Palladium-catalyzed decarboxylative aminocarbonylation with alkynoic acid and tertiary amine for the synthesis of alkynyl amide

Article abstract of DOI:10.1016/j.tet.2019.04.030

We developed a method for the synthesis of alkynyl amides via the carbonylation of alkynoic acids and C-N activation of tertiary amines. The reaction of alkynoic acid and tertiary amine with carbon monoxide using a palladium catalyst in the presence of oxygen, KI, and K₃PO₄, gave the desired alkynyl amides in good yields.

Full text of DOI:10.1016/j.tet.2019.04.030

Accepted Manuscript
Palladium-catalyzed decarboxylative aminocarbonylation with alkynoic acid and
tertiary amine for the synthesis of alkynyl amide
Idris Muhammad Aliyu, Myungjin Kim, Jeung Gon Kim, Sunwoo Lee
PII:
S0040-4020(19)30442-9
https://doi.org/10.1016/j.tet.2019.04.030
TET 30275
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 March 2019
Revised Date: 10 April 2019
Accepted Date: 12 April 2019
Please cite this article as: Aliyu IM, Kim M, Kim JG, Lee S, Palladium-catalyzed decarboxylative
aminocarbonylation with alkynoic acid and tertiary amine for the synthesis of alkynyl amide, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.04.030.
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ACCEPTED MANUSCRIPT
Palladium-Catalyzed Decarboxylative Aminocarbonylation with Alkynoic Acid and
Tertiary Amine for the Synthesis of Alkynyl Amide
Idris Muhammad Aliyua, Myungjin Kima, Jeung Gon Kimb*, Sunwoo Leea*
aDepartment of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea.
bDepartment of Chemistry and Research Institute of Physics and Chemistry, Chonbuk
National University, Jeonju 54896, Republic of Korea
Corresponding Authors: S. Lee (sunwoo@chonnam.ac.kr),
J. G. Kim (jeunggonkim@jbnu.ac.kr)
Keywords : alkynyl amide, carbonylation, tertiaryamine, decarboxylative coupling, propiolic
acids
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Graphic Abstract
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Abstract
We developed a method for the synthesis of alkynyl amides via the carbonylation of alkynoic
acids and C-N activation of tertiary amines. The reaction of alkynoic acid and tertiary amine
with carbon monoxide using a palladium catalyst in the presence of oxygen, KI, and K3PO4,
gave the desired alkynyl amides in good yields.
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1. Introduction
The amide functionality is an important scaffold in many biologically active compounds and
is the key structure of peptides and proteins [1]. In particular, the alkynyl amide functionality
has attracted much attention in organic synthesis because it can be readily transformed into
several useful building blocks for pharmaceutical and materials chemistry [2].
A number of methods have been reported for the preparation of alkynyl amides. A classical
method in this regard is the Pd/Cu-catalyzed coupling reaction with a terminal alkyne and
carbamoyl chloride (Scheme 1a) [3]. However, the use of carbamoyl chloride is problematic
because it is moisture sensitive and not many commercially available. It has been reported
that alkynoic acid can be converted to a carbonyl compound possessing a leaving group and
that it further reacts with an amine to give the corresponding alkynyl amide, but this method
requires multiple steps and has a narrow substrate scope (Scheme 1b) [4]. Another reported
strategy involves the transition metal-catalyzed oxidative carbonylation of terminal alkynes
with amines in the presence of carbon monoxide (Scheme 1c) [5]. Although this method is
straightforward, the preparation of terminal alkynes has disadvantages in terms of high
environmental load and poor cost effectiveness. Alkynoic acid has been widely used as a
terminal alkyne surrogate since our first report on the decarboxylative coupling reactions of
alkynoic acid in 2008 [6]. Specifically, aryl alkynoic acids could be readily prepared via a
direct coupling reaction with aryl halides and propiolic acid and purified in a simple and
convenient step [7]. Many decarboxylative coupling reactions with aryl alkynoic acids have
been developed by our group [8] as well as other research groups [9].
