Fe3O4 nanoparticle-supported copper(I) pybox catalyst: Magnetically recoverable catalyst for enantioselective direct-addition of terminal alkynes to imines

Article abstract of DOI:10.1021/ol102759w

An Fe₃O₄ nanoparticle-supported copper(I) pybox catalyst, which exhibits excellent reactivity and yields products with good enantioselectivity, was developed. As a proof of concept, six optically active propargyl amines were obtained

Full text of DOI:10.1021/ol102759w

ORGANIC
LETTERS
2011
Vol. 13, No. 3
442-445
Fe3O4 Nanoparticle-Supported Copper(I)
Pybox Catalyst: Magnetically
Recoverable Catalyst for
Enantioselective Direct-Addition of
Terminal Alkynes to Imines
Tieqiang Zeng,†,‡ Luo Yang,‡ Reuben Hudson,‡ Gonghua Song,*,†
Audrey R. Moores,‡ and Chao-Jun Li*,‡
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and
Pharmaceuticals, East China UniVersity of Science and Technology,
Shanghai 200237, P.R. China, and Department of Chemistry, McGill UniVersity, 801
Sherbrooke St. West, Montreal, Quebec, Canada, H3A 2K6
ghsong@ecust.edu.cn; cj.li@mcgill.ca
Received November 14, 2010
ABSTRACT
An Fe3O4 nanoparticle-supported copper(I) pybox catalyst, which exhibits excellent reactivity and yields products with good enantioselectivity,
was developed. As a proof of concept, six optically active propargyl amines were obtained in excellent yields. The catalyst can be magnetically
removed and recycled easily six times without a decrease in activity or enantioselectivity.
The use of more environmentally benign catalysts coupled
with practical and efficient processes for catalyst separation
and reuse provides both economical and ecological benefits.1
Because of the ease of magnetic separation from the reaction
mixture, this strategy, taking advantage of magnetic nano-
particles, is typically more effective than filtration or
centrifugation as it prevents loss of the catalyst.2 Magnetic
separation of nanoparticles is simple, economical, and
promising for industrial applications.3 In recent years, the
direct use of magnetic Fe3O4 (magnetite) nanoparticles as
magnetically recoverable catalysts for organic reactions was
† East China University of Science and Technology.
‡ McGill University.
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10.1021/ol102759w  2011 American Chemical Society
Published on Web 12/28/2010

developed by us and others.4 Furthermore, Fe3O4 nanopar-
ticles have emerged as robust and high-surface-area hetero-
geneous catalyst supports,5 and various strategies have
successfully demonstrated the applications of Fe3O4 nano-
particle-immobilized or -supported catalysts.6
Optically active propargyl amines, products of the asymmetric
three-component aldehyde-alkyne-amine coupling (AA3 cou-
pling), are useful building blocks and important skeletons for
biologically active compounds or natural products.7 Recently,
great efforts have been made to develop the methodology for
generating optically active propargylamines.8 We pioneered a
highly enantioselective addition of terminal alkynes to imines
to afford optically active propargylamines by using a chiral
Cu(I)-bis(oxazolinyl)pyridine (pybox) complex catalyst (Figure
1).8a,b Pybox ligands, which demonstrate great versatility in
complexation of the transition metals, were effective in a
number of highly enantioselective catalytic processes. While
several methods for the preparation of immobilized or
supported pybox ligands have been demonstrated,9 to the
best of our knowledge, no example of magnetic nanoparticle-
supported pybox complex has been reported. Herein, we wish
to report a novel magnetically recoverable Fe3O4 nanopar-
ticle-supported copper(I) pybox catalyst and its application
Figure 1. (A) Fe3O4 nanoparticle-supported copper(I) pybox catalyst
dispersion in reaction solution. (B) Fe3O4 nanoparticle-supported
copper(I) pybox catalyst adsorbed on the magnetic stirring bar.
in enantioselective direct-addition of terminal alkynes to
imines. It was found that the Fe3O4 nanoparticle-supported
copper(I) pybox exhibits high reactivity, yielding products
with good enantioselectivity. Recovery of the catalyst by
decantation of the reaction mixture in the presence of an
external magnet is easy and efficient. The catalyst was
recycled over six times without any significant loss in activity
and enantioselectivity.
The 4-bromo-substituted phenyl-pybox ligand 1, generated
from chelidamic acid 2, was selected as a suitable derivative
for further functionalization. Chelidamic acid 2 was trans-
formed to dimethyl 4-bromopyridine-2,6-dicarboxylate 3 in
high yield (Scheme 1).9b
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Scheme 1. Synthesis of 4-Bromo-Substituted Phenyl-Pybox
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Org. Lett., Vol. 13, No. 3, 2011
443

