Simple, convenient, and efficient synthesis of 2-aryl-substituted benzo[b]furans

Article abstract of DOI:10.1080/00397910701860323

A simple, convenient, and efficient one-pot method for the preparation of benzofuran is reported. Sonogashira coupling reaction of aryl iodides with 2-methyl-3-butyn-2-ol was used as an acetylene source in the presence of Pd(PPh3)2Cl2 and CuI. Deprotection of the acetylene moiety in the same pot using a strong base and the second Sonogashira coupling/cyclization of and substituted o-iodophenols led to the formation of the appropriate benzo[b]furans. These protocols also can be used in the synthesis of natural products and indoles. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701860323

This article was downloaded by: [University of Memphis]
On: 01 October 2012, At: 09:11
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Simple, Convenient, and
Efficient Synthesis of 2-Aryl-
substituted Benzo[b]furans
Yong Jiang a , Botao Gao a , Wenjuan Huang a ,
Yongmin Liang a , Guosheng Huang a & Yongxiang Ma
a
a State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou, China
Version of record first published: 22 Dec 2008.
To cite this article: Yong Jiang, Botao Gao, Wenjuan Huang, Yongmin Liang, Guosheng
Huang & Yongxiang Ma (2008): Simple, Convenient, and Efficient Synthesis of 2-Aryl-
substituted Benzo[b]furans, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:2, 197-204
To link to this article: http://dx.doi.org/10.1080/00397910701860323
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,

sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 39: 197–204, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701860323
Simple, Convenient, and Efficient Synthesis
of 2-Aryl-substituted Benzo[b]furans
Yong Jiang, Botao Gao, Wenjuan Huang, Yongmin Liang,
Guosheng Huang, and Yongxiang Ma
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, China
Abstract: A simple, convenient, and efficient one-pot methodfor the preparation of
benzofuran is reported. Sonogashira coupling reaction of aryl iodides with 2-methyl-
3-butyn-2-ol was used as an acetylene source in the presence of Pd(PPh3)2Cl2 and
CuI. Deprotection of the acetylene moiety in the same pot using a strong base
and the second Sonogashira coupling=cyclization of and substituted o-iodophenols
led to the formation of the appropriate benzo[b]furans. These protocols also can be
used in the synthesis of natural products and indoles.
Keywords: Aryl iodide, benzo[b]furan, 2-methyl-3-butyn-2-ol, o-iodophenol,
Sonogashira reaction
Benzo[b]furan derivatives are an important class of organic compounds
that occur in many compounds and natural products because of their
biological activities,[1] including antitumor properties.[2] They can be used
as inhibitors of 5-lipoxygenase,[3] antagonists of the angiotensin II
receptor,[4] blood coagulation factor Xa inhibitors,[5] ligands of adenosine
A1 receptor[6] and so forth.
Generally, preparing benzofurans via a palladium catalytic reaction
is an effective and a widely used method.[7] This is accomplished through
a tandem Sonagashira coupling=5-endo-dig cyclization starting from
either o-iodophenols or o-ethynyl-phenols. In comparison to the tradi-
tional methods, these palladium-based methods offer increased functional
group tolerance and improved yields of the desired benzofuran, but
Received March 18, 2007.
Address correspondence to Guosheng Huang, State Key Laboratory of Applied
Organic Chemistry, Lanzhou University, Lanzhou, China. E-mail:hgs2368@163.com
197

