Palladium-Catalyzed Three-Component Coupling of Ynamides

Article abstract of DOI:10.1021/acs.orglett.0c01426

A palladium-catalyzed regioselective three-component coupling of ynamides was developed. The reaction proceeded smoothly to furnish the desired products when carried out at 70 °C in acetonitrile/water with potassium carbonate in the presence of 2.5 mol percent Pd2(dba)3·CHCl3 without a ligand. Various iodides and boronic acids were used in this reaction, and a carbon-carbon bond was formed with satisfactory regioselectivity from the ynamides.

Full text of DOI:10.1021/acs.orglett.0c01426

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Letter
Palladium-Catalyzed Three-Component Coupling of Ynamides
Hideaki Wakamatsu,* Ayano Takahashi, Ayaka Ishii, Youhei Kikuchi, Madoka Sasaki, Yukako Saito,
Yoshihiro Natori, and Yuichi Yoshimura*
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ABSTRACT: A palladium-catalyzed regioselective three-component
coupling of ynamides was developed. The reaction proceeded smoothly
to furnish the desired products when carried out at 70 °C in acetonitrile/
water with potassium carbonate in the presence of 2.5 mol % Pd2(dba)3·
CHCl3 without a ligand. Various iodides and boronic acids were used in
this reaction, and a carbon−carbon bond was formed with satisfactory
regioselectivity from the ynamides.
Scheme 1. Palladium-Catalyzed Hydroarylation of Ynamides
he development of new carbon−carbon bond-forming
reactions is important in the field of synthetic organic
T
chemistry.1 The reaction between ynamides and transition-
metal complexes has been studied in the past by several research
groups.2 Currently, ynamides are recognized as important
alkynes serving as a stepping stone for bond-forming reactions.3
We reported the ruthenium-catalyzed ring-closing metathesis of
ene-ynamides,4 and in 2010, we reported the palladium-
catalyzed Sonogashira coupling in the absence of copper salts
for ynamides without terminal substituents.5 More recently, a
palladium-catalyzed regioselective hydroarylation of ynamides
with terminal substituents was reported.6 Herein the palladium-
catalyzed three-component coupling7,8 of substituted ynamides
is described.
First, we focused on the palladium(II) complex B, which was
previously generated as an intermediate in the hydroarylation
(Scheme 1). The reaction was carried out in the presence of a
transmetalative reagent to form a carbon−carbon bond via
transmetalation with palladium(II) complex B.
A THF/H2O solution of ynamide 1a9 with a small excess of
aryl halide 2a and tolylboronic acid 3a was heated with sodium
hydroxide in the presence of catalytic amounts of palladium
acetate and DPPF (Table 1, entry 1). After 18 h, the three-
component coupling yielded 26% of the desired compound 4aa.
It seemed that ynamide 1a did not play a role in this reaction,
and compound 5aa was produced in 73% yield by the Suzuki−
Miyaura coupling that proceeded between compounds 2a and
3a. Conducting the reaction at room temperature (22−25 °C)
significantly reduced the yield of 4aa, whereas the yield of
compound 5aa increased (entry 2).
Next, the catalysts and ligands were screened (Table 2). Using
PPh3 and P(C6F5)3 as ligands generated results similar to DPPF
(entries 1 and 2). Applying dichlorobis(benzonitrile)−
palladium(II) improved the yield of 4aa (entry 3). The best
result was obtained when using tris(dibenzylideneacetone)−
dipalladium(0), producing 4aa in 58% yield (entry 4). The yield
of 4aa was, however, significantly reduced when triphenylphos-
phine was used as the ligand under the same reaction conditions
as entry 4 (see entry 5).
