 0.11
mmol), 2-phenyl-1-pentene (2d) (83 mg, 0.45 mmol),
titanium tetrachloride (0.14 mL, 1.0 M in a dichloro-
methane solution, 0.14 mmol), and dichloromethane
(4 mL). Reaction time; 4 d. 3bd (22 mg, 65%). A dia-
stereomeric mixture: colorless oil; 1H NMR (400 MHz,
CDCl3) d 7.60 (d, J¼7.1 Hz, 0.9H, minor diastereomer),
7.44 (d, J¼7.7 Hz, 1.1H, major diastereomer), 7.41–7.17
(m, 3H), 7.19 (d, J¼8.6 Hz, 1.1H, major diastereomer), 7.04
(d, 8.6 Hz, 0.9H, minor diastereomer), 6.87 (d, J¼8.6 Hz,
1.1H, major diastereomer), 6.81 (d, J¼8.6 Hz, 0.9H, minor
diastereomer), 6.39–6.23 (m, 1H), 5.79 (dd, J¼10.0,
2.0 Hz, 0.55H, major diastereomer), 5.62 (dd, J¼10.0,
1.3 Hz, 0.45H), 3.80 (s, 1.65H, major diastereomer), 3.78 (s,
1.35H, minor diastereomer), 3.67–3.58 (m, 0.55H, major
diastereomer), 2.92–2.84 (m, 0.45H, minor diastereomer),
2.54 (dd, A part of AB, J¼13.5, 5.3 Hz, 0.55H, major
diastereomer), 2.47 (dd, A part of AB, J¼13.0, 4.2 Hz,
0.45H, minor diastereomer), 2.40–2.16 (m, 2H), 2.02–1.84
(m, 1H), 1.40–1.21 (m, 1H), 1.13–0.92 (m, 1H), 0.89 (t,
J¼7.2 Hz, 1.65H, major diastereomer), 0.79 (t, J¼7.4 Hz,
1.35H, minor diastereomer); IR (CHCl3): 3063, 3028, 2959,
2936, 2874, 2839, 1611, 1512, 1466, 1443, 1300, 1250,
1601, 1493, 1447, 1331, 1169, 1130, 1072, 907 cm21
;
EI-MS (70 eV) m/z: 396 (Mþ, 13), 363 (22), 215 (10), 198
(23), 180 (100), 179 (37), 165 (58), 91 (25); HRMS calcd for
C24H19F3S (Mþ): 396.1159, found 396.1163.
4.6.12. 4-Benzyl-2,2-diphenyl-3,4-dihydro-2H-thiopyran
(3ea). According to the general procedure, the reaction was
done using trans-4,4-dimethyl-2-(3-phenylpropenyl)-1,3-
oxathiane (1e) (43 mg, 0.17 mmol), 1,1-diphenylethylene
(2a) (124 mg, 0.69 mmol), titanium tetrachloride (0.17 mL,
1.0 M in a dichloromethane solution, 0.17 mmol), and
dichloromethane (4 mL). Reaction time; 1 h. 3ea (32 mg,
1
54%). Colorless oil; H NMR (400 MHz, CDCl3) d 7.40–
7.35 (m, 2H), 7.30–7.14 (m, 11H), 7.08–7.04 (m, 2H), 6.18
(dd, J¼10.2, 2.3 Hz, 1H), 5.58 (dd, J¼10.2, 1.5 Hz, 1H),
2.69 (d, J¼8.7 Hz, 2H), 2.61 (dd, A part of AB, J¼12.5,
4.3 Hz, 1H), 2.49 (t, B part of AB, J¼12.5 Hz, 1H), 2.08–
1.98 (m, 1H); 13C NMR (100 MHz, CDCl3) d 146.4, 144.4,
139.5, 129.0, 128.4, 128.3, 128.1, 128.0, 127.0, 126.9,
126.6, 126.1, 125.1, 120.8, 55.8, 41.7, 40.8, 34.0; IR
(CHCl3): 3086, 3063, 3028, 2013, 2924, 2855, 1601, 1493,
1443, 1312, 1088, 1018, 910 cm21; EI-MS (70 eV) m/z: 342
(Mþ, 9), 251 (100), 217 (61), 202 (14), 191 (13), 180 (18),
179 (19), 178 (17), 165 (33), 129 (12), 123 (13), 115 (15), 91

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1869
(40), 77 (9); HRMS calcd for C24H22S (Mþ): 342.1442,
found 342.1446.
