Regioselective synthesis of pyrano[3,2-c]coumarins via Cu(II)-catalyzed tandem reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.061

Efficient synthesis of pyrano[3,2-c]coumarins has been achieved via copper(II) triflate catalyzed tandem reaction of 4-hydroxycoumarin with α,β-unsaturated carbonyl compounds in high yields. The catalytic reaction proceeded very smoothly under solvent-fre

Full text of DOI:10.1016/j.tetlet.2013.05.061

Tetrahedron Letters 54 (2013) 3892–3895
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Tetrahedron Letters
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Regioselective synthesis of pyrano[3,2-c]coumarins via
Cu(II)-catalyzed tandem reaction
⇑
Avik Kumar Bagdi, Adinath Majee, Alakananda Hajra
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthesis of pyrano[3,2-c]coumarins has been achieved via copper(II) triflate catalyzed tandem
Received 28 February 2013
Revised 11 May 2013
Accepted 14 May 2013
Available online 21 May 2013
reaction of 4-hydroxycoumarin with
a,b-unsaturated carbonyl compounds in high yields. The catalytic
reaction proceeded very smoothly under solvent-free conditions and showed high regioselectivity. The
synthetic potential of this methodology was explored to 4-hydroxy-6-methyl-2-pyrone successfully.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrano[3,2-c]coumarins
Tandem reaction
Copper triflate
Regioselectivity
Solvent-free
Pyranocoumarins are privileged structural motifs in naturally
occurring oxygen-ring compounds which are ubiquitous to a vari-
ety of biologically active products and have been shown to a wide
range of biological activities such as antifungal, insecticidal, anti-
cancer, anti-HIV, anti-inflammatory, antioxidants, and antibacte-
rial activities.1 Recently, they have been receiving special attention
in medicinal chemistry for the treatment of skin disorder.2 A large
number of pyranocoumarin derivatives having several structural
arrays between the coumarin and the pyran rings have been iso-
lated from nature. Notably a few important pyranocoumarins are
xanthyletin (predominantly isolated from Zanthoxylum america-
num), khellactone (isolated from Ligusticum elatum), arisugacins,
and pyripyropenes (Fig. 1).3
and a
,b-unsaturated carbonyl compounds are POCl3,4g Bronsted
acid,4e AuCl3/3AgOTf,4h etc. But these methods have many limita-
tions such as, POCl3 is not environmentally friendly, Bronsted acid
is not easily available and AuCl3/3AgOTf is highly expensive. In
addition, regioselectivity is also a major issue for these cycliza-
tions.4d In consideration of these limitations, the search for finding
a cost-effective, simple and selective protocol for the synthesis of
pyrano[3,2-c]coumarins is highly desirable.
During the past few years, significant interest has been focused
on the development of new protocols for environmentally benign
processes that are both economically and technologically feasible.
Due to their wide occurrence in nature and associated broad
ranges of pharmacological activities, the synthesis of pyra-
nocoumarins is of extremely attractive domain in bioorganic
chemistry. However, synthesis of pyrano[3,2-c]coumarins among
various pyranocoumarin derivatives has gained special interest as
they are being synthesized from 4-hydroxycoumarin, a commer-
cially available and inexpensive starting material (Scheme 1).
The usual strategy is the reaction of 4-hydroxycoumarin with
various types of electrophiles such as 1,3-diarylallylic com-
O
O
O
OH
O
O
O
OH
Xanthyletin
Khellactone
OMe
O
O
O
N
O
O
O
HO
H
pounds,4a propargylic alcohols,4b,c and
a,b-unsaturated alde-
OH
hydes4d–f or ketones.4g,h Pyranocoumarins have also been
synthesized using multicomponent reaction.5 Reagents as well as
catalysts used for tandem reaction between 4-hydroxycoumarin
OH
AcO
OAc
AcO
OH
Arisugacin H
AcO
Pyripyropene A
⇑
Corresponding author. Tel./fax: +91 3463 261526.
E-mail address: alakananda.hajra@visva-bharati.ac.in (A. Hajra).
Figure 1. Natural products containing pyranocoumarin moieties.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.061

