Synthesis of α,β-unsaturated oxathiolanes

Article abstract of DOI:10.1016/S0040-4020(02)01428-X

The formation of α,β-unsaturated oxathiolanes 2 from α,β-unsaturated carbonyl derivatives was achieved selectively and in high yields using the heterogeneous catalyst APSG·HCl.

Full text of DOI:10.1016/S0040-4020(02)01428-X

Tetrahedron 58 (2002) 10455–10462
Synthesis of a,b-unsaturated oxathiolanes
a
Sebastien Kerverdo, Louisette Lizzani-Cuvelier and Elisabet Dunach
a
b
,
*
´
˜
a
ˆ
`
´
Laboratoire Aromes, Syntheses, Interactions, Universite de Nice Sophia-Antipolis, Parc Valrose, 06108 Nice, Cedex 2, France
´
Laboratoire de Chimie Bio-organique, UMR CNRS 6001, Universite de Nice Sophia-Antipolis, Parc Valrose, 06108 Nice, Cedex 2, France
b
Received 1 July 2002; revised 16 October 2002; accepted 28 October 2002
Abstract—The formation of a,b-unsaturated oxathiolanes 2 from a,b-unsaturated carbonyl derivatives was achieved selectively and in high
yields using the heterogeneous catalyst APSG·HCl. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
undergo both 1,2 and 1,4 addition. Double addition of the
mercapto alcohol is also possible. To the best of our
knowledge, only two references deal briefly with oxathio-
acetalisation of a,b-unsaturated carbonyl derivatives.14,17
In the first one, cinnamaldehyde was reacted with
2-mercaptoethanol in presence of ZrCl4 as the catalyst to
afford the 1,2 adduct in good yield.14 In the second case, the
reaction proceeded by exchange of the O–(CH2)2–S moiety
between 2,2-dimethyloxathiolane and a carbonyl com-
pound; however, when crotonaldehyde was used,
polymerization of the substrate was observed.17 Therefore,
there is, up to now, no general method described allowing
the clean and efficient synthesis of a,b-unsaturated
oxathiolanes.
Acetals, oxathioacetals and dithioacetals are frequently used
for the protection of aldehydes or ketones in multi-step
syntheses.1 Acetals are also used to protect diols and
hydroxy groups.1 On the other hand, Corey and Seebach
reported that carbanions stabilized by an adjacent sulfur
atom such as 2-lithio-1,3-dithianes were appropriate acyl
anion equivalents.2 Since, the use of dithioacetals and later
of oxathioacetals, as masked acyl anion equivalents for
carbon–carbon bond formation, has been well documen-
ted.3–5 Furthermore, the oxathioacetal heterocycles have
been shown to be very useful for the synthesis of chiral
synthons: for example, Eliel has described the use of a chiral
oxathiane moiety to induce chirality in the addition reaction
to carbonyl compounds.6–8 Oxathianes were also used as
chiral ylides for the epoxidation of carbonyl derivatives.9,10
In addition, some five-membered ring oxathiolanes present
interesting biological properties as nucleoside analogues, as
those displayed by (2)-2-deoxy-30-thiacytidine (3TCw,
Epivir) against HIV.11
Recently, we reported the use of unsaturated-1,3-oxathio-
lanes as masked heterodienes for thio Diels–Alder reac-
tions,18 showing that these derivatives have potential
synthetic interest. We present here our results on the
selective formation of oxathiolanes from a,b-unsaturated
carbonyl derivatives or from the corresponding acetals.
We have been interested in the oxathiolane ring, and
particularly in a,b-unsaturated oxathiolanes. The most
commonly used way leading to cyclic 1,3-oxathioacetals
2. Results and discussion
is the condensation of a mercaptoalcohol with an aldehyde
12–15
or a ketone, catalyzed by Bronsted or Lewis acids.
Their synthesis can also be achieved by transoxathio-
acetalisation between an acetal and a mercaptoalcohol or a
carbonyl derivative.16,17 These methods allow the formation
of simple oxathianes or oxathiolanes in good yields.
For the synthesis of unsaturated oxathiolanes, we examined
three strategies based on the coupling of a,b-unsaturated
carbonyl compounds with 1,2 thioalcohols. Thus, we
¨
¨
screened the use of conventional Bronsted and Lewis
acids; we further examined the transoxathioacetalisation
method between acetals and mercaptoalcohols. Finally, we
successfully applied heterogeneous catalysis using an acid-
supported silica gel reagent.
However, some problems are encountered when reactions
are performed with a,b-unsaturated carbonyl derivatives.
Indeed, the thiol moiety being a soft nucleophile, it can
2.1. Formation of a,b-unsaturated oxathiolanes
¨
catalyzed by conventional Bronsted and Lewis acids
Keywords: oxathiolane; supported catalyst; 1,2-thioalcohol; acid catalysis.
*
Our first attempts to prepare a,b-unsaturated oxathiolanes
2 from a,b-unsaturated carbonyl compounds 1 and
Corresponding author. Fax: þ33-4-92-07-61-51;
e-mail: dunach@unice.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01428-X

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S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
Scheme 1. Formation of a,b-unsaturated oxathiolanes 2 and by-products.
2-mercaptoethanol (Scheme 1), rapidly raised the problem
of selectivity: a mixture of sulfur derivatives 2–5 was
obtained. The reactions were generally carried out using an
initial 1:1 mixture of 1 and 2-mercaptoethanol in diethyl
ether or dichloromethane in the presence of dehydrating
towards 2a, respectively of 98 and 84% (entries 3, 4),
though with a low conversion. A better conversion could not
be obtained without loss of selectivity and it was
accompanied by an increasing formation of 3a and 4a.
