Synthesis of a novel class of benzofurans via a three-component, regiospecific intramolecular heterocylization reaction

Article abstract of DOI:10.1016/j.tetlet.2013.03.124

A new, convenient, and environmentally benign three-component synthesis of a novel class of benzofurans is developed by condensing different arylglyoxals, benzamide, and phenolic substrates under solvent-free conditions. These reactions are catalyzed by tungstate sulfuric acid (TSA) as a safe, clean, and recyclable solid acid. The method is operationally simple and provides access to a variety of 2-aryl-3-benzamido benzofurans in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.03.124

Tetrahedron Letters 54 (2013) 3583–3585
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a novel class of benzofurans via a three-component,
regiospecific intramolecular heterocylization reaction
⇑
Bahador Karami , Saeed Khodabakhshi, Fatemeh Hashemi
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:
A new, convenient, and environmentally benign three-component synthesis of a novel class of benzofu-
rans is developed by condensing different arylglyoxals, benzamide, and phenolic substrates under
solvent-free conditions. These reactions are catalyzed by tungstate sulfuric acid (TSA) as a safe, clean,
and recyclable solid acid. The method is operationally simple and provides access to a variety of
2-aryl-3-benzamido benzofurans in good to excellent yields.
Received 1 November 2012
Revised 12 March 2013
Accepted 28 March 2013
Available online 8 April 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Benzofuran
Arylglyoxal
Phenol
Benzamide
Three-component
Benzo-fused heterocycles play important roles in both drug
discovery and chemical biology.1 Among benzoheterocycles con-
taining an oxygen atom, benzofurans are present in various biolog-
ically active molecules possessing, for example, antibacterial,2
antifungal,3 anti-inflammatory,4 antidepressant,5 and anticonvul-
sant6 activity. For example, benzbromaron is a uricosuric agent
used in the treatment of gout,7 cloridarol is a vasodilator,8 oxeto-
rone is an antimigraine agent,9 and amiodarone is an anti-arrhyth-
mic agent used for various types of cardiac dysrhythmias, both
ventricular and atrial.10
Several strategies for the synthesis of benzofurans are known.
Almost all the reported methods can be classified into two catego-
ries: (1) intramolecular cyclization of benzene derivatives and (2)
creation of an annellated carbocyclic ring.11 The traditional
methods for the synthesis of benzofuran derivatives involve the
preparation, via O-alkylation of salicylaldehyde with chloroacetic
acid, followed by dehydration of the resulting ether (category 1)12
or via Perkin rearrangement in which a coumarin is reacted with
a hydroxide (category 2).13–15 New strategies have also been
employed for the synthesis of benzofurans such as Claisen rear-
rangement and ring-closing metathesis,16 condensation of benzil
with phenols and aryl ethers mediated by SnCl2,17 a one-pot meth-
od for synthesizing 4-acetoxy-2-amino-3-arylbenzofurans,18 and
the synthesis of 2-imino-3-aminobenzofurans via multicomponent
reactions from TosMIC.19 It is important to mention that Wang et al.
have reported a three-component process for the synthesis of
2-aryl-3-aminobenzofuran derivatives from phenols, arylglyoxal
monohydrates, and para-toluenesulfonamide promoted by indium
trichloride. Using this method, benzofurans were obtained in good
O
OH
Ar
OH
H
O
Ar
1
+
catalyst
HN
G
O
solvent-free
o
OH
O
OH
120
C
NH
2
G
4
2
3
O
O
Ar
O
N
G
HN
Ar
HO
G
5
6
O
S
O
Catalyst: HO
O
O
O
W
S
O
OH
O O
⇑
Corresponding author. Tel.: +98 7412223048; fax: +98 7412242167.
E-mail address: karami@mail.yu.ac.ir (B. Karami).
Scheme 1. Synthesis of 2-aryl-3-benzamido-benzofuran derivatives.
