Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization

Article abstract of DOI:10.1021/jo051299c

2,3-Disubstituted benzo[b]furans are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with I₂, PhSeCl, Or

Full text of DOI:10.1021/jo051299c

Synthesis of 2,3-Disubstituted Benzo[b]furans by the
Palladium-Catalyzed Coupling of o-Iodoanisoles and Terminal
Alkynes, Followed by Electrophilic Cyclization
Dawei Yue, Tuanli Yao, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received June 24, 2005
2,3-Disubstituted benzo[b]furans are readily prepared under very mild reaction conditions by the
palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed
by electrophilic cyclization with I2, PhSeCl, or p-O2NC6H4SCl. Aryl- and vinylic-substituted alkynes
undergo electrophilic cyclization in excellent yields. Biologically important furopyridines can be
prepared by this approach in high yields.
Introduction
important calcium blockers13 and phytoestrogens.14 For
instance, XH-1415 was the first reported potent non-
nucleoside adenosine A1 agonist16 and obovaten is known
as an active antitumor agent.17
The benzo[b]furan nucleus is prevalent in a wide
variety of biologically active natural and unnatural
compounds.1 Many 2-arylbenzofuran derivatives are well-
known to exhibit a broad range of biological activities,
including anticancer,2 antiproliferative,3 antiviral,4 an-
tifungal,5 immunosuppressive,6 antiplatelet,7 antioxida-
tive,8 insecticidal,9 antiinflammatory,10 antifeedant,11 and
cancer preventative activity.12 These compounds are also
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There has been growing interest in developing a
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10.1021/jo051299c CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/11/2005
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J. Org. Chem. 2005, 70, 10292-10296

Synthesis of 2,3-Disubstituted Benzo[b]furans
SCHEME 1
ylphenols are also relatively unstable. In another paper,
Cacchi has demonstrated an analogous cyclization of
benzylic ethers to generate furopyridines and reported
that the o-hydroxyalkynylpyridines are not stable and
cyclize spontaneously to give furopyridines (eq 1).23 We
SCHEME 2
have attempted to make this overall approach more
attractive synthetically by examining the preparation
and cyclization of the corresponding methyl ethers using
a variety of commercially available electrophiles. Herein,
we wish to report an efficient approach to 2,3-disubsti-
tuted benzo[b]furans and furopyridines involving the
palladium/copper-catalyzed coupling of various iodo-
anisoles and an iodomethoxypyridine and terminal
alkynes, followed by electrophilic cyclization.
indoles,21 and isoquinolines22 has been electrophilic cy-
clization of the corresponding 2-(1-alkynyl)phenols, -thio-
anisoles, -anilines, and -imines, respectively (Scheme 1).
Our and other’s recent success in this area encouraged
us to examine the possibility of preparing benzo[b]furans
by the same strategy involving a palladium/copper-
catalyzed alkyne coupling, followed by electrophilic cy-
clization. Cacchi and co-workers have previously reported
an approach to the synthesis of 3-iodobenzo[b]furans by
a related process involving iodocyclization (Scheme 2).19
Unfortunately, the protecting and deprotecting steps
required to synthesize the alkynylphenol are not par-
ticularly attractive synthetically. Some of the alkyn-
Results and Discussion
The arylalkynes required for our approach to benzo-
[b]furans are readily prepared by the Sonogashira cou-
pling24 of commercially available o-iodoanisole (5.0 mmol)
and terminal alkynes (6.0 mmol) with use of a catalyst
consisting of 2 mol % of PdCl2(PPh3)2 and 1 mol % of CuI
in the presence of Et3N (12.5 mL) as the solvent at room
temperature. The yields of this process range from 70%
to 94% and this procedure should readily accommodate
considerable functionality.
We first examined the reaction of our methoxy-
substituted aryl alkynes (0.25 mmol in 3 mL of CH2Cl2)
with I2 (2.0 equiv in 2 mL of CH2Cl2) under our well-
established reaction conditions for the synthesis of benzo-
[b]thiophenes20 and indoles21 (Scheme 1). We were pleased
to see that 2-(phenylethynyl)anisole reacted in less than
3 h at room temperature to afford 3-iodo-2-phenylbenzo-
[b]furan in an 87% yield (Table 1, entry 1). To extend
this approach to other benzo[b]furans, we have also
looked at a range of other readily available electrophiles.
