Synthesis of thiepin-annulated pyrone and coumarin heterocycles by Grubbs' second generation catalyst mediated enyne metathesis

Article abstract of DOI:10.1246/cl.2006.1430

Synthesis of thiepin-annulated pyrone and coumarin derivatives has been achieved by the ring-closing enyne metathesis using the second generation Grubbs' catalyst under a nitrogen atmosphere. Copyright

Full text of DOI:10.1246/cl.2006.1430

1430
Chemistry Letters Vol.35, No.12 (2006)
Synthesis of Thiepin-annulated Pyrone and Coumarin Heterocycles
by Grubbs’ Second Generation Catalyst Mediated Enyne Metathesis
K. C. Majumdar,Ã S. Muhuri, H. Rahaman, R. Islam, and B. Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B. India
(Received October 10, 2006; CL-061175)
Synthesis of thiepin-annulated pyrone and coumarin deriva-
This prompted us to investigate the metathesis reactions using
catalyst B on the substrates 2-pyrone and coumarin containing
sulfur atoms to verify the compatibility and effectiveness of
the catalyst B towards the sulfur-containing substrates to achieve
the synthesis of some hitherto unreported thiepin-annulated het-
erocyclic systems of interest. Herein, we report our results.
Compounds 5a–5d were prepared by the treatment of
4-sulfanylbenzopyran-2-one 3 with 1-aryloxy-4-chlorobut-2-
ynes (or 1,4-dichlorobut-2-yne) 4a–4d at room temperature for
5–6 h under phase transfer catalyzed condition using benzyltri-
ethylammonium chloride (BTEAC). Compound 3 in turn was
synthesized by the reaction of 3-allyl-4-tosyloxybenzopyran-
2-one 2 with NaSH in dry ethanol at room temperature for 2 h
under nitrogen atmosphere (Scheme 1).
Attempts to carry out the metathesis reaction of the
substrates 5a–5d with Grubbs’ catalyst A in dichloromethane,
benzene, and toluene proved unsuccessful. Only decomposition
of the catalyst was observed. This observation supports earlier
reports that the sulfide substrates poison the catalyst A. We then
decided to use the ruthenium catalyst B for the enyne metathesis
of the sulfur-containing substrates. Accordingly the substrate 5a
in the presence of 10 mol % catalyst B was refluxed for 6 h in
benzene. Cyclized product 6a was obtained in 65% yield. Other
substrates 5b–5d were similarly treated with catalyst B to give
6b–6d in 65–72% yields, respectively (Scheme 2).
tives has been achieved by the ring-closing enyne metathesis
using the second generation Grubbs’ catalyst under a nitrogen
atmosphere.
Coumarin and 2-pyrone are important heterocyclic com-
pounds because these nuclei are found in many natural prod-
ucts.1 Coumarins fused with other heterocycles have interesting
biological and photodynamic properties.2 Several natural3 and
synthetic4 2-pyrones exhibit remarkable biological activity.
Recently, we have demonstrated the synthesis of pyrone and
coumarin-annulated heterocycles by the application of the
Claisen rearrangement5 and radical cyclization.6 However there
is no report on the thiepin-annulated coumarin and pyrone deriv-
atives. In recent years, the metathesis7 (ring-closing metathesis
or ring-closing enyne metathesis) strategies have been found to
be practical methods for the synthesis of medium-sized rings,8
spirocyclic and polycyclic systems,9 and several natural prod-
ucts.10 Metathesis reactions on substrate bearing diverse func-
tionalities and heteroatoms are fully documented.7b,7c Surpris-
ingly, however very limited examples of substrates containing
sulfur atom have so far been reported. The limited number of
examples of metathesis with sulfur containing substrates can
be partly explained by the fact that middle to late transition
metals used as catalyst may interact favorably with soft sulfur
atom.
Tungsten,11 molybdenum,12 and titanium13 catalysts were
until lately the only three catalysts to display efficiency in
