A novel tandem [4++2] cycloaddition-elimination reaction of 4,4- dimethyl-2-styryl-1,3-oxathianes with olefins

Article abstract of DOI:10.1016/S0040-4039(99)02064-X

A novel tandem [4⁺+2] cycloaddition-elimination reaction of 1,3- oxathianes 1a, b with olefins promoted by titanium tetrachloride to give 3,4- dihydro-2H-thiopyrans 3 was developed. 4,4-Dimethyl-2-styryl-1,3-oxathiane (1a) was used as a synthet

Full text of DOI:10.1016/S0040-4039(99)02064-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 371–375
A novel tandem [4++2] cycloaddition–elimination reaction of
4,4-dimethyl-2-styryl-1,3-oxathianes with olefins
Kiyoharu Nishide, Shin-ichi Ohsugi and Manabu Node ∗
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 15 October 1999; revised 27 October 1999; accepted 29 October 1999
Abstract
A novel tandem [4++2] cycloaddition–elimination reaction of 1,3-oxathianes 1a,b with olefins promoted by
titanium tetrachloride to give 3,4-dihydro-2H-thiopyrans 3 was developed. 4,4-Dimethyl-2-styryl-1,3-oxathiane
(1a) was used as a synthetic equivalent of a highly reactive thiocinnamaldehyde. Geminal dimethyl substituents at
the 4-position of 1,3-oxathianes 1 are an intrinsic part of this cycloaddition–elimination reaction. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: oxathianes; tandem [4++2] cycloaddition–elimination reaction; thiocarbonyl compounds; thiopyrans.
The hetero Diels–Alder reaction of α,β-unsaturated thioketones is an important method for the synthe-
sis of six-membered heterocycles containing a sulfur atom.1 The α,β-unsaturated thioketones used in this
cycloaddition2 and its asymmetric versions3 are, however, limited to relatively stable phenyl thioketone
derivatives (such as thiochalcone) in most cases. On the other hand, α,β-unsaturated thioaldehydes and
aliphatic thioketones are known to be highly reactive to polymerization or dimerization. For example,
thioacrolein generated by pyrolysis of diallyl sulfide polymerizes even at low temperature4 and methyl
vinyl thioketone readily dimerizes through a hetero Diels–Alder reaction.5 A little attention has been
directed to the Diels–Alder trapping of α,β-unsaturated thioaldehydes.6 Therefore, the challenge lies
in controlling their chemical reactivity for utilization in organic synthesis. We report herein a novel
tandem [4++2] cycloaddition–elimination reaction of 1,3-oxathianes A as synthetic equivalents of α,β-
unsaturated thioaldehydes with olefins to give 3,4-dihydro-2H-thiopyrans D, as shown in Scheme 1.
Thienium cations can be subjected to cationic [2++4] polar cycloadditions as hetero dienophiles7 or to
cationic [4++2] polar cycloadditions as 2-heterodienes.8 Consequently, if the alkyl moiety on the sulfur
atom were designed to be eliminated from the sulfonium cation intermediate C, the α,β-unsaturated
thienium cation B, as a 1-heterodiene, would open a new type of reaction, a [4++2] cycloaddition with an
olefin to give a 3,4-dihydro-2H-thiopyran D. The thienium cation B must therefore be readily generated
by coordination of a hard Lewis acid with the monothioacetal A, which can control polymerization of
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02064-X
tetl 15992

372
Scheme 1.
the α,β-unsaturated thioaldehyde. For the above strategy to work, the selective coordination of a Lewis
acid to the oxygen of monothioacetal A and the subsequent elimination of the exocyclic substituent on
the sulfur atom from the cationic cycloadduct C were required. Accordingly, we designed 1,3-oxathianes
1a,b with dimethyl substituents at the carbon adjacent to the sulfur atom. The methyl groups would retard
the coordination of the Lewis acid to the sulfur atom because of steric hindrance and would facilitate the
elimination of the exocyclic substituent due to the stability of the carbocation to be removed.
The results of this tandem [4++2] cycloaddition–elimination reaction of 1,3-oxathianes 1a,b9 with
olefins 2 are summarized in Table 1. Treatment of 1a and 1,1-diphenylethylene (2a) with titanium tetra-
chloride in dichloromethane at −78°C gave the desired 3,4-dihydro-2H-thiopyran 3aa in 88% yield (entry
1). The reactions of 1a with α-alkylstyrenes 2b–e afforded 3ab–3ae in lower yields than those with 2a
(entries 2–5). The moderate yields are attributable to competitive polymerization of the α-alkylstyrenes
2b–e promoted by titanium tetrachloride. Although the reaction of 40-bromo-α-methylstyrene 2f gave the
3,4-dihydro-2H-thiopyran 3af (entry 6), the o-bromo- and o-methoxy substituents on the phenyl group
of α-methylstyrene resulted in unreacted starting material. Allyltrimethylsilane (2g) also afforded the
desired 3,4-dihydro-2H-thiopyran 3ag, along with the γ-allylated alcohol (trans-3,3-dimethyl-7-phenyl-
4-thia-5,9-decadien-1-ol) (entry 7). The reactions of 1b having the 4-methoxyphenyl substituent as R1
Table 1