graphy gave the optically active 3,4-dihydro-2H-thiopyran
3 and g-vinylated alcohol.
4.6.13. 4-Methyl-2,2-diphenyl-3,4-dihydro-2H-thiopyran
(3fa). According to the general procedure, the reaction was
performed using trans-4,4-dimethyl-2-(1-propenyl)-1,3-
oxathiane (1f) (36 mg, 0.21 mmol), 1,1-diphenylethylene
(2a) (150 mg, 0.83 mmol), titanium tetrachloride (0.21 mL,
1.0 M in a dichloromethane solution, 0.21 mmol), and
dichloromethane (4 mL). Reaction time; 0.5 h. 3fa (20 mg,
Dichloropyrocatecholatetitanium as a Lewis acid was
prepared by the following method: To an ethereal solution
(2 mL) of catechol (18 mg, 0.17 mmol) was added n-butyl-
lithium (0.11 mL, 3.0 M in hexane, 0.33 mmol) at 2788C,
followed by addition of titanium tetrachloride (18 mL,
0.17 mmol), and the mixture was warmed to room
temperature. After concentration of the reaction solution
in vacuo, dichloromethane (1 mL) was added to the
resulting reddish-brown solid. The supernatant solution
was added by syringe to the above reaction flask at 2788C.
1
37%). Colorless oil; H NMR (400 MHz, CDCl3) d 7.45–
7.41 (m, 2H), 7.32–7.18 (m, 8H), 6.15 (dd, J¼10.1, 2.4 Hz,
1H), 5.54 (dd, J¼10.1, 2.2 Hz, 1H), 2.60 (dd, A part of AB,
J¼12.8, 4.9 Hz, 1H), 2.47 (dd, B part of AB, J¼12.8,
11.6 Hz, 1H), 1.80–1.70 (m, 1H), 1.06 (d, J¼7.2 Hz, 3H);
IR (CHCl3): 3063, 2963, 2932, 2870, 1601, 1493, 1443,
1308, 1034 cm21; EI-MS (70 eV) m/z: 266 (Mþ, 67), 233
(74), 219 (17), 198 (16), 180 (100), 179 (53), 178 (37), 165
(76), 91 (53), 77 (13); HRMS calcd for C18H18S (Mþ):
266.1129, found 266.1116.
4.7.1. (S)-2,2,4-Triphenyl-3,4-dihydro-2H-thiopyran
(3aa). According to the general procedure, the reaction
was done using (1R,3R,6R,9R)-trans-5,5,9-trimethyl-3-
styryl-2-oxa-4-thiabicyclo[4.4.0]decane (4) (50 mg, 0.16
mmol), 1,1-diphenylethylene (2a) (119 mg, 0.66 mmol),
titanium tetrachloride (0.16 mL, 1.0 M in a dichloro-
methane solution, 0.16 mmol), and dichloromethane
(4 mL). The reaction mixture was warmed to 2408C, and
stirred for 17 h to afford (S)-2,2,4-triphenyl-3,4-dihydro-
2H-thiopyran (3aa) (45 mg, 82%). 51% ee; CHIRALCEL
4.6.14. (1R,3R,6R,9R)-trans-5,5,9-Trimethyl-3-styryl-2-
oxa-4-thiabicyclo[4.4.0]decane (4). To a dichloromethane
(8 mL) solution of (2)-(1R,2R,5R)-2-(1-mercapto-1-methyl-
ethyl)-5-methylcyclohexanol12 (250 mg, 1.33 mmol) was
added cinnamaldehyde (147 mg, 1.11 mmol), followed by
