Bi(OTf)3-catalyzed solvent-free synthesis of pyrano[3,2-c]coumarins through a tandem addition/annulation reaction between chalcones and 4-hydroxycoumarins

Article abstract of DOI:10.1016/j.tetlet.2013.05.008

A Bi(OTf)₃-catalyzed tandem addition/annulation reaction is described in order to synthesize pyrano[3,2-c]coumarins under solvent-free conditions. Substituted/unsubstituted chalcones were conveniently condensed with various 4-hydroxycoumarins b

Full text of DOI:10.1016/j.tetlet.2013.05.008

Tetrahedron Letters 54 (2013) 3773–3776
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bi(OTf)3-catalyzed solvent-free synthesis of pyrano[3,2-c]coumarins
through a tandem addition/annulation reaction between chalcones
and 4-hydroxycoumarins
⇑
Mukut Gohain, Johannes H. van Tonder, Barend C. B. Bezuidenhoudt
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A Bi(OTf)3-catalyzed tandem addition/annulation reaction is described in order to synthesize pyrano
[3,2-c]coumarins under solvent-free conditions. Substituted/unsubstituted chalcones were conveniently
condensed with various 4-hydroxycoumarins by means of this environmentally benign method which
produces water as the only side product.
Received 15 February 2013
Revised 22 April 2013
Accepted 3 May 2013
Available online 11 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bismuth trifluoromethanesulfonate
Addition
4-Hydroxycoumarin
Chalcone
Annulation
Pyrano[3,2-c]coumarin
Pyranocoumarins and related heterocyclic systems occur
widely in natural products as well as in synthetic molecules, exhib-
iting a broad spectrum of biological activities such as antifungal,
insecticidal, anticancer, anti-HIV, anti-inflammatory, and antibac-
terial.1 There are several patterns of pyranocoumarin scaffolds
among which coumarins containing a pyrano[3,2-c]coumarin moi-
ety are key structural units in many biologically active com-
pounds.2 For this reason chemists and biologists alike have been
attracted toward these compounds.3
Pyrano[3,2-c]coumarins are usually synthesized via cyclization
of commercially available 4-hydroxycoumarins with appropriate
electrophiles.2 The reported methods available for their prepara-
tion, however, suffer from either employing a strong acid, for
example, H2SO4,2a complex metal catalysts,2b stoichiometric
amounts of reagents such as DDQ,2c other toxic reagents,2d or are
limited by the availability of catalysts2e and substrates2j together
with low yields. Regioselectivity represents another challenge dur-
ing the synthesis of this important group of compounds.2c,4
Although a promising method for the synthesis for pyrano[3,2-
c]coumarins has recently been reported by Liu et al.,4 this proce-
dure is not attractive from an economic point of view since AuCl3
and AgOTf were employed as the catalyst and co-catalyst, respec-
tively. Thus, it is still desirable to develop an efficient, cost
effective, environmentally benign, and selective protocol for the
synthesis of pyrano[3,2-c]coumarins.
Bismuth compounds have attracted significant attention due to
their low toxicity, low cost, ease of handling, high catalytic effi-
ciency, and stability.5 The electronic configuration of bismuth is
[Xe] 4f145d106s26p3. On account of the weak shielding by the 4f
electrons (lanthanide contraction) bismuth(III) compounds exhibit
Lewis acidity. This property allows for the successful application of
these compounds as Lewis acid catalysts in various organic trans-
formations.5 Bi(OTf)3 is particularly attractive because it is com-
mercially available, or it can be prepared easily in the laboratory
from commercially available bismuth oxide and triflic acid.6
This Letter discloses an efficient, green, Bi(OTf)3-catalyzed tan-
dem conjugate addition/annulation process for the preparation of
pyrano[3,2-c]coumarins from various substituted chalcones and
4-hydroxycoumarins under solvent-free conditions.