In the following experiments, the solvent, reaction temper-
ature, and reaction time were examined (Table 3). When
Received: April 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01426
© XXXX American Chemical Society
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A

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a
Table 1. Palladium-Catalyzed Three-Component Coupling
of Ynamide 1a
Table 3. Screening of Reaction Conditions
time
(h)
yield of
4aa (%)
recovery of
1a (%)
yield of 5aa
(%, based on 2a)
entry
solvent
1
2
3
4
5
DMF
DCE
DME
CH3CN
CH3CN
CH3CN
CH3CN
18
18
18
18
24
24
45
68
40
22
33
27
4
76
8
44
58
63
52
58
61
33
38
36
37
b
6
7
15
a
Reaction conditions: 2.5 mol % Pd2(dba)3·CHCl3, no use of ligand,
b
NaOH (1.5 equiv), solvent/H2O. Reaction was carried out at reflux.
Table 4. Screening of Bases
time yield of 4aa recovery of
yield of 5aa
(%, based on 2a)
entry temp.
(h)
(%)
1a (%)
1
2
reflux
rt
18
22
26
8
54
86
73
80
yield of 4aa recovery of 1a
yield of 5aa
dimethylformamide (DMF) or dichloroethane (DCE) was
employed as the solvent, the desired product 4aa was not
obtained (entries 1 and 2). Dimethoxyethane (DME) led to a
slight decrease in the yield of 4aa (entry 3). Acetonitrile gave
similar results as those obtained with tetrahydrofuran (THF)
(entry 4). Extending the reaction time slightly improved the
yield of 4aa (entry 5), and heating under reflux conditions
decreased the yield and the recovery of 1a (entry 6). A reaction
time of more than 24 h worsened the overall recovery (entry 7).
Because the reaction proceeded well in the presence of an
aqueous sodium hydroxide solution, the effects of inorganic
bases were verified (Table 4). Lithium and potassium hydroxide
caused a slight decrease in the yield of 4aa (entries 1 and 2),
whereas the reaction with barium hydroxide did not proceed at
all (entry 3). Sodium carbonate produced 4aa in moderate yields
(entry 4), but potassium carbonate generated the desired
product in 74% yield, which was the best result (entry 5).
Although cesium carbonate provided adequate results (entry 6),
potassium carbonate was identified as the best base for this
reaction.
On the basis of these results, the optimal reaction conditions
were 2.5 mol % tris(dibenzylideneacetone)dipalladium com-
bined with 1.5 equiv of potassium carbonate in acetonitrile/
water at 70 °C for 18 h without the phosphine ligand.
Furthermore, the scope and limitations of aryl iodide 2 and
boronic acid derivative 3 were examined (Table 5). First, the
reactivity of various boronic acids toward to ethyl iodobenzoate
2a was investigated (entries 1−5). In combination with
entry
base
(%)
(%)
(%, based on 2a)
1
2
3
4
5
6
LiOH
KOH
Ba(OH)2
Na2CO3
K2CO3
Cs2CO3
42
28
10
39
74
61
40
58
71
35
12
23
11
66
3
3
27
35
phenylboronic acid 3b, the target product 4ab was obtained in
moderate yield (entry 1). The three-component coupling
reaction proceeded smoothly for every reaction using phenyl-
boronic acids and either the electron-donating methoxy group
or the electron-withdrawing cyano group, providing the desired
products 4ac and 4ad in satisfactory yields (entries 2 and 3).
A similar result was obtained when using β-naphthylboronic
acid 3e (entry 4), but a slight decrease in yield was observed
when employing 1-pentenylboronic acid 3f (entry 5). Next,
reactions with various iodides were conducted using tolylbor-
onic acid 3a, and the desired product was generated in
acceptable yield with respect to the electron-donating and
electron-withdrawing groups (entries 6−9). However, no
product was yielded with methyl o-iodobenzoate 2f (entry
10). The reaction was probably inhibited by a steric hindrance
due to the presence of a substituent at the ortho position.