˚
agent such as MgSO4 or 4 A molecular sieves. As catalysts,
The use of trimethylorthoformate as the desiccant (entry 5)
in dichloromethane led to a rapid conversion of 1a, but with
a poor selectivity for 2a of 47%. The loss of selectivity was
attributed to the enhancement of the polarity of the solvent
by the presence of methanol, formed during the reaction. In
comparison, dehydrating agents such as magnesium sulfate
we used p-TsOH or Lewis acids such as BF3·Et2O, ZnCl2,
ZrCl4, MgBr2 and LiBF4. Table 1 summarizes the main
results obtained. Thus, the reaction of 4-phenylbutenone 1a
in refluxing ethyl ether in the absence of catalyst afforded a
mixture of oxathiolane 2a and Michael adduct 3a with a
poor conversion after 24 h (entry 1). The rate of the reaction
was enhanced with acid catalyst (p-TsOH, 5%, entry 2), but
the selectivity for 2a was only of 20%. In this case, the
major compound was the 1,4-addition product 3a, obtained
with 56% of selectivity. The adduct 4a, issued from a double
1,2 and 1,4 addition was also obtained in 24% selectivity.
The same reaction run at room temperature with either
MgSO4 or molecular sieves afforded a good selectivity
˚
or 4 A molecular sieves led to lower conversions, but 2a
could be obtained with better ratios (compare entries 3–5).
Different Lewis acids were tested as catalysts for the
reaction of 1a in order to orientate the addition of the
mercapto ethanol in a 1,2 fashion (entries 6–10). The best
catalyst concerning selectivity towards 2a was BF3·Et2O
(entry 6). ZnCl2 led almost exclusively to the Michael
Table 1. Reaction of 2-mercaptoethanol with a,b-unsatured carbonyl derivatives 1
Entry
Carbonyl derivate 1
Desiccant
Solvent
T (8C)
Acid (molar %)
Time (h)
Conversion of 1a (%)
Selectivitya 2/3/4/5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
MgSO4
MgSO4
MgSO4
MS 4 A
HC(OCH3)3
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
Et2O
Et2O
Et2O
Et2O
CH2Cl2
Et2O
Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Reflux
reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
–
24
1.5
4.5
3
18
80
40
42
85
35
75
81
2
40
63
61
65
58:42:0:0
20:56:24:0
98:2:0:0
84:15:1:0
47:50:3:0
68:32:0:0
5:95:0:0
2:67:31:0
50:50:0:0
52:48:0:0
31:0:0:69b
14:82:4:0
34:0:30:36
p-TsOH (5%)
p-TsOH (5%)
p-TsOH (5%)
p-TsOH (5%)
BF3·Et2O (10%)
ZnCl2 (1 equiv.)
ZrCl4 (5%)
MgBr2 (10%)
LiBF4 (10%)
p-TsOH (5%)
p-TsOH (5%)
p-TsOH (5%)
1
1.5
1.5
0.5
4
6
0.5
1
9
10
11
12
13
Et2O
Et2O
1
a
Determined by GC.
Determined by 1H NMR.
b

S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
10457
Scheme 2. Formation of a,b-unsaturated oxathiolanes 2 by transoxathioacetalisation.
addition product 3a (entry 7). Similarly, ZrCl4 (5%) did not
afford the expected oxathiolane 2a, but led to 3a and to 4a in
a 67 and 31% selectivity, respectively (entry 8). The use of
MgBr2 did not catalyze the reaction, since after 4 h at room
temperature, only 2% conversion was observed (entry 9).
LiBF4 was not selective and gave a mixture of oxathiolane
2a and the Michael addition product 3a in almost the same
amounts (entry 10).
the formation of a,b-unsaturated oxathiolanes. Indeed, the
main advantage of acetals for the synthesis of 2 (Scheme 2)
is the decrease in electrophilicity of the b-carbon, due to the
absence of conjugated system, thus limiting the 1,4-addition
reaction leading to derivatives 3 and 4.
The synthesis of the acetals from the corresponding
carbonyl derivatives 1 has been reported to proceed
efficiently in the case of unsaturated aldehydes,21–23 but is
less common in the case of unsaturated ketones. Indeed,
only a few examples of unsaturated ketones have been
described: 2-cyclohexenone has been reported to reacted
with alkoxytrimethylsilane and TMSOTf as the catalyst,
leading to its corresponding acetal.24 Aromatic a,b-
unsaturated ketones such 1a25 and chalcone 1f26 were also
readily converted into the corresponding acetals. Following
these examples, we prepared several dimethyl acetals 6
from a,b-unsaturated carbonyl derivatives 1 in quantitative
yields. We carried out the exchange reaction between 6 and
2-mercaptoethanol using the aminopropylated silica gel
hydrochloride (APSG·HCl) as supported catalyst (Scheme
2) for the transoxathioacetalisation step. This catalyst is
known to be efficient under mild conditions.25 The reactions
were run in methanol at room temperture, with 5%
catalyst,27 and led to the oxathiolane 2 in modest to good
yields (Table 2).
The conditions for the best selectivity obtained in entry 3
were extended to other a,b-unsaturated carbonyl com-
pounds. Thus, the reaction of cinnamaldehyde 1b led to the
corresponding oxathiolane 2b and to the dithioacetal 5b in a
31:69 ratio, respectively (entry 11). Formation of 5b was
attributed to a second addition of 2-mercaptoethanol on the
hemithioacetal intermediate, rather than to the attack of the
mercapto alcohol on 2b to re-open the cycle. This fact was
confirmed by stirring 2-mercaptoethanol and 2b with
p-TsOH (5%), which did not lead to 5b in any significant
ratio.
The comparison between entries 3 and 11 indicated that the
reaction was very strongly dependent on the nature of the
substrate: cinnamaldehyde preferentially formed 5b,
whereas the corresponding methyl ketone afforded selec-
tively 2a. An aliphatic ketone such as 1c gave preferentially
the 1,4-addition product 3c, with a selectivity of 82% (entry
12). However, the aliphatic aldehyde 1d led to a mixture of
2d, 4d and 5d in almost the same proportions (entry 13).
Under the same reaction conditions, differently substituted
unsaturated ketones and aldehydes afforded different
reaction products: either 2, 3 or 5 could be obtained as
main reaction products, respectively with 1a, 1c or 1b.
The transoxathioacetalisation reaction of methyl acetals of
a,b-unsaturated carbonyl compounds was less selective
than expected. Starting acetals 6a and 6f gave the best
results concerning the selectivity towards 2, 2a and 2f were
isolated in yields of 71 and 72%, respectively (entries 1, 5).
