Catalyst-free regioselective synthesis of benzopyran-annulated thiopyrano[2,3-b]thiochromen-5-(4H)-one derivatives by domino-Knoevenagel-hetero-Diels-Alder reaction of terminal alkynes with 4-hydroxy dithiocoumarin in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2010.02.118

The synthesis of novel pentacyclic benzopyran-annulated thiopyrano[2,3-b] thiochromen-5(4H)-ones has been described by domino-Knoevenagel-hetero-Diels-Alder reaction of 4-hydroxy dithiocoumarin and O-propargylated salicylaldehyde in aqueous medium and in

Full text of DOI:10.1016/j.tetlet.2010.02.118

Tetrahedron Letters 51 (2010) 2297–2300
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free regioselective synthesis of benzopyran-annulated
thiopyrano[2,3-b]thiochromen-5-(4H)-one derivatives by domino-
Knoevenagel-hetero-Diels–Alder reaction of terminal alkynes with
4-hydroxy dithiocoumarin in aqueous medium
*
K. C. Majumdar , Abu Taher, Sudipta Ponra
Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel pentacyclic benzopyran-annulated thiopyrano[2,3-b] thiochromen-5(4H)-ones has
been described by domino-Knoevenagel-hetero-Diels–Alder reaction of 4-hydroxy dithiocoumarin and
O-propargylated salicylaldehyde in aqueous medium and in the absence of any catalyst. The single step
reaction is highly regioselective and provides polycyclic heterocycles in high yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 January 2010
Revised 15 February 2010
Accepted 20 February 2010
Available online 24 February 2010
Keywords:
Domino-Knoevenagel-hetero-Diels–Alder
reaction
Unactivated alkynes
4
-Hydroxy dithiocoumarin
Reaction in aqueous medium
Coumarin derivatives are widely distributed in nature and show
various biological activities such as anticoagulant, antifungal, insec-
ticidal, anthelmintic, hypnotic,antioxidant,anticarcinogenicandHIV
Diels–Alder reaction. A variety of heterocycliccompoundshavebeen
synthesized by domino-Knoevenagel-hetero-Diels–Alder reaction.8
Tietze extensively described the domino-Knoevenagel-hetero-
Diels–Alder reaction of unsaturated aromatic and aliphatic alde-
hydes with several 1,3-dicarbonyl compounds for the synthesis of
1
protease inhibition. Thieno[2,3-b]benzothiopyran-4-one skeleton
has been used as an intermediate for the synthesis of a series of
2
9
anti-psychotic drugs. Similarly, pharmacophores containing a chro-
tetracycles with a pyran ring. There are several reports on the intra-
mone moiety show biological activity and many of them also have
useful medicinal applications. These wide range of biological appli-
molecular domino-Knoevenagel-hetero-Diels–Alder reaction with
alkenes but those with alkynes are rare. The reason may be the
3
10
cations have stimulated considerable interest in evolving newer
synthetic methods for the construction of polycyclic coumarin deriv-
low reactivity of unactivated alkynes compared to the correspond-
ing alkenes. Recently, Balalaie and co-workers examined a few
hetero-Diels–Alder reaction with unactivated alkynes11 using Cu -
catalyst. But to our knowledge there are no reports of domino-Knoe-
venagel-hetero-Diels–Alder reaction with unactivated alkynes in
the absence of any catalyst. Very recently, we have reported a cata-
lyst free domino-Knoevenagel-hetero-Diels–Alder reaction of unac-
I
atives. There are several examples for the synthesis of thieno[2,3-b]
4
thiochromen-4-one
one
and thiopyrano[2,3-b]thiochromen-5(2H)-
4
a,c,d,5
derivatives. In our laboratory we have synthesized couma-
rin- and pyrone-annulated [6,6]-fused benzopyranothiopyran deriv-
atives using sequential Claisen rearrangement and tributyltin
hydride-mediated radical cyclization, respectively.6 To our knowl-
edge there is no report of the synthesis of thiochromone-annulated
12
tivated alkynes. In order to expand the scope of this catalyst-free
methodology, we focused our attention on the domino-Knoevena-
gel-hetero-Diels–Alder reaction of 4-hydroxy dithiocoumarin with
unactivated terminal acetylenes. Herein, we report our results.
Necessary precursors 2a–g were prepared in high yields and
purity by the reaction of substituted salicylaldehydes 1a–g and
propargyl bromide in the presence of anhydrous potassium
[
6,6]-fused benzopyranothiopyran derivative. However, a thiochro-
mone-annulated [6,5]-fused benzofurothiopyran has been
5
b
reported. We, therefore, became interested to synthesize thiochro-
mone-annulated [6,6]-fused benzopyranothiopyran derivatives.