To optimize the experimental conditions for the preparation of
pyrano[3,2-c]coumarins, the condensation between 4-hydroxy-
coumarin (1a) and chalcone (1.15 equiv) 2a was selected as a mod-
el reaction (Scheme 1). Initially the reaction was performed in both
⇑
Corresponding author. Tel.: +27 51 401 9021; fax: +27 51 444 6384.
E-mail address: bezuidbc@ufs.ac.za (B.C.B. Bezuidenhoudt).
Scheme 1. Reaction between 4-hydroxycoumarin (1a) and chalcone 2a.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.008

3774
M. Gohain et al. / Tetrahedron Letters 54 (2013) 3773–3776
protic and aprotic solvents7 (Table 1) with 5 mol % of Bi(OTf)3. No
reaction was, however, observed in protic solvents, that is, metha-
nol and ethanol (Table 1, entry 1), under reflux conditions. A sim-
ilar result was obtained upon substitution of the alcohols with THF
(Table 1, entry 2). In other aprotic solvents such as dichlorometh-
ane (CH2Cl2), acetonitrile (CH3CN), and 1,2-dichloroethane (DCE)
the reaction proceeded when heated to reflux, but full conversion
could not be achieved over 12 h (Table 1, entries 3–5). Other metal
triflates such as Al(OTf)3, Sc(OTf)3, In(OTf)3, Zn(OTf)2, and Cu(OTf)2
(all at 5 mol %) were also tested in DCE as the solvent (Table 1,
entries 6–10), but these catalysts were found to be inferior to
Bi(OTf)3. It was gratifying to find that when the model reaction
was performed with Bi(OTf)3 under solvent-free conditions7 full
conversion of 1a was achieved (monitored by TLC and GC–MS)
after 7 h at 100 °C and the desired product was isolated in excellent
yield (entry 11). Under these conditions Bi(OTf)3 was again found
to be superior to the other metal triflates (entries 12–15). Interest-
ingly, when DMF was employed as the solvent the intermediate
1,4-addition product was isolated as the major product (51%) along
with a trace amounts (5%) of the annulated analog and unreacted
starting materials (NMR, GC–MS). Hence, it was confirmed that po-
lar aprotic basic solvents were not suitable to carry out this tandem
addition/annulation reaction.
The reaction would appear to occur via a nucleophilic 1,4-addi-
tion pathway9 followed by intramolecular cyclization of the inter-
mediate product 3aa leading to the final product 4aa (Scheme 1).
Support for this came to light when the 1,4-conjugate addition
product 3aa, was isolated as the major product (51%) using DMF
as the solvent (Table 1, entry 16). Heating the isolated intermediate
product 3aa to 100 °C in the presence of 5 mol % Bi(OTf)3 under sol-
vent-free conditions led to the annulated compound being ob-
tained within 4 h confirming the proposed reaction pathway. It is
interesting to note that all of the above-mentioned reactions, with
the exception of entry 16, gave the annulated product as the major
product (as confirmed by 1H NMR, GCMS). The intermediate could,
however, be isolated by means of column chromatography (hex-
ane/EtOAc, 20:1) from aliquots obtained early in the reaction, al-
beit in low quantities (<10%).
Table 1
Evaluation of Lewis acid catalysts and optimization of the reaction conditionsa
Entry Catalyst
Cat.
(mol %)
Solvent
Time
(h)
Yield (4aa)b
(%)
1
Bi(OTf)3
5
MeOH or
EtOH
THF
CH2Cl2
CH3CN
DCE
DCE
DCE
DCE
DCE
2
—
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Al(OTf)3
Sc(OTf)3
In(OTf)3
Zn(OTf)2
Cu(OTf)2
Bi(OTf)3
Al(OTf)3
Sc(OTf)3
Cu(OTf)2
Zn(OTf)2
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
12
12
12
12
12
12
12
12
7
12
12
12
12
24
8
—
55
70
75
65
67
45
50
60
88
80
75
65
60
5c
DCE
Neat
Neat
Neat
Neat
Neat
DMF
Neat
Neat
Neat
Neat
Neat
2.5
1
10
2.5
2.5
92
80
85
80d
88e
12
7
15
7
a
General reaction conditions: 1a (1 mmol), 2a (1.1 mmol), catalyst, and solvent
(5 ml) were heated under reflux or 100 °C for DMF.
b
Isolated yield after column chromatography.