Reaction of acetals 6b, 6d and 6e, derived from aldehydes,
led to a poor selectivity and to modest yields of 2 (entries
2.2. Formation of oxathiolanes from a,b-unsaturated
acetals
Table 2. Formation of oxathiolanes 2 by transoxathioacetalisation
catalyzed by APSG·HCl
We also considered the possibility to prepare compounds 2
more selectively by a transoxathioacetalisation reaction.
The exchange of the alkoxy groups of acetals by other
alcohols in presence of an acidic catalysis is known to
proceed smoothly.19 This exchange reaction has been
recently applied to mercapto alcohols for the formation of
oxathiolanes and oxathianes.16 The reaction proceeded in
good yields without solvent under microwave irradiation,
with Montmorillonite clay K10 as the catalyst.
Entry
Acetals 6
Conversiona
Selectivity
2/3/4/5a
Isolated yields
of 2b
1
2
3
4
5
6a
6b
6d
6e
85
85
88
72
89
94:6:0:0
71
53
16
25
72e
68:0:0:32
21:12:0:44
25:0:61:0
92:8:0:0d
6fc
a
Determined by GC.
b
c
d
e
Isolated after silica gel column chromatography.
The reaction was performed in dichloromethane.
Ratio determined by 1H NMR.
However, the reactivity of unsaturated acetals with
mercapto alcohols has, to our knowledge, not yet been
reported.20 We thus decided to apply this methodology to
Isolated yield after alumina oxide gel column chromatography.

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S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
Scheme 3. Formation of a,b-unsaturated oxathiolanes 2 and by-product 7.
2–4). In the case of 6d, the formation of the dithioacetal 5d
was predominant with 44% of selectivity. The formation of
5b in 32% selectivity was also observed with 6b. Acetal 6e
led preferentially to the Michael-type addition product 4e.
These results were attributed to the low steric hindrance of
the acetals derived from aldehydes. Some attempts to work
in diluted solution or at lower temperature did not allow
significant improvement of the selectivities.
and 2e were obtained in low yields. This lack of generality
led us to undertake further studies, particularly on the use of
mild and efficient APSG·HCl as the catalyst.
2.3. Formation of a,b-unsaturated oxathiolanes via
heterogeneous catalysis
The silica gel supported catalyst, APSG·HCl, resulted to be
efficient for the selective synthesis of oxathiolanes 2 directly
from a,b-unsaturated carbonyl derivatives 1 and 2-mercap-
toalcohol, in reactions performed in the presence of 10% of
the catalyst and 1 equiv. of trimethylorthoformate. For
Although the two step synthesis produced the expected
oxathiolanes 2a, 2b and 2f in moderate to good yields,
substrates such as 6d and 6e did not react selectively and 2d
Table 3. Formation of oxathiolanes 2 catalyzed by APSG·HCl
Entry
Carbonyl derivative 1
R5
Conditions
Product 2
Yielda
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1g
1b
1a
H
H
H
H
H
H
Me
n-hex
MeOH, 08C, 1 h
2a
2b
2c
2d
2e
2g
2h
2i
77
91b
60
56
73
CH2Cl2 refluxing, 1 h
MeOH, 2158C, 5 h
CH2Cl2 refluxing, 1 h
CH2Cl2 refluxing, 1 h
CH2Cl2 refluxing, 2 h
CH2Cl2, rt, 1 h
42
76c
73d
MeOH, 08C, 2 h
9
H
H
CH2Cl2 refluxing, 1.5 h
2j
72
53
10
MeOH, 08C, 6 h
2k
11
H
H
CH2Cl2 refluxing, 2 h
2l
77
54
12
MeOH, 2158C, 5 h
2m
a
Isolated yields after silica gel column chromatography.
b
c
d
Reaction was carried out using 1% of catalyst, and purified by distillation in a bulb to bulb oven.
A 70:30 mixture of diastereoisomeres was obtained.
A 55:45 mixture of diastereoisomeres was obtained.

S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
10459
unsaturated aldehyde derivatives, reactions were best
carried out in refluxing methylene chloride, and in cold
methanol (215 to 08C) for a,b-unsaturated ketones. In
methanol reactions at higher temperatures, we could
observed the formation of an oxathiolane derivative 7, in
which MeOH was added in a 1,4-fashion on the product 2
(Scheme 3). Thus, in the case of the reaction of mesityl
oxide 1c, the by-product 7c was obtained in a 55%
selectivity after 2 h at room temperature. When operating
in methanol at 08C to 2158C, adducts 7 were formed in less
than 5% yield, and under optimized conditions, oxathio-
lanes 2 were obtained selectively and in good isolated
yields, as summarized in Table 3.
has three coupling constants of 13.0 Hz, which correspond
2
to one J coupling and two axial–axial couplings. This
indicates that H9 is in an axial position, and thus, that the
methyl-14 is in an equatorial position. This fact was
4
confirmed by the W type long range coupling J¼2.1 Hz
between the equatorial H10 and the second H8, necessarily in
an equatorial position. Moreover, the NOESY spectrum
showed a correlation spot between one H4 a to oxygen and
the protons of methyl-13. We could therefore, conclude that
one H of the methylene group at the 4-position should be in
an equatorial position close to the methyl-13, and that the
oxygen and the methyl-14 are on a relative cis position.
The reaction proceeded well when the double bond was in a
cycle such as in aldehyde 1l, which led to the corresponding
oxathiolane 2l in a 77% yield (entry 11). The reaction of
3-methylcyclohexenone 1m led to the spiro derivative 2m in
54% yield (entry 12). We could notice that the substitution
at the 3-position of the unsaturated ketone avoided Michael
addition products. Indeed, under the same conditions, the
reaction of cyclohexenone did not provide 2, but exclusively
the Michael addition product 3 in quantitative yield.
The reaction of aromatic carbonyl derivatives such as
4-phenylbutenone 1a or cinnamaldehyde 1b, readily
afforded the corresponding oxathiolanes 2a and 2b in
isolated yields of 77 and 91%, respectively (entries 1, 2).
