Single and double A3-coupling (aldehyde-amine-alkyne) reaction catalyzed by an air stable copper(I)-phosphole complex

Article abstract of DOI:10.1016/j.tetlet.2017.09.031

An air stable copper(I)-phosphole complex, [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}₂] (1), was utilized as a catalyst in single and double A³-coupling reactions for preparing mono- and bi-propargylamines. A variety of aldehydes, a

Full text of DOI:10.1016/j.tetlet.2017.09.031

Accepted Manuscript
Single and double A3-coupling (aldehyde-amine- alkyne) reaction catalyzed by
an air stable copper(I)-phosphole complex
José Ricardo Cammarata, Rocío Rivera, Franmerly Fuentes, Yomaira Otero,
Edgar Ocando-Mavárez, Alejandro Arce, Juan M. Garcia
PII:
S0040-4039(17)31158-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.031
TETL 49301
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 July 2017
8 September 2017
13 September 2017
Please cite this article as: Cammarata, J.R., Rivera, R., Fuentes, F., Otero, Y., Ocando-Mavárez, E., Arce, A., Garcia,
J.M., Single and double A3-coupling (aldehyde-amine- alkyne) reaction catalyzed by an air stable copper(I)-
phosphole complex, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.031
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Single and double A3-coupling (aldehyde-
amine- alkyne) reaction catalyzed by an air
stable copper(I)-phosphole complex
Leave this area blank for abstract info.
José Ricardo Cammarata, Rocío Rivera, Franmerly Fuentes, Yomaira Otero,* Edgar Ocando-Mavárez,
Alejandro Arce and Juan M. Garcia*
R2
R1
R3
L2CuCl
(0.1 mol%)
N
O
R4
R3R2NH +
L=
+
H
P
R1
5h, 100°C
S
N
S
R4
15-94% isolated yields
R2
R3
R1
R2
R1
R3
L2CuCl
(1 mol%)
N
O
+
+ 2 R3R2NH
H
2
R1
24h, 80°C
19-82% isolated yields

1
Tetrahedron Letters
journal homepage: www.els evier.com
Single and double A3-coupling (aldehyde-amine- alkyne) reaction catalyzed by an air
stable copper(I)-phosphole complex
José Ricardo Cammarata, a Rocío Rivera, a Franmerly Fuentes, a Yomaira Otero, a* Edgar Ocando-Mavárez,
b
Alejandro Arce a and Juan M. Garcia, b*
a Laboratorio de Metales de Transición, Centro Química-IVIC, Caracas 1020-A, Venezuela
b Laboratorio de Fisico-Química Orgánica, Centro de Química-IVIC, Caracas 1020-A, Venezuela
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An air stable copper(I)-phosphole complex, [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2] (1),
was utilized as a catalyst in single and double A3-coupling reactions for preparing mono- and bi-
propargylamines. A variety of aldehydes, amines and terminal alkynes were tested. Most of
these reactions led to formation of the expected propargylamines in good yields using low
amounts catalyst and obviating both the use of purified reagents as employ of a glovebox.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
A3-coupling reaction
Propargylamine
Phosphole
Copper(I) complex
Propargylamines are used in organic chemistry as precursors
and versatile building blocks for the preparation of various
nitrogen-containing heterocyclic compounds as well as key
intermediates for the synthesis of biologically active
pharmaceuticals and natural products.1-4 Some propargylamines
have been used for the treatment of neuropsychiatric disorders
such as Parkinson's and Alzheimer's disease.5 Because of their
importance, many synthetic methods have been developed.6
However, the most direct and efficient method for the preparation
of propargylamines is through transition-metal catalyzed three-
component coupling between an aldehyde, an amine and a
terminal alkyne, which is known as an A3-coupling reaction.7
Under homogeneous or heterogeneous conditions, a wide variety
of transition metal salts and complexes have been employed in
the synthesis of propargylamine via A3-coupling reaction,8
among which those from copper have been most studied because
of its abundance, low cost, low toxicity and high reactivity.9
phosphole
complex,
[CuCl{2,5-bis(2-thienyl)-1-
phenylphosphole}2] (1), which was easily obtained from reaction
of CuCl with two equivalent of 2,5-bis(2-thienyl)-1-
phenylphosphole using dichloromethane as solvent at RT.14
Scheme 1. Synthesis of copper(I)-phosphole complex (1).
Complex (1) exhibits a trigonal planar coordination geometry
consisting of a chlorine atom and two symmetric phosphole
ligands. Furthermore, this complex resulted to be stable under
atmospheric conditions both in solid state as in different solvents
such as CH2Cl2, CH3Cl, DMSO, acetone and hexane. Recently,
we have reported the synthesis, structural characterization and
biological activity evaluation for complex (1), however its
catalytic potential have not been studied to date. Thus, herein we
report the use of [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2]
(1) as catalyst for preparing propargylamines. A low coordination
number, high stability and an easy preparation make this complex
a promising candidate for A3-couplig (aldehyde-amine-alkyne)
reactions.
It is well-known that trivalent phosphorus compounds are
versatile ligands capable of exerting a subtle control on the metal
center, which leads to metal catalysts with improved reactivity
and stability.10 However, there are few reports that describe the
use of copper(I) catalysts bearing trivalent phosphorus
compounds as ligand in A3-coupling reactions.11 We have
recently reported that a tetramer copper(I) complex with
diallylphosphine ligands efficiently catalyzes A3-coupling
reaction for preparing propargylamine.12
We have selected reaction of benzaldehyde, piperidine and
phenylacetylene as model to evaluate catalytic potential of (1)
and optimize the reaction conditions, results are shown in Table
1. Results indicate that then 1 hour reaction at 100 °C was
reached 99% conversion. With reaction temperature set at 100°C,
catalytic loading was decreased to 0.5 and 0.1 mol% (Table 1,
Despite that 2,5-disubstituted phosphole derivatives are
considered phosphine cyclic analogues and offer relatively stable
transition metal complexes, metal-phosphole complexes have
been used scarcely in catalysis.13 We have prepared a copper(I)-