A. K. Bagdi et al. / Tetrahedron Letters 54 (2013) 3892–3895
3893
HO
R1
screened, but no further improvement was observed (20–60%).
Surprisingly when the reaction was carried out under neat condi-
tions at 110 °C, the yield was obtained in 84% (entry 6). Inferior
yield (63%) was obtained at low temperature (entry 7). Increasing
the amount of catalyst did not improve the yield significantly (en-
try 9) while decreasing the amount of catalyst decreased the yield
(entry 8). Other copper salts (CuI, CuCl2, Cu(OAc)2) were found to
be less effective for this tandem reaction. Other metal triflates such
as In(OTf)3, Zn(OTf)2, La(OTf)3 were not so effective as Cu(OTf)2. Fi-
nally optimized yield was obtained using 10 mol % copper triflate
under neat conditions at 110 °C (entry 6).
R2
I2/H2SO4 [ref. 4b]
Ru-complex [ref. 4c]
R2
O
OH
O
OH
O
O
O
R1
R2
R1
R2
R1
DDQ [ref. 4a]
O
O
AuCl3/AgOTf [ref. 4h]
O
O
R2
Phosphric acid derivative [ref. 4e]
H
Scheme 1. Synthetic methods for the formation of pyranocoumarin.
After optimizing the reaction conditions, different types of a,b-
unsaturated ketones were studied with 4-hydroxycoumarin to ver-
ify the general applicability of the present methodology and the re-
sults are summarized in Table 2. It was observed that a wide range
R2
O
OH
O
of a,b-unsaturated ketones were converted into the corresponding
O
R1
pyranocoumarins in high yields. Chalcones bearing electron-
donating groups such as –Me and –OMe (3ab, 3ac, 3ah) and elec-
tron-withdrawing groups such as –NO2, –Cl (3ad, 3ae, 3ai, 3aj)
afforded the desired products with high yields. Acid sensitive chal-
cone was also unaffected under these reaction conditions (3af). In
general, the reaction is clean and proceeded smoothly. However,
under the present reaction conditions cinnamaldehyde produced
a mixture of unidentified products. We next turned our attention
to extend our present methodology to other structural analogue
of 4-hydroxycoumarin. Gratifyingly, 4-hydroxy-6-methyl-2-pyr-
one reacted well with chalcones to give the corresponding prod-
ucts (3ba, 3bb, 3bc, 3bf) without any difficulty. All these
reactions were carried out in open atmosphere and are not sensi-
tive to air and moisture. In addition, the reaction is highly regiose-
lective. No other regio-isomer was isolated under the present
reaction conditions.
Cu(OTf)2 (10 mol%)
+
R1
R2
110°C, 6 h
neat
O
O
O
2
1
3
Scheme 2. The tandem coupling of 4-hydroxycoumarin with enones.
In this context, design of solvent-free catalytic reaction has drawn
considerable attention in the area of green synthesis.6 As a part of
our research to provide a greener methodology,7 here we report an
efficient synthesis of pyrano[3,2-c]coumarin derivatives using cop-
per triflate as the catalyst under solvent-free conditions
(Scheme 2).
Reaction conditions were optimized using various catalysts, sol-
vents, and temperatures employing 4-hydroxycoumarin and 1,3-
diphenylpropenone as the model substrates (Table 1). Initially
the reaction was carried out using copper triflate (10 mol %) as
the catalyst and toluene as the solvent under reflux conditions (en-
try 1). Under these conditions 70% desired product was isolated.
Other solvents such as 1,2-DCE, THF, EtOH, dioxane were also
A proposed mechanism for the tandem reaction is shown in
Scheme 3. Probably the first step is the Michael addition of 4-
hydroxycoumarin to the
a,b-unsaturated ketone which gave the
intermediate 4.4h Copper(II) catalyzed the Michael reaction by
increasing the electrophilicity of the chalcone 2. The intermediate
Table 1
Optimization of the reaction conditionsa
Ph
OH
O
O
Catalyst (mol%)
+
Ph
Ph
Solvent, Temp., 6 h
Ph
O
O
O
O
1a
2a
3aa
Entry
Catalyst (mol %)
Solvent
Temperature (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (15)
Cul (10)
Tolune
DCE
Ethanol
THF
Refluxc
Refluxc
Refluxc
Refluxc
Refluxc
110
80
110
110
110
110
110
110
110
110
110
70
60
55
20
57
84
63
72
85
<10
30
<10
80
70
68
<5
Dioxane
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
CuCl2 (10)
Cu(OAc)2 (10)
Zn(OTf)2 (10)
In(OTf)3 (10)
La(OTf)3 (10)
—
a
b
c
Carried out with 1 mmol of 1a and 1 mmol of 2a in the presence of catalyst for 6 h.
Isolated yields.
Solvent (2 mL) under reflux.

3894
A. K. Bagdi et al. / Tetrahedron Letters 54 (2013) 3892–3895
Table 2
Substrate scope for the reactiona
R2
O
OH
O
O
R1
Cu(OTf)2 (10 mol%)
110 0C, 6 h
R1
+
R2
O
O
O
2
3
1
O
O
O
O
O
O
O
NO2
O
O
O
OMe
O
O
3aa, 84%
3ab, 82%
3ac, 83%
3ad, 86%
O
O
O
O
O
O
O
O
O
O
NO2
O
O
O
O
3ae, 88%
3af, 89%
3ag, 75%
3ah, 55%
Cl
O
O
O
O
O
O
O
O
Cl
O
OMe
O
O
O
3ai, 80%
3ba, 70%
3bb, 74%
3aj, 78%
O
O
O
O
O
O
O
OMe
O
3bf, 80%
3bc, 76%
a
Reactions conditions: 1 mmol of 1 and 1 mmol of 2 in the presence of Cu(OTf)2 (10 mol %) at 110 °C for 6 h; isolated yields.
the compatibility with various functional groups are the advanta-
(TfO)2Cu
O
ges of the present procedure. Further studies on the application
of the present methodology to the synthesis of biologically active
compounds are under investigation in our laboratory.
O
OH
R2
OH
R2
R1
R1
2
Acknowledgments
O
4
O
O
1
O
A.H. and A.M. acknowledge the financial support from DST,
Govt. of India (Grant No. SR/S5/GC-05/2010). We are thankful to
DST-FIST and UGC-SAP. A.K.B. thanks CSIR for his fellowship.
Cu(OTf)2
R2
R2 OH
Supplementary data
H2O
O
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
061.
R1
R1
O
O
O
O
3
5
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