Indium triflate-catalyzed coupling between nitroalkenes and phenol/naphthols: A simple and direct synthesis of arenofurans by a cyclization reaction

Article abstract of DOI:10.1002/asia.201000869

An eye furan eye: A simple and efficient protocol for the synthesis of benzofuran and naphthofuran derivatives catalyzed by indium triflate was developed by coupling α,β-unsaturated nitroalkenes with phenol/naphthols. The present method provides arenofuran derivatives in one pot from readily available starting materials (DCE=1,2-dichloroethane; see scheme). Copyright

Full text of DOI:10.1002/asia.201000869

COMMUNICATION
DOI: 10.1002/asia.201000869
Indium Triflate-Catalyzed Coupling between Nitroalkenes and Phenol/
Naphthols: A Simple and Direct Synthesis of Arenofurans by a Cyclization
Reaction
Dhiman Kundu, Md Samim, Adinath Majee, and Alakananda Hajra*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Arenofurans are an important class of heterocyclic com-
pound and are present in many natural products that exhibit
various types of biologically activities including, fungicidal,
antimicrobial, insecticidal, antisweet, antiproliferative, cyto-
toxic, and antioxidant properties.[1] Apart from being biolog-
Scheme 1. Synthesis of arenofurans.
ically active, arenofurans have potential applications as ad-
vanced hole-transporting materials[2] and photosensitizers.[3]
Therefore, there is continued interest to develop improved
methods for the synthesis of benzofuran and naphthofuran
derivatives.[4] Compared to benzofurans, the methods for the
synthesis of naphthofurans are limited.[5] However, most of
the reported methods for the preparation of arenofuran de-
rivatives are multistep syntheses and lack of generality.
Therefore, the search for a simple, straightforward and cost-
Initially, we did the reaction with 2-naphthol and (E) b-
methyl-b-nitrostyrene in the presence of a catalytic amount
of indium triflate (5 mol%) to check the feasibility of Mi-
chael addition.[8] The reaction mixture was heated under
reflux (60–708C) in tetrahydrofuran (THF) solvent. During
the progress of the reaction, we noticed only the formation
of one product, which was isolated in 30% yield. Initially,
we thought that the isolated product might be the Michael
adduct. After careful analysis, the structure was character-
effective method is highly desirable. Recently, indiumACHTUNTRGNEUNG(III)
compounds have been used as mild and water-tolerant
Lewis acids that impart high regio-, stereo-, and chemoselec-
tivity.[6] Particularly, indium triflate is found to be a more ef-
fective catalyst than conventional Lewis acids in promoting
various transformations. Our own research also found
ized to be 2-methyl-1-phenyl-naphthoACTHNUTRGNEUNG[2,1b]furan. As areno-
furans are important privileged compounds and it is a new
kind of cyclization reaction, we decided to continue the
present work. Optimization of the reaction conditions was
achieved by varying temperature, solvent, and catalyst
(Table 1). The results reported in Table 1 revealed that In-
indiumACHTUNGTRENNUNG(III) compounds to be very efficient catalysts for
two- and three-component coupling reactions.[7] However, to
the best of our knowledge there are no methods available
for one-pot synthesis of arenofuran derivatives catalyzed by
indium salts. Herein, we report the remarkable catalytic ac-
tivity of indium triflate in the one-pot condensation of
phenol/naphthols and a,b-unsaturated nitroalkenes to sub-
stituted benzofuran and naphthofuran derivatives.
Scheme 1
AHCTUNGRTEG(NNUN OTf)3 (5 mol%) was better suited to afford the naphthofur-
an in high yields under reflux (85–908C) in 1,2-dichloro-
ethane (DCE; entry 5). The choice of solvent is very impor-
tant as a decrease in yield is observed when the reaction
was carried out in acetonitrile, toluene, and 1,2-dichloroben-
zene (DCB) instead of DCE. Use of just 5 mol% of In-
AHCTUNGRTEG(NUNN OTf)3 is sufficient to drive the reaction forward (entry 5).
An increase in catalyst loading did not improve the product
formation to a great extent (entry 6). In the absence of In-
AHCTUNGRTEG(NNUN OTf)3, the desired product was not formed (entry 7). How-
ever, naphthofuran was isolated in low yield (10%) from
the reaction mixture after 24 hours at reflux. Other indium
salts such as indium chloride produced the product in mod-
erate yield (72%). We examined this reaction in the pres-
[a] D. Kundu, M. Samim, Dr. A. Majee, Dr. A. Hajra
Department of Chemistry
Visva-Bharati University
Santiniketan 731235 (India)
Fax : (+91)3463-262728
E-mail: alakananda.hajra@visva-bharati.ac.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000869.
ence of various catalysts such as ZnACTHNUGTRNNEUG(OTf)2, CuACHTUNTGERN(NUGN OTf)2, para-
406
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Chem. Asian J. 2011, 6, 406 – 409

