Nickel-catalyzed three-component coupling reaction of terminal alkynes, dihalomethane and amines to propargylamines

Article abstract of DOI:10.1002/aoc.3071

Direct C - H and C - halogen activation is an important and practical task in C - C, C - N bond formation reactions using alkynes. Propargylic amines are synthetically versatile intermediates for the preparation of many nitrogen-containing biologically ac

Full text of DOI:10.1002/aoc.3071

Full Paper
Received: 2 August 2013
Revised: 26 August 2013
Accepted: 27 August 2013
Published online in Wiley Online Library: 24 October 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.3071
Nickel-catalyzed three-component coupling
reaction of terminal alkynes, dihalomethane
and amines to propargylamines
Satish R. Lanke and Bhalchandra M. Bhanage*
Direct C―H and C―halogen activation is an important and practical task in C―C, C―N bond formation reactions using
alkynes. Propargylic amines are synthetically versatile intermediates for the preparation of many nitrogen-containing biolog-
ically active motifs. Herein, a 15 mol% Ni(py)4Cl2/bipyridine-catalyzed three-component coupling reaction of alkynes,
halomethane and amines through C―H and C―halogen activation was developed for the facile synthesis of propargylic
amines. Tetramethylguanidine shows excellent basicity in acetonitrile and works under mild conditions. The reaction has very
good functional group tolerance to aliphatic and aromatic alkynes. Copyright © 2013 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: C―H activation; homogeneous catalysis; multi-component reactions; Nickel complex; propargylic amines
especially Ni(py)4Cl2-catalyzed reactions in organic synthesis,
Introduction
including its reaction mechanism.[11] Herein, we report the
Propargylamines have importance in pharmaceuticals as a key
building block of nitrogen-containing biologically active mole-
cules and as an intermediate for natural product synthesis.[1]
The reactive alkynylides are used for C―C bond formation with
alkynes as a carbon nucleophilic source. For the synthesis of
alkynylides sensitive organometallic reagents like BuLi, EtMgBr
or metal hydrides are used. The direct C―H and C―halogen
activation for C―C bond formation is one of the most versatile
and graceful tasks in organic chemistry as compared with
alkynylide synthesis using conventional techniques.[2] There are
four important pathways which are used for the synthesis of
propargylamines: (i) by transition metal-catalyzed reactions of
imines (or enamines), which can be generated from aldehydes
and amines; (ii) by stoichiometric nucleophilic reactions; (iii) by
a three-component coupling reaction of aldehydes, alkynes and
amines (A3 coupling), catalyzed by various transition metals;[3]
and (iv) more interestingly, by the catalytic coupling of an sp
C―H and sp3 C―halogen activation by C―C, C―N bond
formation with a secondary amine (AHA coupling).[4–7] Recently,
Contel and co-workers reported the Au-catalyzed activation
of C―H and C―halogen bonds to a new building of C―C
and C―N bonds via the three-component coupling reaction of
alkynes, halomethanes and amines (AHA) for propargylamine
synthesis.[4] Later Cu(I),[5] nano-In2O3,[6] Fe(III)[7] and cobalt[8]
were also proved to catalyze this kind of AHA coupling reaction.
Xi and co-workers have reported the use dihalomethane as a
carbon source, as well as a geminal dihalide to also act as a car-
bon source.[9] Unfortunately, the requirement for specially
designed nano-sized catalysts and the use of precious transition
metals such as Au or In are some of the drawbacks of this
protocol.
application of Ni(py)4Cl2 complex as
a precursor for
three-component coupling reaction of alkynes, haloalkanes
and secondary amines (AHA), using bipyridine as a ligand with
1,1,3,3-tetramethylguanidine (TMG) as a base to synthesize
propargylamines, as shown in Scheme 1.
