An efficient and facile one-pot synthesis of propargylamines by three-component coupling of aldehydes, amines, and alkynes via C-H activation catalyzed by NiCl2

Article abstract of DOI:10.1016/j.tetlet.2010.08.043

NiCl₂ was found to be a highly efficient and effective catalyst for the one-pot three-component (A³) coupling of aldehydes, amines, and alkynes to produce propargylamines in nearly quantitative yields. Structurally divergent aldehydes, amines, and alkynes were converted into the corresponding propargylamines. No co-catalyst or activator is needed and water is the only byproduct of this novel protocol.

Full text of DOI:10.1016/j.tetlet.2010.08.043

Tetrahedron Letters 51 (2010) 5555–5558
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and facile one-pot synthesis of propargylamines
by three-component coupling of aldehydes, amines, and alkynes via
C–H activation catalyzed by NiCl2
⇑
Subhasis Samai, Ganesh Chandra Nandi, M. S. Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
NiCl2 was found to be a highly efficient and effective catalyst for the one-pot three-component (A3)
coupling of aldehydes, amines, and alkynes to produce propargylamines in nearly quantitative yields.
Structurally divergent aldehydes, amines, and alkynes were converted into the corresponding propargyl-
amines. No co-catalyst or activator is needed and water is the only byproduct of this novel protocol.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 18 May 2010
Revised 9 August 2010
Accepted 13 August 2010
Available online 18 August 2010
Keywords:
Three-component A3-coupling
C–H bond activation
NiCl2
Propargylamines
Aldehydes
Amines
One-pot multicomponent reactions (MCRs) are an attractive
synthetic strategy1 to generate multiple molecular scaffolds and
to increase structural as well as skeletal diversity from simple
and easily available molecules. In a MCR, several organic moieties
are coupled in one-pot exhibiting economy of atom and steps, and
often selectivity. Three-component coupling of an aldehyde,
alkyne, and amine (A3-coupling) is one of the best examples of
acetylene-Mannich MCR and has received much attention in recent
times.2 The resultant propargylamines3 are important building
blocks for a variety of organic transformations and also are valu-
able precursors for therapeutic drug molecules4a–c such as b-lac-
tams, oxotremorine analogs, conformationally restricted peptides,
isosteres, allylamines, oxazoles, and other natural products.
A series of propargylamines were shown to suppress the apop-
totic cascade preventing collapse of mitochondrial membrane po-
tential, activation of caspase, and fragmentation of nucleosomal
DNA.4d Among propargylamines; (R)-N-propargyl-1-aminoindane
(Rasagiline 1, Fig. 1) was the most potent at preventing cell death.
Several propargylamine derivatives have been synthesized, and
shown to be highly potent and selective irreversible monoamine
oxidase type-B (MAO-B) inhibitors.5 Some of these new inhibitors
have even been tested in the treatment of neuropsychiatric disor-
ders (Alzheimer’s disease6). The MAO-B inhibitor deprenyl (Seleg-
iline 2, Fig. 1) has been used as an effective adjuvant to L-DOPA in
the treatment of Parkinson’s disease.7
Classical methods for the preparation of propargylamines have
usually exploited the relatively high acidity of the terminal acety-
lenic C–H bond to form alkynyl-metal reagents by reaction with
strong bases such as butyl lithium,8a organomagnesium com-
pounds,8b or LDA9 in a separate step. Unfortunately, these reagents
are used in stoichiometric ratios, are highly moisture-sensitive,
and require strictly controlled reaction conditions.
In recent years, enormous progress has been made on C–H bond
activation reaction of terminal alkynes. The alkyne C–H bond can
be activated by employing various homogeneous metal catalysts
such as Cu(I) salts,10 Au(I)/Au(III) salts,11 Au(III) salen complexes,12
silver(I) salts,13 zinc salts,14 iron(III) salts,15 InCl3,16a InBr3,16b
Ir-complexes,17 Hg2Cl2,18 and Cu/Ru(II) bimetallic system.19 Differ-
ent heterogeneous catalysts such as LDH-AuCl4,20 AgI,21a–d silver
CH3
N
H
H
CH3
HN
Rasagiline (Azilect)
1
2
Deprenyl (Selegiline)
⇑
Corresponding author. Tel.: +91 542 2307320x102; fax: +91 542 2368127.