addition of boron trifluoride etherate (27 mL, 0.22 mmol) at
08C. The reaction mixture was stirred at room temperature
for 40 min. The reaction mixture was neutralized with
saturated NaHCO3 solution, and the aqueous layer was
extracted with CHCl3, washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo. Purification of the
residue by silica gel column chromatography gave 4
(380 mg, 94%). Colorless solid; mp 84–858C (hexane);
[a]1D9¼þ59.8 (1.00, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.40–7.20 (m, 5H), 6.75 (br d, J¼16.2 Hz, 1H), 6.23 (dd,
J¼16.2, 5.8 Hz, 1H), 5.60 (dd, J¼5.8, 1.2 Hz, 1H), 3.51 (dt,
J¼10.4, 4.2 Hz, 1H), 2.03 (br d, J¼12.4 Hz, 1H), 1.91–1.84
(m, 1H), 1.76–1.69 (m, 1H), 1.60–1.45 (m, 2H), 1.48 (s,
3H), 1.35–1.15 (m, 2H), 1.28 (s, 3H), 1.02–0.85 (m,
1H), 0.94 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 136.3, 131.7, 128.5, 127.8, 126.7, 126.0, 78.4, 77.1,
50.4, 43.7, 41.8, 34.7, 31.5, 29.4, 24.4, 22.9, 22.1; IR
(CHCl3): 3084, 3063, 3030, 2964, 2928, 2872, 1497,
OJ,
hexane/iPrOH¼99/1,
flow
rate¼1.0 mL/min,
UV¼254 nm, 258C, [major (S)-enantiomer; 12 min, minor
(R)-enantiomer; 35 min].
4.8. Determination of the absolute configuration of (2)-
3aa by X-ray crystallographic analysis
An enantiomeric mixture (3aa, 51% ee) was separated using
liquid chromatography (CHIRALCEL OJ, hexane/
iPrOH¼99/1); major enantiomer (þ)-3aa: [a]2D5¼þ70.1
(0.13, CHCl3), minor enantiomer (2)-3aa: [a]2D3¼271.6
(0.17, CHCl3). Optically pure (2)-3aa (minor enantiomer)
was obtained as prisms by recrystallization from ethyl acetate
at ambient temperature. The absolute configuration of the
minor enantiomer (2)-3aa was determined as R by X-ray
crystallographic analysis (Fig. 1). The Flack parameter
converged to 0.04381, a reliable figure for the determining
the absolute configuration. Therefore, the absolute configur-
ation of the major enantiomer of (þ)-3aa was revealed to be S.
1458, 1387, 1373, 1151, 1123, 1051, 964, 692 cm21
;
Crystal data for (R)-2,2,4-triphenyl-3,4-dihydro-2H-thio-
pyran [(2)-3aa]: C23H20S, M¼328.47, orthorhombic, space
group P212121 (#19), a¼10.657(2), b¼16.064(2),
EI-MS (20 eV) m/z: 302 (Mþ, 89), 155 (19), 138 (100),
137 (36), 123 (20), 95 (48), 81 (66); HRMS calcd
for C19H26OS (Mþ): 302.1704, found 302.1707. Anal.
calcd for C19H26OS: C, 75.40; H, 8.66. Found: C, 75.22; H,
8.65.
