Propargylic amines constructed via copper-catalyzed three-component coupling of terminal alkynes, benzal halides and amines

Article abstract of DOI:10.1016/j.tetlet.2011.07.099

A method for the synthesis of propargylic amines has been developed via an efficient copper(I)-catalyzed three-component coupling reaction of alkynes, benzal halides and amines through C-H and C-halogen activation. This reaction is conducted under mild co

Full text of DOI:10.1016/j.tetlet.2011.07.099

Tetrahedron Letters 52 (2011) 4967–4970
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Propargylic amines constructed via copper-catalyzed three-component
coupling of terminal alkynes, benzal halides and amines
⇑
Zhewang Lin, Dingyi Yu, Yugen Zhang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the synthesis of propargylic amines has been developed via an efficient copper(I)-catalyzed
three-component coupling reaction of alkynes, benzal halides and amines through C–H and C-halogen
activation. This reaction is conducted under mild conditions and provides an alternative method for
the synthesis of propargylic amines.
Received 20 April 2011
Revised 12 July 2011
Accepted 22 July 2011
Available online 28 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alternative propargylic amine synthesis
Copper-catalyzed
AHA coupling
R''
Transition metal catalyzed multi-component coupling reactions
(MCRs) are an important class of reactions in synthesis. MCRs
leading to the formation of new C–C bonds are particularly attrac-
tive.1–6 The well-documented three-component coupling of termi-
nal alkynes, aldehydes and amines (A3 coupling) is an excellent
example of an MCR and provides an elegant synthetic method for
the preparation of propargyl amines which are important building
blocks for many biologically active compounds (Scheme 1a).7–11
Recently, an alternative synthetic method for the preparation of
propargylic amines from terminal alkynes, dihalomethanes and
amines (AHA coupling) with a copper12 or gold catalyst13 was
developed (Scheme 1, reaction 1b). This AHA coupling reaction of-
fers a new approach to propargylic amines with C–C and C–N bond
formation via C–H and C-halogen activation. However, the re-
ported AHA catalytic system was limited to dihalomethanes as
the key component (Scheme 1, reaction b). Herein, we extend this
AHA coupling methodology to terminal alkynes, benzal halides and
other amine systems (Scheme 1, reaction 1c). This extension
greatly widens the substrate scope of the AHA coupling reaction
and introduces a chiral center in the product.
R'
R'
R''
H
NR'2
N
(a)
RCHO
R'2NH
CH
R
Cat. [Cu]
R
Alkyne-Aldehyde-Amine (A3) coupling
R''
NR'2
NR'2
RCHX2
CH
(b)
(c)
Cat. [Cu] / DBU
R
R = H
- 2HX
R''
H
R'2NH
R''
RCHX2
Cat. [Cu] / DABCO
CH
R
R = Ph
Alkyne-Haloalkane-Amine (AHA) coupling
Scheme 1. A3- and AHA-coupling reactions.
The coupling reaction of tert-butylacetylene (1 mmol), benzal
bromide (1.5 mmol) and diethylamine (2.0 mmol) with 10 mol %
of copper(I) chloride and 100 mol % of DBU in acetonitrile at 60 °C
afforded the propargylic amine in moderate yield (50%) (Table 1,
entry 1). We then chose these substrates for optimization of the
reaction conditions (Table 1). The reaction proceeded smoothly at
ambient temperature. This lower reaction temperature compared
to previously reported couplings of alkynes, dihalomethanes, and
amines (60 °C), is possible probably due to the altered kinetics
of the reaction as benzal bromide is more reactive than
dihalomethanes. Higher temperatures lead to the formation of cis-
and trans-stilbenes via homocoupling of the gem-dihalides.14,15
Similar to the first generation catalytic system, organic bases were
generally better than inorganic bases, possibly because of their im-
proved solubility in the reaction system.12 It turned out that trieth-
ylamine or 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base gave
the best yields ranging from 93% to 95%. Among the bases screened,
⇑
Corresponding author. Tel.: +65 64787162; fax: +65 64789081.
E-mail address: ygzhang@ibn.a-star.edu.sg (Y. Zhang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.099

4968
Z. Lin et al. / Tetrahedron Letters 52 (2011) 4967–4970
Table 1
Table 2
Optimization of the reaction conditionsa
Substrate scopea
R''
NR'2
X
X
CuCl (10 mol%), base
CH3CN
N
CH
B
Br
Br
CuCl (10 mol%), base
solvent, temperature
R'2NH
+
+
R''
H
CH
1B
H
+
+
HN
A1
Entry
H
A2
1A1
1H1
1A2
Alkyne (A1)
X
Amine (A2)
Yield (%)
95
Entry
Solvent
Base
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
DBU
DBU
60
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
72
79
48
76
95
93
79
89
0
H
H
H
H
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
1
2
Br
Na2CO3
NaHCO3
K3PO4
Et3N
DABCO
Et3N
H
Br
Br
Br
Br
Cl
Br
Br
Cl
Br
Cl
Cl
Cl
76
74
H
3
NC
Et3N
Et3N
Et3N
H
10
11
THF
Hexane
4
22
0
a
Reaction conditions: tert-butylacetylene (1.0 mmol), benzal bromide
H
H
5
50b
25c
60
(1.5 mmol), diethylamine (2.0 mmol), base (1 mmol), solvent (2 ml), 36 h.