Recently, we have synthesized indole-annulated [6,6]-fused ben-
zopyranothiopyran derivatives7 by domino-Knoevenagel-hetero-
13
carbonate in dry DMF at room temperature (Scheme 1).
A number of reactions including Diels–Alder reaction have been
carried out in aqueous medium. Water is environment friendly,
safe and easily available in nature. Therefore, we explored the
*
Corresponding author. Tel.: +91 033 2582 7521; fax: +91 033 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
1
4
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.118

2
298
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 2297–2300
Table 2
a. R1 = R = H
2
OH
O
a
1
2
Domino-Knoevenagel-hetero-Diels–Alder reaction of 3 and 2a–g in aqueous medium
CHO
R2
b. R = Me, R = H
(i)
CHO
1
2
R1
c. R = OMe, R = H
OH
1
2
d. R = Br, R = H
R2
O
2
R
O
1
2
O
e. R = Cl, R = H
R1
H O
R1
+
2
1
2
f. R = t-Bu, R = H
R1
CHO
1a-g
reflux
1
2
S
S
2
a-g
g. R = Cl, R = Me
R2
a-g
3
S
S
2
Scheme 1. Reagents and conditions(i) propargylbromide, anhydrousK
2
CO , DMF, rt.
3
4
a-g
Entry
Aromatic aldehyde (2)
Product (4a–g)
Yieldb
use of water as a solvent for our proposed work. Accordingly, the
domino-Knoevenagel-hetero-Diels–Alder reactions of 4-hydroxy
dithiocoumarin 3 with 2a–g were carried out in aqueous medium
under refluxing condition. We have first chosen 2a as a model sub-
strate to optimize the reaction conditions (Scheme 2). The results
are summarized in Table 1.
We have examined the influence of Lewis acid, base and sol-
vents in the reaction. In our first attempt, when the reaction of 3
and 2a was carried out in the absence of any Lewis acid in water
under reflux conditions for 4 h the product 4a was obtained in
O
O
O
1
2
3
CHO
80
2a
S
S
4a
O
O
O
CHO
75
76
2b
8
0% yield (entry 1). When 20 mol % CuI was employed, the product
4
b
S
MeO
S
S
S
S
was obtained in 58% yield after 4 h (entry 2). Increasing the
amount of catalyst loading decreases the yield of the product (en-
try 3). The reason may be due to the coordination of soft sulfur
O
1
5
10
O
O
atom with the d copper ions which prevents the hetero-Diels–
Alder reaction and thereby decreasing the yield of the product.
When the reaction was carried out in the presence of triethyl
amine and CuI (20 mol %) in refluxing water for 4 h, the yield
MeO
CHO
2c
4c
S
Br
was increased to 65% (entry 4). A series of solvents (MeOH, CH
,4-dioxane, toluene) were investigated (entries 5–8). Among them
water was found to be superior to others. Similar trend was also
observed when (NH HPO was used as a base in place of triethyl
3
CN,
O
1
O
O
Br
CHO
4
5
6
79
77
72
4
)
2
4
2d
amine (entries 9–12). Further variation of the catalyst, solvent and
base proved that running the reaction in aqueous media without
any catalyst provides the best results (Table 1). Using the opti-
mized conditions, we have examined hetero-Diels–Alder reaction
of 3 and several O-propargylated salicylaldehydes (2b–g). The re-
sults are listed in Table 2.
4
d
S
Cl
O
O
S
O
Cl
CHO
2
e
4e
O
OH
S
O
O
S
O
CHO
O
O
CHO
(
i)
+
2f
S
S
S
Cl
S
S
4f
3
2a
4
a
O
Scheme 2. Reagents and conditions (i) reflux in water.
O
Cl
CHO
O
7
69
2
g
Table 1
Influence of catalyst, solvent and base on the domino-Knoevenagel-hetero-Diels–
S
4
g
Alder reactiona of 3 and 2a
a
All the reactions were carried out in refluxing aqueous medium for 4 h.
Isolated yields.