Aliphatic substrates 1c–1e and 1g were less selective
toward the addition of the mercapto alcohol, but led to 2 in
moderate to good yields (entries 3–6). Crotonaldehyde 1d
led to oxathiolane 2d in a 56% yield. This yield was low
compared to that obtained for the analogous substrate 1e
(compare entries 4, 5), and this fact could be attributed to the
low boiling point of 2d, and to its partial evaporation during
removal of solvent upon treatment. In the case of 1g, the
presence of an alkyl group at the a position of the carbonyl
group of 1 increasing the steric hindrance may explain the
lower yield of 2g (42%, entry 6).
This a,b-unsaturated oxathiolane formation method was
shown to be very versatile. A large variety of carbonyl
derivatives and mercapto alcohols reacted in good isolated
yields. Moreover, the double bond of the a,b-unsaturated
carbonyl compounds (aldehydes or ketones) could either be
in a linear chain (entries 1–9), or in a cycle (entries 11, 12)
or in an exocyclic position (entry 10).
When the 2-mercaptoalcohol had an alkyl group such as
methyl or n-hexyl28 at the 1-position, the reaction proceeded
without significant loss of reactivity, and 2h and 2i could be
obtained in 76 and 73% yields, respectively from 1b or 1a
(entries 7, 8).
Except for 2b,14 all other oxathiolanes 2a–m were prepared
and characterized for the first time.
The reaction described here with the use of APSG·HCl as
the supported catalyst was clean and the workup procedure
was very simple. Filtration of the catalyst was followed by
removal of the solvent in vacuo. Crude products were
purified by silica gel column. The catalyst could be further
reused after washing with no significant loss of activity.
Thus, the reaction of 1b under the same conditions as entry 2
led, with the regenerated catalyst, to the oxathiolane 2b in
an isolated yield of 90%.
The reaction was also performed successfully on natural
terpenic products. For example, citral 1j (mixture cis/trans
of geranial and neral) led after 1.5 h to the corresponding
oxathiolane 2j in good yield (72% of cis/trans mixture,
entry 9). Moreover, reaction occurred without isomerization
of the a double bond, and the unsaturation of the terminal
chain of 1j remained unaffected under the reaction
conditions.
The reaction of pulegone 1k afforded 2k in fairly good yield
(53%, entry 10). Interestingly, this reaction proceed with
excellent stereoselectivity, and a diastereomeric excess of
98% was obtained, as determined by GC/MS. The
stereochemistry of the main diastereoisomer of 2k was
examined by 1H NMR (Scheme 4). The coupling constants
of H7, H8, and of two H10 were calculated. The signals of H9
and of the second H7 and H8 were superimposed. One H8
3. Conclusion
In summary, we have shown that the formation of various
unsaturated oxathiolanes from a,b-unsaturated aldehydes or
ketones could be easily effected in good yields with
supported APSG·HCl as the catalyst. The workup of the
reaction was achieved by filtration of the catalyst and
removal of the solvent. Most of the oxathiolanes are
new compounds and were obtained in isolated yields of
53–91%.
4. Experimental
4.1. General
All solvents used were dried and distilled according to the
1
Scheme 4. Configuration of main isomer of 2k.
standard procedures. H and 13C NMR data were recorded

10460
S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
on a Bruker AC 200 FT spectrometer with TMS as internal
1
reference. 2D H NMR spectra were recorded on a Bruker
tography using a gradient of hexane and dichloromethane as
the eluents.
AC 500 spectrometer. GC analysis was carried out using an
HP-5890 gas chromatograph. GC/MS analysis was accom-
plished by using an HP-5890 chromatograph coupled to a
5970A mass selective detector. Mass spectra were obtained
by electron ionization at 70 eV and source temperature of
2508C. Elemental analysis were performed at the service of
ICSN at Gif sur Yvette, France. Infrared spectra were
recorded neat, as KBr pellets, on a Mattson infrared
spectrophotometer.
4.4. General procedure for the synthesis of a,b-
unsaturated oxathiolane via heterogeneous catalysis
A mixture of a carbonyl derivative 1 (10 mmol), of
2-mercaptoalcohol (11 mmol), and of trimethylortho-
formate (10 mmol) catalyzed by APSG·HCl (1.0 g) in the
solvent and at the temperature given in Table 3 was stirred
under nitrogen atmosphere. After complete consumption of
1 according to GC analysis, the mixture was filtered off and
the solvent evaporated in vacuo. The crude product was
purified by silica gel column chromatography using a
gradient of hexane and dichloromethane as the eluents.
Chromatographic separations were performed using
70–260 mesh (SDS) silica gel eluted with hexane/
dichloromethane mixtures by changing the gradient
from 95/5 to 80/20. Thin-layer chromatography was carried
out on SDS precoated silica plates (60/15 m layer
thickness).
4.5. Synthesis and regeneration of APSG·HCl
The procedure was followed according to Gasparrini:25
Lichroprep-NH2e 25–40 mm, Merck (10.0 g) was sus-
pended in methanol (50 ml), and 10 ml HCl (37%) were
added. After 15 min stirring at room temperature, the
mixture was filtered off and the collected precipitate was
washed successively with methanol (100 ml) and dichloro-
methane (10 ml), and dried under vacuum. Regeneration of
the catalyst: the filtered solid was washed with methanol,
water and again with methanol and treated as described.
4.2. General procedure for the synthesis of a,b-
unsaturated oxathiolanes by conventional catalysis
The reactions were performed with 1a–d (10 mmol) and
2-mercaptoethanol (10 mmol) under nitrogen atmosphere in
dry solvent. The temperature, the catalyst and the desiccant
are indicated in Table 1. MgSO4 was heated at 1208C before
˚
use and 4 A molecular sieves were heated under vacuum.
The monitoring of the reaction was made by GC, and the
conversions were determined by comparison with dodecane,
used as internal standard. Compounds 2a–4a and 2b–2d
were isolated by silica gel column chromatography. 5b was
purified by crystallization in dichloromethane. The other
by-products from 1c and 1d were not isolated and were
analysed by their MS spectra.
