Expeditious and highly efficient synthesis of propargylamines using a Pd-Cu nanowires catalyst under solvent-free conditions

Article abstract of DOI:10.1002/aoc.4917

A heterogeneous Pd-Cu NWs-catalyzed expeditious and solvent-free synthesis of propargylamines via A³-coupling of aldehydes, alkynes, and amines has been proposed. A wide range of aldehydes, alkynes and amine substrates undergo A³-coupling to produce propargylamines in good to excellent yields with good functional tolerance, such as that towards alkoxy, hydroxy, C-X (X?=?F, Cl, Br) as well as amide and C=C bonds. Furthermore, the catalyst could be recovered easily and reused for at least 5?cycles without showing significant loss of catalytic activity.

Full text of DOI:10.1002/aoc.4917

Received: 3 January 2019
DOI: 10.1002/aoc.4917
Revised: 11 February 2019
Accepted: 27 February 2019
F U L L P A P E R
Expeditious and highly efficient synthesis of
propargylamines using a Pd‐Cu nanowires catalyst under
solvent‐free conditions
Rongnan Yi1
| Zheng‐Jun Wang1 | Zhiwu Liang1 | Min Xiao1 | Xinhua Xu1 | Ningbo Li2
1 State Key Laboratory of
A heterogeneous Pd‐Cu NWs‐catalyzed expeditious and solvent‐free synthesis
Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical
Engineering, Hunan University, Changsha
410082, People's Republic of China
2 Basic Medical College, Shanxi Medical
University, Taiyuan 030001, People's
Republic of China
of propargylamines via A3‐coupling of aldehydes, alkynes, and amines has
been proposed. A wide range of aldehydes, alkynes and amine substrates
undergo A3‐coupling to produce propargylamines in good to excellent yields
with good functional tolerance, such as that towards alkoxy, hydroxy, C‐X
(X = F, Cl, Br) as well as amide and C=C bonds. Furthermore, the catalyst
could be recovered easily and reused for at least 5 cycles without showing
significant loss of catalytic activity.
Correspondence
Zhiwu Liang and Xinhua Xu, State Key
Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University,
Changsha, 410082, People's Republic of
China.
KEYWORDS
A3‐coupling, C–H activation, Pd‐cu NWs, propargylamines, solvent‐free
Email: zwliang@hnu.edu.cn;
xhx1581@hnu.edu.cn
Ningbo Li, Basic Medical College, Shanxi
Medical University, Taiyuan, 030001,
People's Republic of China.
Email: ningboli@sxmu.edu.cn
Funding information
Hunan Provincial Innovation Foundation
For Postgradute, Grant/Award Number:
52193376; National Natural Science
Foundation of China, Grant/Award
Numbers: 21536003 and 21802093
1 | INTRODUCTION
Traditionally, propargylamine derivatives are prepared
from terminal alkynes using highly reactive organometallic
Propargylamines are useful building blocks for the con-
struction of N‐ and O‐ heterocycle compoumds (Figure 1),
suchas2‐aminoimidaozels,[1] 2‐benzofuranmethamines,[2]
oxazolidinones,[3] aminoindolizine,[4] 3‐alkylated quino-
lines,[5] pyrroles and pyrrolidine.[6,7] In addition, they
are important skeletal motifs of organic synthesis inter-
mediates, biologically active compounds and natural
products.[8,9] For instance, the second‐generation prod-
ucts of the anti‐HIV drug Sustiva, DPC 961 and DPC
963, have propargylamine structural units.[10]
reagents such as n‐butyllithium (n‐BuLi),[11] EtMgBr[12] or
lithium diisopropylamide (LDA)[13] in separate steps.
Because many metal alkynides require harsh reaction condi-
tions, the reaction must be carried out under anhydrous sol-
vent, inert atmosphere, and low temperature conditions.
Therefore, the development of a simple method for the syn-
thesis of propargylamines under mild conditions is still
highly desirable.
Compared to the separated‐step synthetic methods,
one‐pot, three‐component coupling (A3‐coupling) of an
Appl Organometal Chem. 2019;e4917.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4917

