Concise synthesis of 6-sulfonylated 3,4-dihydro-2H-thiopyrans and 7-sulfonylated 3,4,5,6-tetrahydrothiepines from lactols

Article abstract of DOI:10.1002/jhet.5570380304

A concise method for the synthesis of the title compounds has been developed, which involves condensation of lactols with methylthiomethyl p-tolyl sulfone, followed by mesylation and further cyclisation of the elimination products by refluxing with excess of sodium iodide in dimethyl formamide (DMF).

Full text of DOI:10.1002/jhet.5570380304

May-Jun 2001
Concise Synthesis of 6-Sulfonylated 3,4-Dihydro-2H-thiopyrans and
7-Sulfonylated 3,4,5,6-Tetrahydrothiepines from Lactols
John K. Gallos* and Constantinos C. Dellios
579
Department of Chemistry, Aristotle University of Thessaloniki,
Thessaloniki 540 06, Greece
Received August 31, 2000
A concise method for the synthesis of the title compounds has been developed, which involves condensa-
tion of lactols with methylthiomethyl p-tolyl sulfone, followed by mesylation and further cyclisation of the
elimination products by refluxing with excess of sodium iodide in dimethyl formamide (DMF).
J. Heterocyclic Chem., 38, 579 (2001).
In connection with our ongoing program[1] for the syn-
recent years, because they exhibit interesting biological
activities [5]. Several 1,5-dithiopyranoxylosides and 1,5-
dithipyranoarabosides are valuable therapeutic agents,
possessing antithrombotic and anticoagulant properties[6].
Apart from the well-known 1,5-dithiopyranosides, to the
best of our knowledge, there is no general synthetic method
for polyhydroxylated compounds of the type 3-5 and no
examples of these compounds were found in the literature
[7]. In the non-hydroxylated series, a method for the synthe-
sis of compounds of the type 3-5 (m=0) has been reported
by Fuchs, which involves fluoride ion mediated intramolec-
ular sulfenylation of α-silyl sulfones [4a]. Further Ramberg-
Bäcklund ring contraction led to cyclic olefins. Our
approach towards compounds 3 involves condensation of
methylthiomethyl p-tolyl sulfone with a pyranose or
furanose having the hemiacetal moiety free and protected all
the other hydroxyl groups. The resulting compounds 2 could
be further cyclised to 3 with the sulfide group acting as
nucleophile [8].
thesis of carbocycles from carbohydrates we were inter-
ested in an efficient method for converting carbohydrates 1
to chiral polyhydroxy sulfonylated thiopyrane and thiepin
derivatives 3 (Figure 1). Compounds of this type could be
very useful for a number of further synthetic transforma-
tions [2]. For example, Michael addition to the double
bond, either radical [3] or ionic [2], followed by alkylation
at the 2-position could result in products 4. Conversion of
the last to bis-sulfones 5 and employing the well-estab-
lished Ramberg-Bäcklund reaction conditions [4], chiral
hydroxylated cyclopentene and cyclohexene derivatives 6
could be obtained. In addition, polyhydroxylated com-
pounds 3-5 themselves are expected to be of potential bio-
logical interest. Thiosugars and their derivatives (nucleo-
sides, glycosides, etc.) have gained increasing attention in
2-Hydroxytetrahydrofuran 7a and 2-hydroxy-2H-
tetrahydropyran 7b (Scheme 1) were used as model com-
pounds, since they can be considered as naked sugars in
the furanose and pyranose forms, respectively.
Condensation of methylthiomethyl p-tolyl sulfone with
7a,b using n-butyl lithium (n-BuLi) yielded 8a,b and fur-
ther treatment with methanesulfonyl chloride/pyridine
gave mixtures of 9a,b and 10a,b. The yield in the conver-
sion of 2-hydroxytetrahydrofuran to 8a was moderate evi-
dently due to its instability [9b].
Figure 1
Scheme 1
Reagents and conditions: i, MeSCH SO Tol (3.25 equiv.), 12-crown-4, n-BuLi 1.6 M in hexanes, THF, -60 °C, 12 h, 32-62%; ii, MeSO Cl (2.2 equiv.),
2
2
2
pyridine, 0 °C, 12 h; iii, see text; iv, 10% Pd/C, H , ethyl acetate, 20 °C, 2 h, 80-87%.
2

580
J. K. Gallos and C. C. Dellios
Vol. 38
When a solution of 9a or 10a was refluxed in acetonitrile
Analogous data were obtained for 8b. Regarding com-
pounds 9a,b, 10a,b and 11a,b, the geometry of the double
bond was assigned by comparison with similar examples
found in the literature[3]. The fact also that upon treatment
with sodium iodide they undergo facile cyclisation sup-
ports the assignment given. It is, finally, worth mentioning
that compound 14a in its preferred conformation has the
sulfonyl group axial, as deduced from the coupling con-
stants of 2-H (δ 3.83, dd, J = 4.4 and 3.6 Hz), which
unequivocally show that this proton is equatorial.