4.6. Spectral data
4.6.1. 2-Methyl-2-styryl-1,3-oxathiolane (2a). Colorless
1
oil. H NMR (200 MHz, CDCl3) d 1.80 (3H, s), 3.15 (2H,
m), 4.20 (2H, m), 6.30 (1H, d, J¼15.8 Hz), 6.60 (1H, d,
J¼15.8 Hz), 7.2–7.4 (5H, m). 13C NMR (50 MHz, CDCl3)
d 29.0 (CH3), 34.4 (C-4), 71.0 (C-5), 93.4 (C-2), 126.8,
128.7, 127.4, 127.8, 133.7, 136.6. MS, m/z (%): 77 (43.6),
103 (71.5), 131 (100), 145 (67.0), 146 (40.0), 191 (17.2),
206 (Mþ, 19.1), 208 (1.0). Elemental analysis: found C,
69.78; H, 6.84; O, 7.94; S, 15.43. C12H14OS requires C,
69.85; H, 6.85; O, 7.75; S, 15.54%.
4.3. General procedure for the synthesis of a,b-
unsaturated oxathiolanes from acetals
Acetals 6a, 6b and 6d, 6e were prepared according to the
reported procedure,25 from 1 (50 mmol) in methanol
(100 ml) at room temperature, using APSG·HCl (1.0 g)
and trimethylorthoformate (50 mmol). The reaction was
stopped when the disappearance of 1 was complete as
checked by GC. The mixture was filtered off and the solvent
was removed in vacuo. Derivatives 6 were obtained in 95%
to quantitative yields.
4.6.2. 2-Styryl-1,3-oxathiolane (2b). Colorless oil. 1H
NMR (200 MHz, CDCl3) d 3.12 (2H, m), 3.88 (1H, m),
4.38 (1H, m), 5.68 (1H, d, J¼7.4 Hz), 6.28 (1H, dd, J¼7.4,
15.8 Hz), 6.65 (1H, d, J¼15.8 Hz), 7.2–7.4 (5H, m). 13C
NMR (50 MHz, CDCl3) d 33.6 (C-4), 71.6 (C-5), 86.2
(C-2), 126.7, 127.1, 128.0, 128.5, 132.0, 135.8. MS, m/z
(%): 77 (19.6), 104 (54.8), 115 (21.6), 131 (100), 132 (25.8),
192 (Mþ, 88.9), 194 (4.5). Elemental analysis: found C,
68.55; H, 6.58; O, 8.52; S, 16.33. C11H12OS requires C,
68.70; H, 6.30; O, 8.32; S, 16.68%.
Acetal 6f was obtained according to Ref. 26 from chalcone
1f (50 mmol) in trimethylorthoformate as the solvent
(150 ml) catalyzed by Dowex 50W-X4 cation-exchange
resin (8.0 g) at room temperature. The completion of the
reaction was monitored by GC. After filtration of the
mixture and evaporation of the solvent, 6f was obtained in
93% yield. All the acetals were used with any further
purification.
4.6.3. 2-Methyl-2-[2-methylpropenyl]-1,3-oxathiolane
(2c). Colorless oil. 1H NMR (200 MHz, CDCl3) d 1.71
(3H, d, J¼1.4 Hz), 1.72 (3H, s), 1.78 (3H, d, J¼1.2 Hz),
3.12 (2H, dd, J¼6.3, 5.8 Hz), 4.05 (1H, dt, J¼9.2, 6.5 Hz),
4.19 (1H, dt, J¼9.2, 5.5 Hz), 5.50 (1H, sept., J¼1.3 Hz). 13C
NMR (50 MHz, CDCl3) d 18.9, 26.6, 30.2, 34.0 (C-4), 69.9
(C-5), 93.4 (C-2), 130.9, 133.4. MS, m/z (%): 43 (34.6), 55
(24.2), 83 (100), 98 (14.6), 99 (14.3), 113 (5.5), 143 (18.6),
158 (Mþ, 10.8), 160 (0.6). Elemental analysis: found: C,
60.58; H, 8.88; O, 10.29; S, 20.24. C8H14OS requires C,
60.70; H, 8.93; O, 10.11; S, 20.26%.
The exchange reaction was performed with acetals 6
(10 mmol) and 2-mercaptoethanol (10 mmol) in methanol
at room temperature with APSG·HCl (0.2 g) as the catalyst.
The reactions were stopped when the disappearance of 6
was complete as monitored by GC. The mixture was then
filtered off and the solvent was evaporated in vacuo. The
crude product was purified by silica gel column chroma-

S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
10461
1
4.6.4. 2-Propenyl-1,3-oxathiolane (2d). Colorless oil. H
NMR (200 MHz, CDCl3) d 1.72 (3H, dd, J¼6.4, 1.3 Hz),
3.05 (2H, m), 3.80 (1H, ddd, J¼9.1, 8.2, 6.4 Hz), 4.34 (1H,
J¼9.1, 5.7, 3.5 Hz), 5.45 (1H, d, J¼7.7 Hz), 5.59 (1H, ddq,
J¼14.8, 7.6, 1.4 Hz), 5.82 (1H, dq, J¼14.8, 6.4 Hz). 13C
NMR (50 MHz, CDCl3) d 17.5, 33.6 (C-4), 71.4 (C-5), 86.3
(C-2), 129.3, 129.8. MS, m/z (%): 39 (39.1), 45 (35.3), 59
(47.1), 60 (100), 61 (41.2), 69 (50.6), 85 (18.8), 130 (Mþ,
66.7), 132 (3.4). Elemental analysis: found: C, 57.88; H,
8.07; O, 11.91; S, 21.96. C6H10OS requires C, 58.27; H,
8.40; O, 11.09; S, 22.23%.
131 (100), 132 (24.9), 161 (3.3), 206 (Mþ, 68.6), 208 (3.8).
Major: 74 (32.9), 77 (30.5), 104 (97.1), 115 (32.7), 131
(100), 132 (22.9), 161 (3.4), 206 (Mþ, 64.1), 208 (3.5).
Elemental analysis: found C, 69.85; H, 6.83; O, 8.05; S,
15.36. C12H14OS requires C, 69.85; H, 6.85; O, 7.75; S,
15.54%.
