One-pot synthesis of 2,3-disubstituted benzofurans from 2-chlorophenols using palladium–dihydroxyterphenylphosphine catalyst

Article abstract of DOI:10.1016/j.tetlet.2018.07.019

2,3-Disubstituted benzofurans possessing 2-hydroxyphenyl moiety at the C-3 position were synthesized from readily available 2-chlorophenols and terminal alkynes by hydroxy-directed ortho-Sonogashira coupling and subsequent oxypalladation/reductive elimina

Full text of DOI:10.1016/j.tetlet.2018.07.019

Accepted Manuscript
One-pot synthesis of 2,3-disubstituted benzofurans from 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst
Miyuki Yamaguchi, Hayato Ozawa, Haruka Katsumata, Tomoyo Akiyama, Kei
Manabe
PII:
S0040-4039(18)30879-7
https://doi.org/10.1016/j.tetlet.2018.07.019
TETL 50128
DOI:
Reference:
Tetrahedron Letters
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4 June 2018
30 June 2018
5 July 2018
Please cite this article as: Yamaguchi, M., Ozawa, H., Katsumata, H., Akiyama, T., Manabe, K., One-pot synthesis
of 2,3-disubstituted benzofurans from 2-chlorophenols using palladium–dihydroxyterphenylphosphine catalyst,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.019
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Tetrahedron Letters
One-pot synthesis of 2,3-disubstituted benzofurans from 2-chlorophenols using
palladium‒dihydroxyterphenylphosphine catalyst
Miyuki Yamaguchi, Hayato Ozawa, Haruka Katsumata, Tomoyo Akiyama, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2,3-Disubstituted benzofurans possessing 2-hydroxyphenyl moiety at the C-3 position were
synthesized from readily available 2-chlorophenols and terminal alkynes by hydroxy-directed
ortho-Sonogashira coupling and subsequent oxypalladation/reductive elimination, using Pd-
dihydroxyterphenylphosphine catalyst. The catalyst accelerates not only the Sonogashira
coupling but also the introduction of 2-hydroxyphenyl group at the C-3 position of benzofuran.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuran
Palladium
Ligand
Sonogashira coupling
Cyclization
The benzofuran framework is ubiquitously present in many
natural products, biologically active compounds, and
functionalized materials.1 Among them, the 2,3-disubstituted
benzofuran scaffold, often containing one or more hydroxy
groups, has attracted considerable attention. To construct 2,3-
disubstituted benzofurans, a number of synthetic methods have
been developed.2 However, direct approaches to obtain 2,3-
disubstituted benzofurans possessing hydroxy groups are still
limited,3 and efficient synthetic methods from readily available
compounds are highly desired.
that the Pd‒1b catalyst would enable one-pot synthesis of 2,3-
disubstituted benzofurans from readily available 2-chlorophenols
and terminal alkynes via hydroxy-directed ortho-Sonogashira
coupling and oxypalladation/reductive elimination (Scheme 1c).
Herein, we report the one-pot synthesis of 2,3-disubstituted
benzofurans possessing
a hydroxyphenyl group from 2-
chlorophenols using the Pd‒1b catalyst.
We have developed hydroxyterphenylphosphines 1 (Figure 1)
and applied them to Pd-catalyzed site-selective cross couplings.4
In the reactions of dihalogenated phenols or anilines, the catalyst
derived from Pd and 1 binds with the substrate via metal
phenoxides or anilides, and site-selectively accelerates oxidative
addition of the 2-halo group to Pd. We have also reported
benzofuran synthesis from readily available 2-chlorophenols and
terminal alkynes using the Pd‒1b catalyst via hydroxy-directed
ortho-Sonogashira coupling and subsequent cyclization (Scheme
1a).5 This catalytic system enabled the use of 2-chlorophenols,
which are less reactive but more readily available than 2-bromo
or 2-iodophenols. During this study, we observed the formation
of a small amount (~5% yield) of 2,3-disubstituted benzofuran 3
bearing 2-hydroxyphenyl moiety at the C-3 position as a
byproduct (Scheme 1b), presumably via Sonogashira coupling
followed by an oxypalladation/reductive elimination sequence.
This type of sequence, which is known as Cacchi cyclization, is a
powerful method to afford 2,3-disubstituted benzofurans; Pd-
catalyzed annulations of 2-alkynylphenol with aryl iodides or
bromides have been previously reported.6 One-pot synthesis of
2,3-diarylated benzofurans from 2-iodophenol, terminal alkyne,
and aryl iodide has been also conducted.7 Therefore, we expected
Figure 1. Hydroxyterphenylphosphines 1.