E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
Figure 1. Propargylamine inhibitors of type-B monoamine oxidase.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.043

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S. Samai et al. / Tetrahedron Letters 51 (2010) 5555–5558
nanoparticles,21e Ag nanoparticles supported by Ni,21f Cu(I)
complexes,22a–d CuCl,22e silica-immobilized CuI,22f Ni–Y–zeolite,23
Zn dust,24 copper ferrite nanoparticles,25a nanocrystalline copper
(II) oxide,25b copper-nanoparticles,25c impregnated copper on mag-
netite,25d copper-zeolites,25e and Fe3O4 nanoparticles26 have also
been utilized for alkyne C–H activation. They are directly added
to carbon–nitrogen double bonds (imines) either preformed or in
one-pot (from aldehyde and amine) for the synthesis of propargyl-
amines. In addition, microwave10,27a and ultrasonic radiations27b
have also been used in the presence of Cu(I) salt.
N
NiCl2
+
Ph
H
C6H5CHO +
NH
Toluene, 111oC
C6H5
Ph
4
Scheme 1. NiCl2-catalyzed A3-coupling leading to propargylamine.
Although, most of the above described processes work well for
the synthesis of propargylamines, the improved synthesis of prop-
argylamines via the activation of a terminal alkyne C–H bond using
transition metal-catalyzed multicomponent strategies remains of
continued interest to organic chemists in terms of operational sim-
plicity and cost effectiveness. As a continued interest to develop
efficient protocols for the synthesis of biologically active molecular
scaffolds via one-pot multicomponent reactions28 herein, we re-
port a highly efficient three-component coupling of aldehydes,
amines, and alkynes (A3-coupling) catalyzed by NiCl2. Nearly quan-
titative yields were obtained in most of the cases. Furthermore, the
reaction did not require any co-catalyst or activator. In comparison
to other metal catalysts, NiCl2 is relatively cheaper. Thus, it can
replace traditionally costly metal catalysts like Au, Ag, Cu, and
Ru salts making this process more practical and economically
favorable.
A test reaction using benzaldehyde, piperidine, and phenylacet-
ylene in refluxing toluene in the absence of NiCl2 was performed in
order to establish the effectiveness of the catalyst. It was observed
that no conversion to product was obtained even after 12 h of
refluxing. To optimize the reaction conditions, the above model
reaction was carried out under different reaction conditions. The
results are summarized in Table 1. The effects of Ni(OAc)2ꢀ4H2O,
Ni(NO3)2ꢀ6H2O, and NiCl2 have been examined and it was found
that NiCl2 afforded excellent yield (Table 1, entry 5). The lower cat-
alytic activities of Ni(OAc)2ꢀ4H2O and Ni(NO3)2ꢀ6H2O may be due
to their filled coordination sites that hardly interact with C–H bond
of the alkyne (Table 1, entries 13 and 14). The NiCl2 being tetra-
coordinated can increase its coordination number and conse-
quently binds with the C–H bond of the terminal alkyne effectively
showing better catalytic performance (Scheme 1).
solvents such as water, toluene, dioxane, DMF, and DMSO at
100 °C (Table 1, entries 4–12). It was observed that toluene was
the most effective solvent in which the reaction proceeded
smoothly giving the maximum yield in minimum time (Table 1,
entry 5). It is noteworthy that when water was used as the solvent,
only a trace amount of product was observed even after a pro-
longed reaction time (Table 1, entry 4). Employing a lower percent-
age of NiCl2 reduced the yield (Table 1, entry 8). Higher percentage
loading of the catalyst neither increased the yield nor lowered the
reaction time (Table 1, entry 9). We next performed the reaction in
toluene at different temperatures using 5 mol % of NiCl2. It was
found that at lower temperatures the reaction proceeds slowly giv-
ing lower yields (Table 1, entries 6 and 7). Thus, all the reactions
were performed in toluene under an argon atmosphere with
5 mol % of NiCl2 at 111 °C.