2
Tetrahedron
entries 4 and 5). Employing 0.5 mol% of complex (1) was
However, the obtained conversions were lower than that got
under free solvent conditions. Thus, a 0.1 mol% of catalytic
loading at 100°C and absence of solvent were the optimum
conditions selected for A3-couplig (aldehyde-amine-alkyne)
reaction. Under these conditions, activity of (1) proved to be
higher than those achieved in absence of the catalyst, using CuCl
or phosphole ligand separately (Table 1, entries 11-13).
Moreover, Hg test suggests that metallic copper or nanoparticles
are not likely responsible of observed catalytic activity (Table 1,
entry 14).
achieved 99% conversion then 1.5 hours, while using 0.1 mol%
was got 94% conversion after 5 hours. In terms of TON (198 y
940 for entries 4 y 5 respectively) and TOF (132 h-1 y 188 h-1 for
entries 4 y 5 respectively), 0.1 mol% of complex (1) resulted to
be the optimal catalytic loading. Solvent effect was also
evaluated using both polar and non-polar solvents with high
boiling point (Table 1, entries 6-10).
Table 1. Optimization studies for single A3-coupling reactions catalyzed by [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2] catalyst (1) a
Entry
1
Catalyst
Solvent
[Cu] (mol%)
Temperature (°C)
Time (h)
Conversion (%)b
2
25
24
24
1
61
70
99
99
94
84
89
0
2
2
50
3
none
2
100
100
100
100
100
100
100
100
100
100
100
100
4
0.5
0.1
0.1
0.1
0.1
0.1
0.1
---
1.5
5
5c
6
1
Ph-CH3
Ph-Cl
Dioxane
DMF
5
7
5
8
5
9
5
78
81
4
10
11
12
13
14
DMSO
none
5
none
ligand
CuCl
1/Hg
5
none
0.1
0.1
0.1
5
23
70
92
none
5
none
5
aAll the reactions were carried out by using benzaldehyde (3 mmol), piperidine (3.3 mmol) phenylacetylene (4.5 mmol) in various solvents (1 mL). bConversions
were determined by 1H-NMR spectroscopy of the reaction crude, using o-nitroaniline as a internal standard. c Optimal reaction conditions.
different reaction conditions, but all essays led to formation of
Once selected the optimal reaction conditions, we decided to
the corresponding Schiff base.
explore on scope of substrates for A3-couplig (aldehyde-amine-
alkyne) reaction catalyzed by (1), results are shown in Table 2.
Coupling of secondary cyclic amines such as piperidine and
Additionally, we have studied the influence of electron–
donating or –withdrawing groups on the aromatic ring of
aldehyde. When it carried out the reactions with aromatic
aldehydes containing either an electron donating group as CH3O–
at para– position or an electron withdrawing group such as Cl– at
orto– position, the desired products (4m and 4n) are obtained in
good yields (Table 2. entries 14 and 15). Moreover, we examined
the reactivity of our catalyst against to aliphatic alkynes such as
1-octyne and 5-hexynenitrile. Those reactions that involved
benzaldehyde and piperidine (Table 2, entries 12 and 13) gave
the expected products (2k and 2l) in moderate yields past 24
hours. While the reaction that involved paraformaldehyde,
piperidine and 5-hexynenitrile led to the product 2o in excellent
yield, increasing the catalytic loading to 0.5 mol% (Table 2, entry
16).
On the other hand, we have also tested catalyst (1) on double A3-
coupling reactions of aldehyde, amine and terminal diyne to
synthetize bis-propargylamines. In order to optimize reactions
conditions, coupling of benzaldehyde, piperidine and octa-1,7-
diyne was selected as model reaction, results are summarized in
Table 3. The optimum reaction conditions involve the following
parameters: 1 mol% of catalyst at 80°C in absence of solvent. It
is interesting to note that intermediate product (4) was isolated
and fully characterized from reaction intermediate from double
A3-coupling of benzaldehyde, piperidine and 1,7-octadiyne. Until
now, this reaction intermediates have only been observed by GC-
MS spectroscopy.11c
pyrrolidine
using
benzaldehyde,
butyraldehyde
and
paraformaldehyde with phenylacetylene lead to the desired
propargylamines (2a, 2b , 2i, 2j, 2p and 2q) in excellent yields
(Table 2, entries 1, 2, 9, 11, 17 and 18). Nevertheless, for a cyclic
amine less nucleophilic as morpholine, the corresponding
propargylamines (2c and 2r) were obtained in low to moderate
yields (Table 2, entries 3 and 17). Similarly, for the bulky
2,2,6,6-tetramethylpiperidine
with
benzaldehyde
and
phenylacetylene was not obtained any reaction product and
starting material remained intact (Table 2, entry 4), while
changing to paraformaldehyde is possible to obtain the
propargylamine (2s), but in poor yield (Table 2, entry 20). When
the coupling reaction is carried out using secondary acyclic
amines such as diisopropylamine, dicyclohexylamine and N-
methylaniline with paraformaldehyde and phenylacetylene, the
desired propargylamines (2t, 2u and 2v) are obtained in excellent
yields (Table 2 entries 21-23).
However, by changing to benzaldehyde the expected
propargylamines (2e-2g) were not obtained and starting material
stayed intact (Table 2, entries 5-7), except for reaction that
involved ethylbenzylamine in which the propargylamine (2h)
was obtained in 89% yield then 24 hours reaction. We have also
explored the reactivity for a variety of primary amines using
benzaldehyde and paraformaldehyde with phenylacetylene under