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.03.124

3584
B. Karami et al. / Tetrahedron Letters 54 (2013) 3583–3585
Table 1
Synthesis of novel benzofurans in the presence of TSA30
Entry
Product
Yield (%)a
Mp (°C)
O
5a
80
75
230–232
HN
O
Ph
MeO
O
5b
239–241
HN
O
O
Ph
Figure 1. Recyclability of the TSA catalyst in the synthesis of 5a over 3 runs.
Br
5c
85
80
286–288
270–272
H
O
O
O
HA
HN
–H2O
OH
OH
A-
Ar
Ar
G
O
O
Ph
H
H2O
H
H2N
Cl
1
O
O
5d
HN
Ph
OMe
2
OH
Ar
O
H
H
O
O
N
H
O
NH
H
O
Ar
5e
85
75
198–200
220–222
7
G
HN
HO
8
O
Ph
3
H
Ar O
O
Ar
O
HO
A-
-H2O
NH
+
AH
H
O
O
NH
5f
G
HN
5
G
9
O
Ph
Cl
O
S
O
O
S
O
O
O
O
HA:
W
5g
85
75
248–250
225–227
O
HO
O
OH
HN
HN
Scheme 2. Suggested mechanism for the formation of 2-aryl-3-benzamido-benzo-
furans catalyzed by tungstate sulfuric acid.
Ph
HO
O
O
O
Cl
5h
According to previous reports on the synthesis of amidoalkyl
naphthols,29 we treated arylglyoxals 1 (obtained by selenium diox-
ide oxidation of the corresponding phenyl ketones) and benzamide
(2) with phenolic substrates 3 in the presence of a catalytic amount
of tungstate sulfuric acid (TSA) under solvent-free conditions
(Scheme 1). Despite the low probability of intramolecular cycliza-
tion of intermediate 4, we originally thought that the two isomers
5 and 6 would be formed. However, after characterization by IR
and NMR spectroscopy, we found that only 2-aryl-3-benzamido-
benzofurans 5 were actually formed.
The scope of this three-component reaction for the synthesis of
2-aryl-3-benzamido-benzofurans was studied and the results are
summarized in Table 1. It should be mentioned that all the reac-
tions proceeded by in situ generation of intermediate 4 and
showed regiospecificity toward structural isomer 5 rather than
oxazole 6.
Ph
HO
a
Isolated yield.
to excellent yields while the formation of diketones as by-products
was effectively inhibited.20
Multicomponent reactions (MCRs) are powerful tools for the
generation of chemical libraries and they have attracted significant
attention due to their broad applications in medicinal chemistry
for the production of various structural scaffolds, and in combina-
torial synthesis.21
In continuation of our research on the development of novel
techniques for the synthesis of heterocyclic compounds,22–28 here-
in, we describe a new and green strategy for the preparation of no-
vel benzofurans through a three-component reaction (category 1)
similar to that reported earlier.20
In these reactions, electron-rich and -deficient arylglyoxals, as
well as various phenolic substrates worked well. Methods based
on green chemistry principles have attracted growing interest from

B. Karami et al. / Tetrahedron Letters 54 (2013) 3583–3585
3585
4. Mane, B. Y.; Agasimundin, Y. S.; Shivkumar, B.; Shinde, D. B. J. Chil. Chem. Soc.
2009, 54, 77.
5. Malik, W. U.; Mahesh, V. K.; Raishighani, M. Indian J. Chem. 1971, 9, 655.
6. Dauzonne, D.; Gillardin, J. M.; Lepage, F.; Pointet, R.; Risse, S.; Lamotte, G.;
Demerseman, P. Eur. J. Med. Chem. 1995, 30, 53.
