A simple and economic synthesis of propargylamines by cuI-catalyzed three-component coupling reaction with succinic acid as additive

Article abstract of DOI:10.1071/CH08086

A practical and efficient method was developed for the synthesis of propargylamines in a one-pot procedure from aldehydes, amines, and alkynes by using CuI as catalyst and succinic acid as additive. By using this protocol, a wide range of propargylamines was obtained in high yields. CSIRO 2009.

Full text of DOI:10.1071/CH08086

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2009, 62, 75–81
A Simple and Economic Synthesis of Propargylamines
by CuI-Catalyzed Three-Component Coupling Reaction
with Succinic Acid as Additive
Gerui Ren,A Jinli Zhang,A Zheng Duan,A Mengjun Cui,A and Yangjie WuA,B
ADepartment of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University,
Zhengzhou 450052, China.
BCorresponding author. Email: wyj@zzu.edu.cn
A practicaland efficient methodwas developed for the synthesis of propargylamines in a one-potprocedure from aldehydes,
amines, and alkynes by using CuI as catalyst and succinic acid as additive. By using this protocol, a wide range of
propargylamines was obtained in high yields.
Manuscript received: 28 February 2008.
Final version: 2 July 2008.
O
Introduction
Propargylamines are major skeletons[1] and synthetically versa-
tile key intermediates[2] for the preparation of many biologically
active nitrogen-containing compounds such as conformationally
restricted peptide isosteres, oxotremorine analogues, β-lactams,
and therapeutic drug molecules.[3] Traditionally, propargyl-
amines were synthesized by nucleophilic attack of lithium
acetylides or Grignard reagents on imines or their derivatives.[4]
However, these methods require strictly controlled reaction
conditions. Recently, extensive attention has been paid to metal-
catalyzed three-component coupling of aldehyde, amine, and
alkyne (A3 coupling)[5] for the synthesis of propargylamine.
This developed synthetic method is a powerful synthetic route to
access complex structures from simple precursors in a one-pot
procedure and exhibits higher atom economy and selectivity.[6,7]
The extension of the scope of metal-catalyzed A3 coupling
reactions and the search for a more efficient catalyst have
been one of the most popular aims for organic chemists. The
recent progresses in this kind of reaction have been made by
several research groups. Li[8] and Lo[9] reported their highly
efficient three-component coupling reaction in green solvents,
such as water, or ionic liquid.[7c] However, these methods
required relatively expensive Au[8a,9] or Ag[8b,8c] as catalyst.
In addition, cheaper Cu salt-catalyzed A3 coupling reactions
have also received much attention.[10] Tu[10b] and Sreedhar[10g]
reported CuI-catalyzed microwave- and ultrasound-assisted A3
coupling reactions, respectively. Recently Kidwai[10h] reported
an efficient recyclable copper-nanoparticle-catalyzed A3 cou-
pling route using high catalyst loading (15 mol-% of Cu
nanoparticles).
O
CHO
N
Cat./additive
Solvent
ϩ
ϩ
N
H
Scheme 1. A3 coupling of benzaldehyde, morpholine, and phenyl-
acetylene.
Results and Discussion
To find the optimal reaction conditions, the A3 coupling syn-
theses of propargylamines of benzaldehyde, morpholine, and
phenylacetylene with succinic acid at 100◦C under various
conditions were investigated (Scheme 1).
Among various copper salts screened in this three-component
coupling, CuI was found to be the most effective catalyst, with
98% isolated yield, much better than other copper salts such as
CuCl, CuBr, and Cu(OAc)2. By screening the solvents, toluene
was found to give the highest yield of 98% (Table 1, entries
1–7). We then checked the efficiency of the CuI catalyst. As
shown in Table 1 (entries 7–9), when the catalyst loading was
reduced to 1 mol-%, this reaction proceeded well with a slightly
lower isolated yield (88%, entry 8). Even with 0.1 mol-% of
CuI, the expected product was formed in 83% yield within 6 h
(entry 9).
The effect of chain length of dicarboxylic acids on the cou-
pling reaction was also investigated.As shown in Fig. 1, succinic
acid gave the best yield. A possible reason is that the coordina-
tion bond length and angle between succinic acid and CuI might
be suitable to promote this A3 coupling.
Herein, we report a simple CuI-, together with low-cost suc-
cinic acid as additive, catalyzed three-component coupling of
aldehydes, amines, and alkynes to generate propargylamines in
good to excellent yields and with lower catalyst loading (the
loading of CuI could be reduced to 0.1 mol-%).
A variety of aldehydes, amines, and alkynes were cho-
sen to investigate the scope and generality of this catalytic
system and the results are summarized in Table 2. The substi-
tuted aldehydes with both electron-withdrawing (entries 2–7)
© CSIRO 2009
10.1071/CH08086
0004-9425/09/010075