198
Y. Jiang et al.
they need expensive acetylenes, or their substrate preparation needs
tedious operation and expensive reagents. Recently, many new and
efficient methods for the synthesis of benzofuran have been developed,
such as cyclization=oxidation of the allyl aryl ether,[8] the cyclization of
2-arylethynyl anisole,[9] and intramolecular o-arylation of 2-haloaryl
ketones.[10] These methods are very efficient for synthesizing benzofuran;
unfortunately, the substrate preparation also needs tedious operation or
expensive reagents, and there are some limitations for using substrate
extension. So, in the present work, we describe a simple, convenient,
and efficient method for the preparation of benzofuran via a one-pot
process using a tandem a Sonogashira reaction.
ꢀ
Previously, Novak’s group has reported tandem Sonogashira coupling
using the cheap reagent 2-methyl-3-butyn-2-ol.[11] Therefore, the first set of
experiments was directed toward establishing the feasibility of the reaction.
We chose iodobenzene (1) as a model compound and carried out its coupling
with 2-methyl-3-butyn-2-ol (2) in the presence of 2 mol% bis(tri-phenylpho-
sphine)palladium dichloride, 2 mol% copper(I) iodide, and Et3N at room
temperature for about 5 h. The intermediate (3) as a yellow solid was iso-
lated first and characterized; then (3) was reacted with 2-iodo-4-methylphe-
nol in the presence of the same catalyst and a strong base KOBut to give the
desired product (4), 5-methyl-2-phenylbenzo[b]furan, in a yield of 63%. In
following experiments, another portion of the catalyst Pd(PPh3)2Cl2=CuI,
2-iodo-4-methylphenol, and the strong base KOBut were added immediately
after completing conversion of (1) and (2) (monitored by thin-layer chroma-
tography, TLC) without isolating the intermediate (3). The addition of
another portion of the catalyst is neccessary or lower yield of the desired pro-
duct will be obtained. Then the mixture was stirred at 110ꢀ for 24 h to give
the benzo[b]furan (4) in a yield of 75% (as shown in Scheme 1).
To find out the optimum operation, we examined the reaction in
various conditions. It can be seen from Table 1 that beneficial base
and solvent were used and the isolated yields of 16% for NaOH (entry
1), 45% for KOH (entry 3), 75% for KOBut (entry 5), and 8% for
K3PO4 (entry 6) in toluene were obtained. When using K2CO3 or NaOAc
as the base, no desired product was detected by TLC monitoring. A very
interesting result appeared when using KOBut as the base and benzene as
the solvent, and an 80% yield was given. In the following experiments,
Scheme 1.

2-Aryl-substituted benzo[b]furans
199
Table 1. Various condition effects on the reactiona
Entry
Solvent
Base
Isolated yield (%)
1
2
3
4
5
6
7
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NaOH
K2CO3
KOH
16
b
–
45
b
–
NaOAc
KOBut
K3PO4
KOBut
75
8
80
aReacted in a 110 ꢀC oil bath or at the boiling point of the solvent under an
argon atmosphere for 24 h.
bNo benzofuran product was detected by TLC.
Table 2. Synthesis of 2-phenyl substituted benzofurans
Entry
1
o-Iodophenola
Product
Isolated yield (%)
80
2
3
60
45
4
5
75
61
ao-Iodophenols were prepared according to the literature procedure Ref.[13]
.

200
Y. Jiang et al.
Table 3. Synthesis of 5-methyl-2-arylbenzofuran
Entry
1
Arl
Product
Isolated yield (%)
81
2
3
4
5
6
7
8
52
61
51
45
49
69
75
9
65
53
10
a0.02 mmol of Pd(OAc)2 and 0.04 mmol of PPh3 were used instead of
Pd(PPh3)2Cl2 and reacted at 50 ꢀC in the first step.
we chose the Pd(PPh3)2Cl2=CuI-KOBut-benzene system as the standard
protocol and aryl iodides,[12] 2-methyl-3-butyn-2-ol and substituted
o-iodophenols as substrates to synthesize 2-arylbenzo[b]furans.

2-Aryl-substituted benzo[b]furans
201
Scheme 2. Synthesis of cicerfuran.
Using this protocol, a series of 5-functional group substituted 2-phenyl-
benzo-furans in moderate to good yield (Table 2) can be prepared. From
the table, it can be seen that the yield decreases with the increasing electron
withdrawing of the functional group. The ortho group of the iodophenol
also gives the lower yield of the product (entry 5, Table 2). Furthermore,
we successfully synthesized 5-methyl-2-aryl benzo[b]furan in moderate
to good yield (Table 3). From the control experiments (entries 1, 2, 4, 5,
7–9, Table 3), it can be seen that the position of functional group of the aryl
has a distinct effect on the yield. It is likely that the steric hindrance of
the ortho group led to the corresponding yield decrease. In addition,
2-bromovinylbenzene also works in the reaction (entry 10, Table 3). Upon
further study, we found that this protocol can be used for the preparation of
natural products, cicer-furan (Scheme 2) and indole (Scheme 3).
In summary, a simple, convenient, and efficient method is reported
for the one-pot synthesis of various substituted benzo[b]furans starting
from easily prepared aryl iodides and o-iodophenols and the economical
reagent 2-methyl-3-butyn-2-ol. It avoids using expensive reagents, needs
no isolation of the intermediate, greatly simplifies the operational steps,
and can be used in the preparation of natural products and indole.
EXPERIMENTAL
General Procedure for the Preparation of Benzo[b]furan
Under an argon atmosphere, 0.02 mmol of Pd(PPh3)2Cl2, 0.02 mmol of
CuI, 1 mmol of aryl iodide, 1 mmol of 2-methyl-3-butyn-2-ol, and 1 ml
Scheme 3.