Although reactions with primary and secondary amines have a wide substrate scope,
undesired side reactions are often encountered. As an alternative method, the reaction with
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tertiary amines has recently gained considerable attention because of the high stability and
ready availability of the amines and the absence of side reactions. C-N activation of tertiary
amines has been developed via oxidative addition [10], as well as imine, iminium [11],
ammonium [12], and alkyl migration [13], or β-amino elimination [14] to provide the
corresponding secondary amine source. Recently, palladium-catalyzed carbonylation of
tertiary amines via N-dealkylation has been reported for the synthesis of indolin-2-ones [15]
and arylamides [16]. Bhanage and co-workers reported a similar method based on the
carbonylation of tertiary amines for the synthesis of alkynylamides (Scheme 1d)[17].
(a)
O
O
cat. Pd/Cu
R1
H
R1
R1
R1
+
Cl
NR2
NR2
(b)
O
O
O
H NR2
R1
R1
NR2
OH
LG
LG = leaving group
(c)
(d)
(e)
O
cat. Pd
cat. Pd
R1
+ CO
H
H NR2
+
+
NR2
R
N
R
O
R2
R1
R1
+ CO
H
NR2
O
O
cat. Pd
CO2
+ CO
OH
H NR2
Ar
+
Ar
NR2
(f)
This work
O
R
N
R
O
cat. Pd
CO2
R2
Ar
+
Ar
CO
+
NR2
OH
Scheme 1. Synthesis of alkynyl amides
We reported the palladium-catalyzed oxidative decarboxylative aminocarbonylation for the
synthesis of alkynylamides via the reaction of alkynoic acid and secondary amine (Scheme
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1e) [18]. Thus, we envisioned that the reaction involving the use of a tertiaryamine could be
selectively controlled at the C-N activation stage to afford the desired alkynylamide by tuning
the reaction parameters (Scheme 1f). With this idea in mind, we carried out several trials to
accomplish our goal.
2. Results and discussion
To obtain the optimal conditions for the synthesis of alkynylamides, we chose phenyl
propiolic acid and trimethylamine as the standard substrates. First, we employed di-tert-butyl
peroxide as an oxidant and carried out this carbonylation under various conditions, as shown
in Table 1. When PdCl2 was used in the absence of a ligand, the desired product was not
formed (entry 1). A number of ligands were tested (entries 2–5), among which dppf (1,1′-
bis(diphenylphosphino)ferrocene) gave the best yield, though not more than 50% (entry 5).
Attempts to carry out the reaction using different palladium sources (entries 6–9) and
solvents (entries 10–12) were unsuccessful and did not give satisfactory results. From these
results, we determined that DTBP is not a suitable oxidant for this transformation and hence
turned our attention to oxygen gas as an alternative choice.
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Table 1. Decarboxylative carbonylation with 1a and 2a in the presence of DTBP. a
Entry
1
Cat.
PdCl2
PdCl2
PdCl2
PdCl2
Ligandb
-
Solvent
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
Toluene
o-Xylene
CH3CN
3a Yield (%)c
0
34
3
5
45
3
22
38
22
0
11
0
2
3
4
5
6
7
8
9
dppm
Dppp
dppb
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
PdCl2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
Pd(PPh3)2Cl2
PdCl2
10
11
12
PdCl2
PdCl2
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd (0.015 mmol), ligand (0.015
mmol), NH4Cl (0.03 mmol), and DTBP (0.3 mmol) were reacted under CO (7 atm)
atmosphere in
a
solvent (1.0 mL) at 90 oC for 12 h. bdppm
=
bis(diphenylphosphino)methane, dppp = bis(diphenylphosphino)propane, dppb =
c
bis(diphenylphosphino)butane, dppf = bis(diphenylphosphino)ferrocene. Determined
by gas chromatography using an internal standard (naphthalene).
