CuO/Fe2O3NPs: robust and magnetically recoverable nanocatalyst for decarboxylative A3 and KA2 coupling reactions under neat conditions

Article abstract of DOI:10.1016/j.tetlet.2016.08.066

CuO/Fe₂O₃NPs were found to be robust, green and sustainable nanocatalysts for the synthesis of trisubstituted propargylamines by the reaction of propiolic acid, secondary amines and aldehydes via decarboxylative A3 coupling reaction

Full text of DOI:10.1016/j.tetlet.2016.08.066

Tetrahedron Letters 57 (2016) 4468–4472
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuO/Fe O NPs: robust and magnetically recoverable nanocatalyst for
2
3
decarboxylative A3 and KA2 coupling reactions under neat
conditions
⇑
Upasana Gulati, U. Chinna Rajesh, Diwan S. Rawat
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
CuO/Fe O NPs were found to be robust, green and sustainable nanocatalysts for the synthesis of trisub-
2
3
Received 13 June 2016
Revised 20 August 2016
Accepted 20 August 2016
Available online 22 August 2016
stituted propargylamines by the reaction of propiolic acid, secondary amines and aldehydes via decar-
boxylative A3 coupling reaction under solvent free conditions. Further, we explored the wide
applicability of the present methodology by replacing the more reactive aldehydes with less reactive
ketones to afford the tetrasubstituted propargylamines via decarboxylative KA2 reaction. The present
method showed several advantages such as usage of magnetically recoverable with six times recyclability
of nanocatalyst, follows green chemistry principles including low E-factor and high atom economy for the
A3 and KA2 reactions as well as high turnover numbers through easy catalyst recycling.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Decarboxylative strategies
A3 and KA2 coupling reactions
Green and sustainable chemistry
Magnetically recoverable
Propargylamines
Introduction
nates the requirement of expensive and toxic organometallic
6
–9
reagents.
The decarboxylative CAC bond formation involves
Chemical pollution has been the major environmental issue
since the time of industrial revolution. In order to solve this prob-
lem, green chemistry principles have been introduced in the last
decade of twentieth century. These principles mainly deal with
the minimization of waste production rather than focusing on
usage of relatively neutral reaction conditions as compared to
organometallic reagents.
7
,10–16
However, there have been very limited reports on the utiliza-
tion of decarboxylative coupling strategies for the synthesis of
heterocycles and value-added chemicals such as imidazo[1,2-a]
pyridines, substituted propargylamines, oxazolidin-2-ones, 3-
amino-1,4-enynes and 1,4-diamino-2-butynes using copper based
1
waste treatment. Nanocatalysis has been considered to be an effi-
cient approach to achieve sustainable chemistry with various
advantages such as high surface area, recovery and reusability of
1
7–23
homogeneous catalysts.
To the best of our knowledge there is
2
catalyst with minimum waste generation. Magnetically recover-
no report on decarboxylative A3 and KA2 coupling reactions using
MRNCs. With this background and in continuation of our interest
able nanocatalysts (MRNCs) have attracted great attention due to
their intriguing catalytic properties along with rapid and robust
magnetic separation by external magnet.3 Recently, we reported
4
,5,24–27
towards green and sustainable chemistry,
we herein report
the catalytic potential of CuO/Fe NPs for decarboxylative A3 and
2 3
O
green approach for the one-step synthesis of CuO/Fe
2
O
3
MRNC to
KA2 coupling reactions under solvent free conditions for the first
time (Scheme 1).
afford heterocycles such as aminoindolizines and pyrrolo[1,2-a]
4
quinolones. Moreover, our group has reported that Cu(II)/HM as
a versatile nanocatalyst for the synthesis of tetrasubstituted
propargylamines and pyrrolo[1,2-a]quinolines via KA2, A3 cou-
pling reactions and also included some preliminary results on their
decarboxylative coupling strategies.5 Decarboxylative coupling
reactions have attracted significant attention in organic synthesis
due to in-situ formation of organometallic species which elimi-
Results and discussion
2 3
CuO/Fe O catalyzed decarboxylative A3 coupling reaction
Initially, a model reaction was performed among benzaldehyde
(1a), morpholine (2a) and phenylpropiolic acid (3a) using 5 mg of
2 3
CuO/Fe O as catalyst in the presence of various solvents and under
⇑
Corresponding author. Tel.: +91 11 27662683; fax: +91 11 27667501.
E-mail address: dsrawat@chemistry.du.ac.in (D.S. Rawat).
neat condition at 110 °C as shown in Table 1. Product (4aa) was
obtained in 60% yield in the presence of water (entry 1, Table 1),
http://dx.doi.org/10.1016/j.tetlet.2016.08.066
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

