Synthesis of 2-Arylbenzo[b]furans via Copper(I)-Catalyzed Coupling of o-Iodophenols and Aryl Acetylenes

Article abstract of DOI:10.1021/ol0272040

(Equation Presented) We report a copper(I)-catalyzed procedure for the synthesis of 2-arylbenzo[b]furans. This protocol can be used to synthesize a variety of 2-arylbenzo[b]furans in good to excellent yields. This method can tolerate a variety of functional groups, does not require the use of expensive additives, and is palladium-free.

Full text of DOI:10.1021/ol0272040

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4727-4729
Synthesis of 2-Arylbenzo[b]furans via
Copper(I)-Catalyzed Coupling of
o-Iodophenols and Aryl Acetylenes
Craig G. Bates, Pranorm Saejueng, Jaclyn M. Murphy, and D. Venkataraman*
Department of Chemistry, UniVersity of Massachusetts-Amherst,
710 North Pleasant Street, Amherst, Massachusetts 01003
dV@chem.umass.edu
Received October 30, 2002
ABSTRACT
We report a copper(I)-catalyzed procedure for the synthesis of 2-arylbenzo[b]furans. This protocol can be used to synthesize a variety of
2-arylbenzo[b]furans in good to excellent yields. This method can tolerate a variety of functional groups, does not require the use of expensive
additives, and is palladium-free.
Benzo[b]furans are prevalent in many compounds and natural
products that have important biological properties.1 These
include: antitumor properties,2 inhibition of protein phos-
phatase 1B,3 5-HT2 and 5-HT3 antagonist activity,4 inhibition
of 5-Lipoxygenase (5-LO),4b and anti-fungal properties.5
Pharmaceutically, these properties are relevant in the treat-
ment for cancer, cardiovascular disease, type 2 diabetes,
migraines, dementia, and anxiety.2,4b
The current methods for the synthesis of benzo[b]furans
include the dehydrative cyclization of R-(phenoxy)alkyl
ketones, cyclofragmentation of oxiranes, acidic dehydration
of o-hydroxybenzyl ketones, and base-mediated decarbox-
ylation of o-acylphenoxyacetic acids and esters.6 These
traditional methods are often multistep reactions, limited to
a particular substrate, and do not tolerate a variety of
functional groups. More recently, palladium-based cross-
coupling reactions with copper iodide as a cocatalyst have
been developed for the synthesis of benzofurans.7 This is
accomplished through a tandem Sonagashira coupling/5-
endo-dig cyclization starting from either o-iodophenols or
o-ethynylphenols. In comparison to the traditional methods,
these palladium-based protocols offer increased functional
group tolerance and improved yields of the desired benzo-
furan.
In recent years, the DV group,8 Buchwald group,9 and
others10 have been interested in developing copper-catalyzed
cross-coupling reactions. In contrast to the traditional Ull-
mann coupling, these methods are mild and tolerate a wide
(7) (a) Arcadi, 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. K. C. J. Org. Chem. 1995, 60, 3270-3271. (e) Arcadi,
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) Kundu, N. G.;
Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815-
2820. (h) Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39,
5101-5104. (i) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
Synlett 1999, 1432-1434. (j) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000,
2, 297-299. (k) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001,
57, 8017-8028.
(1) Donnelly, D. M. X.; Meegan, M. J. ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., 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) Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W. X.;
McDevitt, R.; Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.;
Taylor, J. R. J. Med. Chem. 2000, 43, 1293-1310.
(4) (a) Watanabe, Y.; Yoshiwara, H.; Kanao, M. J. Heterocycl. Chem.
1993, 30, 445-451. (b) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67-
76.
(8) (a) Gujadhur, R.; Venkataraman, D. Synth. Commun. 2001, 31, 2865-
2879. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791-4793. (c) Gujadhur, R. K.; Bates, C. G.; Venkataraman,
D. Org. Lett. 2001, 3, 4315-4317. (d) Bates, C. G.; Gujadhur, R. K.;
Venkataraman, D. Org. Lett. 2002, 4, 2803-2806.
(5) McAllister, G. D.; Hartley, R. C.; Dawson, M. J.; Knaggs, A. R. J.
Chem. Soc., Perkin Trans. 1 1998, 3453-3457.
(6) Katritzky, A. R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chem. 2001,
66, 5613-5615 and references therein.
10.1021/ol0272040 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2002