Protected D- and L-erythrose (7c,d) (Scheme 2), are
sugars in the furanose form, readily available [10] from the
naturally abundant D- and L-arabinose, respectively, with
the free hemiacetal group. Upon their condensation with
methylthiomethyl p-tolyl sulfone, using n-BuLi they
afforded 8c,d in 6% yield, isolated as single enantiomers.
We did not try to determine the absolute configuration of
the newly formed stereocenters in 8c,d, which were further
mesylated (both hydroxyl groups) to give, after elimina-
tion, compounds 9c,d in 80% yield; the respective chlo-
rides were not formed this time. Reflux of 9c,d in acetoni-
trile in the presence of 10 equivalents of sodium iodide
gave the respective iodides 11c,d as the main products and
13c,d in low yields (<10%). However, in refluxing DMF,
the desired cyclic compounds 13c,d were obtained in good
yield. These products were eventually converted to satu-
rated 14c,d by conventional hydrogenation.
for 4 hours in the presence of 10 equivalents of sodium
iodide, these compounds were completely converted to the
cyclic product 13a in good yield [8]. Compounds 9b or 10b
under the same reaction conditions gave traces of the cyclic
product 13b, the known iodide 11b [3a] being formed as
the main product. Reflux, however, of 11b in dimethyl for-
mamide (DMF) in the presence of 10 equivalents of sodium
iodide gave the heterocyclic product 13b in good yield. The
same product was formed directly from 9b and 10b by
refluxing their solution in DMF in the presence of 10 equiv-
alents of sodium iodide. It is apparent that the cyclisation of
9a or 10a proceeds via the respective iodide 11a, which
spontaneously cyclised to 13a in a reaction favored by the
six-membered ring formed, compared to the seven-mem-
bered ring of 13b. The double bond in compounds 13a,b
was easily hydrogenated to give 14a,b in high yields.
A cyclic sulfonium ion similar to 12B has been suggested
as intermediate in analogous cyclisations towards sulfur het-
erocycles [8], which undergoes further cleavage of the S-Me
bond, by the iodide. The fact, however, that the presence of
sodium iodide is necessary for the cyclisation of compounds
11, makes the formation of intermidiate 12B not likely and
this is due to the lessened nucleophilicity of sulfur, caused
by the conjugated double bond. The formation of the inter-
mediate 12A is more possible in the present case, generated
from abstraction of the methyl group in 11 by the iodide,
which is then readily cyclised to 13.
The absolute configuration of the newly formed chiral
center in compounds 14c,d and their preferred conforma-
Compounds 8a,b were isolated as inseparable mixtures
1
1
of diastereoisomers in ca. 3:1 ratios, as shown by H nmr.
tion were deduced by the H nmr spectra (Figure 2). The
For the major isomer of 8a, the 5-H appeared at δ 3.74 as a
singlet and the 4-H at δ 4.48 (dd, J = 8.7 and 2.4 Hz),
while for the minor isomer of 8a the respective resonances
were δ 3.90 (d, J = 6.3 Hz) and δ 4.19 (ddd, J = 8.9, 6.3
proton spectral assignment was made by successive proton
decouplings, starting from the unequivocally assigned 2-H
signal, which appeared at δ 4.11 as a doublet of doublets
with J = 12.4 and 6.0 Hz, indicative for an axial position
of this proton. The neighboring axial 3-Ha resonated at δ
1.83 as a quartet with J = 12.4 Hz, which implies that this
proton has three equal (one geminal and two axial-axial)
13
and 2.4 Hz). The C-5 and C-4 signals in the C nmr spec-
trum appeared at δ 68.9 and 77.2 for the major isomer and
δ 69.6 and 76.0 for the minor isomer of 8a, respectively.
Scheme 2
Reagents and conditions: i, MeSCH SO Tol (3.25 equiv.), 12-crown-4, n-BuLi 1.6 M in hexanes, THF, -60 °C, 12 h, 61%; ii, MeSO Cl (2.2 equiv.),
2
2
2
pyridine, 0 °C, 12 h, 80%; iii, see text; iv, NaI, DMF, reflux, 6 h, 66%; iv, 10% Pd/C, H , ethyl acetate, 20 °C, 5 h, 44%.
2

May-Jun 2001
Concise Synthesis of 6-Sulfonylated 3,4-Dihydro-2H-thiopyrans
581
stirring for 12 hours at this temperature, the mixture was
decanted into a10% aqueous Na CO (100 ml) solution and
coupling constants, confirming that 4-H is also axial. The
all-cis geometry of 14c,d is the expected one, since the
hydrogen can be added to the double bond of 13c,d from
the less hindered face. It is interesting to note the different
conformation preferred by compounds 14a and 14c,d: as
shown in the first case the sulfonyl group is axial (stabi-
lized by the anomeric effect), whereas in compounds 14c,d
it is equatorial, apparently because this conformation min-
imizes the steric interactions of all-cis substituents.