3
3
˚
˚
c¼10.471(1) A, V¼1792.5(3) A , Z¼4, Dc¼1.217 g/cm ,
m¼15.73 cm21, T¼296 K, 1905 measured reflections, 1876
unique reflections, 1876 reflections with I.2.0s(I) used in
refinement, direct methods and Fourier techniques,
R¼0.116, Rw¼0.202. The data were collected using a
Rigaku AFC7R diffractometer with graphite-mono-
4.7. General procedure for the tandem [4112]
cycloaddition–elimination reaction of chiral oxathiane 4
with olefins 2 (Table 2)
˚
chromated Cu Ka radiation (l¼1.54178 A) by the v–2u
scan technique in the range 50.57,2u,58.508. Flack
parameter¼0.04381. The structure was solved by direct
methods and expanded using Fourier techniques. The non-
hydrogen atoms were refined anisotropically. Hydrogen
atoms were included but not refined. Complete crystal-
lographic data (excluding structure factors) have been
deposited at the Cambridge Crystallographic Data Centre
under the reference number CCDC 201692. Copies of the
data can be obtained free of charge, on application to
To a dichloromethane solution of (1R,3R,6R,9R)-trans-
5,5,9-trimethyl-3-styryl-2-oxa-4-thiabicyclo[4.4.0]decane
(4) was added the olefin 2 followed by addition of a Lewis
acid (1.0 M solution) at 2788C. The reaction mixture was
quenched with a saturated NaHCO3 solution, and the
aqueous layer was extracted with CHCl3, washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo.
Purification of the residue by silica gel column chromato-

1870
S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
Figure 1. Minor enantiomer of (2)-3aa.
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
þ44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
C15H20OS (Mþ): 248.1235, found 248.1224. We should
correct the structure of the allylated alcohol described in the
preliminary communication.8 The estimated chemical shifts
of each methine proton of the g-allylated and the a-allylated
alcohol were very close. In addition, the spin system of the
methine protons is the same. The NOESY experiment
revealed that the product 6 was not the g-allylated but rather
the a-allylated alcohol 6. The correlations were observed
between two olefinic protons and the o- and m-protons on
the phenyl ring, and no correlation was observed between
the methine proton adjacent to the sulfur atom and the o- and
m-protons on the phenyl ring.
4.8.1. 2-Methyl-2,4-diphenyl-3,4-dihydro-2H-thiopyran
(3ab). According to the general procedure, the reaction
was carried out using (1R,3R,6R,9R)-trans-5,5,9-trimethyl-
3-styryl-2-oxa-4-thiabicyclo[4.4.0]decane (4) (150 mg,
0.49 mmol), a-methylstyrene (2b) (234 mg, 1.98 mmol),
titanium tetrachloride (0.49 mL, 1.0 M in a dichloro-
methane solution, 0.49 mmol), and dichloromethane
(6 mL). The reaction was conducted at 2788C for 1 h and
afforded 3ab (28 mg, 21%). The resulting diastereomeric
mixture was separated by preparative high performance
liquid chromatography (Japan Analytical Industry
Co.LTD, LC 908 series, silica gel column; JAIGEL SIL-
043-15, hexane). cis-3ab: colorless oil; CHIRALCEL OD,
hexane/iPrOH¼99/1, flow rate¼1.0 mL/min., UV¼254 nm,
258C, (minor enentiomer; 24 min, major enantiomer;
29 min), 28% ee. trans-3ab: colorless oil; CHIRALCEL
4.8.3. (5E)-3,3-Dimethyl-7-phenyl-4-thia-5,9-decadien-1-
ol (7) and 4-Phenyl-2-trimethylsilylmethyl-3,4-dihydro-
2H-thiopyran (3ag). The reaction was carried out accord-
ing to the general procedure of Table 1 using 4,4-dimethyl-
1,3-oxathiane 1a (150 mg, 0.64 mmol), allyltrimethylsilane
(2g) (293 mg, 2.56 mmol) and titanium tetrachloride
OJ,
hexane/iPrOH¼9/1,
flow
rate¼1.0 mL/min.,
(0.64 mL, 1.0 M in
a
dichloromethane solution,
UV¼254 nm, 258C, (25 min, 27 min), 0% ee.
0.64 mmol in dichloromethane (20 mL). The reaction was
conducted at 2788C for 40 min and afforded (5E)-3,3-
dimethyl-7-phenyl-4-thia-5,9-decadien-1-ol (7) (66 mg,
37%) and 4-phenyl-2-trimethylsilylmethyl-3,4-dihydro-
2H-thiopyran (3ag) (54 mg, 32%).
