A one-pot, three-component synthesis of new pyrano[2,3-h]coumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.01.024

The reaction between 5,7-dihydroxy-4-substituted coumarin, malononitrile, and aromatic aldehydes in the presence of a catalytic amount of K ₂CO₃ as a basic catalyst leads to new pyrano[2,3-h] coumarin derivatives in good to excellent

Full text of DOI:10.1016/j.tetlet.2012.01.024

Tetrahedron Letters 53 (2012) 1445–1446
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot, three-component synthesis of new
pyrano[2,3-h]coumarin derivatives
⇑
Bahador Karami , Saeed Khodabakhshi, Khalil Eskandari
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between 5,7-dihydroxy-4-substituted coumarin, malononitrile, and aromatic aldehydes in
the presence of a catalytic amount of K2CO3 as a basic catalyst leads to new pyrano[2,3-h]coumarin deriv-
atives in good to excellent yields.
Received 25 July 2011
Revised 16 December 2011
Accepted 6 January 2012
Available online 13 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5,7-Dihydroxy-4-methylcoumarin
Malononitrile
Aromatic aldehyde
Pyrano[2,3-h]coumarin
The synthesis of pyrano[2,3-c]coumarin derivatives via multi-
component reactions (MCRs) has attracted significant interest
because of their biological and pharmacological activities.1–3 Also,
MCRs have drawn special attention due to the advent of
high-throughput screening techniques that have enabled rapid
identification of potential new medicines among large collections
of organic compounds.4,5 It should be mentioned that three-compo-
nent reactions have emerged as useful methods because the combi-
nation of three components to generate new products in a single
step is extremely economical. A broad spectrum of biological
activity has been reported for coumarin derivatives.6 Dihydropyran
rings fused with a coumarin nucleus are important as they are valu-
able synthons for the synthesis of pharmacological agents.7,8
Pyrano[2,3-h]benzopyran has been used as the key intermediate
for the synthesis of urea and thiourea derivatives, thioxo-imidazo-
lidinedione, dithioxodiazetidine and Schiff’s bases.9
The 1H NMR spectrum of 6a exhibited five sharp singlets iden-
tified as methyl (d = 2.55), methine (d = 4.61), a methine ortho to
the OH group (d = 5.80), an olefinic C–H of the coumarin ring
(d = 6.10), and NH2 (d = 6.88) protons. Two multiplets (d = 7.13–
7.18) and (d = 7.23–7.27) corresponded to the protons of the phe-
nyl group. The proton decoupled 13C NMR spectrum of 6a showed
18 distinct resonances in agreement with the proposed structure.
In another investigation, and in order to optimize the proce-
dure, we performed the reaction in two steps involving the synthe-
sis of arylmethylene 7 through the Knoevenagel condensation of 4
and 5 under solvent-free grinding conditions, and then treatment
of arylmethylene 7 with 5,7-dihydroxy-4-substituted coumarin 3
to afford product 6a. Although, the reaction of arylmethylene 7
with 3 occurred in a shorter reaction time (about 25 min) com-
pared to the three-component reaction (about 40 min), it required
Firstly, we decided to prepare 5,7-dihydroxy-4-substituted
coumarin 3 via the ZrOCl2Á8H2O/SiO2-catalyzed Pechmann conden-
sation of phloroglucinol (1) with b-ketoester 2 under thermal and
solvent-free conditions (Scheme 1).10,11 Subsequently, the multi-
component reaction of 3, malononitrile (4) and suitable aromatic
aldehydes 5 in the presence of a catalytic amount of K2CO3 in
refluxing methanol gave a range of new dihydropyrans fused with
a coumarin nucleus 6 (pyrano[2,3-h]coumarin) (Scheme 2, Table
1). The structures of the products were deduced from their IR, 1H
NMR, and 13C NMR spectral data.12
OH
OH R1
HO
OH
ZrOCl2.8H2O/SiO2
(10 mol%)
solvent-free, 90 oC
1
+
O
O
HO
O
O
R1
OR2
3
2
R1: CH3, CH2Cl, Ph
R2: CH3, CH3CH2
⇑
Corresponding author. Tel.: +98 7412223048; fax: +98 7412242167.
