A new insight into palladium-catalyzed reaction of 2-alkynylphenol with carbon monoxide

Article abstract of DOI:10.1021/ol202478u

A novel and efficient pathway for the generation of 3-(benzofuran-3- ylmethylene)benzofuran-2(3H)-ones via a palladium-catalyzed carbonylative reaction of 2-alkynylphenol with carbon monoxide is described. The reaction proceeds through a double insertion

Full text of DOI:10.1021/ol202478u

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5858–5861
A New Insight into Palladium-Catalyzed
Reaction of 2-Alkynylphenol with Carbon
Monoxide
Yong Luo† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
jie_wu@fudan.edu.cn
Received September 13, 2011
ABSTRACT
A novel and efficient pathway for the generation of 3-(benzofuran-3-ylmethylene)benzofuran-2(3H)-ones via a palladium-catalyzed carbonylative
reaction of 2-alkynylphenol with carbon monoxide is described. The reaction proceeds through a double insertion of triple bonds during the
reaction process. The products are obtained in good yields with high selectivity. A one-pot synthesis starting from 2-iodophenol and alkyne is
presented as well.
Recently, we have disclosed a novel transformation for
access to indeno[1,2-c]chromenes A via a Pd-catalyzed
reaction of 2-alkynylhalobenzene with 2-alkynylphenol
in the presence of PCy3 (Scheme 1, eq 1).1 In the reaction
process, a double insertion of triple bonds was found
crucial for the successful conversion.2 Additionally, the
effect of several side reactions such as Pd-catalyzed di-
rect cyclization of 2-alkynylphenol and formation of 2,
3-diarylbenzo[b]furan were minimized under the con-
ditions.3,4 Prompted by this result, we conceived that
carbon monoxide might be involved in this transforma-
tion, which would afford benzo[b]oxepin-2(5H)-ones B
(Scheme 1, eq 2) based on the mechanism we proposed
previously.1 Thus, the model reaction was explored by
using 1-bromo-2-(2-phenylethynyl)benzene and 2-(2-
phenylethynyl)phenol 1a as the substrates in the presence
of carbon monoxide (balloon, Scheme 1, eq 3). The reac-
tion was initially catalyzed by 5 mol % of palladium
† Fudan University.
‡ Chinese Academy of Sciences.
i
acetate in the presence of Pr2NEt and oxygen in toluene
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under reflux conditions. Interestingly, we did not observe
the formation of B, and a small amount of product was
isolated in 8% yield. After structural elucidation by X-ray
diffraction analysis (see Supporting Information), the
product was identified as 3-(benzofuran-3-ylmethylene)
benzofuran-2(3H)-one 2a. From this result, we noticed
that 1-bromo-2-(2-phenylethynyl)benzene was not in-
volved in the conversion, and 2a was generated solely from
the Pd-catalyzed reaction of 2-(2-phenylethynyl)phenol 1a
and carbon monoxide.
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The Pd(II)-catalyzed/mediated cascade carbonylative
annulation of 2-alkynylphenols has proven to be a
highly efficient method for rapidly generating diverse
r
10.1021/ol202478u
Published on Web 10/11/2011
2011 American Chemical Society