4.8.2. trans-5-Styryl-4-thia-7-octen-1-ol (6). The reaction
was effected according to the general procedure of Table 1
using 1,3-oxathiane 5 (100 mg, 0.48 mmol), allyltrimethyl-
silane (2g) (221 mg, 1.94 mmol), titanium tetrachloride
(0.48 mL, 1.0 M in a dichloromethane solution, 0.48 mmol),
and dichloromethane (8 mL). The reaction was conducted at
2788C for 5 min afforded trans-5-styryl-4-thia-7-octen-1-ol
(6) (30 mg, 25%) Colorless oil; 1H NMR (300 MHz,
CDCl3) d 7.40–7.20 (m, 5H), 6.38 (d, J¼15.7 Hz, 1H),
6.02 (dd, J¼15.7, 9.5 Hz, 1H), 5.84 (ddt, J¼17.1, 10.1,
17.0 Hz. 1H), 5.12 (dm, J¼17.1 Hz, 1H), 5.07 (dm,
J¼10.1 Hz, 1H), 3.73 (t, J¼6.1 Hz, 2H), 3.44 (dt, J¼9.5,
7.8 Hz, 1H), 2.67–2.50 (m, 2H), 2.45 (br t, J¼7.0 Hz, 2H),
1.87–1.78 (m, 2H), 1.60 (br s, 1H, OH); IR (CHCl3): 3690–
3130 (br), 3626, 3082, 3065, 2930, 2883, 1639, 1599, 1493,
1448, 1437, 1250, 1069, 1043, 1003, 964, 922 cm21; EI-MS
(20 eV) m/z: 248 (Mþ, 5), 207 (33), 189 (10), 156 (73), 141
(36), 129 (43), 115 (100), 91 (35), 78 (11); HRMS calcd for
(5E)-3,3-Dimethyl-7-phenyl-4-thia-5,9-decadien-1-ol (7):
colorless oil; 1H NMR (400 MHz, CDCl3) d 7.33–7.17
(m, 5H), 6.12–6.03 (m, 2H), 5.71 (ddt, J¼17.1, 10.2,
7.3 Hz, 1H), 5.03 (dm, J¼17.1 Hz, 1H), 5.00 (dm,
J¼10.2 Hz, 1H), 3.80 (t, J¼6.6 Hz, 2H), 3.45 (q,
J¼7.3 Hz, 1H), 2.50 (tt, J¼7.3, 1.3 Hz, 2H), 1.96–1.87
(br s, 1H, OH), 1.81 (t, J¼6.6 Hz, 2H), 1.30 (s, 6H); IR
(CHCl3): 3690–3120 (br), 3630, 3078, 2970, 2928, 2870,
1639, 1601, 1493, 1454, 1385, 1369, 1254, 1138, 1069,
1003, 968, 918, 833 cm21; EI-MS (20 eV) m/z: 276 (Mþ, 1),
235 (51), 217 (3), 149(100), 115 (61), 69 (29); HRMS calcd
for C17H24OS (Mþ): 276.1548, found 276.1547.
The resulting diastereomeric mixture of 3ag was separated

S. Ohsugi et al. / Tetrahedron 59 (2003) 1859–1871
1871
8932–8933. (b) Ishibashi, H.; Kitano, Y.; Nakatani, H.;
Okada, M.; Ikeda, M.; Okura, M.; Tamura, Y. Tetrahedron
Lett. 1984, 25, 4231–4232. (c) Fuji, K.; Khanapure, S. P.;
Node, M.; Kawabata, T.; Ito, A. Tetrahedron Lett. 1985, 26,
779–782. (d) Ishibashi, H.; Okada, M.; Nakatani, H.; Ikeda,
M.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1 1986,
1763–1767. (e) Shimizu, H.; Miyazaki, S.; Kataoka, T.;
Hori, M. Tetrahedron Lett. 1991, 32, 5571–5574. (f) Shimizu,
H.; Miyazaki, S.; Kataoka, T.; Hori, M. J. Chem. Soc., Chem.