Using the optimized reaction conditions, the scope of the
reaction was tested finding excellent results for the different
combinations of aldehydes, amines, and alkynes. To generalize
the applicability of the NiCl2-promoted A3-coupling reaction,29
we used a variety of structurally divergent aldehydes, amines,
and alkynes (Table 2). The results in Table 2 indicate that the
aromatic aldehydes with both electron-donating and electron-
withdrawing substituents displayed high reactivity and generated
the desired products in good to excellent yields. However, unfortu-
nately, 4-nitrobenzaldehyde did not yield the desired product,
which is in accordance with earlier studies21b,22c (Table 2, entry
27). In addition to aromatic aldehydes, aliphatic aldehydes such
as formaldehyde, isobutyraldehyde, and cyclohexanecarboxalde-
hyde afforded the corresponding propargylic amines in good yields
(Table 2, entries 11–14). Similarly, heteroaromatic thiophene-2-
carboxaldehyde also participated well in this protocol (Table 2, en-
try 9). To extend the scope of the reaction, various cyclic secondary
amines such as piperidine, morpholine, pyrrolidine, N-phenyl
piperazine, N-methyl piperazine, and ethyl-1-piperazinecarboxy-
late, and acyclic secondary amines such as dibenzylamine and
N-methyl aniline were used and tolerated well. Further, some pri-
mary amines such as aniline, benzyl amine, methyl amine, n-butyl
amine, and ammonia were used but unfortunately, in the case of
methyl amine and n-butyl amine only trace of the desired product
was obtained even after a prolonged period of time (Table 2,
entries 37 and 38). Furthermore, several terminal alkynes such as
phenylacetylene, 4-methyl phenylacetylene, and TMSacetylene
were examined for the synthesis of various propargylamines. On
the other hand, when 1-octyne was used in place of phenylacety-
lene, the corresponding propargylamine was obtained in low yield
after a longer reaction time (Table 2, entry 26).
To check the solvent effect on the outcome of the reaction, the
above model reaction was carried out with 5 mol % of NiCl2 in sol-
vents such as THF, EtOH, and CH3CN at 65 °C (Table 1, entries 1, 2
and 3). Further, the above reaction was performed in high boiling
Table 1
Optimization of the reaction conditionsa
Entry
Solvent
Catalyst (mol %)
Temp (°C)/time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
THF
EtOH
CH3CN
Water
NiCl2 (5)
NiCl2 (5)
NiCl2 (5)
NiCl2 (5)
NiCl2 (5)
NiCl2 (5)
NiCl2 (5)
NiCl2 (2)
65/12
65/12
65/12
100/14
111/8
100/8
80/8
111/12
111/8
100/12
100/12
100/12
111/12
111/12
72
10
52
Trace
95
80
60
80
95
22
17
20
60
40
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
DMF
DMSO
Toluene
Toluene
A tentative mechanism (Scheme 2) is proposed for the probable
sequence of events involving the activation of the C–H bond of al-
kyne 3 by NiCl2. The nickel–acetylide intermediate A generated by
the reaction of acetylene and NiCl2 reacted with the iminium ion B
(generated in situ from aldehyde 1 and amine 2) to give the corre-
sponding propargylamine 4.
In conclusion, an efficient NiCl2-catalyzed three-component one-
pot coupling of aldehydes, amines, and alkynes has been achieved.29
The process is simple and generated a diverse range of propargylam-
ines in good to excellent yields. The reaction has high atom effi-
9
NiCl2 (10)
NiCl2 (5)
NiCl2 (5)
10
11
12
13
14
NiCl2 (5)
Ni(OAc)2ꢀ4H2O (10)
Ni(NO3)2ꢀ6H2O (10)
a
Phenylacetylene:piperidine:benzaldehyde (1.5:1.2:1).
Yields of isolated pure products.
