[Zn(l-proline)2] Catalyzed One-Pot Synthesis of Propargylamines Under Solvent-Free Conditions

Article abstract of DOI:10.1007/s10562-018-2449-6

A simple, one-pot, three-component, green synthesis of a wide range of propargylamines is reported by A³-coupling (aldehyde, alkyne and amine) via C–H activation of alkynes using [Zn(l-proline)₂] as an efficient and reusable heteroge

Full text of DOI:10.1007/s10562-018-2449-6

Catalysis Letters
https://doi.org/10.1007/s10562-018-2449-6
[Zn(l-proline)2] Catalyzed One-Pot Synthesis of Propargylamines
Under Solvent-Free Conditions
Samaresh Layek1 · Bhumika Agrahari1 · Shweta Kumari1 · Anuradha1 · Devendra D. Pathak1
Received: 23 February 2018 / Accepted: 6 June 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A simple, one-pot, three-component, green synthesis of a wide range of propargylamines is reported by A3-coupling (alde-
hyde, alkyne and amine) via C–H activation of alkynes using [Zn(l-proline)2] as an efficient and reusable heterogeneous
catalyst. High catalytic activity was achieved in comparatively low temperature under solvent-free conditions. All reactions
were carried out in an open atmosphere without the use of any co-catalyst/additive.
Graphical Abstract
Keywords C–C and C–N coupling reaction · C–H activation · Propargylamines · [Zn(l-proline)2]
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S. Layek et al.
attack of lithium acetylides or Grignard reagents to imines
or their derivatives [14, 15]. However, these approaches
were associated with some drawbacks such as, use of
stoichiometric amount of organometallic catalyst, harsh
reaction conditions, low atom economy and limited scope
of reactions. In order to circumvent these drawbacks,
A3-coupling reactions were introduced [16, 17].
Fig. 1 Propargylamines with biological activities
In 2002, Wei et al. first reported three-component prop-
argylamines synthesis using RuCl3 and CuBr as a catalyst
[18]. Subsequently, a variety of homogeneous catalysts, such
as NiCl2 [12], Zn(OAc)2 [19], AgI [20], Au-salt [21], FeCl3
[22], CdI2 [23], InCl3 [24], InBr3 [25], Hg2Cl2 [26], differ-
ent copper salts [27] and various heterogeneous catalysts
such as, polystyrene supported silver(I), lanthanum loaded
copper(II) oxide, copper(II) exchanged molecular sieves,
copper–aluminum nanocomposite, gold(III)-supported on
ceria, Ag(I) and Cu(I) in ionic liquids, Zn dust, supported
Au(III), Fe3O4 nanoparticles, nano indium oxide [28–35]
and copper nanoparticles [36–38] etc. were successfully
used for the synthesis of propargylamines. Most of the
reported reactions were carried out in an inert atmosphere
in hazardous solvents like acetonitrile, toluene, and DMF
etc. Solvent-free organic synthesis has recently gained
momentum from green and sustainable chemistry point of
view [39]. Therefore, rational design of air-stable catalyst
and solvent-free synthesis is one of the important goals of
the contemporary research.
Fig. 2 Various protocols for the synthesis of propargylamines
The complex [Zn(l-proline)2] has been used as an effec-
tive catalyst for the synthesis of pyrazoles [40], cis-β-thio-
α-amino acid derivatives via thio-Michael addition reaction
[41], aldol reactions [42], 1,5-benzodiazepines [43] and
other miscellaneous organic transformations [44]. A perusal
of the literature reveals that there is hardly any report on
the use of readily synthesized and air-stable complex [Zn(l-
proline)2] for the synthesis of propargylamines. However,
use of zinc acetate [19]/zinc dust [45]/ZnO nanoparticles
[46] and silver immobilized on ZnO for the synthesis of vari-
ous propargylamines [47] hinted us that the [Zn(l-proline)2]
complex may catalyze the reaction. Keeping this in mind and
our continued ongoing research interest in transition-metal-
catalyzed organic transformations [48–51], we herein report
a simple, convenient and efficient method for the preparation
of propargylamines using [Zn(l-proline)2] as a heterogene-
ous catalyst under solvent-free condition.
1 Introduction
The environmentally benign synthesis of fine chemicals
and bio-active molecules by avoiding toxic reagents and
solvent has attracted a lot of interest [1]. To achieve this
objective, an increasing number of multi-component