We next investigated the parameters for the reaction of phenyl propiolic acid and
trimethylamine under oxygen atmosphere (Table 2). When the reaction was conducted with
PdCl2 as the palladium source in the absence of a ligand, the product was obtained in 14%
yield in anisole solvent (entry 1), while the yield increased to 55% in CH3CN solvent (entry
2). Among the palladium sources we tested (entries 3–7), Pd(PPh3)Cl2 showed the best result
and the product was obtained in 74% yield (entry 7). The reactions performed with ligands
such as dppf and dppb did not improve the yield of the product (entries 8 and 9). Changing
the solvent to 1,4-dioxane, THF, and toluene led to very low yields of the product or no
product (entries 10–12).
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Table 2. Decarboxylative carbonylation with 1a and 2a in the presence of oxygen.a
Pd (5 mol%)
Ligand (5 mol%)
O
O
CO
+
Et3N
+
OH
KI (0.5 equiv)
NEt2
K3PO4 (3.0 equiv)
O2, Solvent, 90 oC
2a
1a
3a
Entry
1
Pd
PdCl2
PdCl2
PdI2
Ligand
Solvent
Anisole
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
dioxane
THF
3a Yield (%)b
-
-
-
-
-
-
-
14
55
34
59
50
41
74
35
40
5
2
3
4
5
6
7
8
9
Pd(TFA)2
Pd/C 10%
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
dppf
dppb
10
11
12
4
trace
Toluene
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd (0.015
mmol), ligand (0.015 mmol), KI (0.15 mmol), and K3PO4 (0.9
mmol) were reacted under CO (7 atm) and O2 (1 atm) atmosphere
o
b
in solvent (1.0 mL) at 90 C for 12 h. Determined by gas
chromatography with an internal standard (naphthalene)..
With these conditions, we further investigated the effect of the mole ratio of all reagents. The
results are summarized in Table 3. When the pressure of carbon monoxide was decreased to 3
atm or increased to 9 atm, 3a was formed in 6% and 72% yields, respectively (entries 1 and
2). With a decrease in the amount of KI to 0.3 equiv or an increase in the amount of K3PO4
to 2.0 equiv, the product 3a was obtained in 94% yield (entries 3 and 4). However, when the
reaction was performed with 1.0 equiv of K3PO4, the yield of 3a decreased to 74% (entry 5).
It was noteworthy that 3a was formed even in the absence of K3PO4, although the yield was
not satisfactory (entry 6). Moreover, no product was formed in the absence of KI (entry 7).
Decreasing the amount of Pd(PPh3)2Cl2 to 3 mol% provided the product in 65% yield (entry
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8). No amide product was formed when the reaction conducted in the absence of CO gas.
(entry 9). This result support that the source of “CO” in the amide product might come from
CO gas. No product was formed in the absence of oxygen (entry 10). Finally, we established
the optimal conditions as follows: reaction of 1a (1.0 equiv), tertiary amine (1.5 equiv), CO
(7 atm), O2 (1 atm), Pd(PPh3)2Cl2 (5 mol%), KI (0.3 equiv), and K3PO4 (2.0 equiv) in CH3CN
at 90 oC for 12 h.
Table 3. Optimal conditions for the synthesis of 3a from 1a, 2a, and carbon monoxide. a
Entry
Pd(PPh3)2Cl2
K3PO4
(equiv)
KI
(equiv)
0.5
0.5
0.3
0.3
0.3
0.3
0
CO
(atm)
3a
(mol%)
Yieldc(%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
3
5
5
3
3
3
2
1
0
3
2
2
2
3
9
7
7
7
7
7
7
0
7
6
72
94
94
74
60
0
65
0
0
0.3
0.3
0.3
9
10b
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd(PPh3)2Cl2 (X mol%), KI (Y
equiv), and K3PO4 (Z equiv) were reacted under CO (x atm) and O2 (1 atm) atmosphere
o
b
c
in CH3CN (1.0 mL) at 90 C for 12 h. No oxygen was used. Determined by gas
chromatography with an internal standard(naphthalene)..