metathesis reactions on substrate bearing sulfur atom. Literature
report reveals that Grubbs’ catalyst A (Figure 1)14 and several
modified recyclable catalysts15 can promote metathesis reactions
on substrate containing sulfonyl groups but these are inactive to-
wards the corresponding diene sulfides with a few exceptions.16
Catalyst B was also found to be effective for the ring-closing
metathesis (RCM) of sulfonyl substrates.17 Only limited exam-
ples of the RCM of diene sulfides by the catalyst B18 and C19
are reported in the literature but there is only one example of
intermolecular enyne metathesis of sulfur containing alkyne
with ethylene using catalyst B is known.20 So far there is no re-
port of successful application of catalyst B in intramolecular
enyne metathesis of sulfur-containing heterocyclic substrates.
Once we are successful with the cyclization of the enynes
bearing coumarin sulfides, we have also investigated the poten-
tiality of catalyst B in case of enyne bearing 2-pyrone sulfide.
Compounds 10a, 10c, 10d and 11a, 11b were prepared accord-
ing to the above mentioned procedure (Scheme 3).
Compound 10a and 10 mol % of catalyst B, were refluxed in
OH
OTs
TsCl, Py,
rt, 1 h
O
1
O
O
O
2
quant. yield
NaSH, EtOH(dry),
rt, stirring, 2 h
R
S
Cl
+
SH
CHCl3 - H2O
BTEAC, 1% aq.
NaOH, rt, stirr.,
O
O
PCy3
O
O
N
N
N
N
Mes
Ph
Mes
Mes
Mes
Ph
5a - 5d
5-6 h
R
3
Cl
Cl
Ph
Ru
Cl
Cl
Cl
Cl
4a - 4d
Ru
Ru
H
PCy3
H
H
5a, R = - O-2Me-C6H4. 5b, R = -O-4Cl-C6H4
5c, R = - Cl. 5d, R = -O- 2,4Cl2-C6H3
Scheme 1.
PCy3
PCy3
A
B
C
Figure 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.12 (2006)
1431
R
( )n
O
O
O
O
S
( )n
( )n
S
S
S
m-CPBA
cat. A, 6 mol %
rt, stirring, 9 h
10 mol % cat B
DCM, rt.
O
O
O
O
5a - 5d
O
O
7 h
C6H6
11a, n = 1
11b, n = 2
13a, 82%
13b, 80%
14a, 74%
14b, 76%
O
O
reflux,
5-6 h
6a - 6d 65-72%
Scheme 5.
Scheme 2.
the first time by the catalyst B in good yield. In addition, with
the advent of well-defined metathesis catalyst we have achieved
the synthesis of structurally unique thiepin-annulated pyrone and
coumarin heterocycles which may exhibit potential biological
activity.
OH
OTs
TsCl, Py,
rt, 1 h
quant. yield
O
O
O
O
7
8
This work was financially supported by the CSIR (New
Delhi). Two of us (S. M. and R. I.) are grateful to the CSIR
(New Delhi) for providing the Senior Research Fellowship and
Mr. H. R. is grateful to the University of Kalyani for providing
a Senior Research Fellowship.
NaSH, EtOH (dry),
rt, stirring, 2 h
SH
CHCl3-H2O,
BTEAC, 1% aq.
n
Br
O
O
References
9
CHCl3-H2O, BTEAC, 1% aq.
NaOH, rt, stirr., 10 h
NaOH, rt, stirr.,
1
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Scheme 3.
R
S
8
9
10 mol % cat B
C6H6
reflux, 10 h
10a,10c,10d
O
O
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12a,12c,12d
Scheme 4.
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benzene for 10 h, under nitrogen atmosphere to give 12a in 77%
yield. Other substrates 10c and 10d were similarly treated to
afford the cyclized products 12c and 12d in 72 and 75% yields
respectively (Scheme 4).
The literature report reveals that the sulfonyl oxygen can
coordinate with the ruthenium in catalyst A.21 The sulfonyl
group is less likely to induce poisoning of the catalyst. With this
presumption compounds 13a and 13b were prepared according
to the standard m-CPBA oxidation procedure at room tempera-
ture in dichloromethane for 9 h (Scheme 5) and subjected
to the RCM reaction. Diallyl sulfone 13a and allyl–homoallyl
sulfone 13b underwent facile RCM utilizing 6 mol % of catalyst
A to yield the corresponding medium-sized cyclic sulfones 14a
and 14b in 74 and 76% yields respectively.
In conclusion metathesis reaction of enyne sulfides of differ-
ent heterocyclic systems have been successfully carried out for
Published on the web (Advance View) November 25, 2006; doi:10.1246/cl.2006.1430