Ligand modified CuFe2O4 nanoparticles as magnetically recoverable and reusable catalyst for azide-alkyne click condensation

Article abstract of DOI:10.3987/COM-12-S(N)125

A ligand can make the trick: 2,2'-bipyridine was found to promote the activity of copper ferrite nanoparticles as catalysts for the azide-alkyne "click" coupling reaction. The reaction proceeded in excellent yields at room temperature, and the catalyst co

Full text of DOI:10.3987/COM-12-S(N)125

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1023 - 1030. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 27th September, 2012, Accepted, 1st November, 2012, Published online, 14th November, 2012
DOI: 10.3987/COM-12-S(N)125
LIGAND MODIFIED CuFe2O4 NANOPARTICLES AS MAGNETICALLY
RECOVERABLE AND REUSABLE CATALYST FOR AZIDE-ALKYNE
CLICK CONDENSATION
Shingo Ishikawa,1 Reuben Hudson,1 Audrey Moores,1* and Chao-Jun Li1*
Center for Green Chemistry and Catalysis, Department of Chemistry, McGill
University, 801 Sherbrooke St. West, Montreal, QC, H3A 0B8, Canada e-mail:
Audrey.moores@mcgill.ca. cj.li@mcgill.ca
Abstract – A ligand can make the trick: 2,2’-bipyridine was found to promote the
activity of copper ferrite nanoparticles as catalysts for the azide-alkyne “click”
coupling reaction. The reaction proceeded in excellent yields at room temperature,
and the catalyst could be magnetically separated and recycled. Phosphorus and
nitrogen containing ligands were tested and 2,2’-bipyridine proved to be the most
efficient for this reaction.
With nanoparticles (NPs) emerging as a powerful class of catalysts,1 there is a great need to develop
means to ensure their recovery.2 One of the most promising strategies has been the use of magnetically
recoverable NPs as recyclable catalysts and many organic transformations have already been developed.3
These systems allow an easy recovery in the presence of an external magnet, avoiding the need for
centrifugation. Iron-based materials are particularly interesting as they combine magnetic properties with
low toxicity and earth-abundance and they have proved effective catalysts for coupling,4 hydrogenation5
and oxidation reactions.6 Other simple magnetic NPs have allowed the scope expansion of such systems.
Copper ferrite (CuFe2O4) NPs are inexpensive, air-stable, magnetically separable, and recyclable catalysts,
which can catalyze C-C,7a C-N,7b C-O,7c C-S7d and C-Se7e cross-coupling reactions and other
transformations.7f-7j
The azide-alkyne cycloaddition (AAC) reaction is a good illustration of these developments. The AAC8
is of great interest because this ‘click chemistry’ can rapidly create molecular diversity through the use of
reactive modular building blocks.9 The catalyzed AAC reaction has found a wide range of applications in
various research areas, including medicinal chemistry10 and material science.11 Typically the AAC
reaction is catalyzed by Cu(I) salts; alternatively, Cu(II) may be used if coupled with a mild reducer such
Dedicated with respect to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
as sodium ascorbate.12 Cu(I) species may be immobilized onto polymers,13 zeolite,14 or magnetic
nanoparticles to ease recovery.15 Heterogeneous systems have also been developed including Cu(0) on
charcoal,16 Cu(0) NPs,17 microwave irradiated Cu turnings,18 and CuO nanostructures.19 Recently, we
demonstrated that simple, unfunctionalized heterogeneous copper-plated iron NPs are effective catalysts
for the AAC.20 This study was based on the rationale that the addition of Cu(II) salts to Fe(0) NPs
provided the Cu(I) species necessary for AAC catalysis. In the course of this work, we attempted to
achieve a similar outcome by adding sodium ascorbate to CuFe2O4 NPs to afford in situ reduction.
Unfortunately, this resulted in the complete dissolution of the NPs, and thus prevented recovery. In the
present work, we explored the addition of electron donating ligands to a Cu(II) containing material,
CuFe2O4 NPs. This system provided a recoverable and very active catalyst for the AAC reaction.
Our initial studies began with the model cyclization of benzyl azide and phenyl acetylene using a catalytic
amount of copper ferrite (Scheme 1). The coupling product was obtained in 15% NMR yield in the
absence of ligand, however the reaction could be accelerated by heating up at 80 ˚C, providing the
product in excellent yield as a single regioisomer.
N
N
N
10 mol% CuFe2O4
Et3N, EtOAc, 24 h
N3
+
15% NMR yield at room temperature
96% NMR yield at 80 oC
Scheme 1. CuFe2O4-catalyzed AAC reaction
Table 1. Screening of reaction conditions for AAC reaction[a]
In search of milder conditions, we sought
to determine the best ligand for the
nano-CuFe2O4-AAC reaction at room
temperature. The results are summarized
in table 1. The use of phosphine ligands
led to increased yields (Table 1, entries 1
and 2). Trace amounts of product were
obtained in the presence of acetylacetone
(Table 1, entry 3). Monodentate nitrogen
ligands such as pyridine did not
significantly affect the reaction (Table 1,
entries 4 and 5). Among the bidentate
nitrogen ligands, TMEDA and 1,10
phenanthroline gave very poor results
N
10 mol% CuFe2O4
N
N
10 mol% ligand
N3
+
Et3N, EtOAc, rt
24 h
Entry
Catalyst
Ligand
Yield [%][b]
1
2
CuFe2O4 PPh3
CuFe2O4 DIPHOS
49
29
3
4
CuFe2O4 acetylacetone
CuFe2O4 pyridine
trace
19
5
6
CuFe2O4 2-phenylpyridine
CuFe2O4 TMEDA
9
30
7
8
9
10
11
CuFe2O4 1,10-phen
CuFe2O4 2,2'-bipyridine
CuFe2O4 2,2':6',2''-terpyridine
4
96, 100[c]
trace
trace
trace
none
Fe3O4
2,2'-bipyridine
2,2'-bipyridine
[a] Reaction conditions: Benzyl azide (1.0 mmol), phenylacetylene (1.5
mmol), catalyst (10 mol%), ligand (10 mol%), base (1.0 mmol), EtOAc
(2 mL), T = rt
[b] NMR yield using an internal standard.
[c] 5 mol% of catalyst and 5 mol% of ligand were used.