6
Cl
H
Na2CO3, NaHCO3, K3PO4 and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) resulted in low conversions (Table 1). CH3CN was the best
solvent for the reaction. At room temperature and using Et3N as
the base, the reaction in CH3CN delivered the corresponding prop-
argylic amine in 95% yield while the reaction in dimethylsulfoxide
(DMSO) and N,N-dimethylformamide (DMF) gave 79% and 89%
yields, respectively. No product was observed when the reaction
was carried out in tetrahydrofuran (THF) or hexane under the same
conditions (Table 1).
The substrate scope was investigated using the optimized con-
ditions: alkyne (1.0 mmol), benzal halide (1.5 mmol), amine
(2.0 mmol) and Et3N (100 mol %) in CH3CN at room temperature
(Table 2). Firstly, it was found that both benzal bromide and benzal
chloride worked well for this three-component coupling reaction
(Table 2, entries 1 and 13). However, the reaction temperature
for benzal chloride had to be elevated to 80 °C. DABCO was found
to be a better base for benzal chloride reactions (Table 2, entries
12 and 13).
The reaction worked well for alkyl-substituted alkynes, giving
good to excellent yields of propargylic amines (Table 2, entries
1–3). However, aromatic alkynes were generally less active in this
new AHA coupling reaction affording the corresponding propargyl
amines in lower yields 22–60% (Table 2, entries 4, 7, 8 and 10). This
is because aromatic alkynes are more likely to dimerize than alkyl-
substituted alkynes under these conditions.16,17 As shown in Table
2, electron-donating aromatic alkynes were more reactive in this
reaction. Yields of 61% and 70% were achieved for 4-methoxyphe-
nylacetylene and 4-methylphenylacetylene, respectively, under
the optimized conditions (Table 2, entries 9 and 11). In contrast,
electron-withdrawing aromatic alkynes were relatively inert.
Coupling reactions of phenylacetylene with either benzal bromide
or benzal chloride resulted in unsatisfactory yields of the corre-
sponding propargylic amines (Table 2, entries 4 and 6). However,
a stepwise reaction in which benzal bromide (1.5 mmol), diethyl-
amine (2.0 mmol) and Et3N (100 mol %) were stirred for 2 h at
room temperature followed by the addition of phenylacetylene
(1.0 mmol), copper(I) chloride (10 mol %) and acetonitrile (2 ml),
improved the yield of the propargylic amine from 22% to 50%
(Table 2, entry 5).
7
O
O
H
H
8
50
H3C
9
61c
32
H3C
H3C
H
10
11
12
13
H3C
H
70c
45
H
H
H
93c
H
H
N
14
15
Br
Br
80
81
H
H
N
N
H
16
Br
0
NH2
H
H
17
18
Br
Br
0
0
NH2
a
Unless otherwise noted, the reaction conditions are as follows: alkyne
(1.0 mmol), benzal halide (1.5 mmol), amine (2.0 mmol), Et3N (100 mol %), CH3CN
(2 ml), CuCl (10 mol %), rt 36 h.
Stepwise reaction: benzal bromide (1.5 mmol), diethylamine (2.0 mmol) and
Et3N (100 mol %) were mixed and stirred for 2 h at rt followed by the addition of
phenylacetylene (1.0 mmol), copper(I) chloride (10 mol %) and acetonitrile (2 ml).
b
c
Reaction at 80 °C with DABCO as the base.
amines (Table 2). There was no reaction for bulky amines, such
as diisopropylamine and aniline, probably due to the extra steric
hindrance.
The reaction worked well for both cyclic and non-cyclic
secondary amines while no product was observed for primary

Z. Lin et al. / Tetrahedron Letters 52 (2011) 4967–4970
4969
To summarize, the efficient copper(I)-catalyzed three-compo-
nent coupling reaction of alkynes, benzal dihalides and amines
through C–H and C-halogen activation to form propargylic amines
under mild conditions has been explored. These reactions offer an
alternative procedure for the synthesis of propargylic amines.