2
Tetrahedron Letters
mesitylene, the yield of 3a was decreased and that of 4a was
increased (Entries 7 and 8). Use of heptane also resulted in
similar yields (Entry 9). When THF was used, only a small
amount of 3a was obtained (Entry 10). On the other hand,
reaction using 1,4-dioxane proceeded smoothly to give 60% yield
of 3a along with only 5% of 4a (Entry 11). 1,2-Dimethoxyethane
solvent gave 3a in moderate yield (Entry 12), whereas DMF was
not effective for the reaction (Entry 13). While both toluene and
1,4-dioxane gave almost the same yields of 3a, smaller amounts
of byproducts formed in 1,4-dioxane enabled easier purification
of 3a. Therefore, we decided to use 1,4-dioxane as the solvent for
screening
various
ligands.
Reaction
with
dihydroxyterphenylphosphine 1c, bearing a diphenylphosphino
group afforded 3a in moderate yield (Entry 14). Use of
monohydroxyterphenylphosphine 1a resulted in low yield of 3a
(Entry 15). When XPhos was used,8 small amounts of 3a and 4a
were obtained (Entry 16). Other ligands, including the hydroxy-
group-containing ligand 6 and bidentate ligands, were found to
be ineffective (Entries 17-22). Reaction using 2-bromophenol
instead of 2 also proceeded smoothly to afford 3a in 69% yield
with 16% of 4a (Entry 23).
Scheme 1. (a) Pd‒1b-catalyzed benzofuran synthesis from
chlorophenols (previous work). (b) Proposed mechanism of the
formation of byproduct 3. (c) 2,3-Disubstituted benzofuran
synthesis from 2-chlorophenols (this work).
First, the reaction conditions were optimized using 4-
ethynylanisole and 2-chlorophenol 2 (2 equiv) and as model
substrates, t-BuOLi as base, and toluene as solvent (Table 1).
When the reaction was conducted with 2 mol% of the catalyst
derived from PdCl2(CH3CN)2 and 1b, the desired C-3-arylated
benzofuran 3a was obtained in 23% yield, along with 31% of C-
3-protonated benzofuran 4a and <16% of 2-alkynylphenol 5a
(Entry 1). When 4 mol% of the catalyst was used, the yield of 3a
was increased and that of 5a was decreased (Entry 2). When 6
mol% of the catalyst was used, 64% yield of 3a was obtained and
formation of 4a was suppressed (Entry 3). Reaction using 8
mol% of the catalyst gave 3a in slightly lower yield (Entry 4).
Use of other Pd sources resulted in moderate yield of the product
(Entries 5 and 6). Thus, 6 mol% was identified as the optimum
loading amount for the catalyst. Then, various solvents were
screened using 6 mol% of the catalyst. For xylenes and

Table 1. Optimization of reaction conditions.
Entry
Pd source (x mol%)
Ligand (2x mol%)
Solvent
Yield (%)a
3a
4a
31
30
13
10
22
25
22
38
37
46
5
5a
1
PdCl2(CH3CN)2 (2)
PdCl2(CH3CN)2 (4)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (8)
Pd(OAc)2 (6)
1b·HBF4 (4)
1b·HBF4 (8)
1b·HBF4 (12)
1b·HBF4 (16)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1b·HBF4 (12)
1c (12)
toluene
23
<16
<4
2
toluene
41
3
toluene
64
2
4
toluene
56
2
5
toluene
51
4
6
Pd2(dba)3 (3)
toluene
49
3
7b
8b
9
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
PdCl2(CH3CN)2 (6)
xylenes
46
2
mesitylene
heptane
31
n.d.c
n.d.c
n.d.c
n.d.c
n.d.c
n.d.c
n.d.c
trace
trace
trace
n.d.c
trace
n.d.c
n.d.c
n.d.c
n.d.c
38
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
THF
<12
60
1,4-dioxane
1,2-dimethoxyethane
DMF
44
7
<4
18
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
37
1a·HBF4 (12)
XPhos (12)
17
3
<6
9
Cy-JohnPhos (12)
6 (12)
trace
trace
trace
trace
n.d.c
n.d.c
69
n.d.c
7
PCy3 (12)
n.d.c
10
n.d.c
n.d.c
16
(t-Bu)3P·HBF4 (12)
2,2’-bipyridyl (12)
Xantphos (12)
1b·HBF4 (12)
b
c
d
aIsolated yield. 120 °C. Not detected. 2-Bromophenol was
used instead of 2.
obtained. We assume that oxypalladation did not proceed after
Sonogashira coupling due to the steric hindrance of the
remaining 3-chloro group of the intermediate alkynylphenol.
With the optimized conditions in hand, reactions using various
2-chlorophenols and terminal alkynes were studied (Table 2).
Both aromatic and aliphatic alkynes gave the corresponding 2,3-
disubstituted benzofurans 3a-e in good yields. When 2-
chlorophenol bearing electron donating groups were employed,
the reaction proceeded smoothly, and the desired products 3f-i
were obtained in good yield. In addition, 2-chloro-4-fluorophenol
afforded 3j and 3k in moderate-to-good yield. It is noteworthy
that 2,4-dichlorophenol selectively gave 3l in good yield,
indicating that oxidative addition of 2,4-dichlorophenol to Pd(0)
occurs selectively at the 2-chloro group. On the other hand,
reaction with 2,3-dichlorophenol did not afford the C-3-arylated
3m at all and only the C-3-protonated benzofuran 4m was
Table 2. Substrate scope study.