benzo[b]furan-3-carbonyl compounds.4 For instance,
Yang et al.4cꢀg reported the synthesis of benzo[b]furan-3-
carboxylic acids, esters, and ketones via a Pd(II)-catalyzed
cascade carbonylative annulation of 2-alkynylphenols
with carbon monoxide. In their protocol, the triple bond
was activated by an acylpalladium species, which initiated
an intramolecular cyclization to afford the corresponding
benzo[b]furan compounds. From our result shown in
Scheme 1, we conceived that a double insertion of triple
bonds would occur in the reaction of 2-alkynylphenol and
carbon monoxide since 2 equiv of 2-alkynylphenol were
incorporated in the transformation.
biologically important molecules6 and frequently used as
a building block in materials science and in organic
synthesis.7 The benzofuran-2-one moiety can be found
in many natural products as well. Compounds with
this substructure usually display remarkable biolog-
ical activities.8 For instance, Calycin, extracted from
the lichen C. concolor, shows significant antibacterial
activity.8a A naturally occurring isoaurone (40,6-dihy-
droxy-4-methoxyisoaurone) from Trichosanthes kirilowii
seeds has been identified as an inhibitor of HIF-1 and NF-
κB.8b Recently, compounds containing the 3-(furan-3-
ylmethylene)furan-2(3H)-one skeleton9 were shown to be
an important class of photoswitches that complement
diarylethenes and spiropyrans.10 Upon wavelength-speci-
fic illumination, they undergo reversible color changes and
ring-closing/opening reactions which are thus of great
interest for a range of applications. Thus, generation of
the related molecules in a novel and concise pathway
would be of high interest.
Scheme 1. An Unexpected Result for the Palladium-Catalyzed
Reaction of 2-Alkynylphenol 1a with Carbon Monoxide
With the above promising result in hand, we started to
optimize conditions for the formation of 3-(benzofuran-3-
ylmethylene)benzofuran-2(3H)-ones. The screening re-
sults are shown in Table 1. To our delight, the expected
product 2a was isolated in 54% yield when PdCl2(PPh3)2
was used as a replacement (Table 1, entry 2). Only a trace
amount of product was detected when the reaction oc-
curred in the presence of K2CO3, Na2CO3, or KOAc
(Table 1, entries 3ꢀ5). No reaction took place when
tBuONa was employed as the base (Table 1, entry 6). A
comparable yield of the desired product was obtained
when DABCO was utilized (Table 1, entry 7). Neither
PdCl2 or Pd(PPh3)4 was successful in catalyzing the reac-
tion of 2-(2-phenylethynyl)phenol 1a with carbon mon-
oxide (Table 1, entries 8 and 9). Adding extra ligands
proved to be unhelpful for the outcome (Table 1, entries
10ꢀ15). Changing of the oxidant to benzoquinone (BQ)
resulted in a lower yield (Table 1, entry 16). The solvent
effect was studied as well. However, inferior results were
obtained (Table 1, entries 17ꢀ20). In terms of temperature
effects, the reaction was found to be more effective at
50°C, whichaffordedthe expectedproduct2ain62%yield
It is well-known that benzofuran is a very important
heterocycle that is broadly found in natural5 and
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Org. Lett., Vol. 13, No. 21, 2011
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Table 1. Initial Studies for the Palladium-Catalyzed Reaction of
2-(2-Phenylethynyl)phenol 1a and Carbon Monoxide
Table 2. Palladium-Catalyzed Reaction of 2-Alkynylphenol 1
with Carbon Monoxide
a Isolated yield based on 2-(phenylethynyl)phenol 1a. DPPF: 1,10-
bis(diphenylphosphino)ferrocene. b The reaction occurred at 70 °C.
c The reaction was performed at 50 °C. d The reaction occurred at 25 °C.
(Table 1, entry 22). The reaction was retarded when the
reaction occurred at rt (Table 1, entry 23).
With the optimized conditions in hand [PdCl2(PPh3)2
(5mol%),iPr2NEt (2.0 equiv), toluene, 50 °C, CO/O2 (v/v=
1:1) ], we next focused on the generality of the Pd-catalyzed
reaction of 2-alkynylphenol 1 with carbon monoxide. The
results are summarized in Table 2. We noticed that these
cascade reactions are effective to produce the expected
3-(benzofuran-3-ylmethylene)benzofuran-2(3H)-ones in
moderate to excellent yields. For example, Pd-catalyzed
carbonylative annulation of 2-alkynylphenol 1b afforded
the desired product 2b in 94% yield (Table 2, entry 2). A
similar outcome (92%) was obtained when substrate 1c
was used with the R2 group replaced by 4-methylphenyl
(Table 2, entry 3). A lower yield was obtained with
2-alkynylphenol containing an electron-withdrawing
group at the R2 position. For instance, 2e was generated
in 40% yield when 2-alkynylphenol 1e was employed in the
reaction (Table 2, entry 5). Further investigation revealed
that the conditions were not suitable for substrates with an
alkyl group attached to the triple bond (data not shown in
Table 2). No desired product was generated when R2 was
an alkyl group (n-butyl or cyclopropyl group). Reactions
of 2-alkynylphenols with different substitutions on the
aromatic ring were examined subsequently. Good yields
a Isolated yield based on 2-alkynylphenol 1.
were obtained when methyl, phenyl, or tert-butyl substi-
tuted 2-alkynylphenol was utilized in the Pd-catalyzed
5860
Org. Lett., Vol. 13, No. 21, 2011