With the optimal conditions in hand, we evaluated a variety of aryl propiolic acids for the
reactions with triethyl amines and trimethyl amines, as shown in Scheme 1. As expected, the
reaction with phenyl propiolic acid and triethylamine provided the desired product 3a in 94%
isolated yield. Methyl-substituted aryl propiolic acids such as o-, m-, and p-tolyl propiolic
acids gave the corresponding products 3b, 3c, and 3d in good yields. Methoxy-substituted
aryl propiolic acids also led to the formation of 3e, 3f, 3g, and 3h in good yields. Chloro- and
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fluoro-substituted aryl propiolic acids provided 3i and 3j in 91% and 89% yields, respectively.
Cyano-substituted aryl propiolic acid furnished the product in good yield. 2-Thiophenyl
propiolic acid afforded 3l in 72% yield. The use of trimethyl amine in the reactions with
phenyl propiolic acid and tolyl propiolic acids also resulted in good product yields. These
results indicated that there was no notable difference between the yields obtained with aryl
propiolic acids having electron-withdrawing or electron-donating groups.
Table 4. Synthesis of alkynyl amides from the reaction of substituted-aryl propiolic acidsa
Pd(PPh3)2Cl2 (5 mol%)
O
O
Et3N
or
Me3N
KI (0.3 equiv)
CO
+
+
K3PO4 (2 equiv)
O2, CH3CN, 90 oC
OH
NR2
(7 atm)
1a
2
3
O
O
O
O
NEt2
NEt2
NEt2
NEt2
Me
Me
3b (88%)
3d
(92%)
O
3a (94%)
3c
(86%)
Me
O
O
O
NEt2
MeO
MeO
NEt2
NEt2
NEt2
MeO
OMe
MeO
OMe
3e (85%)
3h
(95%)
3f (91%)
3g (94%)
O
O
O
O
NEt2
NEt2
NEt2
NEt2
S
Cl
NC
F
3l
(72%)
3i
3k
(81%)
(91%)
NMe2
3j (89%)
O
O
O
O
NMe2
NMe2
NMe2
Me
Me
Me
3m (90%)
3n (81%)
3p
(94%)
3o (84%)
aReaction conditions: 1 (1.0 equiv), tertiary amine (1.5 equiv), CO (7 atm), O2 (1 atm),
Pd(PPh3)2Cl2 (5 mol%), KI (0.3 equiv), and K3PO4 (2.0 equiv) in CH3CN at 90 oC for 12 h.
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In addition, tripropylamine and N-methylpiperidine were used as a tertiaryamine in this
transformation. As shown in Scheme 2, the corresponding amides 3q and 3r were formed in
good yields.
Scheme 2. Reactions with tripropylamine and N-methylpiperidine.
We next carried out control experiments for understanding the reactivity of the starting
materials in this transformation (Scheme 3). When equal amounts of 3-(4-
methoxyphenyl)propiolic acid and phenyl acetylene were allowed to react with
trimethylamine under the optimal standard conditions, 3g and 3a were formed in 60% and
2% yields, respectively, implying that the reactivity of the alkynoic acid is higher than that of
the terminal alkyne in this transformation. In order to understand the steric effect of the
substituent in tertiary amine, a similar control experiment using trimethylamine and
trimethylamine was carried out. When two tertiary amines were allowed to react with phenyl
propiolic acid under the optimal standard conditions, 3a was formed as the major product and
3m was formed in very low yield. This result supports that the size of alkyl group in tertiary
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amine is not a major factor in the C-N bond cleavage.
Scheme 3. Control experiments
To understand the reaction mechanism, trioctylamine was allowed to react with phenyl
propiolic acid under optimal condition. As shown in Scheme 4, the desired product 3s was
formed with 84 % yield, and the octanal was found in the reaction mixture.
Scheme 4. Reaction with trioctylamine.
Based on our experiment result and previous report of the C-N bond cleavage of tertiary
amine [17], we proposed the reaction mechanism as shown in Scheme 5. Tertiary amine
reacts with palladium in the presence of oxygen to afford N-palladated complex A and follow
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by CO insertion to give intermediate B. Alkynoic acid reacts with intermediate B to give C
and intermediate D is formed through decarboxylation. Finally, the reductive elimination
provides the desired product and palladium (0). Palladium (II) active species is regenerated
through oxidation.
