Facile and diverse microwave-assisted synthesis of secondary propargylamines in water using CuCl/CuCl2

Article abstract of DOI:10.1039/c4ra16005c

A highly efficient microwave-assisted three-component reaction between an aldehyde, a primary amine and an alkyne was developed using an inexpensive Cu(i)/Cu(ii) catalytic system and water as solvent. A wide range of diversely substituted secondary propargylamines was prepared in good and high yields within a short period of time.

Full text of DOI:10.1039/c4ra16005c

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Facile and diverse microwave-assisted synthesis of
secondary propargylamines in water using CuCl/
CuCl2†
Cite this: RSC Adv., 2015, 5, 28921
a
a
Tran Thi Thu Trang,ab Denis S. Ermolat'ev and Erik V. Van der Eycken
*
Received 9th December 2014
Accepted 17th March 2015
A highly efficient microwave-assisted three-component reaction between an aldehyde, a primary amine
and an alkyne was developed using an inexpensive Cu(I)/Cu(II) catalytic system and water as solvent. A
wide range of diversely substituted secondary propargylamines was prepared in good and high yields
within a short period of time.
DOI: 10.1039/c4ra16005c
www.rsc.org/advances
alkyne (KA2-coupling) in the presence of copper(I) or copper(II)
catalysts.15 However, to the best of our knowledge, there is only
Introduction
one example of secondary propargylamines prepared in a
domestic microwave oven in water as solvent.16,17 Therefore, we
wish to report here a simple but effective procedure for the
microwave-assisted three-component reaction between an
aldehyde, a primary amine and an alkyne using a Cu(I)/Cu(II)
catalytic system and water as solvent.
We started our initial investigations applying the recently
reported reaction conditions14 for microwave-assisted A3-
coupling using 20 mol% of CuBr in water (Table 1, entry 1).
However, the desired propargylamine was obtained only in 57%
yield. Similarly, other copper(I) and silver(I) sources afforded the
Multicomponent reactions (MCRs) have attracted much atten-
tion in the framework of combinatorial and green chemistry
owing to their synthetic efficiency and procedural simplicity.1
These reactions constitute a valuable tool for the creation of
large libraries of structurally related, drug-like compounds,
thereby enabling rapid lead identication and lead optimiza-
tion in drug discovery. MCRs provide a viable synthetic strategy
to access complex structures from rather simple starting
materials via a one-pot methodology, and in particular, exhibit
high atom economy and selectivity.2 A typical example of such a
process is a three-component coupling of an aldehyde, an
amine and an alkyne (A3-coupling) affording propargyl-
amines.3–5 Secondary propargylamines are generally used in
organic synthesis as precursors and versatile building blocks for
the preparation of nitrogen-containing heterocyclic compounds
such as pyrrolidines,6 pyrroles,7 oxazolidinones,8 amino-
indolizines9 and 2-aminoimidazoles10 and also act as key
intermediates11 for the construction of biologically active
compounds like isosteres, b-lactams, oxotremorine substrates,
conformationally restricted peptides, and therapeutic drug
molecules.12 However, there are only few direct approaches to
secondary propargylamines via classical A3-coupling. Consid-
erable progress in the synthesis of secondary propargylamines
has been made using ionic liquids13 and microwave irradia-
tion14 in the presence of copper(I) catalysts. Very recently the
synthesis of secondary propargylamines was reported via a
three-component coupling of a ketone, a primary amine and an
Table 1 Optimization of the reaction parametersa
Entry Catalyst (mol%)
Temp. (ꢀC) Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
CuBr (20)
CuCl (20)
CuI (20)
AgOTf (20)
Cu(OTf)2 (20)
CuCl2 (20)
CuCl (10) + CuCl2 (10) 100
CuCl (10) + CuCl2 (10) 110
CuCl (10) + CuCl2 (10) 110
100
100
100
100
100
100
25
25
25
25
25
25
25
25
10
25
57
54
58
51
69
74
83
96
71
87
aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven,
Belgium. E-mail: erik.vandereycken@chem.kuleuven.be; Fax: +32 16327990
bDepartment of Chemistry, Hanoi National University of Education, Xuan Thuy 136,
Hanoi, Vietnam
CuCl (5) + CuCl2 (5)
110
a
Molar ratio: aldehyde/amine/alkyne ¼ 1 : 1.3 : 1.6; reactions were
performed on 2 mmol of aldehyde in H2O (3 mL) under microwave
irradiation applying 100 W maximum power. b Isolated yield.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra16005c
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Table 2 Scope of the protocol
Table 2 (Contd.)
Yieldc, %
Entry Compound Product
Yieldc, %
Entry Compound Product
10
11
12
13
14
15
16
17
4ja
89
1
4aa
85
4ka
73
66
78
87
81
83
74
2
3
4
5
6
7
8
4ba
4ca
4da
4ea
4fa
64
41
72
59
83
85
84
4la
4mb
4nb
4ob
4pb
4qb
4ga
4ha
18
4rb
67
9
4ia
87
28922 | RSC Adv., 2015, 5, 28921–28924
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Table 2 (Contd.)
The catalytic cycle proposed for this reaction involves
condensation of amine and aldehyde with subsequent attack of
the resulting imine by the metal acetylide formed from the
terminal alkyne and CuCl. We assume that CuCl2 plays a role as
Lewis acid promoting both the imine formation and its activa-
tion for subsequent attack.15b–d
Entry Compound Product
Yieldc, %
Conclusions
In summary, we have demonstrated a novel protocol for the
preparation of secondary propargylamines using the relatively
cheap Cu(I)/Cu(II) catalytic system and water as solvent. This
microwave-assisted procedure offers several notable advantages
including operational simplicity, high yields and little envi-
ronmental impact.
19
20
4sb
69
4tb
84
82
Acknowledgements
The authors wish to thank the F.W.O. (Fund for Scientic
Research – Flanders (Belgium)), the Research Fund of the
University of Leuven (KU Leuven) and the Industrial Research
Fund of the University of Leuven (KU Leuven) for nancial
support to the laboratory. D.S.E. is grateful to the F.W.O. for
obtaining a postdoctoral fellowship and T.T.T.T. is grateful to
the Vietnamese government for obtaining a PhD-scholarship.
21
4ub
a
b
Molar ratio: aldehyde/amine/alkyne ¼ 1 : 1.3 : 1.6. Molar ratio:
aldehyde/amine/alkyne ¼ 1 : 1.5 : 1.6; reactions were performed on 2
mmol of aldehyde in H2O (3 mL) under microwave irradiation
applying a ceiling temperature of 110 ꢀC and 100 W maximum power
for 25 min, 10 mol% CuCl and 10 mol% CuCl2 the resulting reaction
mixture was extracted with EtOAc (20 mL), dried and the residue was
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