Asymmetric bifunctional primary aminocatalysis on magnetic nanoparticles

Article abstract of DOI:10.1039/b812958d

MNP-supported chiral primary amine catalysts were developed and evaluated as asymmetric bifunctional enamine catalysts in direct aldol reaction, showing essentially unchanged activity and stereoselectivity after 11 recycles. The Royal Society of Chemistry

Full text of DOI:10.1039/b812958d

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Asymmetric bifunctional primary aminocatalysis on magnetic
nanoparticlesw
Sanzhong Luo,*a Xiaoxi Zhenga and Jin-Pei Cheng*ab
Received (in Cambridge, UK) 28th July 2008, Accepted 8th September 2008
First published as an Advance Article on the web 6th October 2008
DOI: 10.1039/b812958d
MNP-supported chiral primary amine catalysts were developed
and evaluated as asymmetric bifunctional enamine catalysts in
direct aldol reaction, showing essentially unchanged activity and
stereoselectivity after 11 recycles.
As structural and functional mimics of type I aldolases, simple
chiral primary amine catalysts have been shown to be versatile
enamine catalysts that attain new level of catalysis beyond the
reach of classical secondary amine catalysts.1 However, large
Fig. 1
themselves, the cyclohexanediamines are also preferred skele-
catalyst loadings were normally employed in order to over-
come the intrinsic lower turnover of primary aminocatalysis in
many of these cases. Heterogenization of primary amine
catalysts would be an effective way to improve their catalytic
efficiency via catalyst recovery and reuse.2 In this regard,
heterogeneous bifunctional primary amine catalysis has re-
cently been achieved using mesoporous silica as support.3
Unfortunately, those mesoporous primary amine catalysts
are still of low activity and only achiral catalysis has been
attempted. To the best of our knowledge, asymmetric hetero-
geneous primary aminocatalysis has not been reported so far.
As a continuation of our efforts toward developing efficient
primary aminocatalysis,4 we present herein the first example of
magnetic nanoparticle (MNP) supported chiral primary amine
catalysts.
tons for bifunctional thiourea catalysts and chiral ligands in
transitional metal catalysts,8 and so the successful immobiliza-
tion of this series of catalysts may therefore open the door to a
range of asymmetric recoverable catalysts.
The MNP-supported chiral primary amine 2 was prepared
following the procedure shown in Scheme 1. We chose mag-
netite nanoparticles as the support as these nanoparticles were
easily prepared via co-precipitation.9 The magnetite nano-
particles were first protected with a layer of silica to prevent
aggregation. The obtained SiO2–MNP was treated with tri-
methoxysilane 1 in refluxing toluene to afford the MNP-
supported catalyst 2 with 0.39 mmol gÀ1 loading of chiral
amine. Trimethoxysilane 1 was prepared via Pt-catalyzed
hydrosilylation of the allylated precursors in toluene. After
1
complete conversion of the starting material as judged by H
Magnetic nanoparticles (MNPs) have recently appeared as a
new type of catalyst support because of their easy preparation
and functionalization, large surface area ratio, facile separa-
tion via magnetic force as well as low toxicity and price.5 These
fascinating features have made MNPs a promising alternative
to porous/mesoporous catalyst supports. Accordingly, MNPs
have been successfully utilized to immobilize enzymes5c and
chiral transition metal catalysts.6 However, MNP-supported
asymmetric organocatalysts have not been attempted so far,
though a few examples of achiral organocatalysts have re-
cently been reported.7 In this context, we explored the use of
MNP for immobilizing chiral primary amine catalysts, select-
ing chiral primary–tertiary diamine type catalysts developed in
our group (Fig. 1).4 Besides serving as enamine catalysts
NMR (490% purity), the filtered toluene solution of 1 was
directly used for subsequent immobilization without further
purification.10
TEM image confirmed the nanometre dimensions (spherical
particles, 8–10 nm) of the catalyst as well as the existence of
silica coating (1–2 nm coating, Fig. 2, a). Magnetization curves
a Beijing National Laboratory for Molecular Sciences (BNLMS),
Centre for Chemical Biology, Institute of Chemistry, Chinese
Academy of Science, Beijing, 100190, China.