R1
KI / O2
R2
R2
KI / O2
Pd (0)
N
Pd (II)
R1
H
O
C
O
Ar
N R2
R2
O
H
R2
R2
C
Ar
Pd
Pd
N
N
R2
R2
D
A
CO2
O
O
O
H
O
CO
R2
C
O
Pd
N
C
R2
R2
N
C
B
R2
Ar
Ar
OH
Scheme 5. Proposed mechanism
3. Conclusion
Alkynoic acids and tertiary amines were allowed to react with carbon monoxide in the
presence of a palladium catalyst to provide the corresponding alkynyl amides via
decarboxylation, carbonylation, and C-N activation of the tertiary amine. We found that the
optimal conditions are as follows: reaction of aryl propiolic acid (1.0 equiv), tertiary amine
(1.5 equiv), Pd(PPh3)2Cl2 (5 mol%), KI (0.3 equiv), and K3PO4 (2.0 equiv) with CO (7 atm)
13

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in the presence of oxygen (1 atm) in CH3CN at 90 °C for 12 h. A number of substituted aryl
propiolic acids provided the corresponding alkynyl amides in good yields. It was found that
the alkynoic acid showed higher reactivity than the terminal alkyne under these optimal
conditions. In addition, triethyl amine was much more reactive than trimethylamine. However,
the reaction mechanism is not clear at present, and further investigations to elucidate the
mechanism this regard are underway in our lab.
4. Experimental
Aryl propiolic acid (1.0 mmol), tertiary amine (1.5 mmol), Pd(PPh3)2Cl2 (25 mg, 0.05 mmol),
KI (25 mg, 0.3 mmol), and K3PO4 (100 mg, 2.0 mmol) were added to CH3CN (5.0 mL) in a
20-mL sealed tube reactor, which was purged with carbon monoxide and oxygen. The
solution was stirred at 90 °C for 12 h. The resulting mixture was placed in a separating funnel,
followed by the addition of water and NH4Cl, and the mixture was extracted with EtOAc.
The separated organic layer was washed with water and dried over anhydrous MgSO4. After
removal of the organic layer under vacuum, the crude product was purified by silica gel
column chromatography with n-hexane/ethyl acetate as the eluent to obtain the desired
product.
4.1. N,N-Diethyl-3-phenylpropiolamide (3a) [5h]
Phenyl propiolic acid (146 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol) afforded 3a
(189 mg, 0.94 mmol, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 2H), 7.41 – 7.33 (m,
3H), 3.66 (q, J = 7.2 Hz, 2H), 3.47 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.18 (t, J =
13
7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 154.0, 132.3, 129.9, 128.5, 120.8, 89.0, 82.0,
43.6, 39.3, 14.4, 12.9.
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4.2. N,N-Diethyl-3-(o-tolyl)propiolamide (3b) [3d]
3-(o-Tolyl)propiolic acid (160 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol) afforded
3b (189 mg, 0.88 mmol, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.6, 1.0 Hz,
1H), 7.33 – 7.26 (m, 1H), 7.24 – 7.15 (m, 2H), 3.68 (q, J = 7.1 Hz, 2H), 3.49 (q, J = 7.2 Hz,
13
2H), 2.48 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H). C NMR (101 MHz,
CDCl3) δ 154.1, 141.2, 133.0, 129.9, 129.7, 125.8, 120.6, 88.0, 85.8, 43.6, 39.4, 20.7, 14.5,
12.9.
4.3. N,N-Diethyl-3-(m-tolyl)propiolamide (3c)
3-(m-Tolyl)propiolic acid (160 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol)
1
afforded 3c (185 mg, 0.86 mmol, 86% yield). H NMR (400 MHz, CDCl3) δ 7.34 (ddd, J =
6.1, 1.6, 0.6 Hz, 2H), 7.29 – 7.19 (m, 2H), 3.66 (q, J = 7.1 Hz, 2H), 3.47 (q, J = 7.2 Hz, 2H),
2.34 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
154.0, 138.3, 132.8, 130.8, 129.4, 128.4, 120.6, 89.3, 81.7, 43.6, 39.3, 21.2, 14.4, 12.9. ;
HRMS (ESI, TOF) calcd. for C14H18NO [M+H]+ 216.1388, found 216.1386.