Oxazolidinone-derived ynamides 6 gave a complex mixture,
although the starting material 1a disappeared upon TLC
analysis. The aryl bromide 7a was not applied to this reaction,
Table 2. Screening of Catalysts and Ligands
entry
catalyst
Pd(OAc)2
Pd(OAc)2
Cl2Pd(PhCN)2
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
ligand
PPh3
P(C6F5)3
yield of 4aa (%)
recovery of 1a (%)
yield of 5aa (%, based on 2a)
1
2
3
4
5
27
24
49
58
18
67
63
25
33
69
75
63
51
51
78
PPh3
B
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Table 5. Scope and Limitation of Aryl Iodide and Boronic Acid for Three-Component Coupling of 1a
entry
R1
R2
yield of 4 (%)
recovery of 1a (%)
yield of 5 (%, based on 2)
1
2
3
4
5
6
7
8
9
p-EtO2CC6H4− (2a)
p-EtO2CC6H4− (2a)
p-EtO2CC6H4− (2a)
p-EtO2CC6H4− (2a)
p-EtO2CC6H4− (2a)
p-MeOC6H4− (2b)
p-FC6H4− (2c)
p-ClC6H4− (2d)
p-F3CC6H4− (2e)
o-MeO2CC6H4 (2f)
C6H5− (3b)
4ab: 51
4ac: 68
4ad: 63
4ae: 77
4af: 52
4ba: 59
4ca: 73
4da: 70
4ea: 57
26
10
12
8
18
7
7
8
17
27
5ab: 21
5ac: 41
5ad: 37
5ae: 43
5af: 22
5ba: 3
5ca: 16
5da: 8
5ea: 33
5fa: 27
p-MeOC6H4− (3c)
p-NCC6H4− (3d)
β-naphthyl− (3e)
1-pentenyl− (3f)
p-MeC6H4− (3a)
p-MeC6H4− (3a)
p-MeC6H4− (3a)
p-MeC6H4− (3a)
p-MeC6H4− (3a)
10
and most of 1a was recovered. As will be discussed later, the
halogens on the palladium would be likely to have a significant
effect on the insertion of the ynamides in the Pd(II) complex.
When compound 8,10 which is a useful vinyl donor as a borate,
was used, only the Suzuki−Miyaura coupling proceeded, and
ynamides 1a were hardly involved in the reaction (Scheme 2).
Scheme 2. Limitation of Three-Component Coupling
Figure 1. Summary of NOE experiments of compound 4af.
Scheme 3. Plausible Reaction Mechanism to Generate 4aa
carbon bond is generated at the α-position of the ynamide, and a
carbon palladium bond regioselectively is formed at the β-
position. When we previously reported the hydroarylation of
ynamides,6 it was found that the steric repulsion with the
benzyltosylamide unit and the electronic effect of the amino
group lead to the preferential formation of complex II. The
transmetalation of complex II and boronic acid 3a (or boronate
3a′) forms complex III with the retention of stereochemistry,
Furthermore, when the nuclear Overhauser effect (NOE)
experiment was performed on 4af, an NOE correlation was
observed, as shown in Figure 1. Therefore, this reaction was
considered to proceed by syn addition, for which the mechanism
is shown in Scheme 3. That is, complex I is formed by the
oxidative addition of an aryl halide to palladium(0), and
complex II is obtained by inserting ynamide 1 into complex I. A
C
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Table 6. Effect of Alkyl Chain (R1) on the Three-Component Coupling Reaction
entry
R1
yield of 4 (%)
4baa: 33
recovery of 1 (%)
yield of 5aa (%, based on 2a)
1
2
3
4
5
−Me (1b)
22
49
17
49
43
12
32
29
22
36
−CH(CH3)(CH2)5OTBDPS (1c)
−C6H5 (1d)
−C6H4-p-OMe (1e)
−C6H4-p-CO2Et (1f)
4daa: 54
4eaa: 46
4faa: 56
generating product 4aa by reductive elimination and regenerat-
ing palladium(0). In addition, if the insertion of ynamide 1a is
slow after complex I is formed, then the transmetalation with
boronic acid will preferably proceed, and compound 5 will be
obtained through reductive elimination. Therefore, the key to
this reaction is to accelerate the insertion of ynamide 1a and to
slow down the transmetalation of complex I with boronic acid
3a. The phosphine ligands are considered to have a negative
effect in this view.
