Full text of DOI:10.1016/S0040-4039(00)01701-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9345–9349
A thiyl radical mediated cascade sequence for the
co-cyclisation of 1,6-hexadienes with sulfur atom transfer
David C. Harrowven,a,* Joanne C. Hannam,a Matthew C. Lucas,a Nicola A. Newmana
and Peter D. Howesb
aDepartment of Chemistry, The University, Southampton S017 1BJ, UK
bMedicinal Chemistry 2, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage,
Herts. SG1 2NY, UK
Received 31 August 2000; accepted 27 September 2000
Abstract
The paper describes a method for effecting the co-cyclisation of 1,6-dienes with concomitant sulfur
atom transfer. The key step is a cascade reaction involving the addition of a thiyl radical to an alkene,
cyclisation through a chair-like transition state and termination by homolytic substitution at sulfur. It has
been used to synthesise a broad range of fused thiabicyclo[3.3.0]octanes. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: cyclisations; photochemistry; radicals and radical reactions; sulfur heterocycles.
Radical reactions mediated by sulfur have many potential advantages over trialkylstannane
methodologies.1,2 In particular, the lower cost of reagents, the ease of work up and the reduced
toxicity of both reagents and residues are attractive features.3 In practice, sulfur-centred radical
reactions are often capricious. Indeed, the reversible nature of thiyl radical additions to alkenes,
the efficiency of hydrogen atom abstraction from thiols, and regiochemical issues that arise when
unsymmetrical dienes are employed as substrates ensure that complex product mixtures are
produced in most cases (Scheme 1).2
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01701-9

9346
We reasoned that sulfur-mediated radical cyclisations involving 1,6-dienes would be more
efficient if hydrogen atom abstraction was slowed. In particular, provided Beckwith’s guidelines
for ring closure were followed,4 cyclisation would favour generation of a radical intermediate
suitably disposed to effect an SH2 reaction at sulfur.5,6 A second cyclisation to sulfur would then
produce a cis-fused thiabicyclo[3.3.0]octane (e.g. 2) as the major product (Scheme 1).7,8
Initially our attention focused on the co-cyclisation of the commercially available 1,6-diene 3.
We found that photolysing a hexane solution of 3 and di-tert-butyl disulfide in a water cooled
quartz photochemical cell for 5 h gave the corresponding tetrahydrothiophene 4 in good yield
together with some baseline material. Reactions were much slower and less efficient when a
Pyrex photochemical cell was employed. In such cases the addition of triethylborane was found
to accelerate the reaction rate dramatically (Scheme 2).
Scheme 2.
Table 1
Examples of 1,6-diene co-cyclisation with a sulfur atom transfer

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Several related cyclisations were then conducted to explore the generality of the method and
these results are summarised in Tables 1 and 2. In general, reasonable yields were obtained for
the co-cyclisation of heptadiene derivatives and heteroatoms could be tolerated in the linking
Table 2
Examples of 1,6-diene co-cyclisation leading to diastereoisomeric products

9348
chain. The role of quaternary stereogenic centres on the course of the reaction was also
examined (Table 2).
In conclusion, we have developed a method for effecting the co-cyclisation of 1,6-dienes with
concomitant sulfur atom transfer.7 The key step is a cascade reaction involving the addition of
a thiyl radical to an alkene, cyclisation through a chair-like transition state and termination by
homolytic substitution at sulfur. A broad range of fused tetrahydrothiophenes have been
synthesised using the method and we are currently seeking to exploit the reaction in target
oriented synthesis.
Finally, it should be noted that reactions which favour chair-like transition states leading to
a trans relationship between the newly formed radical centre and the sulfide (e.g. 7“8) can also
be efficient processes.9 In such cases cyclisation to sulfur is prohibited, as evinced by our
cyclisation of diene 6 to sulfide 9 in a recent synthesis of ( )-aplysin (Scheme 3).
Scheme 3.
Acknowledgements
The authors would like to thank GlaxoWellcome and the EPSRC for financial support, the
EPSRC X-ray service at Southampton for help with the assignment of relative stereochemistries
(in Table 2) and the EPSRC mass spectrometry service at Swansea for the provision of HRMS
data.
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Department of Health, Education and Welfare: Washington, Nov. 1976.

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