4.4. N,N-Diethyl-3-(p-tolyl)propiolamide (3d) [3d]
3-(p-Tolyl)propiolic acid (160 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol) afforded
3d (198 mg, 0.92 mmol, 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.16 (dd, J
= 8.5, 0.6 Hz, 2H), 3.66 (q, J = 7.1 Hz, 2H), 3.47 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.27 (t, J =
13
7.1 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 154.1, 140.3, 132.3,
129.3, 117.7, 89.4, 81.6, 43.6, 39.3, 21.6, 14.4, 12.9.
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4.5. N,N-Diethyl-3-(2-methoxyphenyl)propiolamide (3e) [3d]
3-(2-Methoxyphenyl)propiolic acid (176 mg, 1.0 mmol) and triethylamine (152 mg, 1.5
mmol) afforded 3e (197 mg, 0.85 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd,
J = 7.6, 1.7 Hz, 1H), 7.38 (ddd, J = 8.4, 7.5, 1.7 Hz, 1H), 6.93 (td, J = 7.5, 0.9 Hz, 1H), 6.89
(d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.73 (q, J = 7.1 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.29 (t, J
13
= 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 160.2, 153.3, 133.3,
130.5, 119.5, 109.6, 109.1, 85.0, 84.8, 54.7, 42.6, 38.3, 13.3, 11.9.
4.6. N,N-Diethyl-3-(3-methoxyphenyl)propiolamide (3f) [3d]
3-(3-Methoxyphenyl)propiolic acid (176 mg, 1.0 mmol) and triethylamine (152 mg, 1.5
mmol) afforded 3f (210 mg, 0.91 mmol, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (m,
1H), 7.13 (dt, J = 7.6, 1.2 Hz, 1H), 7.06 (m, 1H), 6.96 (ddd, J = 8.4, 2.6, 0.9 Hz, 1H), 3.81 (s
3H), 3.66 (q, J = 7.2 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.28(t, J = 7.1 Hz, 3H), 1.18 (t, J =
13
7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 159.3, 154.1, 129.6, 124.8, 121.6, 117.2, 116.6,
89.3, 81.5, 55.4, 43.7, 39.4, 14.4, 12.8.
4.7. N,N-Diethyl-3-(4-methoxyphenyl)propiolamide (3g) [3d]
3-(4-Methoxyphenyl)propiolic acid (176 mg, 1.0 mmol) and triethylamine (152 mg, 1.5
1
mmol) afforded 3g (217 mg, 0.94 mmol, 94% yield). H NMR (400 MHz, CDCl3) δ 7.49 –
7.46 (m, 2H), 6.89 – 6.86 (m, 2H), 3.83 (s, 3H), 3.66 (m, 2H), 3.47 (q, J = 7.2 Hz, 2H), 1.28
13
(t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 160.9, 154.4,
134.1, 114.2, 112.6, 89.8, 81.1, 55.4, 43.6, 39.3, 14.4, 12.9.
4.8. N,N-Diethyl-3-(3,4,5-trimethoxyphenyl)propiolamide (3h)
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3-(3,4,5-Trimethoxyphenyl)propiolic acid (236 mg, 1.0 mmol) and triethylamine (152 mg,
1.5 mmol) afforded 3h (277 mg, 0.95 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ 6.77
(s, 2H), 3.87 (s, 3H), 3.86 (s, 6H), 3.67 (q, J = 7.1 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.29 (t, J
13
= 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 154.0, 153.2, 140.3,
115.6, 109.7, 89.4, 81.2, 61.0, 56.3, 43.6, 39.3, 14.4, 12.9. HRMS (ESI, TOF) calcd. for
C16H22NO4 [M+H]+ 292.1549, found 292.1548.