7. Kuzmits, R.; Bresnik, W.; Muller, M. M. Fortschr Med. 1979, 97, 2057.
8. Mossuti, E.; Nigro, P.; Diene, G.; Petralito, A. Minerva Med. 1976, 67, 1394.
9. Massiou, H. Rev. Neurol. 2000, 156, 79.
10. Punnam, S. R.; Goyal, S. K.; Kotaru, V. P.; Pachika, A. R.; Abela, G. S.; Thakur, R. K.
Cardiovasc. Hematol. Disord. Drug Targets 2010, 10, 73.
the scientific community in recent years. The results in Table 1
indicate the feasibility of these three-component reactions under
solvent-free conditions. All the products were synthesized in very
good yields (75–85%) at 120 °C over 90–240 min. Moreover, the
catalyst (TSA) is safe, separable, and can be reused several times.
For example, the activity of the catalyst was tested in the synthesis
of 5a over three runs, during which little appreciable loss was ob-
served in the catalytic activity (Fig. 1). Therefore, the efficiency of
this strategy under environmentally friendly conditions is in accor-
dance with green chemistry criteria.
A mechanistic rationale for the formation of compounds 5 is
postulated in Scheme 2. The reaction is thought to take place in
three steps. It is reasonable to assume that the initial event in-
volves the generation of intermediate 7 via condensation of amide
and arylglyoxal. In the next step, intramolecular cyclization of
intermediate 8 gives 9 followed by dehydration to form the prod-
uct 5.
In summary, the reaction between arylglyoxals, benzamide, and
phenol derivatives in the presence of a catalytic amount of tung-
state sulfuric acid provides a simple one-pot entry for the synthesis
of 2-aryl-3-benzamido-benzofurans of potential synthetic and
pharmaceutical interest. This method has advantages such as the
use of a safe and recyclable catalyst, avoidance of organic solvents,
high yields of products, short reaction times, and a simple work-up
procedure. It is worthwhile to note that the presence of transform-
able functionalities in the products makes them potentially valu-
able for further synthetic manipulations.
11. Kadieva, M. G.; Oganesyan, T. Chem. Heterocycl. Compd. 1997, 33, 1245.
12. Burgstahler, A. W.; Worden, L. R. Org. Synth. 1966, 5, 251.
13. Perkin, W. H. J. Chem. Soc. 1870, 23, 368.
14. Perkin, W. H. J. Chem. Soc. 1871, 24, 37.
15. Bowden, K.; Battah, S. J. Chem. Soc., Perkin Trans. 2 1998, 1603.
16. Tsai, T.-W.; Wang, E.-C.; Li, S.-R.; Chen, Y.-H.; Lin, Y.-L.; Wang, Y.-F.; Huang, K.-
S. J. Chin. Chem. Soc. 2004, 51, 1307.
17. Morrison, B. J.; Musgrave, O. C. Tetrahedron 2002, 58, 4255.
18. Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S.; Miyauchi, Y.; Saito, S. Org.
Lett. 2005, 7, 1211.
19. García-González, M. C.; González-Zamora, E.; Santillan, R.; Farfán, N. Synlett
2011, 308.
20. Chen, C. X.; Liu, L.; Yang, D.-P.; Wang, D.; Chen, Y.-J. Synlett 2005, 2047.
21. (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Callejo, R.; Ruiz, M. P.; Torres, M.
R. Eur. J. Org. Chem. 2012, 2359; (b) Terret, N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J.; Steel, J. Tetrahedron 1995, 51, 8135; (c) Yavari, I.; Beheshti, S. J.
Iran Chem. Soc. 2011, 8, 1030.
22. Karami, B.; Khodabakhshi, S.; Eskandari, K. Tetrahedron Lett. 2012, 53, 1445.
23. Karami, B.; Ghashghaee, V.; Khodabakhshi, S. Catal. Commun. 2012, 20, 71.
24. Karami, B.; Khodabakhshi, S.; Nikrooz, M. Polycyclic Aromat. Compd. 2011, 31,
97.
25. Khodabakhshi, S.; Karami, B. Catal. Sci. Technol. 2012, 2, 1940.
26. Karami, B.; Farahi, M.; Khodabakhshi, S. Helv. Chim. Acta 2012, 95, 455.
27. Karami, B.; Rooydel, R.; Khodabakhshi, S. Acta Chim. Slov. 2012, 59, 183.
28. Karami, B.; Hoseini, S. J.; Eskandari, K.; Ghasemi, A.; Nasrabadi, H. Catal. Sci.
Technol. 2012, 2, 331.