Table 1. Reaction between 2-naphthol and (E)-b-methyl-b-nitrostyrene
Table 2. Synthesis of naphthofurans.
under different reaction conditions.[a]
Product
t [h] Yield [%][a]
Product
t [h] Yield [%][a]
Entry Catalyst [mol %] Solvent
Temperature
Yield [%][b]
1
2
3
4
5
6
7
8
In
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (10)
G
THF
CH3CN
Toluene reflux (115–1208C)
reflux (65–708C)
reflux (85–908C)
30
20
20
35
84
87
0
72
32
44
30
48
22
9
78
8
84
DCB
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
reflux 1308C
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
reflux (85–908C)
–
9
9
82
83
9
9
86
85
InCl3 (10)
9
ZnACHTUNGTRENNUNG(OTf)2 (10)
10
11
12
13
Cu(OTf)2 (10)
ACHTUNGTRENNUNG
PTSA (10)
CF3SO3H (10)
HCl (30)
[a] Reaction conditions: A mixture of 2-naphthol (2 mmol) and (E)-b-
methyl-b-nitrostyrene (2 mmol) was subjected to the above reaction con-
ditions. [b] Yield of isolated product.
11
8
76
84
80
8
9
9
85
75
45
toluenesulfonic acid (PTSA), CF3SO3H, and HCl under sim-
ilar reaction conditions (entries 9–13), but low conversions
were obtained. It is clear that indium triflate gave the best
results for this transformation. Finally, we chose the reaction
conditions using indium triflate (5 mol%) in DCE under
reflux. A mixture of benzaldehyde, nitroethane, and 2-naph-
thol produced the desired product in low yield under the
present reaction conditions.
8
The scope of the reaction was examined and the results
are shown in Table 2. a,b-Unsaturated nitroalkenes were
prepared by the condensation of corresponding aldehydes
and nitroalkanes.[9] A variety of aryl substituted nitroalkenes
such as fluoro, chloro, nitro, methyl, and methoxy phenyl ni-
trostyrene, was prepared and subjected to the cyclization re-
action. The desired products were obtained in high yields in
all cases. Vinyl (3m), alkyl (3n), and heterocyclic substitu-
ents such as furan (3l) could also be incorporated into naph-
thofuran derivatives. The substrate scope of the present
method has proven to be broad. The yields are reasonably
better compared to that of multistep synthesis. Notably, this
protocol is also useful for 1-naphthol (3o). In general, 2-
naphthol produced naphthofuran derivatives in higher yields
compared to 1-naphthol. The product 3d is a novel anticanc-
er agent and it could be prepared in one step by the present
method. Recently, Negi and co-workers prepared compound
3d by a multistep method.[10] Compared to the reported
method, the present method is very simple in operation.
This method does not require any additives or anhydrous
conditions and no precautions need to be taken to exclude
moisture from the reaction media.
9
78
9
48
15
44[b]
[a] Yield of isolated product. [b] 1-Naphthol was used.
under the present reaction conditions. However, activated
phenols such as resorcinol gave higher yields compared to
phenol itself. The relatively lower yields probably reflect the
lower nucleophilicity of phenol compared to 2-naphthol.
Presumably, this process involves Michael addition of
phenol/naphthols to a,b-unsaturated nitroalkenes followed
by subsequent cyclization, thereby leading to the final prod-
uct, as shown in Scheme 2. We assume that initial formation
of Michael adduct (A) leads to the furan moiety after suc-
cessive intramolecular cyclization followed by elimination of
H2O and nitroxyl (HNO) from the intermediate (B).[11] Al-
though it was not possible to isolate the Michael adduct
from the reaction between 2-naphthol and (E) b-methyl-b-
nitrostyrene, we were able to isolate the intermediate Mi-
Encouraged by the above results, we continued to explore
the reactivity of phenol with a,b-unsaturated nitroalkenes
under the similar reaction conditions (Table 3). It was found
that phenols are poor substrates for this class of reaction
Chem. Asian J. 2011, 6, 406 – 409
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www.chemasianj.org
407