range of functional groups. When compared to noble-metal
catalysts, copper-based methods have an economic attrac-
tiveness and hence remain the reactions of choice in large
and industrial scale reactions. We report here a palladium-
free synthesis of 2-arylbenzo[b]furans via a copper(I)-
catalyzed coupling reaction of o-iodophenols and aryl
acetylenes using [Cu(phen)(PPh3)2]NO3 (1) as the catalyst
and Cs2CO3 as base in toluene.11
of CuI (10 mol %) with 10 mol % of 1,10-phenanthroline
(0) as an additive was least effective. On the basis of these
findings we chose to use [Cu(phen)(PPh3)2]NO3 as the
catalyst for the coupling of o-iodophenols and aryl acetylenes
to synthesize 2-arylbenzo[b]furans.
We then screened various bases using o-iodophenol and
phenylacetylene as the reactants and 1 as the catalyst in
toluene (Table 1). We found that Cs2CO3 was the most
Table 1. Base Effects on the Copper(I)-Catalyzed Synthesis of
2-Arylbenzo[b]furans
% conversion
base
(by GC)
We have previously shown that [Cu(phen)(PPh3)Br] can
be used as a catalyst for the coupling of phenylacetylene
and iodobenzene using K2CO3 as the base in toluene.8c To
study the mechanistic aspects of this reaction, we prepared
a variety of copper(I) complexes bearing bidentate nitrogen-
based ligands and monitored the formation of diphenyl-
acetylene over time (Figure 1). We discovered that the most
Cs2CO3
K3PO4
K2CO3
KOt-Bu
NaOt-Bu
Et3N
>95
67
53
40
29
0
effective base. Other bases such as K3PO4, K2CO3, NaOt-
Bu, and KOt-Bu were less effective and Et3N was ineffective.
Through control experiments we found that CuI, CuBr,
or CuCl could not effectively catalyze the reaction and the
conversion to 2-phenylbenzo[b]furan was 10%, 10%, and
20%, respectively. Finally, 2-phenylbenzo[b]furan was not
observed by GC when the reaction was run in either the
absence of Cs2CO3 or 1. On the basis of these control
experiments, we decided to use 1 as the catalyst and Cs2CO3
as the base in toluene as the standard protocol to synthesize
2-arylbenzo[b]furans from o-iodophenols and aryl acetylenes.
Using our protocol, we were able to couple o-iodophenol
with electron-rich and electron-poor aryl acetylenes in good
(9) (a) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539-10540. (b) Kiyomori, A.; Marcoux, J. F.; Buchwald, S.
L. Tetrahedron Lett. 1999, 40, 2657-2660. (c) Klapars, A.; Antilla, J. C.;
Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727-7729.
(d) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-
3805. (e) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581-584. (f) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973-976. (g) Hennessy, E. J.; Buchwald, S. L. Org. Lett.
2002, 4, 269-272.
(10) (a) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312-2313. (b) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am.
Chem. Soc. 1998, 120, 12459-12467. (c) Kalinin, A. V.; Bower, J. F.;
Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-2987. (d)
Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674. (e) Fagan,
P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000,
122, 5043-5051.
Figure 1. A graph depicting the percent conversion of diphenyl-
acetylene (monitored by GC) from iodobenzene and phenylacetyl-
ene using various copper(I) complexes as a catalyst. Reaction
conditions: 1.00 mmol of phenylacetylene, 1.00 mmol of iodo-
benzene, 10 mol % of Cu complex, 2.0 equiv of K2CO3, in toluene
at 110 °C under Ar atmosphere. Note: Lines are drawn for visual
connectivity of the collected data points.
(11) The use of copper has previously been shown to mediate the
synthesis of benzofurans. Castro and co-workers synthesized 2-phenylbenzo-
[b]furan through the coupling reaction of cuprous phenylacetylene and
o-iodophenol.a This procedure, however, requires the use of a stoichiometric
amount of the preformed cuprous acetylide and refluxing pyridine. Owen
and co-workersb modified Castro’s procedure using cuprous oxide (63 mol
%) and various acetylenes, but this procedure still requires the use of
refluxing pyridine and the amount of copper required is still high. The scope
and potential of these reactions have not been fully explored: (a) Castro,
C. E.; Gauchan, E. J.; Owsley, D. C. J. Org. Chem. 1966, 31, 4071-4078.
(b) Doad, G. J. S.; Barltrop, J. A.; Petty, C. M.; Owen, T. C. Tetrahedron
Lett. 1989, 30, 1597-1598.
active catalyst was [Cu(phen)(PPh3)2]NO3 (O in Figure 1).
[Cu(phen)(PPh3)Br] (b) was slightly less effective and the
use of [Cu(PPh3)3Br] (1) resulted in only 40% conversion
to the desired product in 24 h. Surprisingly, complexes such
as [Cu(neocup)(PPh3)Br] (3) (neocup ) 2,9-dimethyl-1,10-
phenanthroline) and [Cu(bipy)(PPh3)Br] (9) (bipy ) 2,2′-
bipyridine) were found to be much less effective at catalyzing
this reaction. From Figure 1, it can also be seen that the use
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Org. Lett., Vol. 4, No. 26, 2002