76
G. Ren et al.
Agilent 4890D gas chromatograph. 1H NMR and 13C NMR
were recorded on a Bruker DPX 400 instrument using CDCl3
as the solvent and TMS as the internal standard. Elemental
analyses were conducted with a Carlo Erba 1160 elemental ana-
lyzer. High-resolution mass spectra (HRMS) were measured on a
Waters Q-Tof Micro spectrometer. CuI was synthesized accord-
ing to the literature.[10b] The other chemicals were reagent grade
and used without further purification.
Table 1. Effect of solvents and catalyst loading on the A3 coupling
reaction
Reaction conditions: benzaldehyde (1.00 mmol), morpholine (1.2 mmol),
phenylacetylene (1.5 mmol), CuI (0.03 mmol), succinic acid (0.06 mmol),
reflux for 6 h
Entry
Solvent
Mol-% catalyst
YieldA [%]
1
2
3
4
5
6
7
8
9
THF
DMF
CH3OH
H2O
CH3CN
1,4-dioxan
Toluene
Toluene
Toluene
3
3
3
3
3
3
3
1
43
62
68
78
81
89
98
88
83
General Procedure for Three-Component
Coupling Reaction
A mixture of aldehyde (1 mmol), amine (1.2 mmol), alkyne
(1.5 mmol), CuI (3 mol-%), succinic acid (6 mol-%), and toluene
(0.5 mL) was heated at 100◦C under nitrogen for 6 h. After com-
pletion of the reaction as monitored by GC or TLC, the reaction
mixture was filtered through a pad of silica gel and washed
with ethyl acetate. The combined filtrates were concentrated
under vacuum. The residue was purified by chromatography
on silica gel using petroleum ether/ethyl acetate as eluent. The
products were characterized by 1H and 13C NMR spectroscopy.
New compounds were confirmed by HRMS or elemental
analysis.
0.1
AIsolated yields.
98
96
94
92
90
88
Yield
N-(1,3-Diphenylprop-2-yn-1-yl)-morpholine 4a[10b]
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.64–7.62 (m, 2H),
7.52–7.50 (m, 2H), 7.38–7.29 (m, 6H), 4.78 (s, 1H), 3.77–3.68
(m, 4H), 2.66–2.58 (m, 4H). δC (100 MHz, CDCl3) 137.8, 131.9,
128.6, 128.3, 127.8, 123.0, 88.6, 85.1, 67.2, 62.1, 49.9.
N-[1-(4-Bromophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4b[10b]
86
1
2
3
4
5
6
7
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.51–7.45 (m, 6H),
7.30–7.29 (m, 3H), 4.70 (s, 1H), 3.74–3.66 (m, 4H), 2.59–2.57
(m, 4H). δC (100 MHz, CDCl3) 136.8, 131.6131.1, 130.0, 128.2,
122.5, 121.6, 88.8, 84.1, 66.9, 61.2, 49.6.
HOOC(CH2)nCOOH (n ϭ 1–7)
Fig. 1. Effect of various dicarboxylic acids on the three-component
coupling reaction (isolated yields).
N-[1-(2-Bromophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4c
and electron-donating (entries 8, 9) groups could couple with
morpholine and phenylacetylene efficiently to give the desired
substituted propargylamines in good to excellent yields. The
functional groups on the aldehydes, such as bromo, chloro, flu-
oro, and methoxyl are compatible with this three-component
coupling. There is no significant effect on the reaction yield in
the case of ortho-substituted aldehydes used (entries 2, 3).
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.60–7.59 (m, 1H),
7.58–7.57 (m, 1H), 7.51–7.48 (m, 2H), 7.33–7.31 (m, 4H), 7.16–
7.14 (m, 1H), 5.07 (s, 1H), 3.74–3.64 (m, 4H), 2.71–2.62 (m,
4H). δC (100 MHz, CDCl3) 137.0, 133.2, 131.7, 130.6, 129.3,
128.3, 126.8, 125.2, 122.7, 88.5, 84.5, 67.0, 61.2, 49.6. HRMS
(positive electrospray ionization (ESI)) Calc. for C19H18BrNO
[M + H]+: 356.0650. Found: 356.0657.
Conclusions
N-[1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4d[10b]
In summary, we successfully developed a simple and economic
three-component coupling for the synthesis of propargylamines.
This one-pot procedure with aldehydes, amines, and alkynes
was catalyzed efficiently by easily available CuI with succinic
acid as an additive. By using this method, a diverse range of
propargylamines were generated in good to excellent yields.This
methodology could serve as a new avenue for the synthesis of
propargylamines as useful synthetic intermediates.
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.58–7.55 (m, 2H),
7.51–7.49 (m, 2H), 7.33–7.30 (m, 5H), 4.73 (s, 1H), 3.74–3.67
(m, 4H), 2.60–2.58 (m, 4H). δC (100 MHz, CDCl3) 136.3, 133.4,
131.7, 129.7, 128.2, 122.6, 88.8, 84.2, 67.0, 61.2, 49.6.
N-[1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4e[10b]
Experimental
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.76–7.73 (m, 1H),
7.50–7.46 (m, 2H), 7.40–7.37 (m, 1H), 7.32–7.29 (m, 3H),
7.24–7.22 (m, 2H), 5.12 (s, 1H), 3.73–3.63 (m, 4H),
2.67–2.65 (m, 4H). δC (100 MHz, CDCl3) 135.4, 134.5, 131.7,
General
Melting points were measured on an XT-5 microscopic appa-
ratus and are uncorrected. GC analysis was performed on an