Nickel compounds are found to be competent catalysts for the
three-component coupling of secondary amines and terminal
alkynes in chlorinated alkanes. We observed that the coupling
involves a methylene fragment obtained from halomethane,
which plays an unexpected role for dihalomethane as a CH2
partner, by a nickel-catalyzed C―Cl bond activation. This meth-
odology gains attention in environmental chemistry because
such methodology can be used in the degradation of harmful
chlorinated solvents and transition metal chemistry solves such
a problem by carbon–halogen activation involved in organic
reactions.[12] In literature, the activation of dichloromethane is
reported by various transition metal complexes such as Pt,[13]
Pd,[13] Au nanoparticles,[4] Ru,[14] Rh,[15] Cu,[5] In nanoparticles[6]
and Co.[16] Development of a new highly efficient and environ-
mentally benign catalytic system for such C―Cl and C―H bond
activation is still desirable. In this context, we have developed
herein an efficient protocol for the synthesis of propargylamines
from alkynes, secondary amines and dihalomethane using nickel
catalyst. The protocol works under milder reaction conditions
with the additional advantages of easy work-up procedure and
use of inexpensive base.
*
Correspondence to: Bhalchandra M. Bhanage, Department of Chemistry,
Institute of Chemical Technology, Matunga, Mumbai 400019, India. Email:
bm.bhanage@gmail.com
Nickel compounds have many applications in catalysis as
they exhibit good selectivity as well as reactivity.[10,11]
Cardenas and co-workers show activity of nickel precursors,
Department of Chemistry, Institute of Chemical Technology, Matunga,
Mumbai 400019, India
Appl. Organometal. Chem. 2013, 27, 729–733
Copyright © 2013 John Wiley & Sons, Ltd.

S. R. Lanke and B. M. Bhanage
Nipy4Cl2/Bipyridine
MeCN, 70 oC, 28-36 h
N
can activate C―H, C―Cl bonds for catalyzing the AHA coupling
reaction (Table 1, entry 11).
H
N
Ar
Ar
+
CH2X2
+
Noting the importance of base in the reaction, we have
screened various organic as well as inorganic bases such as
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylguanidine
(TMG), triethylamine (TEA) and 1,4-diazabicyclo[2.2.2]octane
(DABCO), K2CO3, K3PO4. We observed that base-free conditions
cannot catalyze the reaction (Table 2, entries 1–6). The base
TMG gives an excellent yield of propargylamine because it has
a very high pKa as compared to others, is very strongly basic
and non-nucleophilic in nature as well as having very good
solubility[17]; therefore it was used for further studies. Further-
more, we have also studied the effect of catalyst loading and it
was found that the yield of propargylamine decreases up to
80%, with catalyst concentration decreasing from 15 to 10 mole
%; hence 15 mol% catalyst loading was used for further studies
(Table 2, entries 7 and 8). The formation of organometallic com-
plex depends upon the metal-to-ligand ratio and we found that
a 1:1 ratio was sufficient to catalyze the reaction efficiently
(Table 2, entries 9 and 10). We have also checked various polar
as well as non-polar solvents, and acetonitrile gave better yields
(Table 2, entries 11–13). In the presence of dichloromethane as
a solvent the reaction yields were lower, as the required temper-
ature of reaction could not be attained (Table 2, entry 13).
Temperature is a crucial factor for this reaction. If we conducted
the reaction above 80°C, we observed some small quantities of
dimerization product of phenyl acetylene. At 70°C, we obtained
an excellent yield of the desired product and at this temperature
dimerization was suppressed (Table 2, entries 14–16). A substrate
ratio of 1:2:3 (alkyne:dichlorometane:amine) gave the highest
yield of propargylamine, and the optimum time required for
catalyzing the reaction was 28 h (Table 2, entries 17–21).
Ar = Aryl, Heteroaryl
X = Cl, Br, I
Scheme 1. Nickel-catalyzed three-component coupling of alkyne,
dihaloalkane and amines (AHA).
Results and Discussion
A series of experiments were performed to optimize the reac-
tion conditions for AHA coupling of phenyl acetylene,
dichloromethane and diethyl amine to propargylamines.