2
3
extracted with CH Cl (3x100 ml). The organic layer was dried
2
2
over Na SO , the solvent was evaporated and the residue was
2
4
chromatographed on silica gel with hexane/ethyl acetate (10:1
v/v) as the eluent to give the desired addition products 8a-d.
5-(Methylthio)-5-[(p-tolyl)sulfonyl]-1,4-pentanediol (8a).
This compound was obtained as colorless crystals in 32%
1
yield, mp 70-80 °C; H nmr (deuteriochloroform): δ 1.65 (m, 3H,
2-H, 3-Ha), 1.93 (m, 1H, 3-Hb), 2.03 (s, 3H, MeS), 2.46 (s, 3H,
MeC H ), 3.24 (br s, 2H, two OH), 3.62 (dd, 2H, 1-H, J = 5.6,
6
4
4.9 Hz), 3.74 (s, 5-H of the major diastereoisomer), 3.90 (d, 5-H
of the minor diastereoisomer, J = 6.3 Hz), 4.19 (ddd, 4-H of the
minor diastereoisomer, J = 8.9, 6.3, 2.4 Hz), 4.48 (dd, 4-H of the
major diastereoisomer, J = 8.7, 2.4 Hz), 7. 37 (d, 2H, J = 8.2 Hz),
13
7.86 ppm (d, 2H, J = 8.2 Hz); C nmr (deuteriochloroform): δ
17.0, 21.6, 28.7, 31.7, 62.1, 68.9, 77.1, 129.5, 129.6, 133.9, 145.3
ppm for the major diastereoisomer and 16.8, 21.6, 28.4, 30.8,
62.3, 69.6, 76.0, 129.4, 129.6, 134.2, 145.2 ppm for the minor
diastereoisomer.
Figure 2
Anal. Calcd. for C
51.28; H, 6.43.
H O S : C, 51.29; H, 6.62. Found: C,
13 20 4 2
In conclusion, we have developed an efficient method
for converting lactols to sulfonylated thiopyrane and
thiepin derivatives, which are all new compounds. These
products are expected to be valuable intermediates for fur-
ther ring contraction to five and six-membered carbocy-
cles. Work to this direction is in progress.
6-(Methylthio)-6-[(p-tolyl)sulfonyl]- 1,5-hexanediol (8b).
This compound was obtained as a colorless oil in 62% yield.
H nmr (deuteriochloroform): δ 1.55 (m, 5H, 2-H, 3-H, 4-Ha),
1.88 (m, 1H, 4-Hb), 2.03 (s, MeS of the major diastereoisomer),
2.11 (s, MeS of the minor diastereoisomer), 2.43 (br s, 2H, two
OH), 2.46 (s, 3H, MeC H ), 3.62 (t, 2H, 1-H, J = 6.1 Hz), 3.70 (s,
1
EXPERIMENTAL
6
4
6-H of the major diastereoisomer), 3.83 (d, 6-H of the minor
diastereoisomer, J = 6.5 Hz), 4.19 (ddd, 5-H of the minor
diastereoisomer, J = 8.7, 6.5, 2.9 Hz), 4.48 (dd, 5-H of the major
diastereoisomer, J = 8.3, 2.9 Hz), 7. 38 (d, 2H, J = 8.2 Hz), 7.86
Melting points were determined on a Kofler hot-stage micro-
scope and are uncorrected. All commercially available reagents
were used without further purification. Solvents were dried by
standard methods. 2-Hydroxytetrahydrofuran [9a], 2-hydroxy-
2H-tetrahydropyran [11] and protected D- and L-erythrose[10]
were prepared according to literature methods. Reaction progress
was monitered by thin layer chromatography (TLC) on Merck
13
ppm (d, 2H, J = 8.2 Hz); C nmr (deuteriochloroform): δ 62.3
(C-1), 68.9 (C-5), 77.0 (C-6) ppm for the major diastereoisomer
and 62.4 (C-1), 69.6 (C-5), 76.0 (C-6) ppm for the minor
diastereoisomer and other peaks at the aliphatic and aromatic
+
+
region; ms: m/z 271 (M -CH S), 253 (M -CH S-H O), 216
3
3
2
silica gel 60F
glass plates (0.25 mm). Column chromatogra-
254
+
(TolSO CH SCH ).
2
2
3
phy was performed with Merck silica gel 60 (0.063-0.200 mm).
Optical rotations were determined at room temperature on an A.