U. Gulati et al. / Tetrahedron Letters 57 (2016) 4468–4472
4469
R
R
N
Ar
Ar
CHO
1
4
Ar
R
R
CuO/Fe O catal.
2 3
+ Ar
COOH
N
H
2
CO
2
+ H
R
2
O
N
Neat, 110 o
C
O
3
R
Ar
5
6
Scheme 1. Decarboxyalative A3 and KA2 coupling reactions.
Table 1
Optimization study for CuO/Fe
2
O
3
catalyzed decarboxylative A3 coupling reactiona
O
CHO
O
N
catal.
+
+
Ph
COOH
Solvent, temp.
N
H
Ph
1a
2a
3a
4aa
S. No.
Catal. (mg)
Solvent
Temp. (°C)
Time (h)
Yield of 4aab (%)
1
2
3
4
5
6
7
8
9
CuO/Fe
CuO/Fe
CuO/Fe
CuO/Fe
CuO/Fe
2
2
2
2
2
O
O
O
O
O
3
3
3
3
3
(5)
(5)
(5)
(5)
(5)
(5)
(10)
(3)
(5)
(5)
(5)
(5)
Water
EG
PEG
100
110
110
110
110
110
110
110
90
70
50
rt
110
110
110
110
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
5
60
78
78
85
82
92
92
88
79
60
35
—
DMF
DMSO
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
2 3
CuO/Fe O
CuO/Fe
CuO/Fe
CuO/Fe
CuO/Fe
CuO/Fe
CuO/Fe
2
O
2
O
2
O
2
O
2
O
2
O
3
3
3
3
3
3
10
11
12
13
14
15
16
8
21
21
8
6
4
Fe
CuO NPs (5)
CuCl (5)
Neat
2
O
3
(5)
30
81
76
—
2
4
Bold value indicate the optimized reaction condition.
a
Reaction conditions: benzaldehyde 1a (1 mmol), morpholine 2a (1 mmol), phenylpropiolic acid 3a (1 mmol), catalyst (5 mg) and solvent (2 mL) were stirred at appro-
priate temperature.
b
Isolated yield.
whereas in other green solvents such as ethylene glycol and poly-
ethylene glycol, the product was isolated in 78% yield (entries 2
and 3, Table 1). Moreover, polar organic solvents such as DMF
and DMSO afforded product (4aa) in 85% and 82% yields respec-
tively (entries 4 and 5, Table 1). To our delight, product (4aa)
was obtained in 92% yield under neat condition (entry 6, Table 1).
Next, we studied the effect of catalyst loading under neat condi-
tion. Upon increasing the catalyst amount to 10 mg, there was no
further improvement in the yield of product (entry 7, Table 1),
whereas upon decreasing the catalyst amount to 3 mg the yield
was dropped to 88% (entry 8, Table 1). The yield of product (4aa)
was dropped gradually upon decreasing the temperature to 50 °C
(entries 9–11, Table 1). There was no product formation at room
temperature even after prolonged reaction time (entry 12,
Table 1,).
Next, we screened Fe
optimized reaction conditions. The results showed that Fe
product in 30% yield while CuO NPs gave 81% yield (entries 13 and
14, Table 1). On the other hand, CuCl yielded product in 76% (entry
2
O
3
and CuO NPs alone as catalysts under
2 3
O
gave
2
15, Table 1). There was no product formation in the absence of cat-
alyst under optimized reaction conditions (entry 16, Table 1).
Therefore, the optimized condition was found to be usage of
5 mg of CuO/Fe
2 3
O catalyst at 110 °C under neat condition to afford
the trisubstituted propargylamines (4aa) in 92% yield.

4
470
U. Gulati et al. / Tetrahedron Letters 57 (2016) 4468–4472
Table 2
CuO/Fe
catalyzed synthesis of trisubstituted propargylamine via decarboxylative A3 coupling reactiona
2
O
3
R
R
N
CuO/Fe O catal.
2
3
R
R
Ar
CHO
Ph
COOH
+
N
H
+
Ar
o
Neat, 110 C
1
2
3a
4
Ph
CHO
F C
CHO
CHO
3
CHO
CHO
CHO
Cl
F
NO2
CF3
1a
1b
1c
1d
CHO
F
1e
1f
O
CHO
CHO
F
CHO
N
H
N
H
OMe
MeO
1g
1h
1i
1j
2a
2b
HN
N
HN
N
NO
2
HN
N
N
N
HN
N
2c
2d
2e
2f
Cl
S No.
Aldehyde (1)
Amine (2)
Product (4)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1d
1e
1e
1f
2a
2c
2d
2c
2f
2d
2e
2d
2e
2b
2d
2a
2f
4aa
4bc
4bd
4cc
4df
4ed
4ee
4fd
4fe
4gb
4gd
4ha
4hf
4id
4ie
92
91
90
92
68
90
92
85
88
90
93
94
75
89
89
90
1f
1
1
1
1
1
1
1
0
1
2
3
4
5
6
1g
1g
1h
1h
1i
2d
2e
2e
1i
1j
4je
a
2 3
Reaction conditions: aldehydes 1 (1 mmol), secondary amines 2 (1 mmol), phenylpropiolic acid 3a (1 mmol), CuO/Fe O (5 mg) were stirred at 110 °C under neat
condition.
b
Isolated yield.
Furthermore, the substrate scope for present method was stud-
ied from various aromatic aldehydes having electron donating as
well as electron withdrawing substituents (Table 2). Secondary
amines were also varied in order to study the versatility of the pre-
sent method and 7-chloro-4-(piperazin-1-yl)quinolone (2f) was
used as a novel secondary amine to generate the biologically
potent framework for the first time as shown in Table 2. The results
showed that the reactions proceeded smoothly with almost all
screened substrates to afford corresponding products in 68–94%
yields (Table 2).
CuO/Fe
2 3
O catalyzed decarboxylative KA2 coupling reaction
Next, we studied the versatile catalytic potential of CuO/Fe
2 3
O
NPs for decarboxylative KA2 coupling among cyclohexanone (5a),
morpholine (2a) and phenylpropiolic acid (3a) under optimized
conditions. The optimization study revealed that the usage of
5 mg of catalyst at 110 °C under solvent free condition was best
to afford product in 85% yield (see SI for details on optimization
table S1). The generality and substrate scope was studied for decar-
boxylative KA2 reaction using various cyclic ketones (5), secondary

