Regiospecific synthesis of novel furo[4,5- c ]coumarins in a one-pot reaction

Article abstract of DOI:10.1055/s-0032-1316895

A new and expedient assembly of an interesting class of amido-substituted furo[4,5-c]coumarins has been successfully achieved through a one-pot sequential coupling and cyclization strategy starting from 4-hydroxycoumarin, aryl glyoxals and benz-amide. All

Full text of DOI:10.1055/s-0032-1316895

998▌
LETTER
lRetteergiospecific Synthesis of Novel Furo[4,5-c]coumarins in a One-Pot Reaction
Furo[4,5-c]coumarins
Bahador Karami,* Saeed Khodabakhshi, Khalil Eskandari
Department of Chemistry, Yasouj University, Yasouj, 75918-74831, Iran
Fax +98(74)12242167; E-mail: karami@mail.yu.ac.ir
Received: 01.01.2013; Accepted after revision: 17.03.2013
OH
O
O
Abstract: A new and expedient assembly of an interesting class of
amido-substituted furo[4,5-c]coumarins has been successfully
achieved through a one-pot sequential coupling and cyclization
strategy starting from 4-hydroxycoumarin, aryl glyoxals and benz-
amide. All the reactions showed selectivity towards furo[4,5-c]cou-
marin, instead of the corresponding isoxazolo-substituted
coumarins.
O
OH
NH2
Ar
+
+
H
O
HO
1
2
3
Key words: library construction, coumarins, glyoxals, benzamide
Furocoumarins have attracted interest due to their estro-
genic activity and their presence in foodstuffs such as soy-
beans.1,2 Several synthetic strategies have been reported
for coumestan derivatives (such as coumestrol) that com-
bine benzofuran and coumarin scaffolds.3–6
O
O
O
OH
Ar
O
Our continued interest in synthesizing a coumarin-based
combinatorial7–9 library led us to develop an efficient
pathway for the preparation of new classes of furocouma-
rin molecules. In recent years, several research groups
have focused on the synthesis of furo[3,2-c]coumarins as
potent biologically active compounds.10–14 Nair and co-
workers have also reported a three-component reaction in-
volving [4+1] cycloaddition, leading to amino-substituted
furo[3,2-c]coumarin derivatives.15 This method was im-
proved by Wu, who developed a microwave-assisted pro-
tocol.16
Ar
O
HN
N
O
O
5
4
Scheme 1
observed formation of the desired product 4a. After con-
firming the regiospecificity of the reaction by NMR spec-
troscopic analysis, we extended our studies to various aryl
glyoxals (Table 1) and were pleased to find that the reac-
tion led regiospecifically to the desired products.
As part of an ongoing program for the construction of het-
erocyclic compounds,17–20 we present herein an expedient
pathway for the preparation of novel amido-substituted
furo[4,5-c]coumarins 4, variously substituted on the five-
membered ring, starting from 4-hydroxycoumarin 1 and
aryl glyoxals 2 (obtained by selenium dioxide mediated
oxidation of the corresponding phenyl ketones21) and
benzamide 3 (Scheme 1). Although this reaction could
provide two structural isomers, the isoxazolo-substituted
coumarins 5 are not observed.
Mechanistically, the following scheme may be invoked to
explain the formation of product 4. The reaction is thought
to take a place in three steps. It is reasonable to assume
that the initial event involves the generation of intermedi-
ate A through condensation of benzamide and the aryl
glyoxal. In the next step, intramolecular cyclization of in-
termediate B gives intermediate C followed by final dehy-
dration to form 4 (Scheme 2).
Our initial study was performed with 1, phenyl glyoxal 2a
and 3 in acetic acid. To prevent the formation of side prod-
ucts, such as bis-aroylcoumarins, we first treated benz-
amide with phenyl glyoxal 2a to form the imine, followed
by addition of 4-hydroxycoumarin 1.22 Gratifyingly, we
In conclusion, we have demonstrated that amido-substi-
tuted furo[4,5-c]coumarins can be produced from 4-hy-
droxycoumarin, aryl glyoxals and benzamide.
SYNLETT 2013, 24, 0998–1000
Advanced online publication: 09.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316895; Art ID: ST-2013-D0002-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Furo[4,5-c]coumarins
999
Table 1 One-Pot Synthesis of Furo[4,5-c]coumarin Derivatives un-
der Reflux in AcOH (continued)
H
O
O
OH
– 2 H2O
HO
AcOH
Ar
Ar
AcO–
+
OH
Yield (%)a
H
Entry Ar
Product
H
OH
NH2
Br
O
3
4-BrC6H4
75
O
NH
O
O
O
H
O
O
O
O
O
+O
O
H
NO2
H
+
H
Ar
N
H
O
NH
O
4
5
6
4-O2NC6H4
4-MeOC6H4
3-MeOC6H4
85
75
70
O
Ar
A
NH
O
O
B
O
HO
O
OMe
O
O
NH
O
O
H
O
AcO–
O
Ar
+
O
O
H
O
AcOH
– H2O
HN
Ar
O
O
MeO
H
HN
O
O
NH
C
O
Scheme 2
O
O
O
O
7
1-naphthyl
90
Table 1 One-Pot Synthesis of Furo[4,5-c]coumarin Derivatives un-
der Reflux in AcOH
O
NH
Entry Ar
Product
Yield (%)a
O
O
O
1
Ph
85
8
2-naphthyl
90
O
NH
NH
O
O
O
O
O
F
a Isolated yield.
2
4-FC6H4
70
O
Acknowledgment
NH
We are grateful to the Yasouj University, Iran, for financial assi-
stance.
O
O
O
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 998–1000