Anal. Calcd. for C
H O S : C, 52.80; H, 6.96. Found: C,
14 22 4 2
1
13
53.15; H, 7.33.
Krüss P3000 Automatic Digital Polarimeter. The H and C nmr
spectra were recorded at 300 and 75 MHz, respectively, on a
Bruker AM 300 spectrometer, with tetramethylsilane (TMS) as
internal standard. Electron impact mass spectra were recorded at
70 eV on a VG TS-250 spectrometer and microanalyses were
performed on a Perkin-Elmer 2400-II Element analyser.
1-[(4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-[(p-tolyl)sulfonyl]-2-(methylthio)-1-ethanol (8c) and
1-[(4R,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-[(p-tolyl)sulfonyl]-2-(methylthio)-1-ethanol (8d).
These enantiomers were isolated in enantiomerically pure
General Procedure for the Condensation of Methylthiomethyl
p-Tolyl Sulfone with Lactols (7).
form as colorless oils in 61% yield each one. For 8c [α] -38.7
D
(c = 2.7, chloroform); for 8d [α] +39.2 (c = 0.8, chloroform);
D
1
H nmr (deuteriochloroform): δ 1.17 (s, 3H), 1.30 (s, 3H), 2.11
All of these reactions were carried out under an argon atmos-
phere. A solution of methylthiomethyl p-tolyl sulfone (2.111 g,
9.76 mmol) and 12-crown-4 (0.229 g, 1.3 mmol) in dry tetrahy-
drofuran (THF) (20 ml) was cooled at -78 °C. The methylth-
iomethyl p-tolyl sulfone was lithiated by slowly adding 6.7 ml of
1.6 M of n-butyllithium in hexane. After the addition was com-
plete, the solution was allowed to warm to 0 °C and was then
cooled again at -78 °C. A solution of lactol 7a-d (3.25 mmol) in
dry THF (5 ml) was added at the same temperature and the result-
ing solution was allowed to warm to room temperature. After
(s, 3H, CH S), 2.44 (s, 3H, CH C H ), 3.19 (br s, 2H, two OH),
3
3 6 4
3.81 (dd, 1H, 1-Ha, J = 11.8, 4.7 Hz) 3.88 (dd, 1H, 1-Hb, J =
11.8, 6.7 Hz), 4.14 (s, 1H, 5-H), 4.32 (m, 2H, one s [4-H] and one
ddd [2-H] overlapping), 5.57, 1H, 3-H, J = 8.8 Hz), 7. 37 (d, 2H,
13
J = 8.2 Hz), 7.87 ppm (d, 2H, J = 8.2 Hz); C nmr (deuteri-
ochloroform): δ 16.9, 21.2, 25.0, 27.1, 59.7, 66.8, 73.7, 75.4,
76.7, 108.4, 129.1, 129.4, 133.6, 145.0 ppm.
Anal. Calcd. for C
H O S : C, 51.05; H, 6.43. Found: C,
16 24 6 2
51.40; H, 6.36.

582
J. K. Gallos and C. C. Dellios
Vol. 38
General Procedure for Conversion of Compounds 8a-d to
Compounds 9a-d and 10a,b.
Anal. Calcd. for C H ClO S : C, 52.73; H, 6.01. Found: C,
14 19 2 2
52.94; H, 5.80.
All of these reactions were carried out under an argon atmos-
phere. To a stirred solution of 8a-d (3 mmol) in dry pyridine (20
ml), methanesulfonyl chloride (0.7 g, 9 mmol) was added at 0 °C,
the mixture was allowed to warm at room temperature and stirred
for 12 hours CH Cl (100 ml) and aqueous 5% HCl (80 ml) were
{(4R,5S)-2,2-Dimethyl-5-[(E)-2-[(p-tolyl)sulfonyl]-2-(methylthio)-
ethenyl]-1,3-dioxolan-4-yl}methyl methanesulfonate (9c) and
{(4S,5R)-2,2-Dimethyl-5-[(E)-2-[(p-tolyl)sulfonyl]-2-
(methylthio)ethenyl]-1,3-dioxolan-4-yl}methyl methanesul-
fonate (9d).
2
2
then added, the organic layer was washed with aqueous 5% HCl
(2x80 ml) and H O (80 ml) and dried over Na SO . The solvent
was then evaporated and the residue chromatographed on silica
gel with hexane/ethyl acetate (4:1 v/v) as the eluent to give firstly
compounds 10a,b, followed by compounds 9a-d.
These enantiomers were isolated in enantiomerically pure
form as colorless crystals in 80% yield each one, mp 126-128 °C.
For 9c [α] +19.4 (c = 0.78, chloroform); for 9d [α] –18.9 (c =
2
2
4
D
D
1
4.2, chloroform); H nmr (deuteriochloroform): δ 1.41 (s, 3H,
CH ), 1.55 (s, 3H, CH ), 2.40 (s, 3H, MeS), 2.44 (s, 3H,
3
3
(E)-5-(Methylthio)-5-[(p-tolyl)sulfonyl]-4-pentenylmethanesul-
fonate (9a).