Table 2. Synthesis of 2-Arylbenzo[b]furans via
Copper(I)-Catalyzed Coupling of o-Iodophenol and Various Aryl
Acetylenesa
Table 3. Synthesis of 2-Arylbenzo[b]furans via
Copper(I)-Catalyzed Coupling of Phenylacetylene and Various
4-Substituted-o-iodophenolsa
a Reaction conditions: 2.00 mmol of o-iodophenol, 2.00 mmol of
phenylacetylene, 5.0 mL of toluene, 24 h. b 4-Substituted-o-iodophenols
were synthesized from readily available phenols following the method
reported by Edgar and Falling: Edgar, K. J.; Falling, S. N. J. Org. Chem.
1990, 55, 5287-5291. See Supporting Information for details.
In summary, we have reported a synthetic protocol for
2-arylbenzo[b]furans from o-iodophenols and aryl acetylenes
using a well-defined copper(I) catalyst. Our protocol tolerates
a wide range of functional groups that can be used to further
functionalize the benzo[b]furan ring. This synthetic route is
palladium-free and avoids the use of expensive and/or air-
sensitive additives.
a Reaction conditions: 2.00 mmol of o-iodophenol, 2.00 mmol of
phenylacetylene, 5.0 mL of toluene, 24 h. b Reaction time of 48 h.
to excellent yields (Table 2). Base-sensitive functional groups
such as methyl ketones (entry 6, Table 2) and methyl esters
(entry 7, Table 2) were tolerated by this protocol. Ortho-
substituted aryl acetylenes could also be coupled to o-
iodophenol in good yields (entries 4 and 8, Table 2). Aryl
acetylenes bearing an alkene as a substitutent could also be
successfully coupled in good yields with no observed Heck-
like coupling; the Heck reaction may be observed if a
palladium-based system is used (entry 9, Table 2). Further-
more, we successfully coupled a variety of 4-substituted-o-
iodophenols with phenylacetylene in good to excellent yields
(Table 3). The potential for further functionalization of the
benzo[b]furan skeleton is made possible by the incorporation
of a terminal alkene, bromine, and chlorine groups (entry 9,
Table 2 and entries 4 and 5, Table 3, respectively). Our
observed yields are comparable to and in some cases better
than the yields reported using palladium-catalyzed reactions.7a,c
Acknowledgment. The University of Massachusetts,
Amherst start-up funds provided the financial support for
this research. D.V. gratefully acknowledges a Camille and
Henry Dreyfus New Faculty Award and an NSF CAREER
Award (CHE-0134287). P.S. thanks the Royal Thai Govern-
ment for financial support. J.M. thanks Bristol-Myers Squibb
for an undergraduate fellowship.
Supporting Information Available: Synthetic procedures
and crystallographic information files (CIF) for 1 and
synthetic procedures and complete characterization data for
entries in Tables 2 and 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0272040
Org. Lett., Vol. 4, No. 26, 2002
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