silica-coated nanoparticles with excess 3-aminopropyltri-
ethoxysilane in toluene at room temperature afforded silica
nanospheres functionalized with amine groups 6.10 CuBr/
BINOL(1,1′-binaphthyl-2,2′-diol)-catalyzed N-arylation reac-
tion of ligand 1 and NPs 6 afforded 7.11 The application of
this CuBr/BINOL-catalyzed N-arylation method was con-
firmed by reaction of 1 and 2-phenylethanamine, which gave
a high yield (81%, yield based on 1). In this reaction, the
pybox ligand remained stable under the mild reaction
conditions of 50 °C and the presence of K3PO4 as the base.
It is worth noting that a control experiment indicated the
stability of the secondary aromatic amine under reaction
conditions of copper(I) pybox catalyzed enantioselective
direct addition of terminal alkynes to imines (and secondary
aromatic amine is also the desired product of this reaction),
suggesting that this secondary amine linker remains intact
throughout the reactions. Compound 7 was washed with
solvents and aqueous EDTA solution several times to
eliminate copper residue12 and then stirred with a dichlo-
romethane solution of (CuOTf)2·toluene, filtered, and washed,
yielding the magnetically recoverable Fe3O4 nanoparticle-
supported copper(I) pybox catalyst 8. The loading process
proceeded cleanly (0.20 mmolg-1 loading, calculated by ICP-
AES test of Cu), and transmission electron microscopy
(TEM) demonstrated that in the core-shell structure of the
nanoparticles there are small Fe3O4 nanoparticle clusters
encapsulated within the silica in the core/shell Fe3O4@SiO2
nanoparticles.
Scheme 2
.
Preparation of Fe3O4 Nanoparticle-Supported
Copper(I) Pybox Catalyst
To evaluate the efficiency of the Fe3O4 nanoparticle-
supported copper(I) pybox catalyst, it was tested in enantio-
selective direct-addition reactions of terminal alkynes to
imines. Our experiments revealed that 8 exhibits high
reactivity and good enantioselectivity. For example, the
reaction of 1.5 equiv of phenylacetylene with N-(4-bro-
mobenzylidene)aniline in dichloromethane in the presence
of 10 mol % of catalyst at 35 °C for 36 h under argon
atmosphere afforded the adduct in 92% yield and 92% ee
(entry 2, Table 1). The optical rotation of the product showed
the same sign as the one obtained from the homogeneous
nanoparticle-supported copper(I) pybox was prepared by the
concise route schematically illustrated in Scheme 2. Mag-
netite (Fe3O4) NPs (<50 nm particle size (TEM)) were
purchased from Sigma-Aldrich (Figure 2). The NPs were
Table 1. Fe3O4 Nanoparticle-Supported Copper(I)
Pybox-Catalyzed Enantioselective Direct-Addition Reactions of
Terminal Alkynes to Iminesa
Figure 2. TEM images of (a) Fe3O4 and (b) core/shell Fe3O4@SiO2
nanoparticles.
yield ee
entry
aldehyde
PhCHO
4-BrC6H4CHO PhNH2
4-ClC6H4CHO PhNH2
4-CF3C6H4CHO PhNH2
aniline
PhNH2
akyne
PhCCH
PhCCH
PhCCH
PhCCH
(%) (%)
1
2
3
4
5
6
91
92
90
80
94
86
92
92
86
84
85
then coated with a silica layer to generate 5.10 This step was
carried out to protect the Fe3O4 NP cores, considering the
potential particle oxidation and aggregation of Fe3O4 NPs
and the potential interactions between Fe3O4 and copper(I)
pybox complex or reaction intermediates. Treatment of the
PhCHO
PhCHO
4-BrC6H4NH2 PhCCH
PhNH2
4-MeC6H4CCH 93b
a Isolated yield of analytically pure product, reaction conditions: 10 mol
% catalyst, CH2Cl2 (0.5 mL), aldehyde (0.2 mmol), aniline (0.24 mmol),
alkyne (0.3 mmol), 35 °C, 36 h, under argon atmosphere. b Reacted for 2
days.
(10) Choi, J.; Kim, J. C.; Lee, Y. B.; Kim, I. S.; Parka, Y. K.; Hur,
N. H. Chem. Commun. 2007, 1644–1646.
444
Org. Lett., Vol. 13, No. 3, 2011