MeC H ), 3.02 (s, 3H, MeSO ), 4.01 (dd, 1H, CH O, J = 12.1,
6
4
2
2
5.1 Hz), ), 4.03 (dd, 1H, CH O, J = 12.1, 5.4 Hz), 4.53 (ddd, 1H,
2
J = 7.3, 5.4, 5.1 Hz), 5.29 (t, 1H, J = 7.3 Hz), 7. 35 (d, 2H, J =
8.3 Hz), 7.38 (t, 1H, =C-H, J = 7.3 Hz), 7.82 ppm (d, 2H, J =
1
This compound was isolated as a colorless oil in 15% yield. H
nmr (deuteriochloroform): δ 1.97 (m, 2H, central CH ), 2.22 (s,
3H, MeS), 2.43 (s, 3H, MeC H ), 2.65 (q, 2H, CH , J = 7.3 Hz),
3.01 (s, 3H, MeSO ), 4.25 (t, 2H, CH O, J = 6.0 Hz), 7. 37 (d, 2H,
J = 8.1 Hz), 7.48 (t, 1H, =C-H, J = 7.3 Hz), 7.80 ppm (d, 2H, J =
2
13
8.3 Hz); C nmr (deuteriochloroform): δ 19.2, 21.6, 25.1, 27.4,
6
4
2
37.7, 66.6, 74.5, 76.0, 110.8, 128.7, 129.8, 134.8, 142.2, 144.9,
2
2
+
145.0 ppm; ms: m/z 358 (M +H-CH SO ).
3
2
Anal. Calcd. for C
H O S : C, 46.77; H, 5.54. Found: C,
13
17 24 7 3
8.1 Hz); C nmr (deuteriochloroform): δ 19.0, 21.4, 26.2, 27.5,
47.03; H, 5.36.
37.2, 68.6, 128.5, 129.4, 139.8, 144.4, 149.9, 152.0 ppm.
Anal. Calcd. for C
46.25; H, 5.27.
H O S : C, 46.13; H, 5.53. Found: C,
14 20 5 3
3,4-Dihydro-2H-thiopyran-6-yl-p-tolylsulfone (13a) by
Cyclisation of Sulfonate 9a and Chloride 10a.
6
[(E)-5-Chloro-1-(methylthio)-1-pentenyl](p-tolyl)dioxo-λ -sul-
fane (10a).
To a solution of sulfonate 9a or chloride 10a (2 mmol) in dry
acetonitrile (20 ml), NaI (3.0 g, 20 mmol) was added and the
mixture was refluxed with stirring for 5 hours CH Cl (30 ml)
1
This compound was isolated as a colorless oil in 50% yield. H
nmr (deuteriochloroform): δ 1.94 (m, 2H, central CH ), 2.21 (s,
3H, MeS), 2.41 (s, 3H, MeC H ), 2.66 (q, 2H, CH , J = 7.4 Hz),
2
2
and saturated aqueous Na S O (30 ml) were then added and the
2
2 3
2
organic layer was washed with H O and dried over Na SO . The
2
2
4
6
4
2
solvent was then evaporated in vacuo and the residue was chro-
matographed on silica gel with hexane/ethyl acetate (12:1 v/v) as
the eluent to give the cyclisation product 13a in 87% yield from
3.55 (t, 2H, CH O, J = 6.1 Hz), 7. 32 (d, 2H, J = 8.1 Hz), 7.49 (t,
1H, =C-H, J = 7.3 Hz), 7.80 ppm (d, 2H, J = 8.1 Hz); C nmr
2
13
(deuteriochloroform): δ 19.0, 21.2, 27.2, 30.5, 43.7, 128.3, 129.2,
1
+
+
9a and 82% yield from 10a. M.p. 138-140 °C. H nmr (deuteri-
135.4, 139.5, 144.1, 150.1 ppm; ms: m/z 306 (M +2), 304 (M ).
ochloroform): δ 1.96 (quint., 2H, central CH , J = 5.5 Hz), 2.31
Anal. Calcd. for C
H ClO S : C, 51.22; H, 5.62. Found: C,
2
13 17 2 2
(dt 2H, J = 5.5, 4.4 Hz), 2.45 (s, 3H), 2.84 (t, 2H, J = 5.5 Hz),
7.02 (t, 1H, J = 4.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.82 ppm (d,
51.35; H, 5.44.
(E)-6-(Methylthio)-6-[(p-tolyl)sulfonyl]-5-hexenylmethanesul-
fonate (9b).