(m, 3H, Ar-H), 5.04 (s, 1H, CH), 2.59–2.68 (m, 2H, CH2), 2.48–2.57
(m, 2H, CH2), 1.08 (t, J = 7.2 Hz, 6H, CH3); 13C NMR (100 MHz,
CDCl3): d = 139.49, 133.93, 132.97, 128.56, 128.26, 128.04,
127.30, 121.76, 87.15, 86.27, 56.88, 44.46, 13.48; GC–MS: m/z:
297; HRMS (EI) calcd for C19H20Cl1N1 (M)+: 297.1284, found
297.1289.
Typical procedure for the production of propargyl amines
(Table 2, entry 1)
N,N-Diethyl-3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-amine
(8B)
A mixture of tert-butylacetylene (1.0 mmol, 82 mg), benzal bro-
mide (1.5 mmol, 250 mg), diethylamine (2.0 mmol, 146 mg), Et3N
(1.0 mmol, 101 mg) and CuCl (10.0 mg, 10.0 mol %) were loaded
in a sealed reaction vial (10 mL) with 2 mL of CH3CN. After stirring
at room temperature for 36 h, the reaction mixture was diluted
with H2O (20 mL), extracted with Et2O (2 Â 10 mL), dried over
Na2SO4 and concentrated to give the crude product which was fur-
ther purified by column chromatography on silica gel (CH2Cl2) to
afford the corresponding propargyl amine. All products gave satis-
factory spectroscopic data.
1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 8.0 Hz, 2H, Ar-H), 7.45
(d, J = 8.0 Hz, 2H, Ar-H), 7.36 (t, J = 8.0 Hz, 2H, Ar-H), 7.28 (t,
J = 8.0 Hz, 1H, Ar-H), 6.87 (d, J = 8.0 Hz, 2H, Ar-H), 5.05 (s, 1H,
CH), 3.83 (s, 3H, CH3), 2.59–2.68 (m, 2H, CH2), 2.50–2.59 (m, 2H,
CH2), 1.08 (t, J = 7.2 Hz, 6H, CH3) 13C NMR (100 MHz, CDCl3):
d = 159.38, 140.06, 133.17, 128.40, 128.01, 127.20, 115.54,
113.69, 87.20, 84.47, 56.97, 55.33, 44.53, 13.59; GC–MS: m/z:
293; HRMS (EI) calcd for C20H23N1O1 (M)+: 293.1780, found
293.1788.
N,N-Diethyl-1-phenyl-3-p-tolylprop-2-yn-1-amine (10B)
N,N-Diethyl-4,4-dimethyl-1-phenylpent-2-yn-1-amine (1B)
1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 7.6 Hz, 2H, Ar-H), 7.40
(d, J = 7.6 Hz, 2H, Ar-H), 7.35 (t, J = 7.6 Hz, 2H, Ar-H), 7.28 (t,
J = 7.6 Hz, 1H, Ar-H), 7.14 (d, J = 7.6 Hz, 2H, Ar-H), 5.05 (s, 1H,
CH), 2.60–2.69 (m, 2H, CH2), 2.50–2.59 (m, 2H, CH2), 2.36 (s, 3H,
CH3), 1.08 (t, J = 7.2 Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3):
d = 138.11, 131.67, 129.04, 128.42, 128.03, 127.26, 120.26, 99.99,
87.57, 85.18, 56.97, 44.55, 21.49, 13.52; GC–MS: m/z: 277; HRMS
(EI) calcd for C20H23N1 (M)+: 277.1830, found 277.1839.
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 7.6 Hz, 2H, Ar-H), 7.32
(t, J = 7.6 Hz, 2H, Ar-H), 7.24 (t, J = 7.6 Hz, 1H, Ar-H), 4.78 (s, 1H,
CH), 2.48–2.55 (m, 2H, CH2), 2.37–2.45 (m, 2H, CH2), 1.30 (s, 9H,
CH3), 1.03 (t, J = 6.8 Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3):
d = 140.61, 128.36, 127.81, 126.92, 96.31, 74.05, 56.21, 44.32,
31.44, 27.67, 13.57; GC–MS: m/z: 243; HRMS (ESI) calcd for
C
17H26N1 (M+H)+: 244.2060, found 244.2065.