Commun. 1992, 1586–1587. (g) Shimizu, H.; Miyazaki, S.;
Kataoka, T.; Hori, M. J. Chem. Soc., Perkin Trans. 1 1995,
1583–15891. (h) Shimizu, H.; Miyazaki, S.; Kataoka, T.;
Hori, M.; Muraoka, O. J. Chem. Soc., Perkin Trans. 1 1994,
3129–3140. (i) Shimizu, H.; Miyazaki, S.; Kataoka, T.
J. Chem. Soc., Perkin Trans. 1 1996, 2227–2235. (j) Shimizu,
H.; Miyazaki, S.; Kataoka, T. Tetrahedron 1997, 53,
4611–4620.
by preparative high performance liquid chromatography
(Japan Analytical Industry Co.LTD., LC 908 series, silica
gel column; JAIGEL SIL-043-15, hexane). cis-3ag: color-
1
less solid; H NMR (300 MHz, CDCl3) d 7.34–7.19 (m,
5H), 6.19 (dd, J¼10.0, 2.0 Hz, 1H), 5.70 (dd, J¼10.0,
2.0 Hz, 1H), 3.59 (ddt, J¼11.8, 5.1, 2.0 Hz, 1H), 3.46 (ddt,
J¼11.8, 7.4, 2.2 Hz, 1H), 2.22 (ddd, A part of AB, J¼13.4,
5.1, 2.2 Hz, 1H), 1.83 (dt, B part of AB, J¼13.4, 11.8 Hz,
1H), 0.91 (d, J¼7.5 Hz, 2H), 0.08 (s, 9H); IR (CHCl3):
3063, 2955, 2905, 2866, 1601, 1493, 1450, 1250, 891,
845 cm21; FAB-MS m/z: 262 (Mþ, 47), 154 (100); HRMS
calcd for C15H22SiS (Mþ): 262.1212, found 262.1219.
1
trans-3ag: colorless solid; H NMR (300 MHz, CDCl3) d
7.45–7.26 (m, 5H), 6.42 (dd, J¼10.0, 0.6 Hz, 1H), 5.92 (dd,
J¼10.0, 5.0 Hz, 1H), 3.77–3.67 (m, 1H), 3.22–3.13 (m,
1H), 2.22–2.04 (m, 2H), 1.02 (dd, A part of AB, J¼14.5,
6.6 Hz, 1H), 0.99 (dd, B part of AB, J¼14.5, 8.3 Hz, 1H),
0.01 (s, 9H); IR (CHCl3): 3063, 2955, 2909, 2862, 1601,
1493, 1454, 976, 891 cm21; FAB-MS m/z: 262 (Mþ, 26),
261 (Mþ2H, 21), 73 (100); HRMS calcd for C15H22SiS
(Mþ): 262.1212, found 262.1206.
7. (a) Tamura, Y.; Ishiyama, K.; Mizuki, Y.; Maeda, H.;
Ishibashi, H. Tetrahedron Lett. 1981, 22, 3773–3774.
(b) Ishibashi, H.; Nakatani, H.; Choi, D. J.; Taguchi, M.;
Ikeda, M. Chem. Pharm. Bull. 1990, 38, 1738–1739.
(c) Beifuss, U.; Gehm, H.; Taraschewski, M. Synlett 1996,
396–397. (d) Shimizu, H.; Araki, N.; Muraoka, O.; Tanabe, G.
J. Chem. Soc., Chem. Commun. 1996, 2185–2186.
(e) Shimizu, H.; Araki, N.; Muraoka, O.; Tanabe, G.
Tetrahedron Lett. 2000, 41, 2161–2164. (f) Katritzky, A. R.;
Button, M. A. C. J. Org. Chem. 2001, 66, 5595–5600.