Initially we checked the effect of various nickel precursors such
as NiCl2, Ni(acac)2, Ni(oAc)2, Ni(tppe)2Cl2, Ni(py)4Cl2 in the pres-
ence of bipyridine ligand, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as a base and acetonitrile as a solvent at 80°C (Table 1,
entries 1–5). Among all the screened catalysts precursors, Ni
(py)4Cl2 was found to be the most effective, providing an
excellent yield of desired propargylamine in 36 h (Table 1, entry
5). We have studied the effect of various nitrogen-containing
bidentate ligands, such as bipyridine, phenanthroline,
bathophenanthroline,
N,N,N′,N′-tetramethylethylenediamine
(TMEDA), N,N′-dimethylethylenediamine (DMEDA-1) and N,N-
dimethylethylenediamine (DMEDA-2) (Table 1, entries 6–11).
Among the screened ligands, bipyridine gives 72% yield of
propargylamine and results can be explained by a bite angle
effect (Table 1, entry 5). We also performed the reaction using
ligand-free conditions, but it gave only 15% yield of N,N-
diethyl-3-phenylprop-2-yn-1-amine, indicating the necessity of
ligand for formation of in situ transition metal complex which
With these optimized reaction conditions, the scope of the
developed protocol was extended for the synthesis of various
propargylamine derivatives. As illustrated in Table 3, the reac-
tion proceeds efficiently with various alkynes and secondary
amine derivatives to provide a wide range of substituted
propargylamines in good to excellent yields. The prominent
feature of the present protocol was that this system had very
good functional group tolerance for aliphatic and heterocyclic
substituted alkynes, secondary amine derivatives as well as
dihalomethanes like dichloromethane, dibromomethane and
diiodomethane (Tables 3 and 4).
Table 1. Catalyst screening for AHA reactiona
N
Catalyst/
Ligand
MeCN,
36 h
H
N
CH Cl
2
+
2
Aromatic acetylene derivatives such as phenylacetylene, 4-methyl
phenylacetylene, 4-methoxyphenylacetylene, 4-hydroxyphenylace
tylene and 4-aminophenylacetylene underwent coupling with
dichloromethane and diethylamine smoothly to afford the respec-
tive propargylamines in good to excellent yields of 82–92%
(Table 3, entries 1–5). It is worth mentioning that the heteroaromatic
acetylene derivatives also gave acceptable yields of 70–72%, but re-
quired more time to complete the reaction (Table 3, entries 6 and 7).
Aliphatic acetylenes such as cyclohexyl acetylene work very well and
gave 86% yield of corresponding propargylamines (Table 3, entry 8).
In the three-component AHA coupling reaction various functional
groups such as 4-CF3 and 4-dimethylamino on the aromatic core of
phenylacetylene also gave good yields of propargylamines
(Table 3, entries 9 and 10). We also checked the reaction of methyl
oct-7-ynoate with dichloromethane and diethylamine but the reac-
tion could not proceed due to low nucleophilicity of alkyne as well
as the carbonyl group present in the molecule (Table 3, entry 11).
Reactions with secondary amines such as morpholine, piperi-
dine, pyrrolidine, diisopropylamine, dipropylamine, dibutylamine
Entry
Catalyst
Ligand
Yield (%)b
1
NiCl2
Bipyridine
Bipyridine
Bipyridine
Bipyridine
Bipyridine
Phenanthroline
Bathophenanthroline
TMEDA
37
35
36
47
72
60
64
58
40
48
15
2
Ni(acac)2
Ni(oAc)2
3
4
Ni(tppe)2Cl2
Ni(py)4Cl2
Ni(py)4Cl2
Ni(py)4Cl2
Ni(py)4Cl2
Ni(py)4Cl2
Ni(py)4Cl2
Ni(py)4Cl2
5
6
7
8
9
DMEDA-1
DMEDA-2
—
10
11
aReaction conditions: phenylacetylene (1 mmol), diethylamine (2 mmol),
dichloromethane (2 mmol), catalyst (20 mol%), ligand (50 mol%), DBU
(2 mmol), MeCN, 3ml; temperature, 80°C); time, 36 h.
bGC yields.