E-mail: luosz@iccas.ac.cn; Fax: +86-10-62554449;
Tel: +86-1062554446
b Department of Chemistry and State-key Laboratory of
Elemento-organic Chemistry, Nankai University, Tianjin, 300071,
China; E-mail: chengjp@mail.most.gov.cn
w Electronic supplementary information (ESI) available: Experimental
details and characterization of catalysts. See DOI: 10.1039/b812958d
Scheme 1 Preparation of MNP-supported chiral primary amine
catalysts.
ꢀc
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Table 2 Asymmetric direct aldol reaction of cyclohexanonea
Entry
R
Time/h
anti : synb Yield (%)c
Ee (%)d
1
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
3-NO2Ph
3-NO2Ph
2-NO2Ph
2-NO2Ph
4-CF3Ph
4-CF3Ph
4-ClPh
24
24
24
24
28
28
28
28
48
48
96
11 : 1
11 : 1
9 : 1
98
94
96
53
89
89
92
89
81
78
76
60
98
94
95
84
92
92
87
85
88
88
92
91
2e
3f
4g
5
3 : 1
10 : 1
10 : 1
8 : 1
10 : 1
6 : 1
6 : 1
6e
7
8e
9
10e
11
12
a
Fig. 2 TEM images of freshly prepared catalyst 2 (a) and catalyst 2
after 11 cycles of reuse (b); (c) magnetization curves of silica-coated
MNP (black line) and catalyst 2 (blue line); (d) catalyst 2 dispersion in
methanol; (e) catalyst separation with a small magnet.
6 : 1
2 : 1
1-Naphth 48
0.25 mmol reaction in 0.1 mL water. Determined by 1H NMR.
d
Isolated yields. Ee value of anti isomer, determined by chiral
b
c
e
f
HPLC. In 0.5 mL of water. Reaction under neat conditions.
g
measured under room temperature showed that the MNP-
supported catalyst 2 is superparamagnetic (Fig. 2, c). The
MNP catalysts are well dispersed in a range of solvents such as
water, alcohols, THF and CH2Cl2 and easily separated by a
small magnet placed nearby (Fig. 2, d and e). The zeta-
potentials of MNPs before and after functionalization were
determined to be À40.6 mV and +49.0 mV, respectively,
indicating good stability of the MNP-supported catalysts in
aqueous conditions (Fig. S5 in ESIw).
Catalyst 4 was used.
selectivity (Table 1, entry 3 vs. 2). Though the selectivity was
inferior to that obtained in homogeneous catalysis, the current
results clearly indicated that asymmetric primary amino-
catalysis could be successfully transferred to the surface of mag-
netic nanoparticles. In addition, the relative lower catalytic
efficiency in the catalysis of MNP supported primary–secondary
diamine catalyst 3 (Table 1, entry 4) or silica-supported
catalyst 4 (Table 1, entry 5 and Table 2, entry 4) also high-
lighted the advantages of the primary–tertiary diamine
skeleton along with its nano-sized support.
For comparison, MNP-supported primary–secondary diamine
311 and silica supported chiral primary amine 4 (commercial
amorphous silica for column chromatography, 200–300 mesh)
was prepared with
a
loading of 1.42 mmol gÀ1 and
0.47 mmol gÀ1, respectively.
The application of catalyst 2 was then examined and some
of the results are summarized in Tables 1 and 2. Both the direct
aldol reactions of acetone and cyclohexanone worked very
well in the presence of 2, affording the desired aldol products
with high yields and high stereoselectivities (Table 1, entries
6–10 and Table 2). Notably, the reactions of cyclohexanone
proceeded smoothly under ‘‘on-water’’ conditions,12 showing
slightly improved diastereoselectivity over the reactions under
neat conditions. In these cases, the use of the weakly acidic
additive TFA was sufficient for effective catalysis and large
amounts of water were tolerated in the reaction to give results
equally as good as that in a small amount of water (Table 2,
entries 2, 5, 7 and 9). The supported catalysis of 1 was
generally limited to aromatic aldehydes; the reactions with
aliphatic aldehydes gave poor yields.