A. Hajra et al.
COMMUNICATION
Table 3. Synthesis of benzofurans.
Conclusion
We have demonstrated a simple, and straightforward one-
pot synthesis of benzofuran and naphthofuran derivatives
from readily available a,b-unsaturated nitroalkenes and
phenol/naphthols catalyzed by indium triflate. The cycliza-
tion reaction enables the facile generation of diversity in the
synthesis of arenofurans, which are important privileged
compounds. Compared with previous step-wise methods,
this present method has the advantages of general applica-
bility, simple operation, and reasonable good yields. There-
fore, considering the above feature and the readily available
starting materials, we believe this one-pot catalytic transfor-
mation would be an attractive choice for synthesis of areno-
furan derivatives in academia as well as pharmaceutical in-
dustries. The present methodology could be extended to the
synthesis of other heterocyclic systems containing sulfur, ni-
trogen, and selenium for various applications.
Product
t [h]
Yield [%][a]
32
15
15
34
15
15
15
38
35
40
Experimental Section
Typical procedure for the synthesis of naphthofuran
A
mixture of 2-naphthol (2 mmol), a,b-unsaturated nitroalkene
(2 mmol), and indium(III) triflate (5 mol%) in dry DCE (5 mL) was
AHCTUNGTRENNUNG
heated under reflux (85–908C) with a CaCl2 moisture guard tube until
completion of the reaction. The reaction mixture was then quenched with
water (10 mL) and extracted with ethyl acetate (2ꢁ10 mL). The extract
was washed with brine and dried (Na2SO4). Evaporation of solvent and
purification by column chromatography over silica gel furnished the cor-
responding naphthofuran.
20
42[b]
[a] Yield of isolated product. [b] 2 Equivalents of nitroalkene was used.
Acknowledgements
This work is supported by the Department of Science and Technology,
Government of India. D. K. thanks Council of Scientific and Industrial
Research (CSIR) for a fellowship. A. M. acknowledges financial support
from CSIR.
Keywords: alkenes · catalysis · cyclization · heterocycles ·
indium triflate
[1] a) B. H. Lipshutz, Chem. Rev. 1986, 86, 795; b) D. M. X. Donelly,
M. J. Meegan in Comprehensive Heterocyclic Chemistry, Vol. 4
(Eds.: A. R. Katritzky, C. W. Ress,) Pergamon Press, Oxford, 1984,
p. 657; c) A. Williams in Furans, Synthesis and Applications, Noyes
Data Corporation, Park Ridge, NJ, 1973, p. 1; d) G. A. Kraus, N.
Zhang, J. G. Verkade, M. Nagarajan, P. B. Kisanga, Org. Lett. 2000,
2, 2409; e) H. Hagiwara, K. Sato, D. Nishino, T. Hoshi, T. Suzuki,
M. J. Ando, J. Chem. Soc. Perkin Trans. 1 2001, 2946.
Scheme 2. A plausible reaction path for the formation of naphthofuran.
[2] H. Tsuji, C. Mitsui, L. Illies, Y. Sato, E. Nakamura, J. Am. Chem.
Soc. 2007, 129, 11902.
[3] P. K. Frederiksen, M. Jorgensen, P. R. Ogilby, J. Am. Chem. Soc.
2001, 123, 1215.
[4] a) K. C. Nicolaou, S. A. Snyder, A. Bigot, J. A. Pfefferkora, Angew.
Chem. 2000, 112, 1135; Angew. Chem. Int. Ed. 2000, 39, 1093; b) M.
Nakamura, L. Illies, S. Otsubo, E. Nakamura, Angew. Chem. 2006,
118, 958; Angew. Chem. Int. Ed. 2006, 45, 944; c) M. Nakamura, L.
Illies, S. Otsubo, E. Nakamura, Org. Lett. 2006, 8, 2803; d) K. K.
chael adduct from the reaction of 2-napthol and (E) b-nitro-
styrene. It is noteworthy that the Michael adduct gave the
final product in high yield in the presence of indium triflate
in DCE under reflux. But low conversion was observed in
the absence of catalyst under similar reaction conditions. It
is clear that indium triflate enhances the rate of transforma-
tion.
408
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 406 – 409