E-mail address: karami@mail.yu.ac.ir (B. Karami).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.024

1446
B. Karami et al. / Tetrahedron Letters 53 (2012) 1445–1446
OH R1
unsuccessful. The problem with alkyl aldehydes is likely to be be-
cause they can undergo enolization.
O
Ar
H
In summary, the reaction between 5,7-dihydroxy-4-substituted
coumarin, various aromatic aldehydes, and malononitrile in the
presence of K2CO3 provides a simple one-pot entry for the synthe-
sis of pyrano[2,3-h]coumarins of potential synthetic and pharma-
ceutical interest. This method has advantages such as the use of
an inexpensive and commercially available basic catalyst (K2CO3),
high yields of products, short reaction times, and a simple work-
up procedure. It is worthwhile to note that the presence of trans-
formable functionalities in the products makes them potentially
valuable for further synthetic manipulations.
K2CO3 (10 mol%)
5
O
O
O
3
+
MeOH, reflux
20-180 min
H2N
Ar
N
N
CN
4
6
Scheme 2.
Table 1
Synthesis of new pyrano[2,3-h]coumarins in the presence of K2CO3 under reflux in
methanol
Acknowledgments
Product
Ar
R1
Yielda (%)
Mp (°C)
The authors gratefully acknowledge partial support of this work
by Yasouj University, Iran.
6a
6b
6c
6d
6e
6f
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
95
98
95
93
90
95
93
255–256
242–244
293–295
295–296
225–226
322–324
265–266
4-Cl-C6H4
3-O2N-C6H4
3-Br-C6H4
4-Me-C6H4
2,4-Cl2-C6H3
4-MeO-C6H4
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.024.
6g
S
6h
CH3
88
250–252
References and notes
6i
6j
6k
6l
6m
6n
3-Cl-C6H4
2-MeO-C6H4
2-Cl-C6H4
4-O2N-C6H4
2-Cl-C6H4
2-Cl-C6H4
CH3
CH3
CH3
CH3
Ph
80
90
95
80
87
78
208–210
303–305
320–322
245–247
243–245
308–310
1. Burgard, A.; Lang, H. J.; Gerlach, U. Tetrahedron 1999, 55, 7555.
2. (a) Na, J. E.; Lee, K. Y.; Seo, J.; Kim, J. N. Tetrahedron Lett. 2005, 46, 4505; (b)
Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.; Showell, G. A. J. Med.
Chem. 1984, 27, 1127.
3. Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.; Watts, E. A. J. Med. Chem.
1983, 26, 1582.
4. (a) Ivachtchenko, A. V.; Ivanenkov, Ya. A.; Kysil, V. M.; Krasavin, M. Y.; Ilyin, A.
P. Russ. Chem. Rev. 2010, 79, 787; (b) Shaabani, A.; Rahmati, A.; Rezayan, A. H.;
Khavasi, H. R. J. Iran Chem. Soc. 2001, 8, 24.
CH2Cl
a
Isolated yield.
more effort. Therefore, we decided to perform these reactions by
employing the one-pot procedure.
5. (a) Nair, V.; Babu, B. P.; Varghese, V.; Sinu, C. R.; Paul, R. R.; Anabha, E. R.;
Suresh, E. Tetrahedron Lett. 2009, 50, 3716; (b) Yavari, I.; Djahaniani, H.; Nasiri,
F. Tetrahedron 2003, 59, 9409.
A mechanistic rationale for the formation of 6 is suggested in
Scheme 3. The reaction is thought to take place in three steps. It
is reasonable to assume that the initial event involves the genera-
tion of arylmethylene 7 via Knoevenagel condensation of the alde-
hyde and malononitrile. In the next step, adduct 8 results from a
Michael type addition of C-8 of 3 to arylmethylene 7 and subse-
quent cyclization of intermediate 8 gives pyrano[2,3-h]coumarin
6. It should be mentioned that our efforts on the synthesis of pyr-
ano[2,3-h]coumarin derivatives using aliphatic aldehydes were
6. (a) Murray, R. D. H.; Mendey, J.; Brown, S. A. The Natural Coumarins; Wiley: New
York, 1982; (b) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa,
H.; Takahashi, D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000, 10,
59; (c) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; McPhail, A. T.; Lee, K.-H. J. Med.
Chem. 2001, 44, 664.