2.5 mol % tris(dibenzylideneacetone)dipalladium and without a
ligand. Various iodides and boronic acids were applied in this
reaction, and a new carbon−carbon bond was formed from
various ynamides with satisfactory regioselectivity. The syn-
thesis of various enamide derivatives was confirmed. Further
studies on this type of reaction will be considered, and
transition-metal-catalyzed carbon−carbon bond-forming reac-
tions using ynamides are presently pursued in our laboratory.
Subsequently, the effect of the carbon chain (R1) on the three-
component coupling was investigated (Table 6). The reaction
was carried out in acetonitrile at 70 °C for 18 h under the
previous conditions. When the reaction was conducted with
ynamide 1b, into which a methyl group was introduced, the yield
of 4baa was 33% (entry 1). Unfortunately, 4baa was very
unstable and decomposed over time, reducing the yield. When
compound 1c containing a branched alkyl chain was reacted, no
product was obtained (entry 2). In this case, 49% of the starting
material was recovered, along with 32% of a compound 5aa,
because the Suzuki−Miyaura coupling occurred between
compounds 2a and 3a. Therefore, ynamide 1c hardly
participated in this reaction and only decomposed under those
reaction conditions. Upon attaching the branched sp3 carbon to
the β-position of the ynamide, the bulkiness around the carbon−
carbon triple bond increased, and the reaction did not proceed.
Thus when the compound 1d with the phenyl group at R1 was
used, the desired compound 4daa was generated in 54% yield,
together with 17% recovery of substrate 1d and 29% yield of 5aa
(entry 3). When compound 1e containing the methoxy group
was introduced at the para position of the phenyl group, the yield
of product 4eaa slightly decreased to 46% (entry 4). On the
contrary, when the reaction was similarly conducted with the
ethoxycarbonyl-containing compound 1f, a 4faa yield of 56%,
was achieved, which was slightly higher compared with the cases
where no para position existed (entry 5).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01426.
General remarks, general procedures for three-compo-
nent coupling, physical and spectral data for 4 and 5, and
copies of NMR spectra for 4 and 5 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Hideaki Wakamatsu − Faculty of Pharmaceutical Sciences,
Tohoku Medical and Pharmaceutical University, Aoba-ku,
Sendai 981-8558, Japan; orcid.org/0000-0003-4802-6288;
Email: hiwaka@tohoku-mpu.ac.jp
Yuichi Yoshimura − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan; Email: yoshimura@tohoku-mpu.ac.jp
Authors
Ayano Takahashi − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan
Ayaka Ishii − Faculty of Pharmaceutical Sciences, Tohoku Medical
and Pharmaceutical University, Aoba-ku, Sendai 981-8558,
Japan
Youhei Kikuchi − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan
Madoka Sasaki − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan
Yukako Saito − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan
Yoshihiro Natori − Faculty of Pharmaceutical Sciences, Tohoku
Medical and Pharmaceutical University, Aoba-ku, Sendai 981-
8558, Japan
As previously described, for the ynamide having an sp2 carbon
directly bonded to the carbon−carbon triple bond, the desired
compound 4 was obtained in acceptable yield. In addition, the
introduction of an electron-donating or electron-withdrawing
group at the para position hardly affected the yield of the desired
product 4.
In conclusion, the development of a new carbon−carbon
bond-forming reaction using a palladium catalyst with ynamides
as a substrate was investigated. It was revealed that the
regioselective three-component coupling smoothly proceeded
to provide various enamide derivatives. The best yield was
obtained when the reaction was carried out at 70 °C in
acetonitrile/water with potassium carbonate in the presence of
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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