Regioselective synthesis of heterocycles by sigmatropic rearrangement: Passage to 3,11a-dimethyl-6a,11a-dihydro-1h,6h-pyrano[3′,4′:5,6]thiopyrano [4,3-b][1]benzofuran-1-one

Full text of DOI:10.1039/b206287a

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Regioselective synthesis of heterocycles by sigmatropic
rearrangement: passage to 3,11a-dimethyl-6a,11a-dihydro-1H,6H-
pyrano[3Ј,4Ј:5,6]thiopyrano[4,3-b][1]benzofuran-1-one†
1
Krishna C. Majumdar,* Uday K. Kundu and Subhojit Ghosh
Department of Chemistry, University of Kalyani, Kalyani, 741235, W.B., India
Received (in Cambridge, UK) 28th June 2002, Accepted 12th August 2002
First published as an Advance Article on the web 30th August 2002
A number of hitherto unreported 3,11a-dimethyl-6a,11a-
dihydro-1H,6H-pyrano[3Ј,4Ј:5,6]thiopyrano[4,3-b][1]benzo-
furan-1-ones 11a,b,c have been synthesized in good yields
(60–67%) by the thermal rearrangement of 4-aryloxymethyl-
7-methylthiopyrano[3,2-c]pyran-5-ones 6a,b,c. Compounds
6a,b,c were in turn synthesized in 75–85% yields by the thermal
rearrangement of 4-(4Ј-aryloxybut-2Ј-ynylthio)-6-methylpyran-
2-ones 5a,b,c. Compounds 5a,b,c were obtained in 54–55%
yields by the phase-transfer catalysed alkylation of 4-mercapto-
6-methyl-2-pyrone 3 with 1-aryloxy-4-chlorobut-2-yne 4a,b,c.
The 4-hydroxy-6-methyl-2-pyrone (triacetic acid lactone)
moiety is important in its occurrence in a number of naturally
occurring compounds.1 Some of these natural products contain
biogenetically plausible groups at C3 or C5 or both. Elasnin,
isolated from Steptomyces sp., for example, is a specific inhib-
itor of human leucocyte elastase, an enzyme involved in
inflammatory processes such as pulmonary emphysema.2 As
a logical extension, many more simple pyrones structurally
analogous to elasnin have been synthesized and evaluated as
inhibitors of several elastases.3 Some 4-hydroxy-2-pyrones have
also been tested as anticoagulant agents.4 As a continuation
of our interest in the synthesis of bioactive heterocycles5 by
the application of sigmatropic rearrangements,6 we recently
reported the synthesis of fused pyranopyrone7 and pyrido-
pyrone8 polyheterocycles. These successful syntheses demanded
that our endeavour be directed towards the utilization of this
novel methodology in order to determine a convenient route to
the corresponding sulfur analogues.
Scheme 1
aryloxybut-2Ј-ynyloxy)-6-methylpyran-2-ones, only exocyclic
products corresponding to 10 were obtained.7 Synthesis of
pyridinopyrone heterocycles from 4-(N-4Ј-aryloxybut-2Ј-ynyl)-
N-methylamino-6-methylpyran-2-ones also afforded chiefly the
exocyclic derivatives along with the endocyclic compounds as
minor products corresponding to 6 only in three cases.8
Formation of 6 from 5 can be mechanistically devised as
outlined in Scheme 2. [3,3] Sigmatropic rearrangement at the
The starting materials for this investigation, 4-(4Ј-aryloxy-
but-2Ј-ynylthio)-6-methylpyran-2-ones 5a,b,c were synthesized
by treating 4-mercapto-6-methylpyran-2-one 3 with 1-aryloxy-
4-chlorobut-2-yne 4a,b,c at room temperature under phase
transfer catalysis conditions using benzyltriethylammonium
chloride (BTEAC). Compounds 5a,b,c were characterised from
their spectroscopic data and elemental analysis. Compound 3,
in turn, was prepared by the reaction of 6-methyl-4-tosyloxy-
pyran-2-one9 2 with NaSH in dry ethanol at room temperature
under a nitrogen atmosphere (Scheme 1).
Substrates 5a,b,c are endowed with a vinyl propargyl‡ sulfide
moiety as well as an aryl propargyl ether segment. Compounds
with this structural feature are expected to be prone to thermal
[3,3] sigmatropic rearrangements. Thus compounds 5a,b,c offer
excellent scope for the study of competition between oxy-
and thio-Claisen rearrangements as well as the synthesis of
new heterocycles. With these premutations, substrate 5a
was refluxed in chlorobenzene (131–132 ЊC). A change was
observed by TLC within 30 min. The starting material
completely disappeared to give a pale yellow solid (mp 126–
127 ЊC) in 5 h (TLC monitoring). The structure of product 6a
was ascertained from its elemental analysis and spectroscopic
data. The pmr spectrum of compound 6a displayed a two-
proton doublet at δ 3.38 (J 6 Hz) due to C2-H and a one-proton
triplate at δ 6.12 (J 6Hz) assignable to C3-H. It is noteworthy
that in the synthesis of pyranopyrone derivatives from 4-(4Ј-
Scheme 2
vinyl propargyl sulfide moiety of compound 5 furnished the
allenyl intermediate 7. Intermediate 7 may undergo tautomeris-
ation to generate 8. A [1,5] H shift in 8 may give 9. 6π Electro-
cyclic ring closure in 9 may finally afford product 6.
Compound 6 still possesses an aryl allyl ether moiety and so
it is expected to undergo a thermal [3,3] sigmatropic rearrange-
ment. We, therefore, subjected compound 6a to thermal
rearrangement in refluxing o-dichlorobenzene (179–181 ЊC) and
the isolated product was shown to be compound 11a from its
elemental analysis and spectroscopic data (Scheme 3). Two
C6-H and the C6a-H appeared as three one-proton doublet of
doublets at δ 2.88 (J 9.9, 13.5 Hz), 3.05 (J 3.9, 13.5 Hz) and 3.57
(J 3.9, 9.9 Hz). Compounds 6b,c were similarly treated to
obtain compounds 11b,c.
Formation of 11 from 6 can be rationalized as shown in
Scheme 4. [3,3] Sigmatropic rearrangement in 6 may produce
† Electronic supplementary information (ESI) available: General experi-
mental procedures. See http://www.rsc.org/suppdata/p1/b2/b206287a/
DOI: 10.1039/b206287a
J. Chem. Soc., Perkin Trans. 1, 2002, 2139–2140
This journal is © The Royal Society of Chemistry 2002
2139