3
Table 2. A3-coupling of terminal alkynes, secondary amines and aldehydes catalyzed by [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2] (1)a
Entry
Aldehyde
Ph–CHO
Ph–CHO
Amine
Alkyne
Product
2a
yield (%)b
1
2
piperidine
pyrrolidine
Phenylacetylene
Phenylacetylene
92
91
2b
3
4
Ph–CHO
Ph–CHO
morpholine
2,2,6,6-tetramethylpiperidine
iPr2NH
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
1-octyne
15(71c)
NR c,d
NR c,d
NR c,d
NR c,d
27(89c)
89
2c
2d
2e
2f
5
Ph–CHO
6
Ph–CHO
dicyclohexylamine
N-Methylaniline
ethylbenzylamine
pyrrolidine
7
Ph–CHO
2g
2h
2i
8
Ph–CHO
9
CH3(CH2)2CHO
CH3(CH2)2CHO
Ph–CHO
11
12
13
14
15
16 e
17 e
18 e
19 e
20 e
21 e
22 e
23 e
piperidine
93
36c
59c
2j
piperidine
2k
2l
Ph–CHO
piperidine
5-hexynenitrile
Phenylacetylene
Phenylacetylene
5-hexynenitrile
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
4-MeOC6H5CHO
2-ClC6H5CHO
paraformaldehyde
paraformaldehyde
paraformaldehyde
paraformaldehyde
paraformaldehyde
paraformaldehyde
paraformaldehyde
paraformaldehyde
94
piperidine
2m
2n
2o
2p
2q
2r
2s
piperidine
85
60(98f)
piperidine
piperidine
92
pirrolidine
91
morpholine
64
2,2,6,6-tetramethylpiperidine
di-isopropylamine
dicyclohexylamine
N-methylaniline
22
89
2t
88
2u
2v
91
aReaction conditions: 3 mmol of aldehyde; 3.3 mmol of amine; 4.5 mmol of alkyne and 0.1 mol% of catalyst [CuCl{2,5-bis(2-thienyl)-1-
phenylphosphole}2] at 100 °C for 5h. bIsolated yield based on aldehyde. After 24 h reaction. Verified by 1H-NMR spectroscopy of the crude
c
d
reaction. eUsing chlorobenzene (1 mL) as solvent. fUsing 0.5 %mol of catalyst loading.
Table 3. Optimization studies for double A3-coupling reactions catalyzed by [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2] (1) a
Yied (%)b
[Cu]
(mol%)
Time
(h)
Entry
Catalyst
Solvent
Temperature (°C)
4
trace
trace
82
3a
trace
trace
trace
trace
21
1
2
3
4c
5
6
7
8
9
2
2
25
50
80
80
80
80
80
80
80
24
24
24
24
24
24
24
24
24
neat
2
1
82
0.5
1
63
1
Toluene
acetonitrile
H2O
16
57
1
trace
12
6
1
8
CH2CH(OH)CH2
1
6
trace
a Reaction conditions: 0.6 mmol of aldehyde; 0.66 mmol of amine and 0.30 mmol of 1,7-octadiyne in various solvents (1 mL). bIsolated yield
c
based on alkyne. Optimal reaction conditions.

