Magnetic nanoparticle-supported proline as a recyclable and recoverable ligand for the CuI catalyzed arylation of nitrogen nucleophiles

Article abstract of DOI:10.1039/b711298j

Magnetic nanoparticle-supported proline ligand was prepared and used for the CuI catalyzed Ullmann-type coupling reactions of aryl/heteroaryl bromides with various nitrogen heterocycles to form the corresponding N-aryl products in good to excellent yields

Full text of DOI:10.1039/b711298j

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Magnetic nanoparticle-supported proline as a recyclable and
recoverable ligand for the CuI catalyzed arylation of nitrogen
nucleophiles{
Gagan Chouhan,a Dashan Wangb and Howard Alper*a
Received (in Cambridge, UK) 24th July 2007, Accepted 28th August 2007
First published as an Advance Article on the web 12th September 2007
DOI: 10.1039/b711298j
to immobilize them.11 Therefore, development of new strategies to
Magnetic nanoparticle-supported proline ligand was prepared
and used for the CuI catalyzed Ullmann-type coupling
reactions of aryl/heteroaryl bromides with various nitrogen
heterocycles to form the corresponding N-aryl products in good
to excellent yields; furthermore, this magnetic nanoparticle-
supported proline ligand could be readily separated using an
external magnet and reused without significant loss of activity.
immobilize these ligands for copper-catalyzed cross-coupling
protocols is of considerable interest. Thus, we have developed a
magnetic nanoparticle-supported proline ligand and evaluated its
activity for the CuI catalyzed N-arylation of various nitrogen
heterocycles.
Magnetite (Fe3O4) nanoparticles were prepared by coprecipita-
tion of iron(II) and iron(III) ions in basic solution at 85 uC using the
method described by Massart.12 Azide functionalized magnetite
(MNP-1) was prepared by treating the nanoparticles with the
phosphonic acid ligand 1 as described in Scheme 1. The IR
spectrum of MNP-1 clearly shows strong absorption at 2092 cm21
due to azide (–N3) asymmetric stretching (see ESI{). The loading
of the ligand on the magnetic nanoparticles was determined by
elemental analysis of nitrogen as 2.3 mmol g21. The TEM images
(see ESI{) of the azide functionalized magnetic nanoparticles
(MNP-1 shows slight aggregation and the size of the particles were
between 6 and 15 nm. Immobilization of the proline ligand was
carried out by the Cu(I)-catalyzed alkyne–azide [2 + 3] cycloaddi-
tion reaction of CuSO4, sodium ascorbate and triethyl amine in a
1 : 1 mixture of tert-butyl alcohol and water at room temperature
for 24 h to give the proline functionalized magnetic nanoparticles
MNP-2. The IR spectrum of MNP-2 (see ESI{) showed virtual
disappearance of the azide signal, and new bands at 1737 and
1693 cm21 which correspond to the tert-butyl-N-Boc prolinate.
The TEM images (see ESI{) shows disperse nanoparticles,
suggesting that the nanoparticles are stabilized from aggregation
after the click reaction with the proline ligand. The thus formed
proline ligand loaded nanoparticles was further treated with
trifluoroacetic acid (TFA) in dichloromethane to deprotect the
tert-butyl groups from the proline ligand (see ESI{ for detailed
Magnetic nanoparticles (MNP) have attracted much attention by
researchers from a wide range of disciplines, including physics,
biomedicine, biotechnology, material science and catalysis, because
of their large ratio of surface area to volume, superparamagnetic
behaviour and low toxicity.1 Recently, magnetic nanoparticles
have been used as a new alternative to porous materials for
supporting catalytic transformations.2 Their simple magnetically
driven separation from a liquid-phase reaction, makes catalyst
recovery and recycling much easier than by cross-flow filtration
and centrifugation. Additionally, the MNP-supported catalysts
also show high dispersion and reactivity with a high degree of
chemical stability. By utilizing these advantages of magnetic
nanoparticles over other supporting materials, various catalysts
and ligands have been immobilized on these particles.3 We recently
examined the use of polyaminoamido (PAMAM) dendron
functionalized magnetic nanoparticles as alternative homogenous
materials to support Rh metal for highly selective hydroformyla-
tion reactions.4 Herein we report the first example of the prepara-
tion of a magnetically separable proline ligand, and its application
towards the filtration-free, recyclable Ullmann-type reaction
between aryl/heteroaryl bromides and nitrogen heterocycles.
Ullmann-type C–N bond formation is a common strategy to
prepare biologically and medicinally important N-aryl/heteroaryl
heterocycles. Recently, various new systems have been developed
involving copper salts and nitrogen and/or oxygen ligands such as
diamines,5 diimines,6 2-aminopyrimidine-4,6-diol,7 8-hydroxyqui-
noline,8 4,7-dimethoxy-1,10-phenanthroline,8 as well as oxime-
containing compounds,9 and amino acids.10 While using these
ligands have led to significant results, little progress has been made
aCentre for Catalysis Research and Innovation, Department of
Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada K1N 6N5. E-mail: howard.alper@uottawa.ca;
Fax: 1 613 562 5871; Tel: 1 613 562 5189
bInstitute for Chemical Process and Environmental Technology,
National Research Council of Canada, 1200 Montreal Road, Ottawa,
Ontario, Canada K1A OR6
{ Electronic supplementary information (ESI) available: Synthesis and
characterisation of magnetic nanoparticles and experimental procedures.
See DOI: 10.1039/b711298j
Scheme 1 Preparation of magnetic nanoparticle-supported proline
ligand MNP-3
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Chem. Commun., 2007, 4809–4811 | 4809