4.6.9. 2-Methyl-2-styryl-5-hexyl-1,3-oxathiolane (2i). The
two diastereoisomers could not be separated after silica gel
column chromatography. Analysis was made on a 55:45
mixture. Colorless oil. 1H NMR (200 MHz, CDCl3) d
0.89þ0.90 (3H, dt, J¼7.2 Hz), 1.2–1.6 (10H, m),
1.80þ1.81 (3H, s), 2.85 (1H, t, J¼10.0 Hz), 3.11 (ddd,
J¼10.0, 4.5, 2.6 Hz), 4.25 (1H, m), 6.30þ6.39 (1H, d,
J¼15.9 Hz), 6.61 (1H, d, J¼15.9 Hz), 7.1–7.4 (5H, m). 13C
NMR (50 MHz, CDCl3) d 14.1, 22.6, 26.4, 29.0, 29.3, 30.0,
31.8, 34.1, 34.2, 39.1 (C-4), 82.9þ83.7 (C5), 92.0þ92.7
(C-1), 126.7, 126.8, 127.0, 127.6, 127.7, 128.1, 128.5,
128.6, 134.6. Elemental analysis: found C, 74.20; H, 9.02;
O, 5.64; S, 11.09. C18H26OS requires C, 74.41; H, 9.04; O,
5.51; S, 11.04%.
1
4.6.5. 2-Hexenyl-1,3-oxathiolane (2e). Colorless oil. H
NMR (200 MHz, CDCl3) d 0.90 (3H, t, J¼7.3 Hz), 1.40
(2H, sex., J¼7.3 Hz), 2.04 (2H, qd, J¼7.3, 1.1 Hz), 3.09
(2H, m), 3.81 (1H, ddd, J¼9.1, 8.2, 6.4 Hz), 4.35 (1H, ddd,
J¼9.1, 5.7, 3.5 Hz), 5.46 (1H, d, J¼7.7 Hz), 5.57 (1H, ddt,
J¼14.7, 7.6, 1.1 Hz), 5.80 (1H, dt, J¼14.7, 6.6 Hz). 13C
NMR (50 MHz, CDCl3) d 13.6, 21.9, 33.6, 34.0, 71.4 (C-5),
86.4 (C-2), 128.0, 134.9. MS, m/z (%): 41 (39.1), 59 (37.8),
60 (100), 61 (42.9), 85 (17.4), 97 (33.6), 98 (88.7), 115
(62.6), 129 (15.0), 158 (Mþ, 37.3), 160 (2.0). Elemental
analysis: found C, 60.35; H, 8.89; O, 10.52; S, 19.86.
C8H14OS requires C, 60.70; H, 8.93; O, 10.11; S, 20.26%.
4.6.10. 2-[2,6-Dimethylhepta-1,5-dienyl]-1,3-oxathiolane
(2j). Colorless oil. Analysis was made on a 55:45 mixture of
cis/trans isomers. 1H NMR (200 MHz, CDCl3) d minor
isomer: 1.60 (3H, m), 1.68 (3H, m), 1.76 (3H, d, J¼1.4 Hz),
2.0–2.2 (4H, m), 3.76 (2H, m), 4.37 (2H, m), 5.08 (1H, m),
5.41 (1H, quint., J¼1.1 Hz), 5.79 (1H, d, J¼3.0 Hz). Major
isomer: 1.60 (3H, m), 1.68 (3H, m), 1.71 (3H, d, J¼1.2 Hz),
2.0–2.2 (4H, m), 3.76 (2H, m), 4.37 (2H, m), 5.08 (1H, m),
5.36 (1H, quint., J¼1.2 Hz), 5.75 (1H, d, J¼3.1 Hz). 13C
NMR (50 MHz, CDCl3) d 16.9, 17.7 (£2), 23.5, 26.2 (£2),
26.7, 32.0, 33.7, 33.8, 39.4, 71.3 (£2, C-5), 82.3þ82.6
(C-2), 122.7, 123.5, 123.6, 123.7, 131.9, 132.3, 141.1 (£2).
MS, m/z (%): Minor: 41 (75.4), 55 (44.9), 69 (100), 84
(33.4), 109 (32.5), 123 (7.2), 143 (14.4), 184 (28.9), 197
(2.5), 212 (Mþ, 11.6). Major: 41 (57.5), 55 (35.5), 69 (100),
84 (39.2), 109 (14.0), 123 (11.7), 143 (26.0), 184 (9.8), 197
(1.0), 212 (Mþ, 2.7). Elemental analysis: found C, 67.57; H,
9.43; O, 7.87; S, 14.98. C12H20OS requires C, 67.86; H,
9.51; O, 7.53; S, 15.10%.
4.6.6. 2-Phenyl-2-styryl-1,3-oxathiolane (2f). White solid,
Mp 54–558C. 1H NMR (200 MHz, CDCl3) d 3.14 (2H, m),
4.11 (1H, dt, J¼9.0, 6.4 Hz), 4.27 (1H, dt, 9.0, 5.8 Hz), 6.50
(2H, s), 7.1–7.4 (8H, m), 7.5–7.6 (2H, m). 13C NMR
(50 MHz, CDCl3) d 34.4 (C-4), 70.7 (C-5), 97.3 (C-2),
126.2, 126.7, 127.7, 127.8, 128.1, 128.4, 129.5, 132.6,
136.1, 143.0. MS, m/z (%): 77 (57.1), 105 (31.4), 131 (27.9),
165 (17.5), 180 (25.1), 207 (100), 208 (38.0), 268 (Mþ,
39.3), 270 (2.5). Elemental analysis: found C, 75.74; H,
6.01; O, 5.94; S, 11.82. C17H16OS requires C, 76.07; H,
6.02; O, 5.96; S, 11.95%.
