Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using palladium–dihydroxyterphenylphosphine catalyst

Article abstract of DOI:10.1016/j.tetlet.2020.151896

2,3-Disubstituted indoles bearing 2-hydroxyphenyl moieties at their C3 positions were synthesized from readily available 2-chlorophenols and alkynylanilines via aminopalladation/reductive elimination using Pd–dihydroxyterphenylphosphine catalyst. The catalyst accelerates the introduction of the 2-hydroxyphenyl group at the C3 position of the indole.

Full text of DOI:10.1016/j.tetlet.2020.151896

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,3-disubstituted indoles from alkynylanilines and
2-chlorophenols using palladium–dihydroxyterphenylphosphine
catalyst
⇑
Miyuki Yamaguchi, Kota Ogihara, Hideyuki Konishi, Kei Manabe
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3-Disubstituted indoles bearing 2-hydroxyphenyl moieties at their C3 positions were synthesized from
readily available 2-chlorophenols and alkynylanilines via aminopalladation/reductive elimination using
Pd–dihydroxyterphenylphosphine catalyst. The catalyst accelerates the introduction of the 2-hydrox-
yphenyl group at the C3 position of the indole.
Received 13 February 2020
Revised 28 March 2020
Accepted 31 March 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Palladium
Ligand
Cyclization
Multisubstituted indoles are often found in biologically active
compounds and functional materials [1], and a variety of synthetic
methods have been developed to prepare these compounds [2].
Among them, 2,3-disubstituted indoles that often bear one or more
hydroxy groups have attracted considerable attention [3]. The Cac-
chi cyclization reaction is a useful method for the synthesis of 2,3-
disubstituted indoles, which involves the palladium-catalyzed cou-
pling of a 2-alkynylaniline and a haloarene (Scheme 1a) [4]. In this
reaction, an aminopalladation/reductive-elimination sequence
affords a 2,3-disubstituted indole with an aryl group at the C3 posi-
tion. However, the synthesis of hydroxyaryl-group-containing
indoles remains challenging, and the use of readily available and
inexpensive aryl chlorides as arylating agents has been limited [5].
We previously reported the one-pot synthesis of 2,3-disubsti-
tuted benzofurans [6] from readily available 2-chlorophenols and
terminal alkynes using a Pd catalyst ligated with dihydroxyter-
phenylphosphine (DHTP, 1) [7]. The complexation between the
hydroxy groups of the catalyst and the 2-chlorophenol via their
lithium phenoxides accelerates oxidative addition of the 2-chlor-
oaryl group to Pd, while the subsequent oxypalladation/reductive
elimination affords the desired 2,3-disubstituted benzofuran bear-
ing the 2-hydroxyphenyl group at the C3 position. We expected
that the use of ligand 1 would also effectively promote the synthe-
sis of 2,3-disubstituted indoles bearing hydroxyphenyl groups.
Scheme 1. (a) 2,3-Disubstituted indoles synthesized by the Cacchi cyclization
reaction. (b) 2,3-Disubstituted indoles synthesized from 2-chlorophenols using the
Pd–1 catalyst (this work).
Herein, we report the synthesis of 2,3-disubstituted indoles bear-
ing 2-hydroxyphenyl groups at their C3 positions from readily
available 2-chlorophenols and alkynylaniline derivatives using
the Pd–1 catalyst (Scheme 1b) [8].
⇑
Corresponding author.
E-mail address: manabe@u-shizuoka-ken.ac.jp (K. Manabe).
https://doi.org/10.1016/j.tetlet.2020.151896
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Yamaguchi, K. Ogihara, H. Konishi et al., Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151896