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Appl. Organometal. Chem. 2013, 27, 729–733

Coupling of alkynes, dihalomethane and amines using Ni complex
Table 2. Optimization of reaction parameters for AHA reactiona
Entry
Catalyst loading (mol%)
Substrate ratio (AHA)
Base
Solvent
Temperature (°C)
Yield (%)b
Base screening
1
2
3
4
5
6
20
20
20
20
20
20
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
TMG
MeCN
80
80
80
80
80
80
86
62
68
80
78
n.r.
TEA
MeCN
MeCN
MeCN
MeCN
MeCN
DABCO
K2CO3
K3PO4
—
Loading of catalyst
7
8
10
15
1:2:2
1:2:2
TMG
TMG
MeCN
MeCN
80
80
74
86
Metal:ligand ratio
9c
10d
15
15
1:2:2
1:2:2
TMG
TMG
MeCN
MeCN
80
80
86
86
Solvent screening
11
12
13
15
15
15
1:2:2
1:2:2
1:2:2
TMG
TMG
TMG
Toluene
Dioxane
DCM
80
80
80
n.r.
n.r.
50
Temperature study
14
15
16
15
15
15
1:2:2
1:2:2
1:2:2
TMG
TMG
TMG
MeCN
MeCN
MeCN
r.t.
60
70
n.r.
80
88
Substrate ratio (alkyne:halomethane:amine)
17
18
19
15
15
15
1:1:1
1:1.2:1.2
1:2:3
TMG
TMG
TMG
MeCN
MeCN
MeCN
70
70
70
60
72
95
Time study
20e
21f
15
15
1:2:3
1:2:3
TMG
TMG
MeCN
MeCN
70
70
95
83
aReaction conditions: phenylacetylene (1 mmol), diethylamine (2 mmol), dichloromethane (2 mmol), Ni(py)4Cl2 (20 mol%), bipyridine (50 mol%),
DBU (2 mmol), MeCN (3ml), time (36 h); n r., no reaction; r.t., room temperature.
bGC yields.
cMetal:ligand ratio (1:2).
dMetal:ligand ratio (1:1).
eTime (28 h).
fTime (22 h).
and N-methylpiperazine were efficiently catalyzed and gave
corresponding propargylamine derivatives with excellent yields
in the range of 50–90% (Table 4, entries 1–7). Among these,
dibutylamine required more time to complete due to steric
hindrance and lower nucleophilicity. Furthermore, we checked
the activity of sterically hindered secondary amines for entitled
reaction and works smoothly to give targeted propargylamines with
appreciable yields (Table 4, entries 8 and 9). Aromatic amines like N-
methylaniline cannot gives the respective propargylamine because
reactivity of aromatic amines are lower as compare to secondary
amines(Table 4, entry 10). We also performed the reaction of 4-
methylphenylacetylene and pyrrolidine with dichloromethane,
which gave a very good yield of the corresponding product
(Table 4, entry 11). Various C1 sources such as dibromomethane
and diiodomethane also showed excellent activity under the
present reaction conditions (Table 4, entries 12 and 13).