Indium Triflate-Catalyzed Coupling between Nitroalkenes and Phenol/Naphthols
Park, J. Jeong, Tetrahedron 2005, 61, 545; e) T. Horaguchi, H. Iwana-
mi, E. Hasegawa, T. Shimizu, J. Chem. Soc. Chem. Commun. 1991,
44; f) T. L. Boehm, H. D. H. Showalter, J. Org. Chem. 1996, 61,
6498; g) N. Takeda, O. Miyata, T. Naito, Eur. J. Org. Chem. 2007,
1491; h) R. V. Nguyen, C. J. Li, Synlett 2008, 1997; i) H. Li, J. Liu, B.
Yan, Y. Li, Tetrahedron Lett. 2009, 50, 2353; j) Y. Wang, L. Xu, D.
Ma, Chem. Asian J. 2010, 5, 74.
[7] a) D. Kundu, A. Majee, A. Hajra, Tetrahedron Lett. 2009, 50, 2668;
b) S. Urinda, D. Kundu, A. Majee, A. Hajra, Heteroat. Chem. 2009,
20, 232; c) B. C. Ranu, S. S. Dey, A. Hajra, Tetrahedron 2002, 58,
2529; d) B. C. Ranu, S. Samanta, A. Hajra, Synlett 2002, 0987;
e) B. C. Ranu, A. Hajra, J. Chem. Soc. Perkin Trans. 1 2001, 355;
f) B. C. Ranu, A. Hajra, J. Chem. Soc. Perkin Trans. 1 2001, 2262;
g) B. C. Ranu, A. Hajra, U. Jana, Tetrahedron Lett. 2000, 41, 531;
h) B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem. 2000, 65, 6270;
i) B. C. Ranu, A. Hajra, U. Jana, Org. Lett. 1999, 1, 1141.
[5] K. Kanao, Y. Miyake, Y. Nishibayashi, Organometallics 2010, 29,
2126.
[8] a) A. Z. Halimehjani, F. Aryanasab, M. R. Saidi, Tetrahedron Lett.
2009, 50, 1441; b) Y. Sohtome, B. Shin, N. Horitsugi, R. Takag, K.
Noguchi, K. Nagasawa, Angew. Chem. 2010, 122, 7457; Angew.
Chem. Int. Ed. 2010, 49, 7299.
[9] B. S. Furniss, A. J. Hannaford, V. Rogers, P. W. G. Smith, A. R.
Tatchell, Vogelꢀs Textbook of Practical Organic Chemistry, 4th ed.,
ELBS/Longman, England, p. 796.
[10] V. Srivastava, A. S. Negi, J. K. Kumar, U. Faridi, B. S. Sisodia, M. P.
Darokar, S. Luqman, S. P. S. Khanuja, Bioorg. Med. Chem. Lett.
2006, 16, 911.
[11] a) H. Shiraishi, T. Nishitani, S. Sakaguchi, Y. Ishii, J. Org. Chem.
1998, 63, 6234; b) B. C. Ranu, A. Hajra, Tetrahedron 2001, 57, 4767;
c) S. Maiti, S. Biswas, U. Jana, J. Org. Chem. 2010, 75, 1674.
[6] a) R. Ghosh, S. Maiti, J. Mol. Catal. A 2007, 264, 1; b) T. P. Loh,
G. L. Chua, Chem. Commun. 2006, 2739; c) K. K. Chauhan, C. G.
Frost, J. Chem. Soc. Perkin Trans. 1 2000, 3015; d) P. Cintas, Synlett
1995, 1087; e) J. Podlech, T. C. Maier, Synthesis 2003, 0633; f) V.
Nair, S. Ros, C. N. Jayan, B. S. Pillai, Tetrahedron 2004, 60, 1959;
g) B. C. Ranu, Eur. J. Org. Chem. 2000, 2347; h) J. Augꢂ, N. Lubin-
Germain, J. Uziel, Synthesis 2007, 1739; i) H. A. F. Hçppe, G. C.
Lloyd-Jones, M. Murray, T. M. Peakman, K. E. Walsh, Angew.
Chem. 1998, 110, 1653; Angew. Chem. Int. Ed. 1998, 37, 1545;
j) B. M. Trost, R. C. Livingston, J. Am. Chem. Soc. 2008, 130, 11970;
k) Y. Nishimoto, H. Ueda, Y. Inamoto, M. Yasuda, A. Baba, Org.
Lett. 2010, 12, 3390; l) M. Yasuda, S. Yamasaki, Y. Onishi, A. Baba,
J. Am. Chem. Soc. 2004, 126, 7186; m) K. Koszinowski, J. Am.
Chem. Soc. 2010, 132, 6032; n) J. S. Yadav, A. Antony, J. George,
B. V. S. Reddy, Eur. J. Org. Chem. 2010, 591.
Received: December 3, 2010
Published online: January 4, 2011
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