reactions (MCR’s) have been reported for the synthesis
of diverse complex molecules through a combination of
three or more starting materials in one-pot [2, 3]. The
three-component (aldehyde, alkyne and amine) coupling
product propargylamines are not only extremely important
as versatile synthetic intermediates in organic synthesis
[4, 5] but also promising candidates as enzyme inhibitors
[6, 7], herbicides [8], antitumor [9], antibiotic [10] and
pharmaceutical [11, 12]. Two of the well-known repre-
sentative examples of propargylamines are Deprenyl and
Rasagiline (Fig. 1). Deprenyl is used as an effective adju-
vant to L-DOPA in the treatment of Parkinson’s disease
while Rasagiline is one of the most potent drugs in pre-
venting apoptosis.
2 Experimental
2.1 Materials and Instrumentations
There are various protocols reported for the synthesis of
propargylamines (Fig. 2). Propargylamines are tradition-
ally synthesized by the direct amination of propargyl hal-
ides, triflates, phosphates, etc. [13] or by the nucleophilic
All reagents and solvents for the synthesis and analysis were
purchased from commercially sources and used as received
without further purification. FT-IR spectra were recorded
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[Zn(l-proline)2] Catalyzed One-Pot Synthesis of Propargylamines Under Solvent-Free…
using KBr pellets on a Perkin Elmer Spectrometer in the
SI (Supplementary Figs. 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,
1
range of 4000–400 cm−1. H and 13C NMR spectra of the
10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S,
22S, 23S, 24S, 25S, 26S, 27S).
isolated organic products were recorded on a Bruker AvIII
HD-400 MHz spectrometer in CDCl3 using TMS as the
internal Standard.
3 Results and Discussion
2.2 Synthesis of [Zn(l‑proline)2] Complex
[Zn(l-proline)2] complex was synthesized by reported
method (Scheme 1) [42]. The complex was found to be
insoluble in all common organic solvents except water. The
catalytic potential of the complex was explored in three com-
ponent coupling of an aldehyde, alkyne and amine to form
propargylamines (Scheme 2).
The [Zn(l-proline)2] complex was synthesized accord-
ing to the reported procedure in the literature and used as
such [42]. To a 10 mL methanolic solution of the l-proline
(0.230 g, 2.0 mmol) in 25 mL round bottomed flask, Et3N
(0.202 g, 2.0 mmol) was added and stirred for 10 min, fol-
lowed by addition of zinc(II) acetate (0.219 g, 1.0 mmol)
at room temperature. After stirring for 45 min, a white pre-
cipitate was collected by filtration and dried in vacuum over
anhydrous CaCl2. Yield: 0.403 g (90%). FT-IR (KBr), cm−1:
3220 (ν NH str.) 1596 (ν CO of COOH group), 1400 and
1363 (ν CH2), 1086 and 1060 (ν C–N).
In order to optimize reaction conditions, various parame-
ters such as, time, temperature, solvents and catalyst loading
were studied and their results are summarised in Table 1. In
the initial optimizations, benzaldehyde, phenylacetylene and
piperidine were used as model substrates. When the reac-
tion was carried out without catalyst under reflux condition,
no product was obtained even after 24 h (Table 1, entry 1).
However, when the reaction was carried out in presence of
0.5 mol% catalyst in toluene at 110 °C for 8 h, 67% yield of
the product was observed (Table 1, entry 2). Further, cata-
lyst loading was increased to 1 mol%, resulted in 83% yield
of the product under the same reaction conditions (Table 1,
entry 3). However, no significant improvement in yield
of the product was noticed when the catalyst loading was
increased from 1 to 2 mol% (Table 1, entry 4). It indicated
that 1 mol% of the catalyst was optimum. After optimization
of the catalyst loading, the reaction was conducted in various
solvents such as water, THF, DMF, ethanol etc. (Table 1,
entries 2–8). No other solvent gave better yield of the prod-
uct (Table 1, entries 5–8). Considering the green chemistry
approach, the reaction was also performed in solvent-free
condition at different temperatures (Table 1, entries 9–11).
2.3 General Procedure for the Synthesis
of Propargylamines
A mixture of aldehyde (1.0 mmol), amine (1.0 mmol),
alkyne (1.2 mmol) and [Zn(l-proline)2] complex (1 mol%)