Product 3aa obtained in 51% yield.
Reaction performed at 80 °C.
Reaction performed at 110 °C.
c
The study was broadened by investigating the efficacy of
Bi(OTf)3 by means of different catalyst loadings (1.0, 2.5, 5.0 and
10.0 mol %) under solvent-free conditions at 100 °C (Table 1,
d
e
Table 2
Reaction between 6-substituted 4-hydroxycoumarins and substituted chalconesa
Entry
Hydroxy-coumarin
R
Chalcone
R1
R2
Time (h)
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
H
2a
2a
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8
8
8
8
9
7
8
8
10
9
7
12
8
8
6.5
8
15
6
6.5
1
4aa2g
4ba2j
4ca4
4da2j
4ab2j
4ac8
4ad2j
4ae8
4af8
92
90
90
93
90
91
90
91
87
91
88
83
90
93
92
80
47
86d
84d
88
Cl
OMe
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl–C6H4
4-MeO–C6H4
Ph
Ph
4-Cl–C6H4
4-MeO–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-MeO–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-MeO–C6H4
4-Cl–C6H4
2-Br–C6H4
2-MeO–C6H4
Ph
2-Thienyl
Ph
H
Me
H
9
10
11
12
13
14
15
16
17
18
19
20
4ag8
4ah8
4ai4
Ph
Ph
4aj8
4ak8
4al8
2-MeO–C6H4
2m
2n
2o
2p
2p
Ph
Me
Ph
Ph
Me
4am8
4an2i
4ao2b
4ap
H
3aq10
a
b
c
Reaction conditions: 1 (1.0 mmol), 2 (1.1 mmol), Bi(OTf)3 (2.5 mol %), 100 °C solvent-free conditions.
References to full analytical data for known compounds or full characterization data for new compounds.
Isolated yield.
d
Reactions were performed in DCE as the solvent under refluxing conditions.

M. Gohain et al. / Tetrahedron Letters 54 (2013) 3773–3776
3775
entries 11 and 17–21), which showed that 2.5 mol % was the opti-
The reaction of an
a,b-unsaturated ketone containing an aro-
mum catalyst concentration (Table 1, entry 17). A decrease in the
catalyst loading to 1.0 mol % resulted in a significant reduction in
the rate of the reaction leading to completion after ca. 12 h (Table 1,
entry 17 vs 18). Catalyst loadings above 2.5 mol % did not lead to a
significant effect on the rate of the reaction, but reflected nega-
tively on the yield which might be due to decomposition of the fi-
nal or intermediate product brought about by side reactions as a
result of the increase in the acid catalyst (Table 1, entry 11 and
19 vs entry 17). The reliance of the conversion on temperature
was also observed and completion of the reaction was not achieved
after 15 h at a lower temperature (Table 1, entry 20 vs 11).
Although a slight increase in the rate of the reaction was observed
at temperatures above 100 °C, a lower isolated yield and discolour-
ation of the reaction mixture again indicated product or intermedi-
ate decomposition at the increased temperature (entries 21 vs 17).
Due to the shorter reaction time and high product selectivity the
optimum conditions for further reactions were chosen as sol-
vent-free with 2.5 mol % of Bi(OTf)3 and heating to 100 °C.