13
2H, J = 8.0 Hz); C nmr (deuteriochloroform): δ 20.7, 21.2,
24.2, 27.0, 127.3, 129.2, 130.9, 136.1, 137.3, 144.1 ppm; ms: m/z
+
1
254 (M ), 189, 175.
This compound was isolated as a colorless oil in 41% yield. H
nmr (deuteriochloroform): δ 1.65 (m, 2H, CH ), 1.79 (m, 2H,
Anal. Calcd. for C H O S : C, 56.66; H, 5.55. Found: C,
57.02; H, 5.59.
2
12 14 2 2
CH ), 2.22 (s, 3H, MeS), 2.43 (s, 3H, MeC H ), 2.55 (q, 2H,
2
6 4
CH , J = 7.3 Hz), 3.01 (s, 3H, MeSO ), 4.24 (t, 2H, CH O, J =
2
2
2
General Procedure for Conversion of Sulfonates 9b-d or
Chloride 10b into Iodides 11b-d.
6.4 Hz), 7. 33 (d, 2H, J = 8.0 Hz), 7.48 (t, 1H, =C-H, J = 7.3
13
Hz), 7.80 ppm (d, 2H, J = 8.0 Hz); C nmr (deuteriochloro-
To a solution of sulfonates 9b-d or chloride 10b (2 mmol) in
dry acetonitrile (20 ml), NaI (3.0 g, 20 mmol) was added and the
mixture was refluxed with stirring for 4 hours CH Cl (30 ml)
form): δ 19.3, 21.5, 24.0, 28.5, 29.2, 37.3, 69.1, 128.6, 129.5,
+
+
135.6, 139.4, 144.3, 151.0 ppm; ms: m/z 378 (M ), 283 (M -
+
CH SO ), 268 (M -CH SO CH ).
2
2
3
3
3
3
3
and saturated aqueous Na S O (30 ml) were then added and the
Anal. Calcd. for C
H O S : C, 47.60; H, 5.86. Found: C,
2
2 3
15 22 5 3
47.53; H, 5.89.
organic layer was washed with H O and dried over Na SO . The
2 2 4
solvent was then evaporated in vacuo and the residue was chro-
matographed on silica gel with hexane/ethyl acetate (12:1 v/v) as
the eluent to give iodides 11b-d, followed by the cyclisation
products in yields less than 10%.
6
[(E)-6-Chloro-1-(methylthio)-1-hexenyl](p-tolyl)dioxo-λ -sul-
fane (10b).
1
This compound was isolated as a colorless oil in 26% yield. H
nmr (deuteriochloroform): δ 1.69 (m, 2H, CH ), 1.79 (m, 2H,
CH ), 2.24 (s, 3H, MeS), 2.44 (s, 3H, MeC H ), 2.55 (q, 2H,
2
6
[(E)-6-Iodo-1-(methylthio)-1-hexenyl](p-tolyl)dioxo-λ -sulfane
2
6 4
(11b).
CH , J = 7.3 Hz), 3.55 (t, 2H, CH O, J = 6.3 Hz), 7. 33 (d, 2H,
2
2
J = 8.0 Hz), 7.50 (t, 1H, =C-H, J = 7.3 Hz), 7.81 ppm (d, 2H, J =
This compound was isolated as colorless crystals in 74% yield
from 9b and 77% yield from 10b, mp 104-106 °C. H nmr (deuteri-
13
1
8.0 Hz); C nmr (deuteriochloroform): δ 19.3, 21.6, 25.2, 29.2,
31.8, 44.3, 128.6, 129.5, 135.6, 139.2, 144.3, 151.4 ppm; ms: m/z
ochloroform): δ 1.63 (quintet., 2H, J = 7.5 Hz), 1.82 (quintet., 2H,
+
+
+
320 (M +2), 318 (M ), 268 (M -CH Cl).
J = 7.4 Hz), 2.24 (s, 3H, MeS), 2.43 (s, 3H, MeC H ), 3.19 (t, 2H,
3
6
4

May-Jun 2001
Concise Synthesis of 6-Sulfonylated 3,4-Dihydro-2H-thiopyrans
583
J = 7.3 Hz), 7.35 (d, 2H, J = 7.9 Hz), 7.49 (t, 1H, J = 7.3 Hz), 7.81
(d, 2H, J = 7.9 Hz); C nmr (deuteriochloroform): δ 5.9, 19.2,
21.4, 28.5, 28.6, 32.4, 128.3, 129.3, 135.5, 138.9, 144.0, 151.1 ppm.
Anal. Calcd. for C H O S : C, 55.19; H, 5.56. Found: C,
15 18 4 2
55.51; H, 5.59.
13
General Procedure for the Hydrogenation of Compounds 13a-d.