1000
B. Karami et al.
LETTER
(15) Nair, V.; Menon, R. S.; Vinod, A. U.; Viji, S. Tetrahedron
Lett. 2002, 43, 2293.
(16) Wu, J. Chem. Lett. 2006, 35, 118.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(17) Khodabakhshi, S.; Karami, B. Catal. Sci. Technol. 2012, 2,
1940.
(18) Karami, B.; Ghashghaee, V.; Khodabakhshi, S. Catal.
Commun. 2012, 20, 71.
(19) Karami, B.; Khodabakhshi, S.; Nikrooz, M. Polycycl.
Aromat. Compd. 2011, 31, 97.
References and Notes
(1) Ndebele, K.; Graham, B.; Tchounwou, P. B. Int. J. Environ.
Res. Public Health 2010, 7, 2045.
(2) Lee, H.-I.; Lee, J.-H.; Park, K.-H.; Sangurdekar, D.; Chang,
W.-S. Appl. Environ. Microbiol. 2012, 78, 2896.
(3) Al-Maharrik, N.; Botting, N. P. Tetrahedron 2004, 60, 1637.
(4) Li, C. C.; Xie, Z. X.; Zhang, Y. D.; Chenand, J. H.; Yang, Z.
J. Org. Chem. 2003, 68, 8500.
(5) DaSilva, A. J. M.; Melo, P. A.; Silva, N. M. V.; Broto, F. V.;
Buarque, C. D.; de Souza, D. V.; Rodrigues, V. P.; Pocas, E.
S. C.; Noel, F.; Albuquerque, E. X.; Costa, P. R. R. Bioorg.
Med. Chem. Lett. 2001, 11, 283.
(6) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70,
9985.
(7) Karami, B.; Khodabakhshi, S.; Eskandari, K. Tetrahedron
Lett. 2012, 53, 1445.
(8) Karami, B.; Eskandari, K.; Khodabakhshi, S. ARKIVOC
2012, (ix), 76.
(9) Karami, B.; Farahi, M.; Khodabakhshi, S. Helv. Chim. Acta
2012, 95, 455.
(10) Lee, C.-J.; Jang, Y.-J.; Wu, Z.-Z.; Lin, W. Org. Lett. 2012,
14, 1908.
(11) Chen, L.; Xu, Y. L. M.-H. Org. Biomol. Chem. 2010, 8,
3073.
(20) Karami, B.; Hoseini, S. J.; Eskandari, K.; Ghasemi, A.;
Nasrabadi, H. Catal. Sci. Technol. 2012, 2, 331.
(21) Riley, H. A.; Gray, A. R. Org. Synth. Coll. 1935, 15, 67.
(22) Synthesis of 2-Phenyl-3-benzamidofuro[4,5-c]coumarin
(4a); Typical Procedure: A solution of phenylglyoxal
monohydrate (1 mmol) and benzamide (1.1 mmol) in AcOH
(10 mL) was stirred and heated at 70 °C for 30 min, then the
4-hydroxycoumarin (1 mmol) was added. The reaction
mixture was heated at reflux (110 °C) and the progress of the
reaction was monitored by TLC (EtOAc–hexane, 1:1). Upon
completion, the reaction mixture was poured onto ice, and
the precipitate was filtered off and thoroughly washed with
water. The pure product 4a (85%) was obtained by
recrystallization from EtOH as pale-yellow crystals; mp
216–218 °C. IR (KBr): 3347, 2924, 1678, 1613, 1565,
1344 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 8.75 (s,
1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.92 (d, J = 7.2 Hz, 2 H),
7.88 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.57–7.45
(m, 5 H), 7.38 (t, J = 8.0 Hz, 2 H). 13C NMR (100 MHz,
DMSO-d6): δ = 166.5, 163.5, 161.6, 152.4, 135.3, 133.5,
132.9, 131.6, 131.6, 128.6, 128.3, 128.2, 127.5, 127.4,
124.2, 123.8, 116.5, 115.9, 102.1. Anal. Calcd for
C24H15NO4: C, 75.58; H, 3.96; N, 3.67. Found: C, 75.69; H,
3.87; N, 3.61. MS: m/z = 381.1.
(12) Cheng, G.; Hu, Y. Chem. Commun. 2007, 3285.
(13) Raffa, G.; Rusch, M.; Balme, G.; Monteiro, N. Org. Lett.
2009, 11, 5254.
(14) Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron
Lett. 2001, 42, 3503.
Synlett 2013, 24, 998–1000
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