Ionic liquid assisted silver-catalyzed one-pot A3-coupling reactions for the synthesis of propargylamines

Article abstract of DOI:10.1016/j.molliq.2019.01.142

A series of ionic liquids with different cations and anions were synthesized and their performances for the silver catalyzed one-pot A³-coupling reactions were investigated. The selection showed that the combination of AgNO₃ and ioni

Full text of DOI:10.1016/j.molliq.2019.01.142

Journal of Molecular Liquids 279 (2019) 289–293
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Ionic liquid assisted silver-catalyzed one-pot A3-coupling reactions for
the synthesis of propargylamines
⁎
⁎
Anlian Zhu , Chunyan Du, Yue Zhang, Lingjun Li
School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Re-
actions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of ionic liquids with different cations and anions were synthesized and their performances for the silver
catalyzed one-pot A3-coupling reactions were investigated. The selection showed that the combination of AgNO3
and ionic liquid [TMG][TFA] showed highest catalytic activity. This catalytic system was then utilized for the pro-
duction a series of propargylamines with satisfactory isolated yields. This reaction system is very simple and easy
to be conducted because no inert gases or any other additional solvents, basic additives are needed. This also led
to the convenience of the following work-up procedures and the recycle and reutilization for the catalytic system.
The ionic liquid was believed to be involved in the catalytic procedure through the interaction with substrates or
catalysts as co-catalyst and ligands.
Received 22 November 2018
Received in revised form 22 January 2019
Accepted 27 January 2019
Available online 28 January 2019
Keywords:
Ionic liquids
Silver salts
One-pot A3 reactions
Propargylamines
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
other researchers found that Ag salts catalyzed A3 reactions have great
improvement in the substrate scope and many catalytic systems have
Multicomponent reactions (MCRs) have been considered as ideal re-
actions to synthesized large compound libraries in organic or medical
chemistry, and have been widely utilized in target-oriented synthesis
[1,2]. MCRs can be conducted as one-pot processes or through a
sequential-addition procedure in a single solvent system. Ionic liquids
which are composed with organic cations and organic or inorganic an-
ions give an excellent reaction platform for MCRs due to its high and ad-
justable solutilities for different kinds of compounds such as organics,
inorganics or even metal salts [3–5]. Additionally, the functionalization
of ionic liquids has endowed them different features as catalyst, co-
catalyst or separating assistants in a reaction procedure [6–11].
Propargylamines are recurrent moieties in many biological active
compounds [12–14], and due to the existence of the amine group on
the β-position of alkyne moiety, they have been used as important syn-
thetic precursors for a large number of heterocycles such as oxazoles,
imidazoles, pyrazoles, and quinolines [15–17]. The wide utilization of
these compounds in synthetic chemistry, pharmacological and pharma-
ceutical chemistry leads to the rapid expansion of their synthetic
method [18]. Transition metal catalyzed A3 coupling is one of the most
intriguing protocols for propargylamines synthesis and various catalytic
systems involving Cu(I) [19–21], Au [22–25], Fe [26–28], In [29,30], Zn
[31,32], Ni [33,34], Co [35,36], have been reported. These catalytic sys-
tems often benefit to the transformation of aromatic aldehydes and
the aliphatic aldehydes often suffered from low conversions. Li and
been developed [37–42]. However, most of these reported reaction sys-
tems suffered from the necessary of inert gas environment and toxic or-
ganic solvents, tedious synthesis of complex ligands, high reaction
temperature, long reaction time and the difficulty to recycle the catalyst.
The application of ionic liquids as solvent in the A3 coupling reactions
has showed good potentials to facilitate the reutilization of Cu or Au cat-
alyst [43,44].
Herein, a series of ionic liquids with different cations and anions
were synthesized and utilized for the synthesis of propargylamines.
The results showed that the ionic liquid and silver salts have synergetic
effect to promote the reactions and the combination of AgNO3 and ionic
liquid [TMG][TFA] lead to the satisfactory catalytic performance for the
one-pot A3 coupling reactions, especially for the reaction involving
aliphalic aldehydes. This reaction system is very simple and easy to be
conducted because no inert gases or any other additional solvents,
basic additives are needed, this also lead to the convenience of the fol-
lowing work-up procedures and the recycle and reutilization for the
catalytic system. The ionic liquid was believed to be involved in the cat-
alytic procedure through the interaction with substrates or catalysts as
co-catalyst and ligands.
2. Experimental section
2.1. Synthesis of functional ionic liquids
0.1 mol carboxyl acid dissolved in 10 ml methanol was drop-wise
⁎
Corresponding authors.
E-mail addresses: alzhuchem@126.com (A. Zhu), lingjunlee@htu.cn (L. Li).
added to the 100 ml flask containing 0.1 mol corresponding amines in
https://doi.org/10.1016/j.molliq.2019.01.142
0167-7322/© 2019 Elsevier B.V. All rights reserved.