The scope of the reaction was investigated next by introducing
electron-withdrawing and electron-donating substituents on both
the 4-hydroxycoumarins as well as the chalcone substrates. All
coumarins substituted with either electron-withdrawing (Table 2,
entry 2) or electron-donating (Table 2, entries 3 and 4) substituents
reacted smoothly with chalcone 2a to produce the annulated prod-
ucts in >90% yield. High yields were obtained on modification of
the chalcone substrate as well. A slight increase in the reaction rate
was observed when an electron-donating p-methoxy group was
introduced on the B-ring (Table 2, entry 6 vs entry 1), whereas
the chloro analog (Table 2, entry 5) exhibited a lower reaction rate.
The additional electron density would assist the dehydration in
the final step, which might account for the higher rate of product
formation. The latter is supported with a further increase in the
reaction rate upon shifting the methoxy substituent to the 2-posi-
tion, which is expected to have a greater influence on the conjuga-
tion in the enone system (Table 2, entry 15).
matic thienyl functionality (Table 2, entry 16) also proceeded well
under the same reaction conditions and gave the corresponding
product in good yield (80%), although lower than that of the phenyl
A-ring counterparts, which is probably due to the high electron
density of the thienyl group which deactivates the b-position to-
ward nucleophilic attack.
It was observed that when the phenyl A-ring of the chalcone
was removed (vinyl phenyl ketone, 2o), the desired annulated
product could still be obtained within the specified time (Table 2,
entry 18). Similarly, when the aryl A-ring was replaced with a
methyl group, as in 2p, the annulated product was still isolated
in very good yield (Table 2, entry 19). Both these reactions oc-
curred much better when solvated in DCE compared to solvent-
free conditions. Although the latter proceeded faster, larger
amounts of impurities were observed (monitored by 1H NMR and
TLC), so it was decided to report the DCE results instead. Surpris-
ingly, only the intermediate compound,9 3aq, could be obtained
upon removal of both aromatic rings (methyl vinyl ketone, 2q;
Table 2, entry 20). Prolonged heating of the intermediate product
induced decomposition (monitored by 1H NMR and TLC), which
suggests that the presence of the aromatic B-ring is essential in or-
der to smoothly perform the annulation under these conditions.
The mechanism of the reaction can be envisaged to entail
Bi(OTf)3 activation of the chalcone carbonyl group allowing 1,4-
A significant drop in product yield was, however, observed
when the B-ring was substituted with a methyl group (Table 2,
entry 17). The decrease in yield might be due to a low reaction rate
since full conversion could not be achieved even after 15 h. In this
regard, a contributing factor is believed to be the equilibrium
between the keto and enol tautomers of the intermediate, which,
in the absence of the aromatic B-ring, is shifted toward the enol
form, which would then be less prone to attack by the coumarin
hydroxy function to initiate formation of the second heterocyclic
ring. The extended reaction time might then induce unexpected
side reactions consuming the intermediate prior to final annula-
tion. This would suggest that an aryl function on the B-ring assists
in the cyclization by favouring the keto tautomer to produce the
pyrano-coumarin product.
Substitution at the ortho- or para positions of the A-ring with
either electron-donating or electron-withdrawing groups did not
influence the course of the reaction significantly (Table 2, entries
7, 8, 13, and 14). Introduction of a p-chloro group on the B-ring
in conjunction with a p-methoxy moiety on the A-ring of the chal-
cone resulted in a slight decrease in yield in addition to a lower
reaction rate (Table 2, entry 9). In contrast, the chalcone containing
an inverted substituted pattern gave the opposite result, that is, the
rate of the reaction increased along with an increase in yield (entry
10). Similar results were obtained for both di-p-methoxy and di-p-
chloro substituted chalcones (Table 2, entries 11 and 12). It was
observed that electron-donating substituents on the B-ring in-
creased the rate of the reaction producing excellent isolated yields,
while, on the other hand, an electron-withdrawing substituent on
the B-ring decreased the reaction rate and also had a negative im-
pact on the yield of the reaction.
Figure 1. ORTEP drawings of the X-ray crystal structures of compounds 4ag and 4aj.

3776
M. Gohain et al. / Tetrahedron Letters 54 (2013) 3773–3776
Zeng, Z.-S.; Li, Y.-L.; Shi, D.-Q.; Tu, S.-J. ARKIVOC 2006, 11, 107; (f) Majumdar, K.