Synthesis of Propargylamines
77
Table 2. Three-component coupling of various aldehydes, amines, and alkynes
R2
R3
N
CuI/succinic acid
Toluene/N2
R1CHO
ϩ
R2R3NH
ϩ
R4
H
R1
R4
1
2
3
4
EntryA
Aldehyde
Amine
Alkyne
Product
Yield [%]B
O
N
O
CHO
4a
1
98
N
H
O
N
O
CHO
4b
2
3
4
5
6
7
99
99
99
84
82
N
H
Br
Br
O
N
O
CHO
Br
Br
4c
N
H
O
N
O
CHO
4d
N
H
Cl
Cl
O
N
O
CHO
Cl
Cl
4e
N
H
O
N
O
CHO
Cl
4f
N
H
Cl
Cl
Cl
O
N
O
CHO
4g
86
N
H
F
F
(Continued)

78
G. Ren et al.
Table 2. (Continued)
EntryA
Aldehyde
Amine
Alkyne
Product
Yield [%]B
O
N
O
CHO
4h
8
85
N
H
H3CO
H3CO
O
OCH3
CHO
O
OCH
3N
9
4i
98
71
61
86
N
H
O
N
O
CHO
10
11
12
4j
N
H
O
N
O
CHO
4k
O
N
H
O
N
CHO
4l
N
H
CH3
N
CH3
N
CHO
N
4m
13
96
N
H
CH3
N
CH3
N
CHO
N
14
85
4n
Br
N
H
Br
(Continued)