290
A. Zhu et al. / Journal of Molecular Liquids 279 (2019) 289–293
Table 1
10 ml methanol under stirring in ice bath. The solution was then stirred
at 40 °C for 48 h. after the completion of the reaction, and then the
methanol was evaporated at 50 °C to get the functional ionic liquids.
Influences of silver salts and ionic liquids.
2.2. General procedures for the synthesis of propargylamine
In a 10 ml round bottom flask, the mixture of [TMG][TFA]
(0.6 mmol), AgNO3 (0.006 mmol), aldehyde (0.6 mmol), secondary
amine (0.72 mmol) and alkyne (0.72 mmol) was stirred at 70 °C for
the desired time. The reaction process was monitored by TLC (the sol-
vent for the TLC is the mixture of ethyl acetate and petroleum ether).
After the completion of reaction, the reaction mixture was extracted
with diethyl ether. The organic layer was evaporated and the residue
was subjected to a silica gel column with EA/Petroleum ether as eluent
to give the target propargylamines.
Entrya,b
Ag(I)/(loading)
Ionic liquid/(molar ratio)
Isolated yield
1
2
3
4
5
6
7
8
AgNO3/0%
AgNO3/5%
AgNO3/5%
Ag2CO3/5%
AgOAc/5%
AgCF3COO/5%
AgI/5%
[TMG][TFA]/1.5
[TMG][TFA]/0
20
65
89
70
65
70
86
58
69
77
48
23
56
65
52
69
47
52
70
84
90
87
85
88
90
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[DMEOA][TFA]/1.5
[ETOA][TFA]/1.5
[DEOA][TFA]/1.5
[NMPK][TFA]/1.5
[SulDMEOA][TFA]/1.5
[DMEOA][Ac]/1.5
[TMG][Ac]/1.5
[NMPK][Ac]/1.5
[TMG][Lac]/1.5
[NMPK][Lac]/1.5
[TMG][Pr]/1.5
[TMG][NO3]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/1.5
[TMG][TFA]/0.5
[TMG][TFA]/1
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/5%
AgNO3/0.5%
AgNO3/1%
AgNO3/3%
AgNO3/1%
AgNO3/1%
AgNO3/1%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2.3. Reutilization of the catalyst system
After the completion of the reactions, the product was extracted
from the reaction mixtures by the addition of diethyl ether. The upper
ether layer was decanted, leaving the ionic liquid and silver salts insol-
uble, which was then evaporated and used for the following catalytic cy-
cles directly without additional activation.
3. Results and discussion
A series of ionic liquids with different cations and anions were synthe-
sized and their structures were illustrated in Scheme 1. Their perfor-
mances in different silver salts catalyzed A3 coupling reactions were
investigated using the reaction among cyclohexanecarboxaldehyde, pyr-
rolidine and phenylethynyl as a model. The results were collected in
Table 1. From the Table 1 it can be seen that the presence of ionic liquid
and silver salt both promoted the target A3 coupling reaction. (Entries
1–3, Table 1). The structures of ionic liquids and the types of silver salts
both influenced the production of target propargylamine (Entries 3,
8–18, Table 1). Then the influences of the loading of silver salts were in-
vestigated using AgNO3. It was shown that when the AgNO3 dosage in-
creased from 0 to 1% mole benefit to the reaction, but further increase
of its amount to 5% mole had negligible effect(Entries 3, 19–21, Table 1).
So, 1% mole AgNO3 based on cyclohexanecarboxaldehyde was se-
lected as the optimal catalyst amount. Then the influence of the
amount of ionic liquid on the model reaction was investigated
under the optimized amount of AgNO3. It is clear that 1.5 eq [TMG]
[TFA] based on cyclohexanecarboxaldehyde is the most favorable
ionic liquid amount(Entries 20, 22–24, Table 1).
[TMG][TFA]/2
a
0.6 mmol cyclohexanecarboxaldehyde, 0.72 mmol pyrrolidine, 0.72 mmol
phenylethynyl, AgNO3 and ionic liquid were mixed and heated at 70 °C for 2 h.
b
Isolated yields.
The results were collected in Table 2. It is clear that 70 °C is the most fa-
vorable reaction temperature.
Next, the substrate tolerance of this catalytic system for the synthesis
of propargylamine analogues through the one-pot multi-component A3
reactions was investigated using different aldehydes, alkynes and pyr-
rolidine/piperidine under optimized conditions, and the results were
collected in Table 3. It is evident that various aromatic alkynes with
electro-donating or electro-withdrawing groups and other alkynyl com-
pounds, such as 2-pyridylacetylene, 1, 9-decadiyne, propargyl ethers
could react with cyclohexanecarboxaldehyde and pyrrolidine smoothly
to give the target compounds with good to excellent isolated yields(en-
tries 1–14, Table 2). Other aliphatic aldehydes like n-hexaldehyde, 3-
phenylpropionaldehyde and 2-ethylbutanal could also be converted to
the corresponding propargylamine analogues with excellent isolated
yields within 6 h(entries 15–17, Table 2). The reaction among
cyclohexanecarboxaldehyde, Piperidine, and aromatic alkyne with dif-
ferent substitutes can also give propargylamines with satisfactory
yields(entries 21–24, Table 2). The corresponding reactions using aro-
matic aldehydes showed lower conversions(entries 18–20, Table 2)
Then the influence of the reaction temperature on the model reac-
tion was investigated under the optimized silver salt and ionic liquid.
Table 2
Influence of reaction temperature on the model reaction.
Entrya
Temperature(°C)
Time(h)
Yield(%)c
1
2
25
50
70
90
4
4
2
2
68
80
90
90
3
4b
a
0.6 mmol cyclohexanecarboxaldehyde, 0.72 mmol pyrrolidine, 0.72 mmol
phenylethynyl, 1 mol% AgNO3 and 1.5 eq [TMG][TFA] were mixed and heated at corre-
sponding reaction temperature for the desired reaction time.
b
Reflux.
Isolated yields.
c
Scheme 1. The cations and anions structures of ionic liquids.