2
M. Yamaguchi et al. / Tetrahedron Letters xxx (xxxx) xxx
We began optimizing the reaction conditions using a catalyst
the solvent gave the product in 50% yield (entry 8). On the other
hand, the use of 1,4-dioxane did not afford any of the desired pro-
duct, providing 6 in 50% yield (entry 9). Other ligands such as
XPhos [10], JohnPhos [11], and (t-Bu)3PÁHBF4 gave no C3-arylated
products, and only byproduct 6 was obtained in moderate yields
(entries 10–12). These results support our hypothesis that the
ligand 1 promotes the reaction by accelerating the oxidative addi-
tion of 2-chlorophenol to Pd through the formation of a complex
between the lithium phenoxides of 2-chlorophenol and 1.
Reactions using other haloarenes were next examined. The use
of 2-bromophenol instead of 2-chlorophenol resulted in a dramatic
decrease in the yield of the C3-arylated product 5 to 19%, and 77%
of 6 was also produced (entry 13). 2-Chloroanisole afforded the
corresponding C3-arylated product 7 in only 19% yield (entry 14),
while the use of 4-chlorotoluene also gave the C3-arylated product
8 in low yield (entry 15), and C3-arylation did not proceed at all in
the case of 4-chlorophenol, with 6 obtained in 40% yield (entry 16).
These results suggest that the ortho relationship between the
hydroxy and chloro groups in these arylating agents plays an
important role in accelerating the reaction.
derived from PdCl2(CH3CN)2 and 1ÁHBF4. 2-(Phenylethynyl)aniline
derivatives 2–4 and 2-chlorophenol were selected as model sub-
strates. Based on our previous indole-synthesis study [9], lithium
tert-butoxide was used as the base (Table 1). Tosyl- and acetyl-pro-
tected 2 and 3 did not afford the desired N-protected 2,3-diarylated
product 5a or N-deprotected 5b; instead, only the C3-protonated
indole 6 was obtained (entries 1 and 2). Trifluoroacetyl-protected
4 was found to effectively give the desired 2,3-disubstituted indole
in 46% yield (entry 3). In this case, both 5b and 5c, in which the
hydroxy group was trifluoroacetylated, were obtained. The trifluo-
roacetyl group of 5c was easily cleaved by methanolysis
(Scheme S1). Neither decreasing nor increasing the amount of
lithium tert-butoxide improved the yield of 5b (entries 4 and 5).
The use of 6 mol% of the Pd catalyst significantly increased the
yield of the product to 57%, with trifluoroacetylated 5c produced
as the major product (entry 6). The reaction was then conducted
at a higher temperature (140 °C) by changing the solvent from
toluene to xylene (entry 7). As a result, the product was obtained
in 56% yield with a higher relative amount of 5b. Mesitylene as
Table 1
Optimizing the reaction conditions.
Entry
R
PdCl2(CH3CN)2
x (mol%)
Ligand
t-BuOLi
y (equiv.)
Solvent
Temp (°C)
Yield (%)a
5 (5a/5b/5c)
6
1
2
3
4
5
6
7
8
Ts (2)
Ac (3)
6
4
4
4
4
6
6
6
4
6
6
6
6
6
6
6
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
XPhos
JohnPhos
(t-Bu)3PÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
1ÁHBF4
3
3.5
3
2.5
3.5
3
3
3
3
3
3
3
3
3
3
3
toluene
toluene
toluene
toluene
toluene
toluene
xylene
mesitylene
1,4-dioxane
xylene
xylene
xylene
xylene
xylene
xylene
xylene
reflux
reflux
reflux
reflux
reflux
reflux
140
160
reflux
140
140
140
140
140
140
140
nd
51b
16
21
34
16
3
14
28
50
55
58
55
77
23
32
40
trace (nd/trace/nd)
46 (nd/23/23)
37 (nd/25/12)
44 (nd/32/12)
57 (nd/11/46)
56 (nd/31/25)
50 (nd/32/18)
nd
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
CF3CO (4)
9
10
11
12
13c
14d
15f
16h
nd
nd
nd
19 (nd/19/nd)
18e
20g
0i
a
b
c
d
e
f
Isolated yield. nd = not detected.
Obtained as 2-phenyl-1-tosyl-1H-indole.
2-Bromophenol was used instead of 2-chlorophenol.
2-Chloroanisole was used instead of 2-chlorophenol.
7 was obtained.
4-Chlorotoluene was used instead of 2-chlorophenol.
8 was obtained.
g
h
i
4-Chlorophenol was used instead of 2-chlorophenol.
9 was not obtained.
Please cite this article as: M. Yamaguchi, K. Ogihara, H. Konishi et al., Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151896

M. Yamaguchi et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Chlorophenol scope.a
a
Isolated yield.
With the optimized conditions in hand, we next examined the
range of 2-chlorophenols tolerated by this reaction (Table 2). The
reaction proceeded smoothly when 2-chloro-5-methylphenol was
used, with the corresponding 3-arylated indole 10 obtained in
51% yield (entry 2). 2-Chloro-4-methoxyphenol can also be intro-
duced (entry 3), and the C3-arylated product 12 was obtained in
45% yield when 2-chloro-4-fluorophenol was used (entry 4). It is
noteworthy that the reaction involving 2,4-dichlorophenol pro-
ceeded selectively at the 2-chloro group to give the desired indole
13 in 69% yield (entry 5). This high site-selectivity is attributable to
the formation of a heteroaggregate involving the lithium phenox-
ides of 2,4-dichlorophenol and ligand 1 which accelerates the
oxidative addition of the 2-chloro group to the Pd.
lated indoles obtained in moderate yields (entries 1–4). An
improved yield was obtained for the 2-decyl-substituted indole,
with 18 obtained in 72% yield (entry 5), while the 2-phenethyl-
substituted indole 19 was also obtained in good yield (entry 6).
However, a low (19%) yield of the 5-methyl-substituted indole 20
was obtained, with 46% of the C3-protonated indole produced (en-
try 7), while the 5-trifluoromethyl-substituted indole 21 was also
obtained in a low yield (entry 8). It should be noted that the 5-
chloro substituted indole 22 was obtained in 32% yield with 39%
of the C3-protonated indole produced and no other byproducts
observed (entry 9). This result reveals that ligand 1 selectively
accelerates the oxidative addition of 2-chlorophenol to Pd.
Although the reason is unclear, the introduction of substituents
on the aniline lowered the yield of the product 20–22.
We next conducted reactions using various 2-alkynylanilines
and 2-chlorophenol (Table 3), with the corresponding 2,3-diary-
Please cite this article as: M. Yamaguchi, K. Ogihara, H. Konishi et al., Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151896

4
M. Yamaguchi et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 3
2-Alkynylaniline scope.a
a
Isolated yield.
Please cite this article as: M. Yamaguchi, K. Ogihara, H. Konishi et al., Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151896

M. Yamaguchi et al. / Tetrahedron Letters xxx (xxxx) xxx
5
for Supporting Innovative Drug Discovery, and Life Science
Research (BINDS)) from the Japan Agency for Medical Research
and Development (AMED).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151896.
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H
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Acknowledgments
This work was partially supported by JSPS KAKENHI (Grant
Numbers 15H04634 and 17K08214), the Hamamatsu Foundation
for Science and Technology Promotion, and the Platform Project
for Supporting Drug Discovery and Life Science Research (Basis
Please cite this article as: M. Yamaguchi, K. Ogihara, H. Konishi et al., Synthesis of 2,3-disubstituted indoles from alkynylanilines and 2-chlorophenols using
palladium–dihydroxyterphenylphosphine catalyst, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151896