So far p-O2NC6H4SCl and PhSeCl have been successfully
employed in this electrophilic cyclization, providing excel-
lent yields of the desired cyclization products (Table 1,
entries 2-4).
The nature of the substituents attached to the triple
bond and the arene has a major impact on the success of
the reaction. Virtually no difference in the rates of
reaction or the overall yields have been observed with
use of a vinylic alkyne and arylalkynes bearing certain
types of functionality on the aromatic ring (entries 1-16).
However, alkynes bearing an alkyl group (entries 19, 20,
and 25) fail to undergo electrophilic cyclization. Instead,
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Yue et al.
TABLE 1. Synthesis of Benzo[b]furans by Electrophilic Cyclizationa
a All reactions were run with 0.25 mmol of the alkyne and 2 equiv of electrophile in 5 mL of CH2Cl2 at 25 °C for 3 h. b The reaction took
12 h. c None of the desired cyclization product was observed. d An inseparable mixture was obtained.
an almost quantitative yield of the product of simple
addition of the electrophile to the alkyne triple bond was
obtained (entries 19, 20, and 25). To form a furan moiety,
the oxygen of the methoxy group has to undergo a five
endo-dig attack on the carbon-carbon triple bond. The
failure to undergo the desired cyclization in entries 19,
20, 21, 22, and 25 is possibly due to more favorable
formation of a “vinylic” cation on the carbon of the triple
bond next to the aryl group bearing the methoxy group,
instead of on the more remote carbon (see the later
mechanistic discussion). Similarly, a methoxy group para
to the triple bond increases the electron density on the
distal end of the triple bond (Figure 1), which favors
electrophilic attack at that position and disfavors a five
10294 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of 2,3-Disubstituted Benzo[b]furans
SCHEME 3
FIGURE 1. Methoxy electron-donating effect on the triple
bond.
FIGURE 2. Nitro electron-withdrawing effect on the triple
While Cacchi reported the successful synthesis of
several furopyridines by electrophilic cyclization of o-
(benzyloxy)alkynylpyridines, we have examined the cy-
clization of an o-methoxyalkynylpyridine and found that
a methyl group can also be a good leaving group in this
reaction. Pyridine derivative 18 was treated with I2 under
our standard electrophilic cyclization conditions to afford
the desired furopyridine in a 67% yield. This provides a
convenient alternative route to the synthesis of furo-
pyridines, since methoxypyridines are more readily avail-
able than (benzyoxy)pyridines in many cases.
Mechanistically, we believe that these cyclizations
proceed by anti attack of the electrophile and the oxygen
of the methoxy group on the alkyne to produce an
intermediate A, which undergoes methyl group removal
via SN2 displacement by nucleophiles present in the
reaction mixture (Scheme 3). In most cases, the nucleo-
phile is presumably the halide remaining in solution.
bond.
FIGURE 3. Nitro electron-withdrawing effect on the triple
bond.
endo-dig cyclization. This, in turn, leads to addition of
the electrophile to the triple bond, rather than cyclization
(entries 17, 18, and 24).
The presence of a nitro group in compound 28 de-
creases the electron density on C1 (Figure 2), and again
favors simple addition of the electrophile to the alkyne
triple bond (entries 21 and 22). On the other hand, the
presence of an electron-withdrawing group, such as a
nitro group, on the methoxy-substituted arene favors
electrophilic cyclization, although a longer reaction time
(12 h) is generally required (entries 11 and 12). The more
electron deficient C2 position is more likely to undergo
attack by the nucleophilic oxygen of the methoxy group
than the C1 position, because of either the resonance
effect of the nitro group para to the carbon-carbon triple
bond (Figure 3) or the inductive effect of the electron-
poor arene. The trimethylsilyl-substituted alkyne 29 also
failed to undergo electrophilic cyclization, providing
instead an inseparable mixture of unidentifiable com-
pounds, which is consistent with Cacchi’s earlier results
(entry 23).19
Compound 20 with both a methoxy and an acetoxy
group in positions ortho to the triple bond, undergoes
exclusive electrophilic cyclization onto the methoxy group
to produce compound 21 in a 95% yield (entry 14). This
should be quite useful for the regioselective synthesis of
benzofurans. Thus, the more nucleophilic methoxy group
more readily attacks the triple bond, affording the
corresponding cyclization product.