Synthesis of Propargylamines
79
Table 2. (Continued)
EntryA
Aldehyde
Amine
Alkyne
Product
Yield [%]B
O
N
O
CHO
CH3(CH2)7C CH
15
86
4o
N
H
(CH2)7CH3
O
N
O
CHO
CH3(CH2)4C
CH
16
17
85
78
4p
N
H
(CH2)4CH3
O
N
O
OH
C
4q
CHO
CH
OH
N
H
AReaction conditions: aldehyde (1.00 mmol), amine (1.2 mmol), alkyne (1.5 mmol), CuI (0.03 mmol), succinic acid (0.06 mmol), toluene (0.5 mL), reflux
for 6 h.
BIsolated yields.
130.4, 129.8, 129.0, 128.2, 126.2, 122.7, 88.2, 84.6, 67.0,
58.8, 49.7.
N-[1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4i
Slightly yellowish solid, mp 74–75◦C. (Found: C 78.15, H 6.89.
Calc. for C20H21NO2: C 78.13, H 6.96%.) δH (400 MHz, CDCl3)
7.64 (d, J 7.6, 1H), 7.47–7.45 (m, 2H), 7.29–7.24 (m, 4H), 6.97
(m, 1H), 6.90–6.87 (m, 1H), 5.19 (s, 1H), 3.82 (s, 3H), 3.71–
3.68 (m, 4H), 2.74–2.60 (m, 4H). δC (100 MHz, CDCl3) 157.2,
131.7, 130.2, 129.1, 128.2, 128.0, 126.0, 123.2, 120.2, 111.2,
86.7, 86.6, 67.1, 55.9, 55.0, 50.1.
N-[1-(2,4-Dichlorophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4f
Slightly yellowish solid, mp 79–80◦C. δH (400 MHz, CDCl3)
7.68 (d, J 8.3, 1H), 7.49–7.47 (m, 2H), 7.41 (s, J 2.1, 1H),
7.33–7.30 (m, 3H), 7.26–7.24 (d, J 8.4, 1H), 5.04 (s, 1H), 3.72–
3.64 (m, 4H), 2.65–2.62 (m, 4H). δC (100 MHz, CDCl3) 135.3,
134.3, 131.8, 131.3, 129.7, 128.5, 128.4, 126.6, 122.6, 88.7, 84.0,
67.0, 58.5, 49.8. HRMS (positive ESI) Calc. for C19H17Cl2NO
[M + H]+: 346.0765. Found: 346.0771.
N-[1,5-Diphenylpent-1-en-4-yn-3-yl]-morpholine 4j
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.52–7.50 (m, 2H),
7.43–7.41 (m, 2H), 7.33–7.23 (m, 6H), 6.89 (d, J 16, 1H), 6.31–
6.26 (dd, J 16, 5.4, 1H), 4.37–4.36 (q, J 1.1, 5.3, 1H), 3.80–3.73
(m, 4H), 2.80–2.75 (m, 2H), 2.66–2.61 (m, 2H). δC (100 MHz,
CDCl3) 136.3, 133.3, 131.7, 128.5, 128.2, 127.8, 126.5, 122.8,
88.4, 84.2, 67.0, 59.8, 49.9. HRMS (positive ESI) Calc. for
C21H21NO [M + H]+: 304.1701. Found: 304.1706.
N-[1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4g
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.61–7.58 (m, 2H),
7.51–7.49 (m, 2H), 7.32–7.30 (m, 3H), 7.06–7.01 (m, 2H), 4.74
(s, 1H), 3.76–3.66 (m, 4H), 2.61–2.58 (m, 4H). δC (100 MHz,
CDCl3) 162.2 (d, J 245), 133.5 (d, J 3.1), 131.7, 130.0 (d,
J 8.1), 128.2, 122.7, 114.9 (d, J 21), 88.6, 84.6, 67.0, 61.2,
49.6. HRMS (positive ESI) Calc. for C19H18FNO [M + H]+:
296.1451. Found: 296.1453.
N-[1-(2-Furanyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4k[10b]
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.51–7.48 (m, 2H),
7.44–7.43 (m, 1H), 7.34–7.26 (m, 3H), 6.51–6.50 (m, 1H), 6.36–
6.35 (m, 1H), 4.88 (s, 1H), 3.82–3.72 (m, 4H), 2.70–2.62 (m,
4H). δC (100 MHz, CDCl3) 150.7, 142.8, 131.8, 128.4, 128.3,
122.5, 110.1, 109.7, 87.0, 82.8, 66.9, 56.0, 49.6.
N-[1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl]-
morpholine 4h[10b]
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.55–7.50 (m, 4H),
7.33–7.30 (m, 3H), 6.91–6.89 (m, 2H), 4.73 (s, 1H), 3.80 (s, 3H),
3.76–3.70 (m, 4H), 2.64–2.60 (m, 4H). δC (100 MHz, CDCl3)
159.1, 131.7, 129.8, 129.6, 128.2, 128.1, 123.0, 113.5, 88.2,
85.3, 67.0, 61.3, 55.1, 49.7.
N-(1,3-Diphenylprop-2-yn-1-yl)-piperidine 4l[10b]
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.64–7.62 (m, 2H),
7.51–7.49 (m, 2H), 7.33–7.27 (m, 6H), 4.79 (s, 1H), 2.56 (s, 4H),
1.63–1.52 (m, 4H), 1.44–1.41 (m, 2H). δC (100 MHz, CDCl3)