4.9. 3-(4-Chlorophenyl)-N,N-diethylpropiolamide (3i) [5h]
3-(4-Chlorophenyl)propiolic acid (181 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol)
1
afforded 3i (214 mg, 0.91 mmol, 91% yield). H NMR (400 MHz, CDCl3) δ 7.461 (m, 2H),
7.34 (m, 2H), 3.65 (q, J = 7.2 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.18
13
(t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 153.8, 136.2, 133.6, 129.0, 119.2, 88.0,
82.7, 43.7, 39.4, 14.4, 12.8.
4.10. N,N-Diethyl-3-(4-fluorophenyl)propiolamide (3j) [3d]
3-(4-Fluorophenyl)propiolic acid (164 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol)
1
afforded 3j (195 mg, 0.89 mmol, 89% yield). H NMR (400 MHz, CDCl3) δ 7.53 (m, 2H),
7.06 (m, 2H), 3.65 (q, J = 7.2 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.18
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.4 (d, JC-F = 252.5 Hz), 153.9, 134.4 (d,
JC-F = 8.1 Hz) 116.9 (d, JC-F = 3.1 Hz) 116.0 (d, JC-F = 23.2 Hz), 88.0, 81.8, 43.6, 39.3, 14.4,
12.8.
4.11. 3-(4-Cyanophenyl)-N,N-diethylpropiolamide (3k) [3d]
3-(4-Cyanophenyl)propiolic acid (171 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol)
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1
afforded 3k (183 mg, 0.81 mmol, 81% yield). H NMR (400 MHz, CDCl3) δ 7.66 (m, 2H),
7.63 (m, 2H), 3.65 (q, J = 7.2 Hz, 2H), 3.49 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.19
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.2, 132.7, 132.2, 125.6, 118.0, 113.3,
86.6, 85.3, 43.7, 39.5, 14.5, 12.8.
4.12. N,N-Diethyl-3-(thiophen-2-yl)propiolamide (3l) [5h]
3-(Thiophen-2-yl)propiolic acid (152 mg, 1.0 mmol) and triethylamine (152 mg, 1.5 mmol)
1
afforded 3l (149 mg, 0.72 mmol, 72% yield). H NMR (400 MHz, CDCl3) δ 7.42 – 7.38 (m,
2H), 7.03 (dd, J = 5.0, 3.9 Hz, 1H), 3.63 (q, J = 7.1 Hz, 2H), 3.47 (q, J = 7.2 Hz, 2H), 1.27 (t,
J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.8, 134.8, 129.7,
127.4, 120.6, 86.0, 82.8, 43.6, 39.3, 14.4, 12.9.
4.13. N,N-Dimethyl-3-phenylpropiolamide (3m) [17]
Phenyl propiolic acid (146 mg, 1.0 mmol) and trimethylamine (89 mg, 1.5 mmol) afforded
1
3m (156 mg, 0.90 mmol, 90% yield). H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.43 –
7.34 (m, 3H), 3.30 (s, 3H), 3.04 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.7, 132.4, 130.0,
128.5, 120.6, 90.2, 81.6, 38.4, 34.2.
4.14. N,N-Dimethyl-3-(o-tolyl)propiolamide (3n)
3-(o-Tolyl)propiolic acid (160 mg, 1.0 mmol) and trimethylamine (89 mg, 1.5 mmol)
afforded 3n (152 mg, 0.81 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.6,
13
0.5 Hz, 1H), 7.30 (m, 1H), 7.23 – 7.15 (m, 2H), 3.30 (s, 3H), 3.04 (s, 3H), 2.48 (s, 3H). C
NMR (101 MHz, CDCl3) δ 154.8, 141.2, 132.9, 130.0, 129.7, 125.8, 120.5, 89.2, 85.5, 38.4,
34.2, 20.8. HRMS (ESI, TOF) calcd. for C12H14NO [M+H]+ 188.1075, found 188.1075.