202
Y. Jiang et al.
of Et3 N were added to a glass tube (2.5 cm in diameter) equipped with a
Teflon1-coated stir bar. The mixture was stirred for about 5 h at room
temperature until the aryl iodide was converted completely (monitored
by TLC). Then 0.02 mmol of Pd(PPh3)2Cl2, 0.02 mmol of CuI, 1 mmol of
o-iodophenol, 3 mmol of KOBut, and 2 ml of benzene were added and
stirred at a reflux condition for 24 h. After cool to rt, the mixture was
extracted by ethyl acetate, washed twice by water brine, and dried over
anhydrous MgSO4. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography on silica gel
with petroleum ether and ethyl acetate as eluent to afford the pure
product.
Preparation of 2-(6-Methoxybenzo[d][1,3]dioxol-5-yl) Benzofuran-6-ol
(Cicerfuran) (Scheme 2)
Under an argon atmosphere, 0.02 mmol of Pd(OAc)2, 0.02 mmol of CuI,
0.04 mmol of PPh3, 1 mmol of 5-bromide-6-methoxybenzo[d][1,3]dioxole,
1 mmol of 2-methyl-3-butyn-2-ol, and 1 ml of Et3N were added to a glass
tube (2.5 cm in diameter) equipped with a Teflon1-coated stir bar. The
mixture was stirred for about 5 h at 50 ꢀ C the until aryl iodide was con-
verted completely (monitored by TLC). Then 0.02 mmol of Pd(OAc)2,
0.02 mmol of CuI, 0.04 mmol of PPh3, 1 mmol of 4-bromobenzene-1,
3-diol, 5 mmol of KOBut, and 2 ml of benzene were added and stirred
at a reflux condition for 24 h. After cooling to rt, the mixture was neutra-
lized with 1 NHCl, extracted by ethyl acetate, washed twice by water
brine, and dried over anhydrous MgSO4. The solvent was evaporated
under reduced pressure, and the residue was purified by column chroma-
tography on silica gel with petroleum ether and ethyl acetꢀate as eluent to
afford the pure product. White crystals; mp: 145–147 C (lit.[7i] 145–
147 ꢀC). 1H NMR (300 MHz, DMSO–d6): d ¼ 9.6 (br, 1H), 7.38 (d,
J ¼ 8.5 Hz, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 6.97 (s, 1H), 6.93 (s, 1H),
6.73 (d, J ¼ 8.5 Hz, 1H), 6.01 (s, 2 H), 3.91 (s, 3 H). 13C NMR (75 MHz,
MHz, DMSO-d6): d ¼ 155.45, 154.03, 151.81, 150.16, 147.73, 141.02,
121.33, 120.97, 111.11, 104.62, 104.41, 101.55, 97.22, 95.41, 56.30. MS
(EI): m=z ¼ 284[Mþ]. Anal. calcd. for C16H12O5: C, 67.60; H, 4.25.
Found: C, 67.78; H, 4.35.
Preparation of 2-Phenyl-1H-indole (Scheme 3)
Under an argon atmosphere, 0.02 mmol of Pd(PPh3)2Cl2, 0.02 mmol of
CuI, 1 mmol of aryl iodide, 1 mmol of 2-methyl-3-butyn-2-ol, and 1 ml
of Et3N were added to a glass tube (2.5 cm in diameter) equipped with