80
G. Ren et al.
138.5, 131.7, 128.4, 128.2, 128.0, 127.3, 123.2, 87.8, 86.0, 62.3,
50.6, 26.1, 24.4.
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7.30–7.26 (m, 3H), 4.77 (s, 1H), 2.66 (s, 4H), 2.50 (s, 4H), 2.30
(s, 3H). δC (100 MHz, CDCl3) 137.3, 131.8, 131.2, 130.1, 128.2,
122.7, 121.5, 88.8, 84.4, 60.9, 55.0, 45.8. HRMS (positive ESI)
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Slightly yellowish oil; δH (400 MHz, CDCl3) 7.56–7.54 (m, 2H),
7.34–7.30 (m, 2H), 7.27–7.23 (m, 1H), 4.52 (s, 1H), 3.72–3.65
(m, 4H), 2.53–2.50 (m, 4H), 2.32–2.28 (m, 2H), 1.61–1.54 (m,
2H), 1.45–1.40 (m, 2H), 1.32–1.28 (m, 8H), 0.88 (t, J 6.8, 3H).
δC (100 MHz, CDCl3) 138.5, 128.6, 128.1, 127.6, 88.8, 75.4,
67.2, 61.7, 49.8, 31.9, 29.3, 29.1, 29.1, 29.0, 22.7, 18.8, 14.2.
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N-(1-Phenyl-2-octyn-1-yl)-morpholine 4p[10b]
Slightly yellowish oil; δH (400 MHz, CDCl3) 7.56–7.54 (m, 2H),
7.35–7.31 (m, 2H), 7.28–7.24 (m, 1H), 4.52 (s, 1H), 3.73–3.66
(m, 4H), 2.54–2.51 (m, 4H), 2.32–2.28 (m, 2H), 1.60–1.57 (m,
2H), 1.44–1.34(m, 4H), 0.91(t, J7.2, 3H). δC (100 MHz, CDCl3)
138.5, 128.6, 128.1, 127.6, 88.8, 75.4, 67.2, 61.7, 49.8, 31.2,
28.8, 22.2, 18.8, 14.1.
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N-[3-(1-Hydroxycyclohexyl)-1-phenylprop-2-yn-1-yl]-
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Calc. for C19H25NO2: C 75.97, H 8.58%.) δH (400 MHz, CDCl3)
7.56–7.54 (m, 2H), 7.35–7.32 (m, 2H), 7.29–7.25 (m, 1H), 4.61
(s, 1H), 3.74–3.66 (m, 4H), 2.56 (s, 1H), 2.54–2.52 (m, 4H),
2.03–1.97 (m, 2H), 1.75–1.72 (m, 2H), 1.66–1.56 (m, 5H), 1.27–
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Acknowledgements
We are grateful to the National Natural Science Foundation of China (Project
20772114) and the Innovation Fund for Outstanding Scholars of Henan
Province (Project 0621001100) for the financial support given to the present
research.
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