Entry
Lewis acid (mol %)
Solvent
Base
Yield (%)
b
1
2
3
4
5
6
7
8
9
—
Water
Water
Water
Water
MeOH
—
—
—
NEt
NEt
NEt
NEt
NEt
(NH
(NH
(NH
(NH
80
58
49
65
35
32
29
45
60
34
28
23
CuI (20)
CuI (30)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
3
3
3
3
3
Reaction of 3 with 1 equiv of 2b in refluxing aqueous medium
gave the product 4b in 75% yield (entry 2). When the same reaction
was carried out with 2c and 2d, the desired products 4c and 4d were
obtained in 76% and 79% yields, respectively (entries 3 and 4). The
product 4e was obtained in 77% yield when the reaction was carried
out with 2e (entry 5). Similar treatment of 2f and 2g separately with
under the same reaction conditions afforded the product 4f and 4g
in 72% and 69% yields, respectively (entries 6 and 7). The structures
of the products were determined from their elemental analyses and
3
CH CN
1,4-Dioxan
Toluene
Water
4
4
4
4
)
2
)
2
)
2
)
2
HPO
HPO
HPO
HPO
4
4
4
4
10
11
12
MeOH
CH CN
3
3
1,4-Dioxan
a
All reactions were carried out for 4 h.

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 2297–2300
2299
O
S
O
O
S
O
Path a
S
S
OH
S
7
6
O
H O
2
+
S
reflux
CHO
3
2
O
O
O
O
Path b
S
S
S
S
4
5
Scheme 3. Probable mechanism of domino-Knoevenagel-hetero-Diels–Alder reaction.
1
spectroscopic data. The characteristic peaks for 4a–g in the H NMR
(New Delhi) for providing Bruker NMR Spectrometer (400 MHz) and
Perkin–Elmer CHN Analyzer under its FIST programme.
spectra are an AB quartet for the –OCH
and 4.94 ppm followed closely by a singlet for the SCH@ proton at
d = 5.99–6.57 ppm. The corresponding carbon signal for the OCH
2
protons between d = 4.62
2
,
References and notes
13
SCH@ and C@O groups of compound 4a in the C spectra appear
at 69.7, 109.4, 177.1 ppm, respectively.16
1.
(a) Ellis, G. P.; Lockhart, I. M.; Meeder-Nycz, D.; Schweizer, E. E. In Chromenes,
Chromanones and Chromones; Ellis, G. P., Ed.; John Wiley and Sons, 1997; (b)
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der reaction of unactivated alkynes occurs without the help of a Le-
wis acid/ catalyst. In this particular case, the reactivity may
perhaps be explained by considering the presence of soft sulfur
atom in the diene moiety of the substrates. The sulfur atom may
offer itself a reactive centre and is more polarizable than the other
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Eds.; Elsevier: Amsterdam, 1996; Vol. 33, p 233.
atom having a matching symmetry with that of the
p-orbitals of
the acetylene moiety for interaction.12
A probable mechanism for the domino-Knoevenagel-hetero-
Diels–Alder reaction is depicted in Scheme 3. The first step is the
Knoevenagel condensation between 4-hydroxy dithiocoumarin 3
and O-propargylated salicylaldehyde 2 to give an alkene interme-
diate, which has not been isolated. The alkene heterodiene inter-
mediate may arrange in two different ways (intermediates 5 and
4.
(a) Majumdar, K. C.; Khan, A. T.; Saha, S. Synlett 1991, 595; (b) Majumdar, K. C.;
Bandyopadhyay, A.; Ghosh, S. K. Synth. Commun. 2004, 34, 2159; (c) Majumdar,
K. C.; Bandyopadhyay, A. Monatsh. für Chem. 2004, 135, 581; (d) Majumdar, K.
C.; Saha, S.; Khan, A. T. Indian J. Chem. 1994, 33B, 216.
5
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(a) Majumdar, K. C.; Khan, A. T.; Saha, S. Synth. Commun. 1992, 22, 901; (b)
Majumdar, K. C.; Bandyopadhyay, A.; Biswas, A. Tetrahedron 2003, 59, 5289.
(a) Majumdar, K. C.; Muhuri, S. Synthesis 2006, 2725; (b) Majumdar, K. C.;
Kundu, U. K.; Ghosh, S. K. Org. Lett. 2002, 4, 2629.
6
), one of which may undergo hetero-Diels–Alder reaction to give
two different hetero-Diels–Alder products (products 4 and 7) that
is, through ‘path a’ or ‘path b’. Here only products 4 were isolated
which shows that the reaction proceeds via ‘path b’ and it may be
attributed to the presence of the sulfur atom. High polarizability
and softness of sulfur atom make the HOMO–LUMO energy gap
smaller when thiocarbonyl group of thioester acts as heterodiene
6
7
8
.
.
Majumdar, K. C.; Taher, A.; Ray, K. Tetrahedron Lett. 2009, 50, 3889.
(a) Yadav, J. S.; Reddy, B. V. S.; Sadashiv, K.; Padmavani, B. Adv. Synth. Catal.