were stirred in a round-bottomed flask at 80 °C for 6–8 h
under solvent free condition. The progress of the reaction
was monitored by TLC. After completion of the reaction,
the reaction mixture was cooled down to room temperature
and the crude product was washed with water and extracted
with ethyl acetate (3×10 mL). The crude product was puri-
fied by the column chromatography using silica gel and ethyl
acetate: petroleum ether as an eluent. The structural studies
were based on FT-IR spectra, 1H and 13C NMR data. Spec-
troscopic data and their spectra of compounds are given in
Scheme 1 Synthesis of [Zn(l-
proline)2] complex
Scheme 2 Synthesis of propar-
gylamines
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S. Layek et al.
Table 1 Optimization of reaction conditions for the synthesis of propargylamines from benzaldehyde, phenylacetylene and piperidine
CHO
H
N
N
[Zn(L-proline)2] catalyst,
solvent
+
+
temperature, time
Entry
Catalyst loading (mol%)
Time (h)
Temp. (oC)
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
–
0.5
1
2
1
1
1
1
24
8
6
6
8
8
8
8
8
6
6
8
8
110
110
110
110
80
120
80
100
70
80
Toluene
Toluene
Toluene
Toluene
THF
DMF
Ethanol
Water
–
–
–
–
–
–
67
83
82
45
55
50
30
82
90
87
55
–
9
1
1
1
10
11
12
13
110
90
90
1 Zn(CH3COO)2
1 l-proline
Bold values indicate the optimised reaction condition
Reaction conditions: benzaldehyde (1.0 mmol), piperidine (1.0 mmol), phenyl acetylene (1.2 mmol)
aIsolated yield after column chromatography
The best yield (90%) of the product was obtained under sol-
vent-free condition in presence of 1 mol% catalyst at 80 °C
(Table 1, entry 10). The reaction was also carried out with
pure zinc acetate (1 mol%) under solvent-free condition to
afford only 55% yield of the product (Table 1, entry 12).
The reaction with 1 mol% of proline alone did not succeed
(Table 1, entry 13).
propargylamine products with good yields (Table 2, entries
4v–4z).
The reaction with secondary cyclic amines i.e. piperi-
dine and morpholine also proceeded well to afford the cor-
responding propargylamines in good yields (Table 2) under
standard conditions. Unfortunately, no product formation
was observed with the use of aromatic amines such as aniline
or benzyl amine, while the reaction of diethylamine (acy-
clic amine) with 4-fluorobenzaldehyde and phenylacetylene
under optimized conditions afford the corresponding product
in 77% yield (Table 2, entry 4za). The reaction using substi-
tuted and unsubstituted aromatic alkynes (phenylacetylene
and 4-methylphenylacetylene) afforded corresponding prod-
uct in 90 and 89% yield (Table 2, entries 4a and 4k). Both
alkynes generated good to excellent yields (Table 2, entries
4a–4b and 4k–4l). Isolated products were fully character-
ized by standard spectroscopic methods. The 1H NMR spec-
trum of the 4b in CDCl3, the methine proton (N–CH–) was
observed at δ=4.79 as a singlet. The 13C NMR spectrum of
4b exhibited two peaks at δ=85.97 and 87.80 characteristic
of two acetylenic carbons. These observations support the
formation of propargylamine.
After optimization of the reaction conditions, the scope
of the reaction was extended to variety of aldehydes, amines
and alkynes (Table 2, entries 4a–4za). All the coupling reac-
tions proceeded smoothly to give the propargylamines in
high yields, which clearly disclosed the efficiency and gen-
erality of the developed protocol. Aryl aldehydes with elec-
tron withdrawing groups (Table 2, entries 4c–4e), afforded
better yields as compared to aldehydes possessing electron
donating groups (Table 2, entries 4s–4u). The reactivity
of 4-methoxybenzaldehyde or 4-methylbenzaldehyde was
found to be less than 4-chlorobenzaldehyde (Table 2, entries
4d and 4s–4u). This may be due to the fact that the iminium
ion formation from the aldehyde and the secondary amine is
very fast in case of electron withdrawing bearing aldehydes.
Heterocyclic aldehydes such as 2-furancarboxaldehyde,
2-thiophenecarboxaldehyde and aliphatic aldehyde such as
formaldehyde also reacted smoothly to afford corresponding
A comparison for the efficiency of the catalytic activity
of [Zn(l-proline)2] complex with several previous reported
catalysts [12, 47, 52–54] is also presented in Table 3. The
1 3