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et al. demonstrated
a
catalytic system based on
chitosan/Zn‐catalyzed A3‐coupling for synthesis of
propargylamines in toluene at 115 °C for 14 hr
(Scheme 1d).[27] Nonetheless, there are disadvantages to
these methodologies, e.g., high catalyst loadings,
improved reaction temperature, utilizing an inert gas,
using solvent, long reaction time, narrow substrate scope,
low tolerance towards functional groups, and unrecycla-
ble catalysts. Therefore, it is necessary to find a simple,
fast and efficient method for propargylamine synthesis.
Recently, nanomaterials have been shown to be an
effective catalyst for organic chemistry.[33–36] Bimetallic
nanocatalysts in particular show significant advantages
compared to monometal counterparts, such as enhanced
catalytic activity, improved stability and selectivity
derived from synergistic effects.[37,38] In recent years, a
large amount of bimetallic Pd‐M (M = Pt, Au, Ag, Ni,
Co) catalysts were constructed and used to catalyze
organic reactions.[39–43] Very recently, we successfully
synthesized Pd‐Cu nanowires (Pd‐Cu NWs) by a facile
and efficient one‐pot wet‐chemical method (see TEM
images in the SI), which show high catalytic activity in
the Suzuki cross coupling reaction under mild condi-
tions.[44] Based on the unique structure of the Pd‐Cu
alloy, we report here that Pd‐Cu NWs are an efficient
and reusable heterogeneous catalyst for synthesis of
propargylamines via A3‐coupling of aldehydes, terminal
alkynes, and amines (Scheme 2). This is a simple and fast
method for the synthesis of propargylamines.
FIGURE 1 Propargylamines for the construction of heterocyclic
compounds
aldehyde, an amine and an alkyne to synthesize
propargylamine is a more attractive and atom‐efficient
strategy.[14,15] Recently, a variety of catalytic systems
using metal catalysts (Ag,[16,17] Au,[18,19] In,[20] Cu,[21–25]
Zn,[26,27] Fe,[28] Co,[29] Mn,[30] etc.[31,32]) have been
reported for the preparation of propargylamines via this
A3‐coupling reaction. For instance, Li et al. described
the three‐component coupling of aldehyde, alkyne, and
amines to generate propargylamines catalyzed by AgI in
water at 100 °C for 14 hr under N2 atmosphere
(Scheme 1a).[16] Furthermore, Wang et al. developed a
method based on InCl3‐catalyzed direct A3‐coupling of
aldehydes, alkynes, and amines in toluene at 120 °C for
14 hr under Ar atmosphere (Scheme 1b).[20] Gholinejad
et al. reported an efficient A3‐coupling method that
involved gold nanoparticles containing phosphorus
ligands in water at 80 °C for 24 hr (Scheme 1c).[19] Qiu
2 | RESULTS AND DISCUSSION
Initially, we selected benzaldehyde, piperidine and
phenylacetylene as substrates to screen reaction condi-
tions. The results are shown in Table 1. Firstly, we tested
the effect of different solvents in the reaction in the pres-
ence of 5 mg of Pd‐Cu NWs at 80 °C. Toluene, EtOH,
H2O, THF, CHCl3, and CH3CN showed a little lower
reactivity (Table 1, entries 1–6). Interestingly, the
solvent‐free reaction at 80 °C proceeded rapidly with
good yields (Table 1, entry 7). Subsequently, the best yield
was obtained and the reaction time was reduced to
10 min by increasing the temperature to 110 °C (Table 1
, entries 8–11). With increased Pd‐Cu NWs, the yield
did not significantly improve (Table 1, entry 12).
SCHEME 1 Previous work: Synthetic routes for propargylamines
SCHEME 2 This work: Synthetic routes for propargylamines

