Thio Diels-Alder reactions of α,β-unsaturated 1,3-oxathiolanes with aliphatic olefins and 1,3-dienes

Article abstract of DOI:10.1016/j.tetlet.2003.09.194

A series of α,β-unsaturated 1,3-oxathiolanes reacted with aliphatic olefins such as norbornene and with various 1,3-dienes in the presence of TiCl₄ leading to dihydrothiapyrans, via a cycloaddition-type reaction. The unsaturated oxathiolanes acted as masked heterodienes in this thio Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2003.09.194

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8841–8844
Thio Diels–Alder reactions of a,b-unsaturated 1,3-oxathiolanes
with aliphatic olefins and 1,3-dienes
Se´bastien Kerverdo,a Louisette Lizzani-Cuveliera and Elisabet Dun˜acha,b,
*
aLaboratoire Aroˆmes, Synthe`ses et Interactions, Universite´ de Nice-Sophia Antipolis, 06108 Nice Cedex 2, France
bLaboratoire de Chimie Bio-Organique, UMR CNRS 6001, Universite´ de Nice-Sophia Antipolis, 06108 Nice Cedex 2, France
Received 7 July 2003; revised 19 September 2003; accepted 23 September 2003
Abstract—A series of a,b-unsaturated 1,3-oxathiolanes reacted with aliphatic olefins such as norbornene and with various
1,3-dienes in the presence of TiCl4 leading to dihydrothiapyrans, via a cycloaddition-type reaction. The unsaturated oxathiolanes
acted as masked heterodienes in this thio Diels–Alder reaction.
© 2003 Elsevier Ltd. All rights reserved.
Thio Diels–Alder reactions have been widely applied in
organic chemistry,1,2 providing useful methodology for
the synthesis of natural products through the formation
of thiapyran structures.3–5 These heterocycles can be
prepared by the cycloaddition of a thiocarbonyl com-
pound with a conjugated diene,6 or by that of an
a,b-unsaturated thiocarbonyl derivative with an olefin.7
However, thioketones or thioaldehydes are generally
unstable, even at low temperature.8,9 These highly reac-
tive thio-compounds are generally not isolated, but
generated and trapped in situ.10 a,b-Unsaturated
oxathioacetals have also been used as masked heterodi-
enes to achieve a thio Diels–Alder cycloaddition.11,12
However, these cycloadditions have only been reported
with styrene derivatives as the dienophiles.
We present here new examples of the reactions of
a,b-unsaturated oxathiolanes13 with aliphatic olefins
and 1,3-dienes. To the best of our knowledge, this is
the first report dealing with the thio Diels–Alder
reactions of oxathiolanes with aliphatic olefins, such
as norbornene, or with 1,3-dienes, reacting as
dienophiles.
Non-activated terminal aliphatic olefins demonstrated a
low reactivity in the thio Diels–Alder reactions with
Scheme 1. Reaction of oxathiolane 1a with 1-decene.
Keywords: thio Diels–Alder; cycloaddition; heterodienes; dihydrothiapyrans; titanium tetrachloride.
* Corresponding author. Fax: +33-(0)4-9207-6151; e-mail: dunach@unice.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.194

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S. Ker6erdo et al. / Tetrahedron Letters 44 (2003) 8841–8844
summarizes the isolated yields of thiapyrans resulting
from the reaction of various oxathiolanes 1 with nor-
bornene. The Table only presents the structures of the
major diastereomer of the thiapyrans 3–7 obtained. The
determination of the relative stereochemistry of these
compounds was achieved by NOESY and COSY H
NMR correlations.
a,b-unsaturated oxathiolanes. Thus, the cycloaddition
performed with oxathiolane 1a and 1-decene in the
presence of TiCl4 (Scheme 1) afforded the thiapyran 2
in only 2% isolated yield, with a cis–trans ratio of 74:26.
Thiapyran 2 was obtained regioselectively: according to
the NMR analysis, the n-octyl group was located at the
2-position of 2 (a to the S) in both stereoisomers.
1
The reaction of 1a with norbornene led to the thiapyran
3 in a 77% isolated yield, as a 98:2 mixture of stereoiso-
mers (entry 1). Only the major diastereomer was iso-
lated and characterized. The NOESY 1H NMR
spectrum showed a correlation between the two protons
H-2 and H-3 located at the ring junctions, indicating
the cis ring fusion. A correlation was also observed
between H-4 and H-4% of the bridging methylene group
The cycloaddition involving 1 is proposed to proceed
by ring-opening of the oxathiolane by the strong Lewis
acid, followed by addition of the olefin and elimination
of an epoxide to furnish the expected thiapyran 2
(Scheme 1).
The use of norbornene, as a more reactive olefin gave
an increased yield of the cycloaddition product. Table 1
Table 1. Thio Diels–Alder reactions with oxathiolanes 1 and norbornenea
a
General procedure: To a vigorously stirred solution of 1 (1.0 mmol) in dichloromethane (10 mL) at −45°C under an inert atmosphere was added
a CH2Cl2 solution of titanium tetrachloride (1.0 mmol). After formation of an orange precipitate, norbornene (3.0 mmol) was added. After the
complete disappearance of the orange precipitate, the solution was quenched with an aqueous solution of potassium hydroxide (1.0 mol/L). After
filtration over Celite, the crude mixture was twice extracted with diethyl ether. The organic layers were dried over MgSO4, and the solvent was
removed in vacuo. The crude product was purified by silica-gel column chromatography with a mixture of hexane/CH2Cl2 (100/0 to 80/20) as
the eluent.
b Calculated by GC (except for entry 3). The structure of the minor isomer was not determined.
c Estimated by 13C NMR. The structure of the other isomer presents H-2 and H-3 (cis) in a trans position relative to the methylene bridge but
now trans to Me-8 which keeps its absolute stereochemistry.