Anal. Calcd. for C
H IO S : C, 40.98; H, 4.67. Found: C,
14 19 2 2
To a solution of compounds 13a-d (0.5 mmol) in ethyl acetate
(10 ml) catalytic ammount of 10% Pd/C was added and the solu-
tion was degassed. Hydrogen was added through an adjusted bal-
loon and the mixture was stirred at room temperature for 2 hours
(13a,b) or 5 hours (13c,d). The catalyst was filtered off and the
solution concentrated and chromatographed on silica gel with
hexane/ethyl acetate 3:1 as the eluent to give compounds 14a-d.
41.08; H, 4.78.
(4S,5S)-4-(Iodomethyl)-2,2-dimethyl-5-[(E)-2-[(p-tolyl)sul-
fonyl]-2-(methylthio)ethenyl]-1,3-dioxolane (11c) and (4R,5R)-
4-(Iodomethyl)-2,2-dimethyl-5-[(E)-2-[(p-tolyl)sulfonyl]-2-
(methylthio)ethenyl]-1,3-dioxolane (11d).
These enantiomers were isolated as colorless crystals in enan-
tiomerically pure form in 80% yield each one, mp 82-84 °C. For
11c [α] +53.4 (c = 0.46, chloroform); for 11d [α] -53.2 (c =
2-[(p-Tolyl)sulfonyl]tetrahydro-2H-thiopyran (14a).
D
D
1
This compound was isolated as colorless crystals in 87% yield,
1.2, chloroform); H nmr (deuteriochloroform): δ 1.40 (s, 3H),
1.55 (s, 3H), 2.42 (s, 3H), 2.46 (s, 3H), 2.91 (dd, 1H, J = 9.8, 6.6
Hz), 3.06 (dd, 1H, J = 9.8, 6.6 Hz), 4.52 (q, 1H, J = 6.6 Hz), 5.25
(dd, 1H, J = 8.7, 6.2 Hz), 7.33 (d, 2H, J = 8.2 Hz), 7.34 (d, 1H,
J = 8.7 Hz), 7.81 ppm (d, 2H, J = 8.2 Hz); C nmr (deuteri-
ochloroform): δ 1.2, 19.4, 21.6, 25.5, 28.0, 75.6, 78.7, 110.5,
128.9, 129.7, 135.2, 142.6, 144.4, 144.9 ppm.
1
mp 83-84 °C; H nmr (deuteriochloroform): δ 1.55-1.83 (m, 2H),
1.95 (m, 1H), 2.03-2.17 (m, 2H), 2.38-2.54 (m, 2H) overlapping
with 2.45 (s, 3H, CH ), 3.26 (ddd, 1H, J = 10.8, 7.4, 3.0 Hz, 6-
3
13
Ha), 3.83 (dd, 1H, J = 4.4, 3.6 Hz, 1-H) 7.35 (d,2H, J = 8.0 Hz),
13
7.83 ppm (d, 2H, J = 8.0 Hz); C nmr (deuteriochloroform): δ
21.3, 21.6, 25.4, 25.5, 26.1, 61.2, 129.1, 129.4, 134.4, 144.6 ppm.
Anal. Calcd. for C
H O S : C, 56.22; H, 6.29. Found: C,
12 16 2 2
Anal. Calcd. for C
41.42; H, 4.56.
H IO S : C, 41.03; H, 4.52. Found: C,
16 21 4 2
56.48; H, 6.26.
2-[( p-Tolyl)sulfonyl]thiepane (14b).
General Procedure for Cyclisation of Sulfonates 9b-d or Halides
10b and 11b-d.
This compound was isolated as colorless crystals in 80% yield,
1
mp 104-106 °C; H nmr (deuteriochloroform): δ 1.5-2.1 (m, 7H),
To a solution of sulfonates 9b-d or halides 10b and 11b-d (2
mmol) in dry DMF (20 ml), NaI (3.0 g, 20 mmol) was added, the
mixture was refluxed with stirring for 4 hours and then parti-
2.45 (s, 3H, CH ) overlapping with 2.5 (m, 2H), 2.80 (ddd, 1H, J
3
= 11.3, 10.4, 2.3 Hz, 7-Ha), 4.06 (dd 1H, 2-H, J = 11.5, 6.1 Hz),
7.35 (d,2H, J = 7.8 Hz), 7.82 ppm (d, 2H, J = 7.8 Hz); C nmr
(deuteriochloroform): δ 21.6, 24.5, 28.4, 28.6, 30.3, 32.4, 68.2,
129.4, 129.6, 134.1, 144.6 ppm.
13
tioned between CH Cl (30 ml) and saturated aqueous Na S O
2
2
2 2 3
(30 ml). The organic layer was washed with H O and dried over
2
Na SO . The volatiles were evaporated in vacuo and the residue
2
4
Anal. Calcd. for C
H O S : C, 57.74; H, 6.71. Found: C,
13 18 2 2
was chromatographed on silica gel with hexane/ethyl acetate (5:1
v/v) as the eluent to give products 13a-d.