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TABLE 1 Screening of silver catalysts and optimization of reaction conditionsa
Entry
Catalyst loading (mg)
Solvent
Temp. [°C]
Time
Yield (%)b
1
5
5
5
5
5
5
5
5
5
5
5
6
4
Toluene
EtOH
H2O
80
80
12 hr
12 hr
12 hr
12 hr
12 hr
12 hr
2 hr
43
57
38
50
61
52
78
82
91
97
97
97
82
2
3
80
4
THF
80
5
CHCl3
CH3CN
Free
80
6
80
7
80
8
Free
90
2 hr
9
Free
100
110
120
110
110
30 min
10 min
10 min
10 min
10 min
10
11
12
13
Free
Free
Free
Free
aCatalyst Pd‐Cu NWs, benzaldehyde (1a, 1.0 mmol), piperidine (2a, 1.2 mmol), phenylacetylene (3a, 1.5 mmol); Solvent‐free; 110 °C;
bIsolated yields.
However, if it was reduced from 5 to 4 mg, the product
yield decreased to 82% yield (Table 1, entry 13). Ulti-
mately, the optimum reaction conditions are as follows:
aldehydes (1.0 mmol), amines (1.2 mmol), alkynes
(1.5 mmol), and Pd‐Cu NWs (5 mg) at 110 °C under
solvent‐free condition. Compared with previously
reported catalysts (Scheme 1), the reaction conditions
and product yield have obvious advantages.
With the optimal reaction conditions determined, we
evaluated the scope and efficiency of the reaction with a
series of substituted aldehydes, amines and alkynes. As
shown in Table 2, a variety of aldehydes were investi-
gated, and we found this protocol to be useful for ali-
phatic as well as aromatic aldehydes with different
functional groups. Benzaldehydes with electron‐
withdrawing groups react smoothly (4e‐4 g, 93–99%),
while substitution of electron‐donating groups on the
benzene ring showed a slight decrease in reactivity (4b‐
4d, 4 k, 82–93%). The reactivity of the aryl aldehydes with
substituent groups at the ortho position (4c, 4e) was
reduced due to steric hindrance. Generally, electron‐
withdrawing groups displayed high reactivity; reactions
were completed in only 10 min and gave higher conver-
sions. The present catalytic system also showed good
tolerance towards a variety of functional groups such as
alkoxy, hydroxyl, bromo, and amide bonds as well as
heterocycles, affording the desired products in good to
excellent yields (4 h‐4 k). Moreover, the alkyl aldehyde
cyclohexanecarboxaldehyde also shows good reactivity,
with 78%–93% yield (4 l‐4n).
In subsequent studies, the scopes and limitations for
terminal alkynes were explored under the optimal condi-
tions as shown in Table 3. Aromatic alkynes with
electron‐donating and electron‐withdrawing groups
showed high reaction activity in the A3 coupling reaction.
The substituent groups in the aromatic ring have minimal
effect on the reactivity (4o‐4w). It is clear that the reactiv-
ity of mono‐substituted phenylacetylene in this reaction
is high, following the sequence: para > meta > ortho,
which is roughly due to the steric hindrance (4o‐4q).
Phenylacetylenes with ethyl, bulky n‐pentyl and tert‐
butyl groups also display high activity, with yields of
90%, 88% and 85%, respectively (4u‐4w). In addition, 1‐
hexyne also shows good reactivity with 75% yield (4x).
Next, we investigated the reactions of different second-
ary amines with benzaldehyde and phenylacetylene
under the optimized conditions as shown in Table 4.
Using secondary amines such as pyrrolidine and azepane,
products 4y and 4z were obtained in 91% and 93% yield,
respectively.
Furthermore,
if
morpholine
and
thiomorpholine were used as substrates, the yields of cor-
responding products 4aa and 4ab were obtained in 87%