Conclusions
We believe that this approach to 3-iodobenzo[b]furans
and furopyridines should prove quite useful in synthesis,
particularly when one considers that there are many
ways to transform the resulting iodide functionality into
other substituents. For example, the resulting hetero-
cyclic iodides should be particularly useful as intermedi-
ates in many palladium-catalyzed processes, like Sono-
gashira,24 Suzuki,25 and Heck26 cross-coupling processes.
Experimental Section
General. 1H and 13C NMR spectra were recorded at 300
and 75.5 MHz or 400 and 100 MHz, respectively. Thin-layer
chromatography was performed with use of commercially
prepared 60-mesh silica gel plates (Whatman K6F), and
visualization was effected with short-wavelength UV light (254
nm) or a basic KMnO4 solution [3 g of KMnO4 + 20 g of K2-
CO3 + 5 mL of NaOH (5%) + 300 mL of H2O]. All melting
points are uncorrected. Low-resolution mass spectra were
recorded on a Finnigan TSQ700 triple quadrupole mass
(25) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Lloyd-
Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145. (c) Suzuki, A.
In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 49-97. (d) Suzuki,
S.; Miyaura, N. Chem. Rev. 1995, 95, 2457.
(26) (a) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427. (b) Brase, S.; de
Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 99-
166. (c) Palladium Reagents in Organic Synthesis; Heck, R. F.;
Academic Press: San Diego, CA, 1985; pp 276-287.
We have also investigated the possibility of carrying
out double iodocyclizations, which might be quite useful
for the quick assembly of systems with extended conjuga-
tion. Compounds 22 and 24 undergo iodocyclization to
afford double cyclization products in 97% and 60% yields,
respectively (entries 15 and 16).
J. Org. Chem, Vol. 70, No. 25, 2005 10295

Yue et al.
spectrometer (Finnigan MAT, San Jose, CA). High-resolution
mass spectra were recorded on a Kratos MS50TC double
focusing magnetic sector mass spectrometer, using EI at 70
eV.
ether layers were dried over anhydrous Na2SO4 and concen-
trated under vacuum to yield the crude product, which was
purified by flash chromatography on silica gel with ethyl
acetate/hexanes as the eluent.
Reagents. All reagents were used directly as obtained
commercially unless otherwise noted. Anhydrous forms of ethyl
ether, hexanes, ethyl acetate, and CH2Cl2 were purchased from
Fisher Scientific Co. 2-Iodoanisole, 2-bromo-1,4-dimethoxy-
benzene, 1-bromo-2,4-dimethoxybenzene, 2-iodo-4-nitroanisole,
2-iodo-5-nitroanisole, resorcinol, 4-iodoanisole, 1-iodo-4-ni-
trobenzene, phenylacetylene, 1-cyclohexenyl acetylene, 1-oc-
tyne, trimethylsilylacetylene, and Et3N were purchased from
Aldrich Chemical Co., Inc. The palladium salts were donated
by Johnson Matthey Inc. and Kawaken Fine Chemicals Co.
Ltd.
General Procedure for the Palladium/Copper-Cata-
lyzed Formation of o-(1-Alkynyl)anisoles. To a solution
of Et3N (12.5 mL), PdCl2(PPh3)2 (2 mol %), 5.0 mmol of
o-iodoanisole, and 6.0 mol of terminal acetylene (stirring for 5
min beforehand) was added CuI (1 mol %) and stirring was
continued for another 2 min before flushing with Ar. The flask
was then sealed. The mixture was allowed to stir at room
temperature for 3-6 h and the resulting solution was filtered,
washed with saturated aq NaCl, and extracted with diethyl
ether (2 × 15 mL). The combined ether fractions were dried
over anhydrous Na2SO4 and concentrated under vacuum to
yield the crude product. The crude product was purified by
flash chromatography on silica gel with ethyl acetate/hexane
as the eluent.