7. (a) El-Agrody, A. M.; Abd El-Latif, M. S.; El-Hadi, N. A.; Fakery, A. H.; Bedair, A. H.
Molecules 2001, 6, 15; (b) El-Agrody, A. M.; Abd El-Latif, M. S.; Fakery, A. H.;
Bedair, A. H. J. Chem. Res. 2000, 26.
8. Shaker, R. M. Pharmazie 1996, 51, 148.
9. Nofal, Z. M.; Fahmy, H. H.; Kamel, M. M.; Sarhan, A. I.; Maghraby, A. S. Egypt. J.
Chem. 2004, 47, 345.
10. General procedure for the synthesis of 5,7-dihydroxy-4-substituted coumarins
3. b-Ketoester
2 (1 mmol) was added to a mixture of phloroglucinol (1)
(1 mmol) and ZrOCl2Á8H2O/SiO2 (0.27 g, 10 mol %) in a screw-cap vial. The
mixture was stirred in a preheated oil bath (90 °C). After completion of the
reaction, the resulting solid product was suspended in H2O (20 ml), filtered and
recrystallized from hot EtOH to give the pure product 3.
OH R1
OH R1
Step 2
11. Karami, B.; Kiani, M. Catal. Commun. 2011, 14, 62.
H
12. Typical procedure for the synthesis of 6a: To a stirred solution of benzaldehyde
(0.106 g, 1 mmol), malononitrile (4) (0.066 mmol), and 5,7-dihydroxy-4-
methylcoumarin 3 (0.192 g, 1 mmol) in MeOH (10 mL), was added K2CO3
(0.014 g, 0.1 mol). The mixture was stirred under reflux for 40 min. The
reaction progress was monitored by TLC (hexane/AcOEt, 1:1). After completion
of the reaction, the mixture was filtered and evaporated and the residue
recrystallized from EtOH to afford pure 6a (0.33 g, 95%) as a light yellow solid,
mp 255–256 °C; 1H NMR (DMSO-d6, 400 MHz): d = 7.27–7.23 (m, 2H), 7.18–
O
C
O
H
O
O
O
O
HN
3
Ar
Ar
B
B
N
N
8
N
7
7.13 (m, 3H), 6.88 (s, 2H), 6.10 (s, 1H), 5.80 (s, 1H), 4.61 (s, 1H), 2.55 (s, 3H); 13
C
Step 3
NMR (DMSO-d6, 100 MHz): d = 163.69, 160.10, 160.05, 155.26, 153.51, 147.59,
145.81, 128.16, 127.01, 126.19, 120.53, 109.70, 107.89, 98.92, 98.57, 57.68,
36.31, 23.97; IR (KBr) v: 3460, 3390, 2191, 1652, 1617, 1399 cmÀ1. Anal. Calcd
for C20H14N2O4: C, 69.36; H, 4.07; N, 8.09. Found: C, 69.50; H, 3.92; N, 7.95; MS
(m/z): 346.1 [M]+.
-H2O
B
OH R1
Step 1
Compound 6m: Pale yellow solid; mp 243–245 °C; 1H NMR (DMSO-d6,
400 MHz): d = 11.16 (s, 1H), 7.52 (s, 5H), 7.39 (d, 1H, J = 7.2 Hz), 7.23 (t, 2H,
J = 6.8 Hz), 7.00 (d, 1H, J = 6.8 Hz), 6.56 (s, 1H), 6.07 (s, 1H), 5.14 (s, 1H), 4.98 (s,
2H); 13C NMR (DMSO-d6, 100 MHz): d = 159.62, 158.84, 158.26, 155.22, 154.30,
147.00, 142.41, 139.74, 132.42, 130.55, 129.78, 128.77, 128.68, 128.32, 128.12,
127.83, 119.25, 112.87, 107.91, 100.92, 99.16, 57.79, 33.96; IR (KBr) v: 3219,
2192, 1649, 1618, 1385, 1157, 833; Anal. Calcd for C25H15ClN2O4: C, 67.80; H,
3.41; N, 6.33. Found: C, 67.45; H, 3.59; N, 6.22; MS (m/z): 443.1 [M+H]+.
O
CN
O
O
O
+
Ar
H
CN
H2N
Ar
5
4
CN
6
B-: HCO3- and OH-
Scheme 3.