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TABLE 2 Scope of the aldehydesa
aCatalyst Pd‐Cu NWs (5 mg), aldehydes (1a‐1n, 1.0 mmol), piperidine (2a, 1.2 mmol), phenylacetylene (3a, 1.5 mmol); Solvent‐free; 110 °C;
bIsolated yields.
and 83% yield. The structure of compound 4ab was con-
firmed by X‐ray crystallography. In addition, noncyclic
secondary amines such as dibenzylamine and
diallylamine were tested in the reaction; the noncyclic
amines show lower reactivity than cyclic secondary
amines, even with prolonged heating (4 ac, 4ad).
The reaction can be directly enlarged to a scale of
10 mmol, giving 4a in 94% yield (2.59 g, Scheme 3), which
is a positive aspect of the catalyst system for industrial
application.
intermediate is formed on the surface of the Pd‐Cu
NWs. The aldehydes and secondary amines form the
iminium ion in situ, which then reacts with the Pd‐Cu‐
acetylide by nucleophilic addition to give the desired
propargylamine and regenerate the active nanoparticle
catalyst for further reactions.
The recyclability of Pd‐Cu NWs in the A3 coupling of
benzaldehyde, piperidine and phenylacetylene was
tested. The catalyst was separated by sample filtration,
and there was a certain loss of catalyst in the recycling
process. To ensure the same amount of catalyst in each
run of the recycling experiment, we conducted several
sets of the experiment in parallel under identical condi-
tions. The reaction of the target set was supplemented
with catalyst from the other parallel sets to make sure
there was 5 mg catalyst in each run. Pd‐Cu NWs still
On the basis of previously well‐documented results,[45]
a plausible mechanism of the Pd‐Cu NWs‐catalyzed one‐
pot, three‐component coupling of aldehyde, amine and
alkyne is proposed in Scheme 4. The reaction is initiated
by the coordination of the terminal alkynes to Pd‐Cu
NWs to activate the C–H bond. The Pd‐Cu‐acetylide

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TABLE 3 Scope of the terminal alkynesa
aCatalyst Pd‐Cu NWs (5 mg), benzaldehyde (1a, 1.0 mmol), piperidine (2a, 1.2 mmol), terminal alkynes (3b‐3 l, 1.5 mmol); Solvent‐free; 110 °C;
bIsolated yields.
display high product yield of 92% at the fifth run
(Figure 2). The leaching of Pd‐Cu NWs was determined
by ICP‐OES and the result indicated that the Pd and Cu
contents in ethyl acetate was less than 1 ppm, indicating
minimal leaching of the Pd‐Cu NWs from the catalyst
during the reaction.
reaction time, (iii) low catalyst loading, (iv) wide sub-
strate scope and (v) good reusability.
4 | EXPERIMENTAL SECTION
Typical
procedure
for
the
synthesis
of
propargylamines (using benzaldehyde, piperidine and
phenylacetylene as an example): benzaldehyde (1 mmol,
108 mg), piperidine (1.2 mmol, 102 mg), phenylacetylene
(1.5 mmol, 153 mg) and Pd‐Cu NWs (5 mg) were added to
a round‐bottom flask. The mixture was stirred at 110 °C
for 10 min and monitored by TLC. Afterward, the reac-
tion mixture was cooled down to room temperature,
and ethyl acetate was added (5 ml). The catalyst was
recovered by filtration, followed by washing thoroughly
with ethyl acetate and water. The filtered residue was
3 | CONCLUSIONS
In conclusion, we have developed a highly efficient and
economic protocol for synthesis of propargylicamines
using Pd‐Cu NWs catalyzed A3 coupling of aldehydes,
secondary amines and terminal alkynes. Compared to
current methods, the main advantages of this protocol
are (i) solvent‐free conditions, (ii) extremely short

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TABLE 4 Scope of the secondary aminesa
aCatalyst Pd‐Cu NWs (5 mg), benzaldehyde (1a, 1.0 mmol), piperidine (2b‐2 g, 1.2 mmol), terminal alkynes (3a, 1.5 mmol); Solvent‐free; 110 °C;
bIsolated yields.
SCHEME 3 Gram‐scale reaction for the synthesis of 4a
FIGURE 2 The recycling test of Pd‐Cu NWs for the A3 coupling
reaction
ACKNOWLEDGEMENTS
The authors thank the National Natural Science Founda-
tion of China (21536003, 21802093), the PhD Start‐up
Foundation of Shanxi Medical University (03201501)
and Hunan Provincial Innovation Foundation For Post-
graduate (52193376) for financial support.
SCHEME 4 A plausible mechanism of the A3 coupling reaction
catalyzed by Pd‐Cu NWs
ORCID
purified by flash column chromatography on silica gel to
afford the product 4a. For the recycling experiments, we
conducted several parallel experiments under identical
conditions and recycled the catalyst for the next test.
The target reactions received catalyst supplements from
the other parallel experiments to ensure the scale of cata-
lyst was within 5 mg in each run.
Rongnan Yi https://orcid.org/0000-0003-2506-7546
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Cu nanowires catalyst under solvent‐free
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