U. Gulati et al. / Tetrahedron Letters 57 (2016) 4468–4472
4471
Table 3
CuO/Fe
catalyzed synthesis of tetrasubstituted propargylamine via decarboxylative KA2 coupling reactiona
2
O
3
R
O
Ar
R
N
R
CuO/Fe
O catal.
2 3
R
HOOC
Ar
O
+
N
H
+
Neat, 110 o
C
5
2
3
6
Ph
O
N
O
O
O
N
N
H
N
H
Ph
5c
5d
5
a
5b
2a
2c
NO2
COOH
COOH
N
S
N
N
N
N
H
H
N
H
N
H
2
d
2e
2g
2h
3a
3b
S No.
Ketone (5)
Amine (2)
Phenylpropiolic acid (3)
Product (6)
Yieldb (%)
1
2
3
4
5
6
7
8
9
5a
5d
5b
5b
5a
5d
5b
5d
5c
5d
5d
5a
2a
2a
2a
2g
2c
2c
2c
2c
2c
2h
2e
2d
3a
3b
3a
3a
3a
3b
3a
3a
3a
3a
3a
3a
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
82
84
85
87
88
85
84
87
85
86
89
1
1
1
0
1
2
6j
6k
6l
a
2 3
Reaction conditions: Ketones 5 (1 mmol), secondary amines 2 (1 mmol), phenylpropiolic acids 3 (1 mmol), CuO/Fe O (5 mg) were stirred at 110 °C under neat condition.
Isolated yield.
b
amines (2) and phenylpropiolic acids (3). The results showed that
almost all screened substrates underwent KA2 coupling smoothly
to afford corresponding propargylamines in 82–89% yields as
shown in Table 3.
and dried in oven at 90 °C for 8 h. The recovered catalyst was
reused up to five more cycles for carrying out the decarboxylative
A3 reaction. The results showed that there was no significant loss
in its catalytic activity as shown in Figure 2.
On the basis of experimental observation, we proposed the
2 3
plausible mechanism for CuO/Fe O catalyzed decarboxylative
coupling reactions as shown in Figure 1. The first step involves
Conclusion
the formation of copper carboxylate species (I) by the reaction of
CuO/Fe O with aryl propiolic acid (3). The copper carboxylate
2 3
intermediate (I) undergo decarboxylation to afford reactive alkynyl
intermediate (II), which further reacts with preformed imine (III)
to afford the propargylamines (4 or 6).
We have studied the utilization of decarboxylative strategy for
the synthesis of trisubstituted and tetrasubstituted propargylami-
nes for A3 and KA2 coupling reactions respectively using
CuO/Fe
ergistic effect of Fe
2
O
3
MRNCs for the first time. The results revealed that syn-
and CuO is responsible for excellent yields of
2 3
O
2 3
The recyclability of CuO/Fe O nanocatalyst was checked for
propargylamines. Furthermore, involvement of neat reaction
condition and magnetic recoverability of nanocatalysts make this
method economically profitable and environment friendly with
easy handling without work up procedures, recyclable for six
decarboxylative A3 coupling for the synthesis of 4aa under
optimized reaction conditions. After carrying out the reaction,
the catalyst was magnetically recovered, washed with ethanol

4
472
U. Gulati et al. / Tetrahedron Letters 57 (2016) 4468–4472
O
O
H+
CuO
CuO
Ar
CuO
Fe O
2
3
CuO
CuO
O
CuO
Ar
OH
(I)
3
CO2
Ar
CuO
CuO
CuO
Fe O
2
3
CuO
CuO
CuO
CuO
CuO
CuO
Fe O
2
3
CuO
CuO
R3
R4
CuO
N
(
II)
R4
R1
R3
R2
Ar
R1
N
O
R2
R3
R4
N
H
4
or 6
R1
R2
(
III)
1
2
Figure 1. Plausible mechanism of CuO/Fe
2
O
3
catalyzed syntheses of propargylamines.
100
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Acknowledgments
1
D.S.R. acknowledges DST-JSPS for financial support. U.G and U.
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Supplementary data associated with this article can be found, in
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0
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