4
Tetrahedron
chlorotoluene instead of 2 to introduce 4-tolyl group at the C-3
position of benzofuran was not successful, and only 9% of the
desired product 10 was obtained, suggesting that the 2-hydroxy
group of 2 is essential for affording 2,3-disubstituted benzofurans
in good yield.
Table 3. Use of two different chloroarenes.
a1.0 equiv of 4-ethynylanisole was used.
We assume that the reaction proceeds as shown in Scheme 2,
and that high reactivity and ortho-selectivity induced by the
Pd‒1b catalyst can be explained by complex formation between
the catalyst and the substrate.5 Hydroxy groups of 1b and 2-
chlorophenol are deprotonated by t-BuOLi to generate lithium
phenoxides, which form heteroaggregates A in which the 2-
chloro group is located close to Pd. Therefore, oxidative addition
of 2-chlorophenol to Pd(0) is accelerated to give intermediate B.
The reaction with an alkyne affords intermediate C and then
alkynylphenol D, which coordinates to B in the second catalytic
cycle. Resulting intermediate E undergoes oxypalladation to give
3-benzofuranylpalladium intermediate F. Subsequently, the
desired 2,3-disubstituted benzofuran is formed by reductive
elimination.
To further broaden the substrate scope of the protocol, we
examined the use of two different chloroarenes for introducing 3-
substituents different from those on the benzene ring of the
benzofuran core (Table 3). After the Sonogashira coupling of 2-
chloro-5-methylphenol and 2 equiv of 4-ethynylanisole for 1 h,
1.5 equiv of 2 was added via syringe, and the mixture was
refluxed for 24 h. The desired reaction proceeded smoothly, and
7 was obtained in good yield along with 15% of C-3-protonated
4f. In this case, formation of the byproduct 3f was not observed.
When dodec-1-yne was employed instead of 4-ethynylanisole,
the desired product 8 was also obtained in good yield. Use of 2-
chloro-4-fluorophenol instead of 2-chloro-5-methylphenol
afforded 9 in moderate yield. On the other hand, use of 4-

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Acknowledgments
This work was partially supported by JSPS KAKENHI (Grant
Numbers 15H04634, 15K18833, and 17K08214), the Society of
Synthetic Organic Chemistry (Japan), the Uehara Memorial
Foundation, and Basis for Supporting Innovative Drug
Discovering and Life Science Research (BINDS) from AMED.
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Supplementary Material
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Supplementary data associated with this article can be found,
in the online version, at htpps://doi.org/10.1016/j.tetlett.
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6
Tetrahedron
Highlights
 One-pot synthesis of 2,3-disubstituted
benzofurans has been achieved.
 Readily available chlorophenols can be
used as substrates.
 Only the Pd‒DHTP catalyst can catalyze
the desired reaction.
 2-Hydroxyphenyl group can be introduced
at C3 of benzofurans.
 Two different chlorophenols can be used.
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One-pot synthesis of 2,3-disubstituted
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catalyst
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Miyuki Yamaguchi, Hayato Ozawa, Haruka Katsumata, Tomoyo Akiyama, and Kei Manabe*
or altere