4
Tetrahedron
Double A3-coupling reactions using an aromatic aldehyde
replaced by an aliphatic aldehyde a decrease in the reaction
yields is observed (bis-propagylamines 3d-f; Table 4, entries 4-
6). In the case of butyraldehyde, it was not possible to isolate any
intermediates.
with different amines such as piperidine, pirrolidine and
morpholine lead to the bis-propargylamines 3a-c in good to
moderate yields (Table 4, entries 1-3). When the benzaldehyde is
Table 4. Double A3-coupling of aldehydes, secondary amines and 1,7-octadiyne catalyzed by [CuCl{2,5-bis(2-thienyl)-1-phenylphosphole}2]
(1)a
Entry
Aldehyde
Amine
Alkyne
Product
3a
yield (%)b
1
2
piperidine
pirrolidine
82
81
3b
Ph–CHO
3
4
5
6
morpholine
piperidine
pirrolidine
morpholine
60
21
19
40
3c
3d
3e
3f
1,7-octadiyne
CH3(CH2)2CHO
aReaction conditions: 0.6 mmol of aldehyde; 0.66 mmol of amine; 0.30 mmol of 1,5-octadiyne and 1 mol% of catalyst [CuCl{2,5-bis(2-
thienyl)-1-phenylphosphole}2] at 80°C for 24h. bIsolated yield based on alkyne.
7. Herrera R. P, Marques-Lopez E. Multicomponent reactions :
In summary, we have found that [CuCl{2,5-bis(2-thienyl)-1-
phenylphosphole}2] (1) is a useful catalyst to promote single and
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double A3-coupling reactions to synthetize mono- and bis
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highly efficient as catalyst on A3-coupling reactions of both
aromatic and aliphatic aldehydes with cyclic amines and
phenylacetylene. An easy preparation, low catalytic loading, high
stability and no need in using either purified reagents or glovebox
is required, describe some advantages offered by our catalytic
system.
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Acknowledgments
We thank the Venezuelan Minister for Sciences and
Technology and the IVIC (Projects 1210 and 1082) for financial
support of this work.
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*Corresponding authors
Juan M. Garcia: e-mail: jmgarcia@ivic.gob.ve; Phone: +58 212
5041326.
Y. Otero: e-mail: yotero@ivic.gob.ve. Phone: +58 212 504163

6
Tetrahedron
Highlights:
An air stable copper(I)-phosphole complex is used
as catalyst for A3-coupling reactions.
A variety of mon- and bis-propargylamines were
obtained in good yields.
Reactions no need in using either purified reagents
or glovebox, and they were carried out by
employing low catalytic loading.