29. Selvam, N. P.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 7481.
30. General procedure for the synthesis of benzofurans 5. A mixture of arylglyoxal
1 (1 mmol), benzamide (2) (1 mmol), and TSA (0.05 mmol) was stirred and
Acknowledgments
heated at 120 °C in
a preheated oil bath for 20 min. Next, the phenolic
The authors gratefully acknowledge partial support of this work
by Yasouj University, Iran.
substrate 3 was added and the mixture was stirred for the appropriate amount
of time (90–240 min). After completion of the reaction as indicated by TLC
(EtOAc/hexane, 1:2), the mixture was added to hot EtOH and the catalyst was
separated by filtration. The solvent was evaporated and the products 5 were
purified by recrystallization from EtOH. Compound 5a. 1H NMR (DMSO-d6,
400 MHz,): d = 10.78 (s, 1H), 8.26 (d, 1H, J = 7.6 Hz), 8.21 (d, 2H, J = 7.2 Hz), 8.09
(d, 1H, J = 8.0 Hz), 8.04–7.90 (m, 4H), 7.74–7.65 (m, 3H), 7.57 (d, 2H, J = 7.6 Hz),
7.53 (d, 2H, J = 8.0 Hz), 7.43 (t, 1H, J = 7.6 Hz); 13C NMR (DMSO-d6, 100 MHz):
d = 167.21, 150.86, 149.10, 134.07, 132.72, 130.92, 129.83, 129.54, 129.47,
129.38, 129.25, 128.27, 127.66, 127.18, 126.87, 125.84, 125.41, 122.67, 121.40,
117.26, 113.05; IR (KBr) v: 3160, 3110, 2089, 1640, 1485, 1260, 1040, 800,
700 cmÀ1. Anal. Calcd for C25H17NO2: C, 82.63; H, 4.72; N, 3.85. Found: C,
82.90; H, 4.65; N, 3.77. Compound 5b. 1H NMR (DMSO-d6, 400 MHz): d = 10.70
(s, 1H), 8.24 (d, 2H, J = 6.8 Hz), 8.22 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 8.0 Hz),
7.89 (m, 4H), 7.74–7.64 (m, 3H), 7.56–7.50 (m, 2H), 3.81 (s, 3H), 7.11 (d, 2H,
J = 9.2 Hz); 13C NMR (DMSO-d6, 100 MHz): d = 167.20, 160.10, 150.46, 149.46,
134.11, 132.66, 130.89, 129.40, 129.35, 128.25, 127.58, 127.45, 126.99, 126.20,
125.28, 122.65, 122.36, 121.54, 115.05, 112.95, 55.77; IR (KBr) v: 3165, 3110,
2950, 1640, 1510, 1475, 1260, 1040, 800, 700 cmÀ1. Anal. Calcd for C26H19NO3:
C, 79.37; H, 4.87; N, 3.56. Found: C, 79.51; H, 4.80; N, 3.45.
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.
03.124.
References and notes
1. (a) Tapia, R. A.; Alegria, L.; Valderrama, J. A.; Cortes, M.; Pautet, F.; Fillion, H.
Tetrahedron Lett. 2001, 42, 887; (b) Yoshida, H.; Shirakawa, E.; Honda, Y.;
Hiyama, T. Angew. Chem. Int. Ed. 2002, 41, 3247; (c) Appukkuttan, P.; Dehaen,
W.; Van der Eycken, E. Org. Lett. 2005, 7, 2723.
2. Kirilmis, C.; Ahmedzade, M.; Suleyman, S.; Koca, M.; Kizirgil, A. Eur. J. Med.
Chem. 2008, 43, 300.
3. Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.; Veitch, N. C.; Hall, D. R. Tetrahedron
2006, 62, 4214.