C.; Debnath, P.; Maji, P. K. Tetrahedron Lett. 2007, 48, 5265; (g) Lin, X.; Dai, X.;
Mao, Z.; Wang, Y. Tetrahedron 2009, 65, 9233; (h) Moreau, J.; Hubert, C.; Batany,
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8963; (i) Berger, S.; Haak, E. Tetrahedron Lett. 2010, 51, 6630; (j) He, Z.; Lin, X.;
Zhu, Y.; Wang, Y. Heterocycles 2010, 81, 965; (k) Sarma, R.; Sarmah, M. M.;
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addition of the enol (4-hydroxycoumarin) to the enone system.
Once the intermediate addition product, 3aa, is formed, the car-
bonyl function of the intermediate, 3aa, is again activated for ring
closure by Bi(OTf)3, which finally induces dehydration to give the
5e,11
desired annulated product.
All the products were characterized by 1H NMR, 13C NMR, GC–
MS, and HRMS, and finally compared with authentic samples. The
structures of compounds 4ag and 4aj (Fig. 1) were further con-
firmed by XRD.12,13
3. (a) Reisch, J. Arch. Pharm. 1966, 299, 806; (b) Appendino, G.; Cravotto, G.; Toma,
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Refouvelet, B.; Bermont, L.; Adessi, G. L.; Leclercq, G.; Xicluna, A. Pharmazie
2002, 57, 233.
In summary, Bi(OTf)3 is shown to be an efficient Lewis acid cat-
alyst for the synthesis of pyrano[3,2-c]coumarins by the reaction of
chalcones and 4-hydroxycoumarins under solvent-free conditions.
Moreover, this method is a cost-effective process toward the syn-
thesis of these compounds where water is the only side product.
4. Liu, Y.; Zhu, J.; Qian, J.; Jiang, B.; Xu, Z. J. Org. Chem. 2011, 76, 9096.
5. (a)Organobismuth Chemistry; Suzuki, H., Matano, Y., Eds.; Elsevier: Amsterdam,
2001; (b) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58,
8373; (c) Gaspard-Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004, 2517; (d)
Ollevier, T.; Nadeau, E. Org. Biomol. Chem. 2007, 5, 3126; (e) Salvadora, J. A. R.;
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M.; Krabbe, S. W.; Mohan, R. S. Chem. Soc. Rev. 2011, 40, 4649; (g) Krabbe, S. W.;
Mohan, R. S. Top. Curr. Chem. 2012, 311, 45; (h) Shinde, P. V.; Labade, V. B.;
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Acknowledgments
6. Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J. Tetrahedron Lett. 2002,
43, 993.
Financial support from Sasol Ltd is gratefully acknowledged. We
would like to express our gratitude to T. J. Muller for his assistance
in the crystal data collection.
7. General method for reactions performed in solvents: To a solution/suspension of
finely powdered 4-hydroxycoumarin (0.162 g, 1.0 mmol) and chalcone
(1.1 mmol) in the appropriate solvent (5 ml) was added the metal triflate
(0.012 g, 2.5 mol %) and the reaction mixture was heated in an oil bath to reflux
for the time indicated in Tables 1 or 2 (monitored by TLC and GCMS). On
completion of the reaction, the solvent was removed in vacuo and the crude
residue was subjected to column chromatography (EtOAc:hexane 1:20) to
afford the desired product. General method for reactions performed under
solvent-free conditions: Finely powdered 4-hydroxycoumarin (0.162 g,
1.0 mmol), chalcone (1.1 mmol), and Bi(OTf)3 (0.012 g, 2.5 mol %) were mixed
thoroughly and heated in an oil bath at 100 °C. After completion of the reaction
(TLC and GC MS) the residue was subjected to column chromatography (EtOAc/
hexane 1:20) to give the desired product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.008
References and notes
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