HETEROCYCLES, Vol. 86, No. 2, 2012
1025
(Table 1, entries 6-7). 2,2’-Bipyridine derivatives gave the desired product in excellent yield (over 96%)
(Table 1, entry 8). The amount of catalyst and ligand could be reduced to 5 mol% and surprisingly
afforded 100% conversion. Tridentate ligands afforded only a trace amount of product (Table 1, entry 9).
Control experiments were carried out to confirm that no product was obtained in the absence of copper
catalyst (Table 1, entry 10). Likewise, entry 11 demonstrates the necessity of copper within the ferrite
lattice, because replacing it with iron (Fe3O4) provides only a trace amount of product.
The influence of the solvent was
Table 2. Screening of solvent for AAC reaction
evaluated
under
the
optimized
N
10 mol% CuFe2O4
N
N
conditions. Diethyl ether, dimethyl
sulfoxide (DMSO) and methanol
afforded the products in moderate
yields (Table 2, entries 4, 6 and 8). The
reaction in water was possible in the
presence of ligands, however, the
nanoparticles dissolved and could not
be recovered. Reactions conducted in
ethyl acetate, acetone, toluene, THF
and acetonitrile gave the product in
excellent yield (Table 2, entries 1-3, 5
and 7). The reaction did not require
strict conditions such as anhydrous
10 mol% 2,2'-bipyridine
N3
+
Et3N, solvent, rt
Entry
Solvent
EtOAc
acetone
toluene
Et2O
Yield [%][b]
1
2
3
4
5
6
7
8
9
96
94
96
67
THF
100
80
100
63
DMSO
MeCN
MeOH
H2O
82
[a] Reaction conditions: benzyl azide (1.0 mmol), phenylacetylene (1.5
mmol), CuFe2O4 (10 mol%), 2,2-bipyridine (10 mol%), Et3N (1.0
mmol), solvent (2 mL), T = rt
[b] NMR yield using an internal standard.
(Table 2, entry 9) or degassed solvent or inert atmosphere – a noteworthy improvement over our previous
report with copper plated iron(0) nanoparticles.20
With the optimized conditions in hand, we focused our attention to substrate generality. Various terminal
alkynes including, aromatic and aliphatic acetylenes, were examined under these optimized conditions
(Table 3). Aromatic alkynes with electron-withdrawing groups (Table 3, entries 4-6) were more reactive
than those with electron-donating groups (Table 3, entries 2-3). Only a trace amount of product was
obtained in the reaction with pyridylacetylene and most of the starting material was recovered. This is
likely due to the strong coordination of the nitrogen in the acetylene, preventing activation of alkyne
moiety. The reaction with an aliphatic alkyne was very sluggish. This reaction, therefore, required slight
heating and a longer reaction time (Table 3, entry 11). The reaction with propargyl alcohol derivatives
afforded the products in moderate to good yields (Table 3, entries 12-14). The reactions of primary, and
secondary alkyl and functionalized azides with various alkynes are also effective to give the products in
moderate yields (Table 3, entries 16-20).