b

S. Samai et al. / Tetrahedron Letters 51 (2010) 5555–5558
5557
Table 2
A3-coupling of aldehydes, amines, and alkynes catalyzed by NiCl2
a
R3
N
R2
R1
NiCl2
R4
H
R1CHO
+
+
R2R3NH
Toluene, 111 oC
Argon
R4
Product
4
3
1
2
Entry
R1
Amine
R4
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Pyrrolidine
Pyrrolidine
Pyrrolidine
N-Phenyl piperazine
N-Phenyl piperazine
Piperidine
Morpholine
Piperidine
Piperidine
N-Methyl aniline
Aniline
Dibenzyl amine
N-Methyl piperazine
Ethyl-1-piperazinecarboxylate
Ammonia
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3(CH2)5
C6H5
p-MeꢀC6H4
(CH3)3Si
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
8
8.5
8
9
8
8
9
8.5
7.5
8
8
9
8
9
8
8.5
8
9
8
95
90
80
85
89
90
87
90
91
85
81
73
83
78
88
81
88
81
84
89
91
87
90
86
81
52
n.r.c
85
86
78
66
74
85
82
25
56
Trace
Trace
p-MeꢀC6H4
o-ClꢀC6H4
p-MeOꢀC6H4
p-BrꢀC6H4
p-FꢀC6H4
p-ClꢀC6H4
m-NO2ꢀC6H4
2-Thiophene
m-ClꢀC6H4
H
Me2CH
H
Cyclohexyl
C6H5
p-MeꢀC6H4
p-BrꢀC6H4
2,4-Cl2ꢀC6H3
p-MeOꢀC6H4
p-FꢀC6H4
C6H5
p-MeꢀC6H4
p-ClꢀC6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
4s
4t
8
8
9
8.5
8
4u
4v
4w
4x
4y
4z
4a0
4b0
4c0
4d0
4e0
4f0
4g0
4h0
4i0
4j0
4k0
4l0
p-MeꢀC6H4
8
C6H5
12
24
7.5
8
9
9
p-NO2ꢀC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
10
9
12
16
16
48
48
C6H5
C6H5
C6H5
Benzylamine
Methyl amine
n-Butyl amine
a
b
c
Aldehyde:phenylacetylene:amine (1:1.5:1.2).
Isolated yields.
n.r. = no reaction.
ciency, since water is the only byproduct. All these facts together
with easy work-up and clean reaction profile, the wide scope of
the substrates, and cost effectiveness of the catalyst permitted us
to anticipate a good future for this protocol not only in academia
but also in industry. The scope, mechanism, stereoselectivity, and
synthetic applications of this reaction are under investigation.
Acknowledgments
This work was carried out under the financial support from
Council of Scientific and Industrial Research (Grant 01(2260)/08/
EMR-II) and Department of Science and Technology (Grant SR/S1/
OC-66/2009), New Delhi. S.S. and G.C.N. are thankful to Council
of Scientific and Industrial Research (CSIR), New Delhi for the
financial support in the form of Senior Research Fellowship (SRF).
R4
H
NiCl2
N
3
R1
NiCl2
R4
4
R4
H
R4
References and notes
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Scheme 2. Tentative mechanism for the nickel-catalyzed synthesis of
propargylamines.

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29/ce:label>Typical procedure for A3-coupling reaction: A 50-mL round-bottomed
flask was charged with aldehyde (1.0 mmol), secondary amine (1.2 mmol), and
phenylacetylene (1.5 mmol) in toluene (5 mL). The reaction mixture was
refluxed at 111 °C under an argon atmosphere in the presence of 5 mol % of
NiCl2. After completion of the reaction (monitored by TLC) the solvent was
evaporated under vacuum. Water (40 mL) was added to the reaction mixture
and the product was extracted with ethyl acetate (3 ꢁ 15 mL). The organic layer
was dried over anhydrous MgSO4 and the solvent was evaporated under
vacuum. The crude product obtained was purified by column chromatography
using ethyl acetate-n-hexane (1:25) to afford the pure desired product.
Spectroscopic data of some of the compounds are given below:
N-[1-(4-Methylphenyl)-3-phenyl-prop-2-ynyl]piperidine (4b)
FT-IR (KBr): 2937, 2744, 1605, 1502, 1320, 1152, 760, 691 cmꢂ1 1H NMR
;
(300 MHz, CDCl3):
d 7.51–7.31 (m, 5H), 7.30 (d, J = 2.7 Hz, 2H), 7.17 (d,
J = 7.8 Hz, 2H), 4.74 (s, 1H), 2.54–2.46 (m, 4H), 2.35 (s, 3H), 1.60–1.56 (m, 4H),
1.45–1.43 (m, 2H); 13C NMR (75 MHz, CDCl3): d 136.9, 135.5, 131.7, 128.6,
128.4, 128.1, 127.9, 123.3, 87.5, 86.3, 62.0, 55.6, 26.1, 24.2, 21.0; ESI-MS: 290.25
(M++1); Anal. Calcd for C21H23N: C, 87.15; H, 8.01; N, 4.84. Found: C, 87.19; H,
8.05; N, 4.76.
11. Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
12. Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529.
13. Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473.
14. (a) Lee, K. Y.; Lee, C. G.; Na, J. E.; Kim, J. N. Tetrahedron Lett. 2005, 46, 69; (b)
Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006, 71, 1558; (c) Ramu, E.;
Varala, R.; Sreelatha, N.; Adapa, S. R. Tetrahedron Lett. 2007, 48, 7184.
15. Chen, W.-W.; Nauyen, R. V.; Li, C.-J. Tetrahedron Lett. 2009, 50, 2895.
16. (a) Zhang, Y.; Li, P.; Wang, M.; Wang, L. J. Org. Chem. 2009, 74, 4364; (b) Jadav, J.
S.; Reddy, B. V. S.; Gopal, A. V. H.; Patil, K. S. Tetrahedron Lett. 2009, 50, 3993.
17. (a) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319; (b) Sakaguchi, S.; Kubo, T.;
Ishii, Y. Angew. Chem., Int. Ed. 2001, 40, 2534; (c) Sakaguchi, S.; Mizuta, T.;
Furuwan, M.; Kubo, T.; Ishii, Y. Chem. Commun. 2004, 1638.
4-(1,3-Diphenyl-prop-2-ynyl)-morpholine (4o)
FT-IR (KBr): 2930, 2745, 1598, 1500, 1318, 1152, 754, 693 cmꢂ1 1H NMR
;
(300 MHz, CDCl3): d 7.63 (d, J = 6.9 Hz, 2H), 7.50 (d, J = 6.9 Hz, 2H), 7.36–7.31
(m, 6H), 4.78 (s, 1H), 3.71–3.64 (m, 4H), 2.62–2.56 (m, 4H); 13C NMR (75 MHz,
CDCl3): d 137.6, 131.6, 128.4, 128.1, 128.1, 128.0, 127.6, 122.8, 88.3, 84.9, 66.9,
61.8, 49.7; ESI-MS: 278.30 (M++1); Anal. Calcd for C19H19NO: C, 82.28; H, 6.90;
N, 5.05. Found: C, 82.38; H, 6.86; N, 5.10.
1-(1,3-Diphenyl-prop-2-ynyl)-4-phenylpiperazine (4x)
18. Hua, L. P.; Lei, W. Chin. J. Chem. 2005, 23, 1076.
FT-IR (KBr): 2933, 2745, 1601, 1510, 1316, 1155, 755, 695 cmꢂ1 1H NMR
;
19. Li, C. J.; Wei, C. Chem. Commun. 2002, 268.
(300 MHz, CDCl3): d 7.68 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 3.3 Hz, 2H), 7.41–7.22
(m, 8H), 6.94–6.82 (m, 3H), 4.98 (s, 1H), 3.22–3.20 (m, 4H), 2.81–2.79 (m, 4H);
13C NMR (75 MHz, CDCl3): d 151.2, 137.9, 131.7, 128.9, 128.4, 128.2, 128.1,
127.6, 122.9, 119.5, 115.9, 88.4, 85.0, 61.6, 49.3, 49.2; ESI-MS: 353.10 (M++1);
Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.16; H, 6.92; N,
7.92.
20. Kantam, M. L.; Prakash, B. V.; Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 2329.
21. (a) Li, Z.; Wei, C.; Chen, L.; Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45, 2443;
(b) Reddy, K. M.; Babu, N. S.; Prasad, P. S. S.; Lingaiah, N. Tetrahedron Lett. 2006,
47, 7563; (c) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358; (d) Li,
P.; Wang, L.; Zhang, Y.; Wang, M. Tetrahedron Lett. 2008, 49, 6650; (e) Yan, W.;
Wang, R.; Xu, Z.; Xu, J.; Lin, L.; Shen, Z.; Zhou, Y. J. Mol. Catal. A: Chem. 2006, 255,
81; (f) Wang, S.; He, X.; Song, L.; Wang, Z. Synlett 2009, 447.