2
004, 346, 607; (b) Yamanaka, M.; Nishida, A.; Nakagana, M. Org. Lett. 2000, 2,
159; (c) Deligny, M.; Carreaux, F.; T oupet, L.; Carboni, B. Adv. Synth. Catal. 2003,
45, 1215; (d) Berkessel, A.; Erturk, E.; Laporte, C. Adv. Synth. Catal. 2006, 348,
3
2
4
23; (e) Baudelle, R.; Melnyk, P.; Deprez, B.; Tartar, A. Tetrahedron 1998, 54,
125.
than that of the carbonyl group of
and thus the reaction proceeds via ‘path b’ to give the products 4.
In conclusion, we have developed mild, efficient and
a,b-unsaturated ketone system
9. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Tietze, L. F.; Brasche, G.; Gericke, K.
Domino Reactions in Organic Synthesis; Wiley-VCH, 2006; (c) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967; (d) Tietze, L. F.; Ott, C.; Gerke,
K.; Buback, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1485.
a
catalyst-free protocol for the synthesis of benzopyran-annulated
thiopyranothiochromen-5(4H)-ones by domino-Knoevenagel-het-
ero-Diels–Alder reaction of unactivated terminal alkynes. The
advantage of the reaction is that water is used as a reaction media
which is benign, environment friendly and easily available in nature.
One interesting feature of this single step reaction is that C–C and
C–S bond formation occurs withoutthe help of any catalyst and base.
1
0. (a) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 1812; (b) Lee, Y. R.;
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Estevez-Braun, A.; Ravelo, A. G.; Feresin, G.; Tapia, A. Tetrahedron 2008, 64,
8938; (d) Jimenez-Alonso, S.; Estevez-Braun, A.; Ravelo, A. G.; Zarate, R.; Lopez,
M. Tetrahedron 2007, 63, 3066; (e) Manikandan, S.; Raghunathan, R.
Tetrahedron 2002, 58, 8957; (f) Yadav, J. S.; Reddy, B. V. S.; Narsimhaswamy,
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1
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Acknowledgments
2009, ix, 114; (c) Khoshkholgh, M. J.; Balalaie, S.; Bijanzadeh, H. R.; Rominger,
F.; Gross, J. H. Tetrahedron Lett. 2008, 49, 6965; (d) Khoshkholgh, M. J.; Balalaie,
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We thank CSIR (New Delhi) and DST (New Delhi) for financial
assistance. Two of us (A.T. and S.P.) are grateful to CSIR (New Delhi)
for a Senior and a Junior Research Fellowship. We also thank the DST
13. Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2004, 45, 1567.

2
1
300
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 2297–2300
4. (a) Grieco, P. A. Organic Synthesis in Water; Blacky Academic & Professonal
Publishers: London, 1998. p. 82; (b) Lindstrom, U. M. Chem. Rev. 2002, 102,
2 4
Na SO . The solvent was distilled off. The crude product was purified by
column chromatography over silica gel (60–120 mesh) using petroleum ether–
2
751; (c) Li, C.-J. Chem. Rev. 2005, 105, 3095; (d) Li, C.-J.; Chan, T.-H.
ethyl acetate mixture (85:15) as eluent to give compound 4a. Yield: 80%,
À1
Comprehensive Organic Reactions in Aqueous Media; Wiley and Sons: New
York, 2007.
colourless solid; mp 212–214 °C; IR(KBr):
m
max = 746, 1144, 1603, 2923 cm
;
1
3 H
H NMR (CDCl , 300 MHz): d = 4.65 (d, J = 12.0 Hz, 1H), 4.94 (d, J = 11.4 Hz,
1
5. Dai, J.; Munakata, M.; Wu, L.-P.; Sowa, T.-K.; Suenaga, Y. Inorg. Chim. Acta 1997,
1H), 5.45 (s, 1H), 6.04 (s, 1H), 6.51 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H),
6.82 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.50–7.65 (m, 3H), 8.51 (d,
J = 7.8 Hz, 1H) ppm. 13C NMR (100 MHz): 35.8, 72.8, 109.4, 117.0, 120.8, 121.6,
258, 65.
1
6. An equi-molar mixture of 4-hydroxy dithiocoumarin
3
and O-propargyl
salicylaldehyde 2a was refluxed in water for 4 h. After completion of the
reaction as monitored by TLC the reaction mixture was cooled and diluted with
water (50 mL). This was extracted with ethyl acetate (3 Â 25 mL). The
combined organic extract was washed with brine and dried over anhydrous
125.1, 127.1, 127.6, 127.8, 129.6, 130.4, 130.6, 131.7, 135.7, 146.1, 154.1,
+
177.0 ppm. HRMS: m/z calcd for
C
19
H
12
O
S
2 2
[M+H] : 337.0352; found;
337.0391.