4.6.7. 2-[1-Methylbutenyl]-1,3-oxathiolane (2g). Color-
less oil. 1H NMR (200 MHz, CDCl3) d 0.97 (3H, t,
J¼7.5 Hz), 1.68 (3H, d, J¼1.0 Hz), 2.06 (2H, Quint.,
J¼7.5 Hz), 3.07 (2H, m), 3.76 (1H, m), 4.43 (1H, m), 5.49
(1H, s), 5.58 (1H, t, J¼7.1 Hz). 13C NMR (50 MHz, CDCl3)
d 10.9, 13.7, 21.0, 33.6 (C-4), 74.0 (C-5), 91.2 (C-2), 131.1,
131.9. MS, m/z (%): 41 (91.5), 55 (37.6), 60 (100), 69
(75.3), 83 (35.5), 89 (21.5), 98 (85.7), 129 (72.8), 143
(16.0), 158 (Mþ, 33.4), 160 (1.7).
4.6.11. 6-Isoprenyl-9-methyl-5,2-oxathiospiro[4.5]de-
1
cane (2k). Colorless oil. H NMR (500 MHz, CDCl3) d
0.88 (1H, qd; J¼13.0, 3.7 Hz), 0.97 (3H, d, J¼6.5 Hz), 1.61
(1H, t, J¼12.2 Hz), 1.71 (3H, d, J¼0.7 Hz), 1.72 (1H, m),
1.85 (2H, m), 1.96 (3H, d, J¼1.5 Hz), 2.00 (1H, ddd,
J¼12.2, 3.9, 2.1 Hz), 2.76 (1H, dt, J¼14.2, 3.5 Hz), 2.97
(1H, ddd, J¼10.0, 8.4, 5.6 Hz), 3.10 (1H, m), 4.09 (1H, ddd,
J¼9.0, 8.4, 5.2 Hz), 4.36 (1H, ddd, J¼9.0, 5.6, 3.6 Hz). 13C
NMR (50 MHz, CDCl3) d 20.4, 21.6, 23.3, 30.9, 32.3, 33.1,
35.5, 51.2, 71.1 (C-5), 101.4 (C-2), 120.6, 133.2. MS, m/z
(%): 41 (38.6), 67 (54.6), 81 (100), 82 (27.3), 109 (44.9),
137 (80.7), 152 (41.8), 197 (77.3), 212 (Mþ, 45.5), 214
(2.8). Elemental analysis: found C, 67.61; H, 9.51; O, 7.69;
S, 14.92. C12H20OS requires C, 67.86; H, 9.51; O, 7.53; S,
15.10%.
4.6.8. 2-Styryl-5-methyl-1,3-oxathiolane (2h). The two
diastereoisomers could not be separated after silica gel
column chromatography. Analysis was made on a 70:30
mixture. Colorless oil. 1H NMR (200 MHz, CDCl3) d Minor
diastereoisomer: 1.39 (3H, d, J¼6.1 Hz), 2.76 (1H, t,
J¼10.1 Hz), 3.21 (1H, dd, J¼10.1, 5.0 Hz), 4.50 (1H,
Hept., J¼5.0 Hz), 5.81 (1H, d, J¼7.2 Hz), 6.29 (1H, dd,
J¼15.8, 7.2 Hz), 6.59 (1H, d, J¼15.8 Hz), 7.2–7.5 (5H, m).
Major diastereoisomer: 1.47 (3H, d, J¼5.9 Hz), 2.79 (1H, t,
J¼9.8 Hz), 3.15 (1H, dd, J¼4.12 (1H, Hept. d, J¼5.4,
1.0 Hz), 5.70 (1H, d, J¼7.7 Hz), 6.29 (1H, dd, J¼15.8,
7.7 Hz), 6.66 (1H, d, J¼15.8 Hz), 7.2–7.4 (5H, m). 13C
NMR (50 MHz, CDCl3) d 19.0 (CH3), 39.6þ40.0 (C-4),
78.5þ80.2 (C-5), 84.0þ85.7 (C-2), 126.7, 126.8, 127.1,
128.0, 128.1, 128.5, 128.6, 131.0, 132.5, 135.9, 136.5. MS,
m/z (%): Minor: 74 (34.4), 77 (30.3), 104 (98.1), 115 (32.8),
4.6.12. 2-Cyclohexenyl-1,3-oxathiolane (2l). Colorless oil.
1H NMR (200 MHz, CDCl3) d 1.5–1.7 (4H, m), 1.9–2.2
(4H, m), 3.05 (2H, m), 3.79 (1H, m), 4.40 (1H, m), 5.50 (1H,
s), 5.86 (1H, m). 13C NMR (50 MHz, CDCl3) d 22.3, 22.9,
25.0, 33.4, 71.9 (C-5), 89.8 (C-2), 128.8, 135.7. MS, m/z

10462
S. Kerverdo et al. / Tetrahedron 58 (2002) 10455–10462
2. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965,
4, 1075–1077.
(%): 39 (49;5), 53 (45.5), 60 (60.4), 79 (62.1), 81 (82.9), 95
(34.7), 109 (29.8), 110 (68.3), 141 (9.1), 170 (Mþ, 100), 172
(4.9). Elemental analysis: found C, 63.21; H, 8.31; O, 9.65;
S, 18.68. C9H14OS requires C, 63.47; H, 8.30; O, 9.39; S,
18.83%.
3. Grobel, B.-T.; Seebach, D. Synthesis 1977, 357–402.
4. Fuji, K.; Ueda, M.; Sumi, K.; Kajiwara, K.; Fujita, E.;
Iwashita, T.; Miura, I. J. Org. Chem. 1985, 50, 657–661.
5. Perrier, H.; Huyer, G.; Young, R. N. Tetrahedron Lett. 1992,
33, 725–728.
4.6.13. 7-Methyl-5,2-oxathiospiro[4.5]dec-6-ene (2m).
1
Colorless oil. H NMR (200 MHz, CDCl3) d 1.66 (3H, s),
6. Ko, K.-Y.; Eliel, E. L. J. Org. Chem. 1986, 51, 5353–5362.
7. Frye, S. V.; Eliel, E. L. J. Am. Chem. Soc. 1988, 110,
484–489.