373
proceeded slowly to give the corresponding dihydrothiopyrans 3ba, 3bb and 3bd, but the yields were
higher than those of 3ab and 3ad (entries 8–10). The electron donating effect of the p-methoxy group
on the phenyl substituent was obviously affected by the stability of the α,β-unsaturated thienium cation
intermediate (B). All these reactions showed cis diastereoselectivity10 varying from 10:1 to 1.2:1.
To prove the significance of geminal dimethyl substituents on 1,3-oxathiane 1a, we tested the reactivity
of 2-styryl-1,3-oxathiane (4), as shown in Scheme 2. The tandem reaction of 4 with α-methylstyrene 2b
(4 equiv.) activated by titanium tetrachloride (1 equiv.) in dichloromethane at −78°C did not take place.
Furthermore, the reaction of 4 with allyltrimethylsilane (4 equiv.) gave only the γ-allylated alcohol in
low yield (25%). The above results indicate that the geminal dimethyl substituents at the 4-position of
1,3-oxathianes 1a,b are an intrinsic part of this tandem [4++2] cycloaddition–elimination reaction.
Scheme 2.
The formation of 3,4-dihydro-2H-thiopyran 3 can be formally interpreted as being the result of a
hetero Diels–Alder reaction of an α,β-unsaturated thioaldehyde with an olefin. Although we cannot rule
out the mechanism of the concerted process (hetero Diels–Alder reaction) at present, we believe that this
[4+2] cycloaddition proceeds 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; and (2) the reactive olefins were limited to α-substituted styrenes and
allylsilane, which generate stable cations by the attack of an electrophile. Furthermore, the generation of
free thiocinnamaldehyde from the thienium cation E can probably be excluded, because the starting 1,3-
oxathiane 1a was recovered in 87% yield when 1a without α-methylstyrene was treated with titanium
tetrachloride (1.0 equiv.) in dichloromethane at −78°C for 1 h. A plausible reaction mechanism of 1a
with α-methylstyrene (2b) is illustrated in Scheme 3.
Scheme 3. A plausible reaction mechanism

374
The selective coordination of titanium tetrachloride to the oxygen of 1,3-oxathiane 1a would initially
generate the α,β-unsaturated thienium cations E. Electrophilic attack of E on α-methylstyrene would
give the carbocation intermediates F and G. 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 six-membered ring and would be transformed into F via reversion to E.
The cleavage of the carbon–sulfur bond of the sulfonium intermediates H and I in path b furnished
the cationic [4++2] cycloaddition reaction to give 3,4-dihydro-2H-thiopyrans 3, while the cleavage of
the other carbon–sulfur bond, via path a, led 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.
In summary, we have exploited a novel tandem [4++2] cycloaddition–elimination reaction using
1,3-oxathianes 1a,b as synthetic equivalents of α,β-unsaturated thioaldehydes to give 3,4-dihydro-2H-
thiopyrans. It is worth noting that, because of their high reactivity, it is difficult to synthesize of α,β-
unsaturated thioaldehydes; however, α,β-unsaturated 1,3-oxathianes, as substrates in this reaction, can be
easily prepared from the corresponding aldehydes by monothioacetalization using mercaptoalcohol. This
tandem reaction therefore offers a new method of controlling the high reactivity toward polimerization
of α,β-unsaturated thioaldehydes. Further studies on the chemistry of 4,4-dimethyl-1,3-oxathianes are in
progress.
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9. 1,3-Oxathianes 1a,b were easily prepared from 3-mercapto-3-methyl-1-butanol and the corresponding aldehydes catalyzed
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