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Table 1 N-Arylation of N-heterocycles with aryl and heteroaryl
bromides by CuI/MNP-3
Entrya Substrate
1
Het-NH Product
Yieldb (%)
98
2
3
98
85
4
80
Fig. 1 TEM image of MNP-3 (scale bar 10 nm)
reaction procedure) to form the proline loaded magnetic
nanoparticles MNP-3. The FTIR spectrum of MNP-3 shows no
tert-butyl or carbonyl group of the tert-butyl ester, and an
absorption at 1620 cm21 corresponds to the free acid functionality
of the proline. The TEM image of the magnetite proline
nanocomposite is illustrated in Fig. 1. Partially aggregated
nanoparticles between 6–20 nm were obtained. Elemental analysis
of the magnetite nanoparticles shows the loading of the ligand to
5
6
98
82
7
8
9
68
96
97
be approximately 2 mmol g21
.
The activity of the nanoparticle-supported proline ligand MNP-
3 was first evaluated for the coupling reaction of p-bromoaceto-
phenone with imidazole in N,N-dimethylformamide (DMF) at
110 uC in the presence of cesium carbonate13 and CuI (10 mol%)
catalyst. Gratifyingly, MNP-3 (at 20 mol% loading) exhibited very
high activity, allowing the quantitative conversion to product
(Table 1, entry 1). The efficacy of the CuI/MNP-3 system was
further demonstrated with a variety of other N-heterocycles such
as pyrazole, indole and benzimidazole providing the corresponding
N-aryl products in good to excellent yields (Table 1, entries 2–4).
Encouraged by these results, a variety of aryl and heteroaryl
bromides were also treated with various N-heterocycles under the
standard reaction conditions (Table 1, entries 5–16). The results
indicated that both aryl and heteroaryl bromides work well, with
the corresponding products in moderate to excellent yields. In
addition, 2-bromopyridine and 2-bromothiophene both provide
good yields of coupling products with the imidazole and the
pyrazole (Table 1, entries 11–12, 14–15). However, the N-arylation
of benzimidazole with 2-bromothiophene provides the target
product in a slightly lower yield compared to 2-bromopyridine
(Table 1, entries 13 and 16).
10
11
30
98
12
13
95
90
14
98
15
16
98
80
The recyclability of the magnetic nanoparticle-supported proline
ligand MNP-3 were also studied. After the completion of the
reaction, the reaction mixture was diluted with ethyl acetate and
the ligand was easily seperated from the product by exposure to a
external magnet and decantation of the reaction solution. The
remaining magnetic nanoparticles were further washed with the
ethyl acetate to remove residual product and dried under vacuum
and subjected to the next run. The recyclability of MNP-3 was
examined for the reaction of p-bromoacetophenone with the
imidazole. As shown in Table 2, the nanoparticle-supported
proline ligand can be reused up to four runs without any
significant loss of activity.
a
All reactions were performed at 110 uC for 24 h in DMF (0.2 ml)
with 0.1 mmol of aryl/heteroaryl bromide, 0.11 mmol of nitrogen
heterocycle, CuI (10 mol%), MNP-3 (20 mol%) and Cs2CO3
(2 equiv.). Determined by 1H NMR spectroscopy.
b
In summary, we have prepared a magnetic nanoparticle-
supported proline ligand and demonstrated its application for
the CuI catalyzed arylation of the nitrogen nucleophiles. This
magnetic nanoparticle-supported proline ligand can easily be
prepared by a click chemistry approach. Furthermore, it can be
4810 | Chem. Commun., 2007, 4809–4811
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Table 2 Recycling of MNP-3 for the coupling reaction of p-bromo-
acetophenone with imidazole
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Entrya
Recycle
Yieldb (%)
1
2
3
4
a
1st
98
98
95
93
2nd
3rd
4th
´
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All reactions were performed at 110 uC for 24 h in DMF (0.2 ml)
with 0.1 mmol of p-bromoacetophenone, 0.11 mmol of imidazole,
CuI (10 mol%), MNP-3 (20 mol%) and Cs2CO3 (2 equiv.).
b
Determined by 1H NMR spectroscopy.
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efficiently recovered from the reaction by decantation of the
reaction mixture in the presence of the external magnet and used in
up to four runs with little loss of activity. We believe that this
magnetic nanoparticle-supported proline ligand can also be useful
in biomedicine/biotechnology and drug delivery by acting as an
anchor to further immobilized biomolecules and drug candidates.
New investigations of magnetic nanoparticle-supported proline
ligands are underway.
We are grateful to Natural Sciences and Engineering Research
Council of Canada (NSERC), and to Sasol Technology, for
support of this research.
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Tetrahedron, 2006, 62, 4756.
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72, 2737.
12 R. Massart, IEEE Trans. Magn., 1981, 17, 1247.
13 Other bases such as K2CO3, Na2CO3 and K3PO4 were found to be less
effective compared to Cs2CO3.
Notes and references
1 For recent reviews, see: (a) A.-H. Lu, E. L. Salabas and F. Schu¨th,
Angew. Chem., Int. Ed., 2007, 46, 1222; (b) J. Fan and Y. Gao, J. Exp.
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Chem. Commun., 2007, 4809–4811 | 4811