catalyst.8a A variety of substrates were examined, the results
of which are summarized in Table 1. In all cases, the
reactions took place smoothly, giving propargylamines in
high yields and good enantioselectivity. The most probable
reason for the higher reactivity of Fe3O4 nanoparticle-
supported copper(I) pybox catalyst over other solid-phase
supported pybox catalysts is that nanoparticles have a much
larger surface area to volume ratio, which can provide a
higher catalytic activity.9 Separate experiments demonstrated
that (CuOTf)2·toluene catalyzed this reaction (substrates in
entry 1, Table 1) to afford only trace amounts of racemic
products, and 1 is not catalytically active in this addition
reaction. It can therefore be assumed that the Fe3O4 nano-
particle-supported copper(I) pybox complex 8 is responsible
both for the activity as well as the enantioselectivity.
Recovery of the catalyst is easy and efficient. When the
magnetic stirring was stopped, the Fe3O4 nanoparticle-
supported copper(I) pybox catalyst adsorbed onto the mag-
netic stirring bar. The catalyst was recovered by decantation
of the reaction mixture in the presence of an external magnet.
The catalyst was then washed with dichloromethane, dried
under high vacuum, and used directly for the next round of
reaction without further purification. The ease of recovery,
combined with the intrinsic stability of both the copper(I)
pybox (under argon atmosphere) and silica-protected Fe3O4
nanoparticle components, allows the catalyst to be recycled
over six times in reactions without any significant loss in
activity and enantioselectivity (Table 2). The possible reason
for the slight ee (%) reduction is that a small amount of
pybox ligand decomposed after several cycles.
Table 2. Recycling of the Fe3O4 Nanoparticle-Supported
Copper(I) pybox Catalysta
cycle
yield (%)
ee (%)
cycle
yield (%)
ee (%)
1
2
3
89
90
92
87
86
86
4
5
6
92
90
82
85
84
81
a Isolated yield of analytically pure product, reaction conditions: 10 mol
% catalyst, CH2Cl2 (0.5 mL), benzaldehyde (0.2 mmol), aniline (0.24 mmol),
phenylacetylene (0.3 mmol), 35 °C, 36 h, under argon atmosphere.
yielding products with good enantioselectivity. The catalyst
can be synthesized from readily available starting materials
or directly on the solid phase easily and remains intact
throughout the reactions. Recovery of the catalyst by
decantation of the reaction mixture in the presence of an
external magnet is easy and efficient. The catalyst was
recycled over six times in reactions without any obvious loss
in activity and enantioselectivity. Several optically active
propargylamines were obtained in excellent yields. Further
study on the wider applications of this efficient strategy is
under investigation in our laboratory.
Acknowledgment. We are grateful to the Canada Re-
search Chair Foundation (to C.J.L. and A.R.M.), the CFI,
FQRNT (Center for Green Chemistry and Catalysis), NSERC,
National Basic Research Program of China (973 Program,
2010CB126100), and McGill University for support of our
research.
In summary, we have developed an Fe3O4 nanoparticle-
supported copper(I) pybox catalyst which exhibits excellent
reactivity in asymmetric aldehyde–alkyne–amine coupling,
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72,
672–674.
(12) The Cu(I)Br will reduce the enantioselectivity of the products.8a
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