carbonylative cascade reaction (Table 2, entries 6ꢀ8,
10ꢀ12). The yields were inferior with 2-alkynylphenols
having a chloro group attached on the aromatic ring
(Table 2, entries 9 and 13).
Thus, a one-pot synthesis starting from 2-iodophenol and
alkyne was investigated. After optimization of the reaction
conditions, we found the reaction worked well when
conducted in a two-step sequence. As presented in Scheme 3,
after completion of the Sonogashira coupling, another
i
5 mol % of PdCl2(PPh3)2, 2.0 equiv of Pr2NEt, and 1.0
equiv of AgNO3 were added to the reaction mixture. The
atmosphere was changed to carbon monoxide and oxygen
(v/v: 1/1). The addition of silver nitrate for removal of
iodide was crucial for the successful one-pot reaction.
Under the conditions, the reactions proceeded smoothly
to afford the corresponding products in good yields.
Scheme 2. A Plausible Mechanism for the Palladium-Catalyzed
Reaction of 2-Alkynylphenols with Carbon Monoxide
Scheme 3. One-Pot Synthesis of 3-(Benzofuran-3-ylmethylene)
benzofuran-2(3H)-ones Starting from 2-Iodophenol and Alkyne
In conclusion, we have described a novel and efficient
pathway for the generation of 3-(benzofuran-3-ylmethyl-
ene)benzofuran-2(3H)-ones via a Pd-catalyzed carbonyla-
tive reaction of 2-alkynylphenol with carbon monoxide.
The reaction proceeds in high yields with good selectivity.
A one-pot synthesisstartingfrom 2-iodophenoland alkyne
is presented as well. During the reaction process, a double
insertion of triple bonds is believed to be the key. Efforts
for focused library construction and exploration of related
transformations are under investigation currently.
Asmentionedabove, adoubleinsertion of triplebonds is
likely to occur in the reaction of 2-alkynylphenol and
carbon monoxide since 2 equiv of 2-alkynylphenol are
involved in the transformation. Thus, a possible mechan-
ism is illustrated in Scheme 2. We envisioned that there
might be two possible pathways for the final outcome.
Takahashi10 and Kuniyasu11 reported the synthesis of
benzofuran-2(3H)-ones in neutral conditions from 2-alky-
nylphenols and carbon monoxide (route I). We believethat
route II cannot be excluded since 2-substituted benzofuran
A5 was the main byproduct in all reactions. Recently,
Lautens reported an example for the synthesis of 2-(2-
(2-butylbenzofuran-3-yl)hex-1-en-1-yl)phenols through a
Rh-catalyzed reaction,12 which illustrates that path II is
also possible.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 21032007,
21172038) and Jiangxi Key Laboratory of Organic Chem-
istry, Jiangxi Science & Technology Normal University is
gratefully acknowledged. We thank Dr. Jason Wong
(Roche Pharma Research and Early Development, China)
for English review.
In the meantime, we noticed that the standard condi-
tions shown in Table 2 are similar to those used in
Sonogashira coupling reactions. Additionally, some 2-al-
kynylphenols are too unstable to be isolated during the
purification process by flash chromatography on silica gel.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 2, and a CIF file of compound 2a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Kuniyasu, H.; Yoshizawa, T.; Kambe, N. Tetrahedron Lett.
2010, 51, 6818.
(12) Boyer, A.; Isono, N.; Lackner, S.; Lautens, M. Tetrahedron
2010, 66, 6468.
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