S. Ker6erdo et al. / Tetrahedron Letters 44 (2003) 8841–8844
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of the norbornene substructure. It is noteworthy that
three new chiral centers were created in 3, indicating
that the reaction proceeded with excellent stereoselec-
tivity. The oxathiolane 1b, an equivalent of thio-cin-
namaldehyde, reacted with norbornene to afford 4 in
56%, yield with a 90:10 ratio of two diastereoisomers
(entry 2). As observed for adduct 3, the major isomer of
4 also presented a cis-ring junction and the phenyl
group in a cis position with respect to H-3.
tion of aliphatic and aromatic unsaturated oxathio-
lanes, as masked heterodienes, with aliphatic olefins.
We then examined the reactivity of some 1,3-dienes in
the thio Diels–Alder reaction with oxathiolanes 1a and
1c under our standard conditions. The results and
yields of the cycloadducts are presented in Table 2 and
indicated that the 1,3-dienes could act, with substrates
1, as electron-rich dienophiles. Thus, the cycloaddition
of 1a and 2,5-dimethylhexadiene gave a 47% isolated
yield of the thiapyran 8 with a 60:40 ratio of the two
diastereomers (entry 1). The reaction proceeded regiose-
lectively, with the remaining double bond of the diene
located a to the S atom in 8. The relative stereochemi-
cal assignment for each isomer was not established. The
reaction of 1a with 1,3-cyclohexadiene led to the forma-
tion of 9 in 20% yield, with very good stereoselectivity,
99:1 (entry 2). By NMR analogy, the main stereoisomer
corresponded to the structure represented shown. In
this case, the formation of adducts (12%) resulting from
the Diels–Alder cycloaddition of 1,3-cyclohexadiene
and the double bond of the oxathiolane 1a was also
observed. Thus, there is competition between the thio
Diels–Alder and the normal Diels–Alder reactions, and
the nature of the major product seems to depend on the
structure of the 1,3-diene. In the case of 2,3-
dimethylbutadiene, we did not observe the formation of
the thio Diels–Alder adducts, but only the normal
Diels–Alder cycloadduct 10 in 43% isolated yield (entry
The reaction of norbornene with aliphatic oxathiolanes
1c–e afforded the cycloadducts 5–7. The optically pure
thio-pulegone analogue 1c13 led to a mixture of two
diastereomers of 5 in 64% isolated yield (entry 3). The
ratio of the two isomers was estimated by 13C NMR to
be close to 50:50. The thiapyrans 6 and 7 were obtained
in 9 and 10% yields, respectively (entries 4 and 5).
These low yields could be explained by the poor stabil-
ity of the corresponding aliphatic oxathiolanes 1d and
1e in the presence of TiCl4, even at low temperature
(−45°C). The stereochemistry of 6 was determined by
NOESY and by comparison with the data for 3 and 4
with the results indicating that a single stereoisomer
was present. In the case of 7, the main stereoisomer
obtained had the same stereochemical arrangement as
found in structures 3 and 4.
It is noteworthy that the reactions presented in Table 1
constitute the first examples of a successful cycloaddi-
Table 2. Cycloaddition of oxathiolanes 1 and 1,3-dienes
a
H-2 and H-3 are cis to one another and, cis or trans with respect to the chiral methyl group.
b Calculated by GC.

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S. Ker6erdo et al. / Tetrahedron Letters 44 (2003) 8841–8844
3). In contrast, the cycloaddition of the aliphatic
oxathiolane 1c with 1,3-cyclohexadiene afforded the
tricyclic thiapyran 11 in a 37% yield via a thio Diels–
Alder process, as a 63:37 mixture of two diastereoiso-
mers, both with a cis-ring junction (entry 4).
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