2-Aryl-substituted benzo[b]furans
203
a Teflon1-coated stir bar. The mixture was stirred for about 5 h at room
temperature until the aryl iodide was converted completely until (moni-
tored by TLC). Then 0.02 mmol of Pd(PPh3)2Cl2, 0.02 mmol of CuI,
1 mmol of N-(2-iodo-phenyl)actamide, and 3 mmol of KOBut, and 2 ml
of benzene were added and stirred at a reflux condition for 24 h. After
cooling to rt, the mixture was extracted by ethyl acetate, washed twice
by water then brine, and dried over anhydrous MgSO4. The solvent
was evaporated under reduced pressure, and the residue was purified
by column chromatography on silica gel with petroleum ether and ethyl
acetate as eluent to afford the pure product (yield 57%). Pale yellow
solid; 1H NMR (300MHz, CDCl3): d ¼ 8.34 (brs, 1H), 7.64 (t, J ¼ 7.5 Hz,
3 H), 7.43 (t, J ¼ 7.5Hz, 2H), 7.39 (d, J ¼ 7.5 Hz, 1H), 7.32 (t, J ¼ 7.5 Hz,
1H), 7.20 (t, J ¼ 7.5 Hz, 1H), 7.13 (t, J ¼ 7.5 Hz, 1H), 6.83 (s, 1 H). 13C
NMR (75 MHz, CDCl3): d ¼ 137.92, 136.95, 132.47, 129.33, 129.01,
127.73, 125.26, 122.45, 120.72, 120.31, 110.93, 100.07. MS(EI):
m=z ¼ 193[Mþ]. Anal. calcd. for C14H11N: C, 87.01; H, 5.74; N, 7.25.
Found: C, 87.11; H, 5.69; N, 7.20.
ACKNOWLEDGMENT
The authors thank the State Key Laboratory of Applied Organic
Chemistry for financial support.
REFERENCES
1. Donnelly, D. M. X.; Meegan, M. J. Comprehensive Heterocyclic Chemistry;
A. R. Katritzky (Ed.); Pergamon Press: New York, 1984; Vol. 4.
2. Erber, S.; Ringshandl, R.; von Angerer, E. Anti-Cancer Drug Des. 1991, 6,
417–426.
3. McCallion, G. D. Curr. Org. Chem. 1999, 3, 67–76.
4. Judd, D. B.; Dowle, M. D.; Middlemiss, D.; Scopes, D. I. C.; Ross, B. C.;
Jack, T. I.; Pass, M.; Tranquillini, E.; Hobson, J. E.; Panchal, T. A.; Stuart,
P. G.; Paton, J. M. S.; Hubbard, T.; Hilditch, A.; Drew, G. M.; Robertson,
M. J.; Clark, K. L.; Travers, A.; Hunt, A. A. E.; Polly, J.; Eddershaw, P. J.;
Bayliss, M. K.; Manchee, G. R.; Donnelly, M. D.; Walker, D. G.; Richards,
S. A. J. Med. Chem. 1994, 37, 3108.
5. Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.;
Yamaguchi, H.; Hara, T.; Iwamoto, M. J. Med. Chem. 1994, 37, 1200.
6. Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C. J. Org.
Chem. 1993, 36, 1425.
7. (a) Areadi, A.; Cacchi, S.; Marinelli, F. Synthesis 1986, 749–751; (b) Torii, S.;
Xu, L. H.; Okumoto, H. Synlett 1992, 515–516; (c) Dyker, G. J. Org. Chem.
1993, 58, 6426–6428; (d) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K.

204
Y. Jiang et al.
K. C. J. Org. Chem. 1995, 60, 3270–3271; (e) Areadi, A.; Cacchi, S.;
Delrosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280–
9288; (f) Fancelli, D.; Fagnola, M. C.; Severino, D.; Bedeschi, A. Tetrahedron
Lett. 1997, 38, 2311–2314; (g) Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron
Lett. 1998, 39, 5101–5104; (h) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2,
´
297–299; (i) Novak, Z.; Timari, G.; Kotschy, A. Tetrahedron 2003, 59,
´
7509–7513.
8. (a) Esen, B.; Ilia, F.; Peter, L. Tetrahedron Lett. 2005, 46, 2185–2187; (b)
Zhang, H. M.; Eric, M.; Ferreira, B. M. S. Angew. Chemie. Int. Ed. 2004,
43, 6144–6148; (c) So, W. Y.; Jeong, I. E. Org. Lett. 2005, 7, 3355–3358.
9. (a) Yue, D. W.; Yao, T. L.; Larock, R. C. J. Org. Chem. 2005, 70, 9985–9989;
(b) Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024–15025; (c)
Nakamura, I.; Mizushima, I.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
15022–15023.
10. (a) Chen, C. Y.; Peter, G. D. J. Org. Chem. 2005, 70, 6964–6967; (b) Micheal,
C. W.; Dawn, T.; Adam, T. G. Org. Lett. 2004, 6, 4755–4757.
ꢀ
11. (a) Novak, Z.; Nemes, P.; Kotschy, A. Org. Lett. 2004, 6, 4917; (b) Nagy, A.;
ꢀ
Novak, Z.; Kotschy, A. J. Organometallic Chem. 2005, 690, 4453.
12. The aryl iodides were prepared according to the literature procedure: Larock,
R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106, 4218–4227.
13. Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55, 5287–5291.