in the initiation process. Propagation steps of the radical chain
reaction involve activation of the terminal alkyne in presence
of base by Ni(I) species to give Ni(III) derivatives. Ni-catalyzed
cross-coupling reactions have been developed recently,[18]
and mechanistic evidence has been obtained both experimen-
tally as well as computationally.[19] Radical Ni(I) derivatives as
the actual catalysts activate the terminal alkyne by oxidative addi-
tion in the presence of base and an Ni(I)–Ni(III) catalytic cycle takes
place.[11] Ni(I) complexes may be formed from Ni(II) precursors with
alkyne or alkyl halide in the presence of nitrogen terdentate ligands
by comproportionation of Ni(II) intermediates with Ni(0) species
formed by reductive elimination of dialkyl–Ni(II) complexes.[20]
Alkyl–Ni(I) complexes containing terdentate ligands such as
terpyridine (terpy) or pyridine bis(oxazoline) (pybox) derivatives
show the unpaired electron delocalized on the p orbitals of the
ligand, and exhibit square-planar geometry. For these reasons they
may be described as Ni(II) complexes with two formally anionic
ligands. In accordance with these models, we considered other
mechanistic alternatives that involved Ni(I)–Ni(III) catalytic cycles
(Scheme 2). In the first cycle (A) transmetalation takes place
Based on the literature results,[4-7,11] the reaction mechanism
was proposed as shown in Scheme 2. The classical mechanism of
AHA coupling of alkyne starts with oxidative addition of the
haloalkane to an Ni(0) complex to give an alkyl–Ni(II) derivative
Appl. Organometal. Chem. 2013, 27, 729–733
Copyright © 2013 John Wiley & Sons, Ltd.
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S. R. Lanke and B. M. Bhanage
Table 3. The scope of Nickel catalyzed AHA coupling of diethyl
amine, dichloromethane with various alkynesa
Entry
Ar
Product
Time (h)
Yield (%)b
1
Ph
a
b
c
d
e
f
28
28
28
28
28
36
36
28
28
28
36
92
90
90
85
82
70
72
86
78
72
n.r.
2
p-CH3―Ph―
p-OCH3―Ph―
p-OH―Ph―
p-NH2―Ph―
2-Pyridyl-
3
4
5
Scheme 2. Plausible reaction mechanism of nickel-catalyzed three-
component coupling of alkyne, dihaloalkane and amines (AHA).
6
7
3-Pyridyl-
G
h
i
8
C6H11―
on Ni(I) before oxidative addition of the alkyne in the presence
of TMG as a base. In the second cycle (B) the active catalyst ox-
idatively adds the haloalkane, and the resulting Ni(III) complex
reacts with the terminal alkyne. The resulting Ni(III) complex
on reductive elimination gives an alkynyl halide which, after re-
action with secondary amine in the presence of strong base
TMG, furnishes a propargylamine product.
9
p-CF3―Ph―
10
11
p-(CH3)2N―Ph―
CH3OCO(CH2)5―
j
k
aReaction conditions: alkyne (1 mmol), dichloromethane (2 mmol),
diethyl amine (3 mmol), Ni(py)4Cl2 (15 mol%), ligand (15 mol%),
TMG (2 mmol), MeCN (3ml); n.r., no reaction.
bIsolated yields.
Conclusion
We have established a novel, efficient, three-component coupling
reaction of alkynes, haloalkanes and amines through C―H and
C―halogen activation for facile synthesis of propargylic amines
under milder conditions using Ni(py)4Cl2/bipyridine catalyst. It was
observed that CH2Cl2 can be activated by nickel catalyst and provide
CH2 as a very good partner for the C1 source in multi-component
reactions. This methodology is environmentally benign because
such a methodology used in the degradation of harmful chlorinated
solvents to useful propargylamines and Ni(py)4Cl2 with bipyridine
ligand and TMG as a base solves the problem of carbon–halogen
activation. The reaction has very good functional group tolerance
to aliphatic and aromatic alkynes, generating the corresponding
propargylic amines in high yields. This multi-component reaction
represents the first-time use of a novel nickel catalyst for C―H
and C―Cl bond activation.
Table 4. The scope of nickel-catalyzed AHA coupling of coupling
partner with various amines and dihalomethanesa
R3
Ni(Py)4Cl2/
Bipyridine
MeCN,
N
R2
H
N
28-36 h
+
+
R2
CH2Cl2
R3
R1
R1
Entry
R2, R3
Product Time (h) Yield (%)b
1
O(CH2―CH2)2―
―(CH2)5―
l
m
n
o
p
q
r
28
28
28
28
28
32
28
28
28
36
28
28
28
90
90
86
50
76
74
78
70
66
n.r.