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Acknowledgements
We thank the CSIR (New Delhi) for financial assistance and the
University of Kalyani for laboratory facilities.
References
‡ The IUPAC name for propargyl is prop-2-ynyl.
Scheme 3
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Scheme 4
intermediate 12. Intermediate 12 may tautomerize to 13 which,
on ‘5-exo’ ring closure, should give compound 11.
Substrates 5a,b,c underwent [3,3] sigmatropic rearrange-
ment at the vinyl propargyl sulfide segment instead of the aryl
propargyl ether moiety. A lesser energy requirement for the
sigmatropic rearrangement in vinyl propargyl systems10 com-
pared to that in aryl propargyl moieties11 may be responsible
for this regioselectivity. Thiopyranopyrone derivatives 6a,b,c
were exclusively obtained in all cases. Thio-Claisen rearrange-
ment of aryl propargyl sulfide is known to give a mixture of two
products viz. 2H-thiochromene and 2-methylthianaphthalene.12
Thio-Claisen rearrangement of heterocyclic substrates is also
known to be accompanied by a [1,3] radical shift.13 However in
the present instance none of the examples gave a mixture of
products which is again a general phenomenon shown by earlier
workers.14
In conclusion, we have successfully exploited thermal sigma-
tropic rearrangements as an expedient avenue towards the
synthesis of fused furanothiopyran heterocyclic ring systems.
This type of ring system is otherwise difficult to construct. The
synthetic approach adopted here may be considered as a mild
and facile pathway for the synthesis of fused furanothiopyran
heterocyclic systems.
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2140
J. Chem. Soc., Perkin Trans. 1, 2002, 2139–2140