N,N-Diethyl-1-phenylhept-2-yn-1-amine (2B)
1-(4,4-Dimethyl-1-phenylpent-2-ynyl)pyrrolidine (14B)
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 7.2 Hz, 2H, Ar-H), 7.32
(t, J = 7.2 Hz, 2H, Ar-H), 7.25 (t, J = 7.2 Hz, 1H, Ar-H), 4.80 (s, 1H,
CH), 2.49–2.59 (m, 2H, CH2), 2.39–2.47 (m, 2H, CH2), 2.32 (dt,
J = 7.2 Hz, J = 2.0 Hz, 2H, CH2), 1.52–1.60 (m, 2H, CH2), 1.43–1.50
(m, 2H, CH2), 1.03 (t, J = 7.2 Hz, 6H, CH3), 0.94 (t, J = 7.2 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3): d = 140.51, 128.37, 127.86,
126.99, 87.48, 75.88, 56.42, 44.38, 31.25, 22.02, 18.50, 13.67; GC–
MS: m/z: 243; HRMS (ESI) calcd for C17H26N1 (M+H)+: 244.2060,
found 244.2064.
1H NMR (400 MHz, CDCl3): d = 7.52 (d, J = 7.2 Hz, 2H, Ar-H), 7.32
(t, J = 7.2 Hz, 2H, Ar-H), 7.26 (t, J = 7.2 Hz, 1H, Ar-H), 4.61 (s, 1H,
CH), 2.57 (t, 4H, J = 6.8 Hz, CH2), 1.75 (t, J = 6.8 Hz, 4H, CH2), 1.27
(s, 9H, CH3); 13C NMR (100 MHz, CDCl3): d = 140.15, 128.31,
128.08, 127.30, 95.77, 75.04, 58.49, 49.99, 31.34, 27.61, 23.44;
GC–MS: m/z: 241; HRMS (EI) calcd for C17H23N1 (M)+: 241.1830,
found 241.1832.
1-(4,4-Dimethyl-1-phenylpent-2-ynyl)piperidine (15B)19
7-(Diethylamino)-7-phenylhept-5-ynenitrile (3B)
1H NMR (400 MHz, CDCl3): d = 7.55 (d, J = 7.6 Hz, 2H, Ar-H), 7.33
(t, J = 7.6 Hz, 2H, Ar-H), 7.26 (t, J = 7.6 Hz, 1H, Ar-H), 4.54 (s, 1H,
CH), 2.43 (t, J = 6.0 Hz, 4H, CH2), 1.56 (quin, J = 6.0 Hz, 4H, CH2),
1.40 (quin, J = 6.0 Hz, 2H, CH2), 1.30 (s, 9H, CH3); 13C NMR
(100 MHz, CDCl3): d = 139.29, 128.61, 127.89, 127.16, 96.82,
74.28, 61.73, 53.29, 31.55, 27.70, 26.21, 24.59; GC–MS: m/z: 255.
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 7.2 Hz, 2H, Ar-H), 7.33
(t, J = 7.2 Hz, 2H, Ar-H), 7.26 (t, J = 7.2 Hz, 1H, Ar-H), 4.81 (s, 1H,
CH), 2.50–2.58 (m, 6H, CH2), 2.37–2.45 (m, 2H, CH2), 1.93(q,
J = 6.8 Hz, 2H, CH2), 1.03 (t, J = 7.2 Hz, 6H, CH3) 13C NMR
(100 MHz, CDCl3): d = 139.91, 128.20, 128.01, 127.23, 119.24,
84.30, 78.34, 56.41, 44.45, 24.96, 18.00, 16.25, 13.53, GC–MS: m/
z: 254; HRMS (EI) calcd for C17H22N2 (M+H)+: 254.1783, found
254.1792.
Acknowledgments
This work was supported by the Institute of Bioengineering and
Nanotechnology (Biomedical Research Council, Agency for Science,
Technology and Research, Singapore).
N,N-Diethyl-1,3-diphenylprop-2-yn-1-amine (4B)18
1H NMR (400 MHz, CDCl3): d = 7.68–7.10 (m, 2H, Ar-H), 7.50–
7.53 (m, 2H, Ar-H), 7.28–7.38 (m, 6H, Ar-H), 5.06 (s, 1H, CH),
2.60–2.69 (m, 2H, CH2), 2.51–2.59 (m, 2H, CH2), 1.09 (t, J = 7.2 Hz,
6H, CH3); 13C NMR (100 MHz, CDCl3): d = 139.85, 131.77, 128.34,
128.27, 128.27, 128.01, 127.22, 123.36, 87.40, 86.07, 56.92, 44.52,
13.56; GC–MS: m/z: 263.
Supplementary data
Supplementary data (analytical data and spectra (1H and 13C
NMR) for all products and HRMS for new products) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.099.
3-(4-Chlorophenyl)-N,N-diethyl-1-phenylprop-2-yn-1-amine
(7B)
References and notes
1H NMR (400 MHz, CDCl3): d = 7.66 (d, J = 7.6 Hz, 2H, Ar-H), 7.43
(d, J = 7.6 Hz, 2H, Ar-H), 7.36 (t, J = 7.6 Hz, 2H, Ar-H), 7.27–7.31
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