86
90
90
2
3
―(CH2)4―
4
R2, R3 = CH(CH3)2―
R2, R3 = CH3(CH2)2―
R2, R3 = CH3(CH2)3―
CH3N(CH2)2―
5
Experimental
6
7
Materials and Instruments
8
―CH2―Ph―(CH2)2―
PhCH2CH(CH2)2―
R2 = Ph, R3 = CH3
―(CH2)5―
s
All chemicals were purchased from Sigma-Aldrich, SD Fine
Chemicals, Lancaster (Alfa-Aesar) and other commercial sup-
pliers. Progress of the reaction was monitored by gas chroma-
tography (GC) on a PerkinElmer Clarus 400 gas chromatograph
equipped with flame ionization detector with capillary column
(30 m × 0.25 mm × 0.25 mm) using an external standard method
and thin-layer chromatography with Merck silica gel 60 F254
plates. The product was visualized with a 254 nm UV lamp. All
yields reported in Tables 1 and 2 are GC yields, and yields in
Tables 3 and 4 are isolated yields. All compounds were reported
and confirmed by comparison with authentic samples using
GC and GC-MS techniques. The GC-MS-QP 2010 instrument
(Rtx-17, 30 m × 25 mm ID, film thickness 0.25 μm) (column flow
9
t
10
11 c
12 d
13e
u
v
w
x
R2, R3 = ―CH2CH3
R2, R3 = ―CH2CH3
aReaction conditions: phenylacetylene (1 mmol), dihalomethane
(2 mmol), amine (3 mmol), Ni(py)4Cl2 (15 mol%), ligand (15 mol%),
TMG (2 mmol), MeCN (3ml); n.r., no reaction.
bIsolated yields.
c4-Methylphenylacetylene.
dCH2Br2 used.
eCH2I2 used.
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Coupling of alkynes, dihalomethane and amines using Ni complex
2 ml minÀ1, 80–240°C at 10°C minÀ1 rise). 1H and 13C NMR
(δ, ppm) spectra were recorded on a Varian Mercury 400 NMR
spectrometer at operating frequencies of 400 and 100 MHz,
respectively, in CDCl3 as solvent. Chemical shifts are reported
in parts per million (δ) relative to tetramethylsilane (TMS) as
the internal standard. J (coupling constant) values are reported
in hertz. Proton splitting patterns are described as s (singlet), d
(doublet), t (triplet) and m (multiplet). All products are known
in the literature.
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In a typical experiment, a mixture of phenylacetylene (1.0 mmol,
102 mg), dichloromethane (2.0 mmol, 169.9 mg), diethylamine
(3.0 mmol, 219.4 mg), TMG (2.0 mmol, 230 mg), Ni(py)4Cl2 catalyst
(66.98 mg, 15 mol%) and bipyridine ligand (23.4 mg, 15 mol%)
was charged in the spin bar containing a sealed tube (10 ml)
with 3.0 ml CH3CN at 70°C for 28 h. After completion of the
reaction, the mixture was diluted with H2O (10 ml) and the
aqueous layers were extracted with diethyl ether (20 × 5 ml),
dried over anhydrous Na2SO4 and concentrated to give the
crude product. The residue obtained was purified by column
chromatography (silica gel, 60:20 mesh; hexane–ethyl acetate,
20:1) to afford the desired pure propargylic amines. The
organic solution was analyzed by GC and confirmed by GC-
MS and NMR. Purity of the compounds was determined by
GC-MS analysis.
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Acknowledgments
The author S. R. Lanke is thankful to the Department of Atomic
Energy (ICT-DAE Centre), Mumbai, India, for providing a senior
research fellowship.
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Appl. Organometal. Chem. 2013, 27, 729–733
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