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HETEROCYCLES, Vol. 86, No. 2, 2012
To expand the utility of nano-CuFe2O4 for AAC, a reaction on a larger scale was carried out with 2 gram
of substrates (Scheme 2). It should be noted that the click reaction successfully afforded the product in
96% yield and 90% of the catalyst was recovered (compared with Table 3, entry 18).
The reusability of the nano-CuFe2O4 catalyst was examined and the results are summarized in Figure 1.
The reaction of benzyl azide with phenylacetylene was chosen as a model reaction. The catalyst was
magnetically separated from the reaction mixture after completion of the reaction, washed with solvent
and used directly for further AAC reaction. Acetonitrile, acetone, toluene, THF and ethyl acetate were
Table 3. CuFe2O4 catalyzed AAC reactions[a]
5 mol% CuFe2O4
N
5 mol% 2,2'-bipyridine
Et3N, rt
R1
N
N
R1 N3
R2
+
R2
1
2
3
Entry
1
Triazole
3
Yield[b]
Entry
11
Triazole
3
Yield[b]
59%[c]
3a
3b
3c
96%
57%
78%
3k
12
13
3l
87%[d]
70%[d]
3
4
3m
3d
3e
85%
94%
14
15
3n
3o
52%[d]
38%[d]
5
6
7
3f
3g
3h
3i
93%
62%
76%
80%
trace
16
17
18
19
20
3p
3q
3r
3s
3t
89%
82%
94%
N
N
N
O
9
85%[d]
59%[c]
OH
EtO
10
3j
[a] Reaction conditions: azide (1.00 mmol), alkyne (1.50 mmol), triethylamine (1.0 mmol), CuFe2O4 (0.05 mmol),
2,2‘-bipyridine (0.05 mmol), ethyl acetate (2.0 mL), room temperature, 24h.
[b] Isolated yields.
[c] The reaction was carried out at 40 oC for 72 h.
[d] The reaction was carried out at room temperature for 72 h.