8. Preliminary communication: Nishide, K.; Ohsugi, S.; Node,
M. Tetrahedron Lett. 2000, 41, 371–375.
References
1. (a) Giles, H. G.; Marty, R. A.; de Mayo, P. J. Chem. Soc.,
Chem. Commun. 1974, 409–410. (b) Giles, H. G.; Marty,
R. A.; de Mayo, P. Can. J. Chem. 1976, 54, 537–542.
2. Beslin, P.; Lagain, D.; Vialle, J.; Minot, C. Tetrahedron 1981,
37, 3839–3845.
9. Kerverdo, S.; Loiseau, M.; Lizzani-Cuvelier, L.; Dun˜ach, E.
Chem. Commun. 2001, 2284–2285.
3. (a) Motoki, S.; Saito, T.; Karakasa, T.; Matsushita, T.; Furuno,
E. J. Chem. Soc., Perkin Trans. 1 1992, 2943–2948.
(b) Moriyama, S.; Karakasa, T.; Inoue, T.; Kurashima, K.;
Satsumabayashi, S.; Saito, T. Synlett 1996, 72–74. (c) Saito,
T.; Kimura, H.; Sakamaki, K.; Karakasa, T.; Moriyama, S.
J. Chem. Soc., Chem. Commun. 1996, 811–812. (d) Gokou,
10. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic: San Diego,
1987; Chapter 8. (b) Boger, D. L. In Heterodiene Additions.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 451–512.
11. (a) Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem.
Soc. 1996, 118, 13103–13104. (b) Node, M.; Nishide, K.;
Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000,
122, 1927–1936. (c) Shiraki, H.; Nishide, K.; Node, M.
Tetrahedron Lett. 2000, 41, 3437–3441. (d) Nishide, K.;
Ohsugi, S.; Shiraki, H.; Tamakita, H.; Node, M. Org. Lett.
2001, 3, 3121–3124.
`
C. T.; Pradere, J.-P.; Quiniou, H. J. Org. Chem. 1985, 50,
1545–1547, and references cited therein.
4. (a) Saito, T.; Fujii, H.; Hayashibe, S.; Matsushita, T.; Kato, H.;
Kobayashi, K. J. Chem. Soc., Perkin Trans. 1 1996,
1897–1903. (b) Saito, T.; Kawamura, M.; Nishimura, J.
Tetrahedron Lett. 1997, 38, 3231–3234. (c) Saito, T.; Suda,
H.; Kawamura, M.; Nishimura, J.; Yamaya, A. Tetrahedron
Lett. 1997, 38, 6035–6038. (d) Saito, T.; Takekawa, K.;
Nishimura, J.; Kawamura, M. J. Chem. Soc., Perkin Trans. 1
1997, 2957–2959. (e) Saito, T.; Takekawa, K.; Takahashi, T.
J. Chem. Soc., Chem. Commun. 1999, 1001–1002, and
references cited therein. Also, see the asymmetric Diels–
Alder reaction of 2-(N-acylamino)-1-thia-1,3-dienes: Bell,
A. S.; Fishwick, C. W. G.; Reed, J. E. Tetrahedron Lett. 1996,
37, 123–126.
12. (a) Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22,
2855–2858. (b) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc.
1984, 106, 2943–2948. (c) Eliel, E. L.; Lynch, J. E.; Kume, F.;
Frye, S. V. Org. Synth. 1987, 65, 214–223.
13. (a) Gopinathan, C.; Gupta, J. Indian J. Chem. 1966, 4, 374.
(b) Gopinathan, C.; Gupta, J. Indian J. Chem. 1973, 11,
948–950. (c) Reetz, M. T.; Kyung, S.-H.; Bolm, C.; Zierke, T.
Chem. Ind. 1986, 824.
5. Block, E.; Zhao, S. H. Tetrahedron Lett. 1990, 31,
5003–5006, and references cited therein.
6. (a) Corey, E. J.; Walinsky, S. W. J. Am. Chem. Soc. 1972, 94,
14. Takayama, H.; Koike, T.; Aimi, N.; Sakai, S. J. Org. Chem.
1992, 57, 2173–2176.