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4.15. N,N-Dimethyl-3-(m-tolyl)propiolamide (3o)
3-(m-Tolyl)propiolic acid (160 mg, 1.0 mmol) and trimethylamine (89 mg, 1.5 mmol)
afforded 3o (157 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m,
2H), 7.27 – 7.21 (m, 2H), 3.29 (s, 3H), 3.03 (s, 3H), 2.34 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 154.7, 138.3, 132.9, 130.9, 129.5, 128.4, 120.5, 90.5, 81.3, 38.4, 34.2, 21.2. HRMS
(ESI, TOF) calcd. for C12H14NO [M+H]+ 188.1075, found 188.1075.
4.16. N,N-Dimethyl-3-(p-tolyl)propiolamide (3p)
3-(p-Tolyl)propiolic acid (160 mg, 1.0 mmol) and trimethylamine (89 mg, 1.5 mmol)
afforded 3p (176 mg, 0.94 mmol, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0
13
Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 3.28 (s, 3H), 3.02 (s, 3H), 2.37 (s, 3H). C NMR (101
MHz, CDCl3) δ 154.8, 140.5, 132.3, 129.3, 117.5, 90.6, 81.2, 38.4, 34.2, 21.6. HRMS (ESI,
TOF) calcd. for C12H14NO [M+H]+ 188.1075, found 188.1075.
4.17. 3-Phenyl-N,N-dipropylpropiolamide (3q) [18]
Phenyl propiolic acid (146 mg, 1.0 mmol) and tripropylamine (215 mg, 1.5 mmol) afforded
3q (188 mg, 0.82 mmol, 82% yield). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 – 7.34
(m, 3H), 3.57 (m, 2H), 3.37 (m, 2H), 1.70 (m, 2H), 1.61 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H),
13
0.93 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 154.7, 132.3, 129.9, 128.5, 120.8,
89.7, 81.96, 51.0, 46.6, 22.2, 20.7, 11.4, 11.3.
4.18. 3-Phenyl-1-(piperidin-1-yl)prop-2-yn-1-one (3r) [18]
Phenyl propiolic acid (146 mg, 1.0 mmol) and 1-methylpiperidine (149 mg, 1.5 mmol)
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1
afforded 3r (169 mg, 0.79 mmol, 79% yield). H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H),
7.43 – 7.33 (m, 3H), 3.77 (m, 2H), 3.63 (m, 2H), 1.69 – 1.67 (m, 4H), 1.65 – 1.58 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 153.0, 132.4, 129.9, 128.5, 120.8, 90.3, 81.5, 48.3, 42.4, 26.5,
25.4, 24.6.
4.19. N,N-dioctyl-3-phenylpropiolamide (3s) [16b]
Phenyl propiolic acid (146 mg, 1.0 mmol) and trioctylamine (531 mg, 1.5 mmol) afforded 3x
(310 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H), 7.37 –
7.25 (m, 3H), 3.55 – 3.49 (m, 2H), 3.36 – 3.29 (m, 2H), 1.62 – 1.47 (m, 4H), 1.27 – 1.17 (m,
20H), 0.82 – 0.76 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 153.4, 131.3, 128.8, 127.5, 119.9,
88.2, 81.2, 48.2, 43.9, 30.78, 30.75, 28.4, 28.3, 28.2, 27.9, 26.5, 26.0, 25.6, 22.1, 21.62, 21.59,
13.07, 13.05.
Acknowledgments
The authors would like to acknowledge the financial support of the Research Base
Construction Fund Support Program funded by Chonbuk National University in 2019 (J.G.K)
and “Basic Research Laboratory” (NRF-2015R1A4A1041036) of the Ministry of Science and
ICT, Republic of Korea. I.M. Aliyu thanks the National Institute for International Education
(NIIED) South Korea for sponsoring his Ph D. Program through the Korean Government
Scholarship Program (KGSP).
Supplementary data
Supplementary data to this article can be found online at..
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Highlights
The C-N bond activation of tertiary amines
The decarboxylative aminocarbonylation with alkynoic acids
Synthesis of alkynyl amides