A. Zhu et al. / Journal of Molecular Liquids 279 (2019) 289–293
291
Table 3
AgNO3-[TMG][TFA] catalyzed synthesis of propargylamines.
Entrya
1
Aldehyde
Amine
Alkyne
Product
Yield(%)d
90
2
3
85
92
4
5
6
87
89
87
7
80
8
9
70
69
10
11
70
89
12
13
85
90

292
A. Zhu et al. / Journal of Molecular Liquids 279 (2019) 289–293
14
80
75
15b
16b
17b
85
80
18c
19c
54
66
20c
21
50
80
22
23
82
72
24
25
60
70
a0.6 mmol aldehyde, 0.72 mmol amine, 0.72 mmol alkyne, 1 mol% AgNO3 and 1.5 eq [TMG][TFA] were mixed and heated at
70 °C for 2 h.
b6h.
c12h.
dIsolated yields.
compared with their aliphatic components, suggesting that this catalytic
system is more suitable for the conversion of aliphatic aldehydes.
The reusability of the silver salts and ionic liquids catalytic system was
also investigated using the reaction among cyclohexanecarboxaldehyde,
pyrrolidine and phenylethynyl as a model, and the results were illustrated
in Fig. 1. It was shown that after five cycles the catalytic activity had a neg-
ligible decrease, suggesting the excellent recyclability of this catalytic sys-
tem in multi-component A3 reaction.
According to the literature report and our previous experience on
the functional ionic liquids catalysis, a plausible reaction mechanism
were proposed and illustrated in Scheme 2. The silver salt activates ter-
minal alkyne and forms silver acetylide, releasing [H]+. The NH2 on the
cation of ionic liquid activates the C_O of aldehyde as hydrogen bond
donor, while the anion of ionic liquid activate N\\H of amine as hydro-
gen bond acceptor. The activated aldehyde and amine were then
reacted under the presence of [H]+ to produce iminium ion and the

A. Zhu et al. / Journal of Molecular Liquids 279 (2019) 289–293
293
100
80
60
40
20
0
Acknowledgements
90
87
87
86
This work was supported by the National Natural Science Founda-
tion of China (21373079) andProgram for Science & Technology Innova-
tion Talents in Universities of Henan Province (14HASTIT015).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.molliq.2019.01.142.
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Scheme 2. Plausible reaction mechanism for the Ag/ionic liquid catalyzed multi-
component A3 reaction.