3-Iodo-2-phenylbenzo[b]furan (2). The product was ob-
tained as a yellow oil: 1H NMR (CDCl3) δ 7.28-7.51 (m, 7H),
8.16-8.19 (m, 2H); 13C NMR (CDCl3) δ 61.3, 111.4, 122.1,
123.7, 125.9, 127.7, 128.7, 129.4, 130.2, 132.7, 153.2, 154.1;
IR (neat, cm-1) 3058, 1450; HRMS calcd for C14H9IO 319.9698,
found 319.9700.
General Procedure for the p-O2NC6H4SCl and PhSeCl
Cyclizations. To a solution of 0.25 mmol of the alkyne and
CH2Cl2 (5 mL) was added 0.375 mmol of p-O2NC6H4SCl or
PhSeCl. The mixture was flushed with Ar and allowed to stir
at 25 °C for 2-6 h. The reaction mixture was washed with 20
mL of water and extracted with diethyl ether. The combined
ether layers were dried over anhydrous Na2SO4 and concen-
trated under vacuum to yield the crude product, which was
further purified by flash chromatography on silica gel with
ethyl acetate/hexanes as the eluent.
2-Phenyl-3-(phenylselenyl)benzo[b]furan (3). The prod-
uct was obtained as a yellow oil: 1H NMR (CDCl3) δ 7.13-
7.17 (m, 3H), 7.22 (t, J ) 4.0 Hz, 1H), 7.27-7.32 (m, 4H), 7.43
(t, J ) 7.6 Hz, 2H), 7.51 (d, J ) 8.0 Hz, 1H), 7.54 (d, J ) 8.0
Hz, 1H), 8.19-8.21 (m, 2H); 13C NMR (CDCl3) δ 99.9, 111.4,
121.4, 123.6, 125.4, 126.4, 128.0, 128.7, 129.4, 129.5, 130.3,
131.6, 132.1, 154.3, 157.4; IR (neat, cm-1) 3058, 2926; HRMS
calcd for C20H14OSe 350.0211, found 350.0220.
2-(Phenylethynyl)anisole (1). The product was obtained
as a yellow oil: 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.89 (d, J )
8.4 Hz, 1H), 6.93 (t, J ) 7.6 Hz, 1H), 7.29-7.33 (m, 4H), 7.50
(d, J ) 7.2 Hz, 1H), 7.55-7.57 (m, 2H); 13C NMR (CDCl3) δ
56.0, 85.9, 93.6, 110.9, 112.6, 120.7, 123.7, 128.2, 128.3, 129.9,
131.8, 133.7, 160.1; IR (neat, cm-1) 3058, 2926, 2855, 2226;
HRMS calcd for C15H12O 208.0888, found 208.0894.
General Procedure for the Iodocyclizations. To a
solution of 0.25 mmol of the alkyne and 3 mL of CH2Cl2 was
added gradually 2 equiv of I2 dissolved in 2 mL of CH2Cl2. The
reaction mixture was flushed with Ar and allowed to stir at
room temperature for the desired time. The excess I2 was
removed by washing with saturated aq Na2S2O3. The mixture
was then extracted by diethyl ether (2 × 10 mL). The combined
Acknowledgment. We thank the National Institute
of General Medical Sciences (GM070620) for support of
this research and Johnson Matthey, Inc., and Kawaken
Fine Chemicals Co., Ltd., for donations of palladium
salts.
Supporting Information Available: General experimen-
tal details, preparation, iodocyclization, and p-O2NC6H4SCl
and PhSeCl cyclizations of o-(1-alkynyl)anisoles, and copies
of 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO051299C
10296 J. Org. Chem., Vol. 70, No. 25, 2005