The MNP-supported catalyst 2 was next evaluated in the
typical enamine-based direct aldol reaction of acetone. As
shown in Table 1, an acidic additive was found to be essential
for the catalysis of 2 and the reaction barely occurred in the
absence of acidic additive (Table 1, entries 1 vs. 2). This
behavior closely resembles its non-supported counterpart.4a
In consistence with the non-supported catalysis, stronger
Brønsted acids such as TfOH gave slightly better enantio-
Table 1 Asymmetric direct aldol reaction of acetone catalyzed MNP
supported catalyst
Entry Cat.
R
Additive Time/h Yield (%)a Ee (%)b
The magnetically driven separation and recycling of MNP-
supported catalyst 2 were quite easy and simple. After the
reaction, ethyl acetate was added to dilute the reaction mixture
and the organic layer was simply decanted, assisted by the use
of a magnet, to afford the desired products. The MNP catalyst
is quickly concentrated to the side wall of the reaction vial
once a magnet is placed nearby (Fig. 2, c). The separated
catalyst was directly used for the next run without any
pretreatment. No extra acid, e.g. TFA and TfOH, was needed
in the recycling experiments, suggesting the initially formed
diamine–Brønsted acid bifunctional moiety was maintained in
the extensive recycling and reuse. Thus, the catalyst could be
1
2
3
4
2
2
2
3
4
2
2
2
2
2
4-NO2Ph None
4-NO2Ph TFA
4-NO2Ph TfOH
4-NO2Ph TFA
4-NO2Ph TfOH
2-NO2Ph TfOH
2-NO2Ph
3-NO2Ph TfOH
4-CF3Ph TfOH
1-Naphth TfOH
48
48
48
24
48
32
32
48
96
96
Trace
86
84
25
30
92
90
91
87
—
66
73
48
80
69
69
66
67
67
5
6
7c
8
c
9
10
91
a
b
Isolated yields. Ee value of anti isomer, determined by chiral
c
HPLC. The 9th reuse of the catalyst 2 employed in entry 6 reaction,
no extra TfOH was added for reuse.
ꢀc
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Table 3 Recycle and reuse of catalyst 2a
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Cycle
Time/h
anti : synb
Yield (%)c
Ee (%)d
1
2
3
4
5
6
7
8
24
24
24
24
24
24
24
24
24
24
24
11 : 1
11 : 1
11 : 1
12 : 1
11 : 1
13 : 1
12 : 1
9 : 1
98
97
98
98
98
97
96
95
95
92
90
98
95
94
97
95
96
96
93
86
87
89
9
3 : 1
3 : 1
4 : 1
10
11
a
0.25 mmol reaction in 0.1 mL water. Determined by 1H NMR.
d
Isolated yields. Ee value of anti isomer, determined by chiral
b
c
HPLC.
reused nine times with essentially no loss of activity and
enantioselectivity in the reaction of acetone (Table 1, entry
7, for details see Table S3 in ESIw). The recyclability and
reusability were also examined in the reaction of cyclo-
hexanone, showing unchanged activity in up to eleven cycles
with slightly reduced stereoselectivity in the last three cycles
(Table 3). TEM images showed that after eleven reuses
catalyst 2 still maintained nanospheric dimensions as well as
the silica coating but with slight aggregation (Fig. 2, b). These
results prove the robustness of the MNP-supported primary
amine catalysts.
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In conclusion, we have developed the first example of
MNP-supported chiral primary amine catalysts. The MNP-
supported catalyst 2 demonstrated high activity and stereo-
selectivity in the enamine-based direct aldol reactions. The
reactions occurred smoothly under ‘‘on-water’’ conditions and
the catalysts could be easily recycled via magnetic force and
reused for up to 11 times with essentially no lose of activity
and stereoselectivity. Further development of MNP-supported
catalysts using the diaminocyclohexane skeleton is currently
under way in our laboratory.
This work was supported by the Natural Science Founda-
tion of China (NSFC 20421202 20632060 and 20702052), the
Ministry of Science and Technology (MoST) and the Institute
of Chemistry, Chinese Academy of Sciences (ICCAS).
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Lee, Angew. Chem., Int. Ed., 2005, 44, 1068–1071.
Notes and references
10 Compound 1 was easily polymerized when concentrated, the
toluene solution of 1 was therefore used directly without purifica-
tion. Consistent purity (490%) was maintained in different
batches as proved by NMR.
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Chem. Commun., 2008, 5719–5721 | 5721