HETEROCYCLES, Vol. 86, No. 2, 2012
1027
N
EtO
N
N
5 mol% CuFe2O4
O
5 mol% 2,2'-bipyridine
O
N3
+
EtO
Et3N, EtOAc, rt
2.0 g
3.4 g, 96%
recovery of CuFe2O4 90 %
Scheme 2. Gram scale synthesis using nano-CuFe2O4 catalyst
tested as solvents over 5 cycles. Ethyl acetate
proved to be the best solvent with very little
attrition of activity over 5 cycles (Figure 1,
ESI). The catalyst loading was also tested in
the recycling context. One or two mol% led to
a decrease in activity over 5 cycles, while 5 or
10 mol% enabled the system to sustain
catalytic activity.21
96
95
100
80
60
40
20
0
91
89
87
1st
2nd
3rd
4th
5th
Recycling tests
To check for potential leaching of metal into
the solution, ICP-OES analysis was carried out.
After the reaction, the nanoparticles were
magnetically removed and the solution was
filtered through Celite. The reaction at room
temperature and 40 ˚C were tested (Table 3,
entries 1 and 11). It was determined to be 0.027
and 0.45 ppm, respectively. This result strongly
suggests a heterogeneous mechanism. Figure
1a, b in ESI shows the TEM images of the
CuFe2O4 catalyst before and after use.
Figure 1. Recycling of the CuFe2O4 catalyst (5
mol%) in ethyl acetate
R1
L
H
N N
+
Et3N +
N
R2
R1
Et3N
L
Fe Cu Cu Fe
O
O
O
Et3N H
Et3N H
R1
N N
R2
N
R1
Fe
L
Fe Cu Cu
Fe Cu Cu
Fe
O
O
O
O
O
O
The reaction mechanism has not yet been
elucidated, but on the basis of the previously
reported Cu(II)-Hydrotalcite catalyst by
Pitchumani and co-workers,22 we propose the
mechanism described in scheme 3. The
reaction may proceed through an activation of
alkyne, followed by cycloaddition of azide and
R2 N3
R1
N
N
R2
N
Fe Cu Cu
Fe
O
O
O
Scheme 3. Proposed mechanism for the CuFe2O4
catalyzed AAC
protonation on the surface of the copper ferrite nanoparticles. The observation of the sole 1,4-adduct as

1028
HETEROCYCLES, Vol. 86, No. 2, 2012
reaction product is in agreement with the proposed mechanism.
In conclusion, we have demonstrated the application of CuFe2O4 nanoparticles for ‘click’ reaction. The
reaction did not require strict conditions such as anhydrous or degassed solvent or inert atmosphere, and
was applicable for gram scale synthesis. The catalyst could be separated and recovered easily by an
external magnet and efficiently reused several times without significant loss of activity. Further
applications of magnetic nanoparticles are in progress in our laboratory.
ACKNOWLEDGEMENTS
We thank the Natural Science and Engineering Research Council of Canada (NSERC), the Canada
Foundation for Innovation (CFI), the Canada Research Chairs (CRC), the Fonds de Recherche sur la
Nature et les Technologies (FQRNT), the Center for Green Chemistry and Catalysis (CGCC), the Green
Chemistry - NSERC Collaborative Research and Training Experience (CREATE) Program and McGill
University for their financial support.
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21. General protocol; To a stirred solution of benzyl azide (1.0 mmol), phenylacetylene (1.5 mmol)
and triethylamine (1.0 mmol) in EtOAc (2.0 mL) were added nano-CuFe2O4 powder (0.05 mmol) and
2,2’-bipyridine (0.05 mmol). The reaction mixture was stirred at rt for 24 h. After completion of the
reaction, the reaction mixture was extracted with EtOAc (2 mL x5). The combined solution was
concentrated in vacuo to give the crude product, which was washed with hexane (10 mL x2) and then
purified by flash column chromatography (Hexane:EtOAc = 5:1) on silica gel to yield the product as
a white solid.
Recycling Experiment for CuFe2O4 Nanoparticles; After completion of the reaction, the catalyst
was recovered magnetically with the aid of an external magnet, and washed with EtOAc. It was
directly used or dried under reduced pressure.
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