57.88; H, 6.57.
(3aS,6R,7aS)-2,2-Dimethyl-6-[(p-tolyl)sulfonyl]tetrahydro-4H-
thiopyrano[3,4-d][1,3]dioxole (14c) and (3aR,6S,7aR)-2,2-
Dimethyl-6-[(p-tolyl)sulfonyl]tetrahydro-4H-thiopyrano[3,4-d]-
[1,3]dioxole (14d).
p-Tolyl 4,5,6,7-tetrahydro-2-thiepinylsulfone (13b).
This compound was isolated as colorless crystals in 59% yield
from 9b, 62% yield from 10b and 55% yield from 11b, mp 104-
1
106 °C; H nmr (deuteriochloroform): δ 1.55 (m, 2H), 1.98 (m,
These enantiomers were isolated as colorless crystals in enan-
tiomerically pure form in 44% yield each one, mp 154-156 °C.
For 14c [α] +83.2 (c = 0.48, chloroform); for 14d [α] -83.5 (c
2H), 2.38 (m, 2H), 2.44 (s, 3H), 2.58 (m, 2H), 7.33 (d, 2H, J =
8.2 Hz), 7.61 (t, 1H, J = 7.2 Hz), 7.82 ppm (d, 2H, J = 8.2 Hz);
13
D
D
C nmr (deuteriochloroform): δ 21.6, 22.5, 28.9, 32.1, 34.1,
1
= 0.5, chloroform); H nmr (deuteriochloroform): δ 1.32 (s, 3H),
1.43 (s, 3H), 1.83 (q, 1H, J = 12.4 Hz, 3-H ), 2.44 (ddd, 1H, J
+
128.5, 129.4, 136.0, 143.3, 144.1, 147.2 ppm; ms: m/z 268 (M ).
axial
Anal. Calcd. for C
H O S : C, 58.17; H, 6.01. Found: C,
13 16 2 2
= 12.4, 6.1, 5.0 Hz, 3-H
) overapping with 2.47 (s, 3H,
equatorial
58.06; H, 6.04.
CH ), 2.68 (dd, 1H, J = 13.7, 7.2, 6-Ha), 2.72 (dd, 1H, J = 13.7,
3
(3aS,7aS)-2,2-Dimethyl-6-[(p-tolyl)sulfonyl]-3a,7a-dihydro-4H-
thiopyrano[3,4-d][1,3]dioxole (13c) and (3aR,7aR)-2,2-
Dimethyl-6-[(p-tolyl)sulfonyl]-3a,7a-dihydro-4H-thiopy-
rano[3,4-d][1,3]dioxole (13d).
10.1, 6-Hb), 4.09 (dd, 1H, J = 12.4, 6.1 Hz, 2-H), 4.16 (ddd, 1H,
J = 12.4, 7.2, 5.0 Hz, 4-H), 4.41 (dt, 1H, J = 10.1, 7.2 Hz, 5-H),
7.37 (d, 2H, J = 8.0 Hz), 7.84 ppm (d, 2H, J = 8.0 Hz); C nmr
(deuteriochloroform): δ 21.6, 24.5, 26.0, 26.2, 27.0, 60.7, 72.8,
73.5, 108.8, 129.6, 129.7, 132.8, 145.3 ppm.
13
These enantiomers were isolated as colorless crystals in enan-
tiomerically pure form in 66% yield each one from 9c,d and 55%
Anal. Calcd. for C
H O S : C, 54.85; H, 6.14. Found: C,
15 20 4 2
54.91; H, 6.09.
yield from 11c,d, mp 121-123 °C. For 13c [α] +181.0 (c =
D
0.62, chloroform); for 13d [α] –179.9 (c = 4.62, chloroform);
D
1
H nmr (deuteriochloroform): δ 1.39 (s, 3H), 1.40 (s, 3H), 2.36
REFERENCES AND NOTES
E-mail: igallos@chem.auth.gr.
(dd ,1H, 6-H
, J = 12.4, 10.5 Hz), 2.45 (s, 3H), 2.86 (dd, 1H,
axial
6-H
, J = 12.4, 3.9 Hz), 4.30 (ddd, 1H, 5-H, J = 12.4, 3.9,
equatorial
*
3.5 Hz), 4.62 (dd, 1H, 4-H, J = 4.6, 3.5 Hz), 7.17 (d, 1H, 3-H, J =
4.6 Hz), 7.35 (d, 2H, J = 8.2 Hz), 7.83 ppm (d, 2H, J = 8.2 Hz);
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13
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73.0, 108.5, 128.6, 129.7, 129.8, 135.5, 143.9, 145.0 ppm; ms:
m/z 326 (M ), 311, 269, 251.
+

584
J. K. Gallos and C. C. Dellios
Vol. 38
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