[Zn(l-proline)2] Catalyzed One-Pot Synthesis of Propargylamines Under Solvent-Free…
Table 2 Synthesis of propargylamines from aldehydes, amines, and alkynes catalyzed by [Zn(l-proline)2] complexa
aReaction conditions: Reactions were performed with aldehyde 1 (1.0 mmol), amine 2 (1.0 mmol) and alkyne 3 (1.2 mmol) under solvent-free
conditions for 6–8 h
1 3

S. Layek et al.
Table 3 A comparison study
of the catalyst [Zn(l-proline)2]
with some of the reported
catalysts
Entry
Catalyst
Conditions
Yields (%)
References
1
2
3
4
5
6
5 mol% NiCl2
Toluene/argon 100 °C, 7–24 h
Water/reflux, 3–10 h
S.F/80 °C, 8–12 h
Acetonitrile/reflux, 4–6 h
S.F/100 °C, 8–12 h
25–95
68–95
85–90
89–94
75–92
77–92
[12]
[47]
[52]
[53]
[54]
This work
20 mg Ag@ nano ZnO
2.5 mol% Cu(I)-MOF
10 mol% Nano ZnS
50 mg Ag(I) clay
1 mol% [Zn(l-proline)2]
S.F/80 °C, 6–8 h
results show that our catalytic system exhibits a better cata-
lytic activity than some of the earlier methods in terms of
yields, catalyst loading and reactions time.
3.1 Recyclability test
The catalyst recyclability is a vital step as it trim down the
cost of the process. They also allow catalyst recovery and
recycling, another interesting eco-friendly aspect of the cata-
lysts. The reusability of the catalyst was checked under the
present optimization condition (Table 2, entry 4a). After
completion of the reaction, the reaction mixture was cooled
down to room temperature and the crude product was washed
with water and extracted with ethyl acetate (3×10 mL). The
crude product was purified by the column chromatography
on silica gel with ethyl acetate: petroleum ether as an eluent.
The catalyst was recovered from the aqueous layer through
precipitation by addition of acetone followed by filtration
Fig. 3 Recyclability of [Zn(l-proline)2] catalyst for the synthesis of
4a
Scheme 3 Plausible mecha-
nisms for the synthesis of
propargylamines
1 3

[Zn(l-proline)2] Catalyzed One-Pot Synthesis of Propargylamines Under Solvent-Free…
the analysis of the samples. Samaresh Layek, Bhumika Agrahari and
and drying at 80 °C for 2 h. The catalyst exhibited good cata-
lytic activity up to four cycles as evident from Fig. 3. The
FTIR spectra of fresh and recycled catalyst were also shown
in Supplementary Fig. 28S. A comparison of the FTIR of the
freshly prepared catalyst and the recovered catalyst, clearly
shows that there was no significant changes in the charac-
teristics peaks.
Anuradha acknowledges the receipt of IIT (ISM) fellowship. Shweta
Kumari also acknowledges the receipt of Dr. D.S. Kothari Post-Doc-
toral Fellowship.
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Furthermore, we have carried out the hot filtration test
to explore heterogeneous nature of [Zn(l-proline)2] catalyst
and to confirm no leaching of Zn during the course of cata-
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heterogeneity of a model reaction for the synthesis of 4a in
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mixture. The filtrate was further continued with stirring at
110 °C to monitor the progress of the reaction for 12 h. No
further catalytic reaction was observed in the filtrated solu-
tion, indicating the absence of catalytically active Zn ions
in the filtrate.
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Affiliations
Samaresh Layek1 · Bhumika Agrahari1 · Shweta Kumari1 · Anuradha1 · Devendra D. Pathak1
1
* Devendra D. Pathak
Department of Applied Chemistry, Indian Institute
of Technology (ISM), Dhanbad 826004, India
ddpathak@yahoo.com
1 3