1.70–2.05 (6H, m), 3.10 (2H, m), 4.12 (1H, ddd, J¼9.2, 6.7,
5.7 Hz), 4.24 (1H, ddd, J¼9.2, 5.8, 5.3 Hz), 5.53 (1H, m).
13C NMR (50 MHz, CDCl3) d 21.4, 23.4, 29.6, 34.1, 37.5,
69.9 (C-4), 92.8 (C-1), 125.6 (C-6), 137.9 (C-7). MS, m/z
(%): 39 (18.9), 60 (13.7), 77 (9.8), 79 (10.9), 82 (79.9), 95
(11.3), 111 (100), 170 (Mþ, 34.0), 172 (1.8). Elemental
analysis: found C, 63.21; H, 8.33; O, 9.55; S, 18.65.
C9H14OS requires C, 63.47; H, 8.30; O, 9.39; S, 18.83%.
8. Bai, X.; Eliel, E. L. J. Org. Chem. 1992, 57, 5162–5166.
´
9. Solladie-Cavallo, A.; Diep-Vahuule, A.; Sunjic, V.; Vinkovic,
V. Tedrahedron: Asymmetry 1996, 7, 1783–1788.
10. Aggarwal, V. K.; Ford, J. G.; Fonguerna, S.; Adams, H.; Jones,
R. V. H.; Fieldhouse, R. J. Am. Chem. Soc. 1998, 120,
8328–8339.
11. Larder, B. A.; Kemp, S. D.; Harrigan, P. R. Science 1995,
269(5224), 696–699.
4.6.14. 4-Phenyl-7-hydroxy-5-thiaheptan-2-one (3a).
1
Colorless oil. H NMR (200 MHz, CDCl3) d 2.05 (3H, s),
12. Djerassi, C.; Gorman, M. J. Am. Chem. Soc. 1953, 75,
3704–3708.
2.45 (2H, t, J¼5.9 Hz), 2.90 (2H, dd, J¼7.2, 3.1 Hz), 3.55
(2H, m), 4.30 (1H, t, J¼7.2 Hz), 7.1–7.3 (5H, m). 13C NMR
(50 MHz, CDCl3) d 30.8, 34.2, 43.8, 50.2, 60.8, 127.6,
128.1, 128.9, 142.0, 205.6. MS, m/z (%): 43 (100), 77 (16.3),
103 (22.0), 105 (19.6), 147 (14.4), 179 (6.0), 206 (2.2), 224
(Mþ, 3.6), 226 (0.2). IR (cm21): 1712, 3432.
13. Wilson, G. H.; Huang, M. G.; Schloman, W. W. J. Org. Chem.
1968, 33, 2133–2134.
14. Karimi, B.; Seradj, H. Synlett 2000, 805–806.
15. Yadav, J. S.; Reddy, B. V. S.; Pandey, S. K. Synlett 2001,
238–239.
16. Perio, B.; Dozias, M.-J.; Hamelin, J. Org. Process Res. Dev.
1998, 2, 428–430.
4.6.15. 2-Methyl-2-[5-hydroxy-2-phenyl-3-thiapentyl]-
1,3-oxathiolane (4a). Colorless oil. 50:50 mixture of two
diastereoisomers. 1H NMR (200 MHz, CDCl3) d 1.39þ1.45
(3H, s), 2.45 (4H, m), 3.05 (2H, m), 3.55 (2H, m), 4.08 (3H,
m), 7.1–7.3 (5H, m). 13C NMR (50 MHz, CDCl3) d 29.7
(£2), 34.3 (£2), 34.5, 45.6, 45.9, 49.0, 49.3, 60.3 (£2), 70.0,
70.3, 127.4, 128.1, 128.7, 143.2. MS, m/z (%): 43 (92.9), 77
(10.0), 103 (100), 147 (18.3), 167 (7.1), 179 (7.6), 206
(12.7), 239 (3.6), 284 (Mþ, 7.0), 286 (0.7).
17. Perio, B.; Hamelin, J. Green Chem. 2000, 2, 252–255.
18. Kerverdo, S.; Loiseau, M.; Lizzani-Cuvelier, L.; Dun˜ach, E.
Chem. Commun. 2001, 2284–2285.
19. Meskens, A. J. Synthesis 1981, 501–522, and references cited
therein.
20. During the submission of this manuscript, a few examples of
exchange reactions with unsaturated acetals and thiols have
been reported in: Ranu, B. C.; Das, A.; Samanta, S. Synlett
2002, 727–730. Kamal, A.; Chouhan, G.; Ahmed, K.
Tetrahedron Lett. 2002, 43, 6947–6951.
4.6.16. 4-Styryl-3,5-dithiaheptan-1,7-diol (5b). White
solid, Mp 87–888C. 1H NMR (200 MHz, DMSO-d) d
2.70 (4H, td, J¼6.4, 3.0 Hz), 3.57 (4H, q, J¼6.4 Hz), 4.80
(1H, d, J¼9.0 Hz), 4.86 (2H, t, J¼5.5 Hz), 6.19 (1H, dd,
J¼15.6, 9.0 Hz), 6.60 (1H, d, J¼15.6 Hz), 7.25–7.55 (5H,
m). 13C NMR (50 MHz, DMSO-d6) d 33.2, 50.8, 60.5,
126.3, 127.8, 128.0, 128.6, 130.3, 135.7. IR (cm21): 3298.4.
Elemental analysis: found C, 57.74; H, 6.76; O, 11.65; S,
23.61. C13H18O2S2 requires C, 57.73; H, 6.72; O, 11.83; S,
23.72%.
21. Hoffman, R. V. Tetrahedron Lett. 1974, 28, 2415–2416.
22. Nieddu, E.; Cataldo, M.; Pinna, F.; Strukul, G. Tetrahedron
Lett. 1999, 40, 6987–6990.
23. Lu, T.-J.; Yang, J.-F.; Sheu, J. Org. Chem. 1995, 60,
2931–2934.
24. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357–1358.
25. Gasparrini, F.; Giovannoli, M.; Misiti, D. Tetrahedron 1984,
40, 1491–1500.
26. Taylor, E. C.; Conley, R. A.; Johnson, D. K. J. Org. Chem.
1980, 45, 3433–3436.
27. The molar ratio of acid per gram of APSG was calculated
according to Ref. 25.
References
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3363–3366.
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