Asymmetric reduction of imines with trichlorosilane catalyzed by valine-derived formamide immobilized onto magnetic nano-Fe3O4

Article abstract of DOI:10.1039/c5ra08516k

Magnetic nano-Fe₃O₄-supported organocatalysts were synthesized by anchoring valine-derived formamide onto the surface of Fe₃O₄ magnetic nanoparticles, which were applied in the asymmetric reduction of imines wit

Full text of DOI:10.1039/c5ra08516k

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Asymmetric reduction of imines with
trichlorosilane catalyzed by valine-derived
formamide immobilized onto magnetic nano-
Fe3O4†
Cite this: RSC Adv., 2015, 5, 65402
Received 8th May 2015
Accepted 27th July 2015
a
a
a
Xin Ge,ab Chao Qian, Xiaoming Ye and Xinzhi Chen
*
DOI: 10.1039/c5ra08516k
www.rsc.org/advances
Magnetic nano-Fe3O4-supported organocatalysts were synthesized N-picolinoyl-L-pyrrolidine,2 L-proline derived C2-symmetric
by anchoring valine-derived formamide onto the surface of Fe3O4 chiral tetraamide,3 N-formyl proline fatty amide4 and N-
magnetic nanoparticles, which were applied in the asymmetric substituted prolines,5 were also developed and could success-
reduction of imines with trichlorosilane at room temperature in fully catalyze the asymmetric reduction of imines. Then Malkov
toluene. The high level of yield and enantioselectivity catalyzed by and Kocovsky6–8 discovered that N-formyl-L-valine derived Lewis-
magnetic nano-Fe3O4-supported organocatalysts was obtained. In basic organocatalysts could signicantly improve enantiose-
the immobilization process, CuI-catalyzed azide-alkyne 1,3-dipolar lectivity. L-pyrrolidine and L-valine have become important
cycloaddition (CuAAC) “click chemistry” was used as the anchored components of Lewis-basic organocatalysts for the asymmetric
bridge. The magnetic nanoparticles can simplify the recovery of the reduction of imines. Sun et al. exploited pipecolinic acid
organocatalyst and its separation from the reaction system. By an derived,9–11 piperazine-2-carboxylic acid derived12 and
external magnet, the catalyst can be recycled and reused five times S-chiral13–15 organocatalysts to reduce imines with tri-
without a remarkable activity decline.
chlorosilane in high enantioselectivity. Recently, we described
carbohydrate-derived pyridinecarboxylic organocatalysts for the
enantioselective reduction of imines with trichlorosilane in
high yield (up to 93%) and with moderate enantioselectivity (up
to 75%).16 In sum, considering the extensive source and catalytic
effective, N-formyl-L-valine derived Lewis-basic organocatalysts
are more successful organocatalysts for the asymmetric reduc-
tion of imine.
However, for typical organocatalytic procedures, the prob-
lems about separation and recovery of catalyst from the reaction
medium arose. To overcome the separation and recovery diffi-
culties, the common solution is the immobilization of organo-
catalyst. In 2009, Malkov and Kocovsky rst developed N-formyl-
L-valine derived organocatalysts immobilised onto gold nano-
particles.17 Then, they prepared soluble polymer-supported
valine derived organocatalyst, which could be recovered
through pouring into the methanol and reused at least ve
times without loss of activity.18 In 2010, they synthesized
dendron-anchored N-formyl-L-valine derived organocatalysts to
catalyze the symmetric reduction of imines with tri-
chlorosilane.19 The dendron-anchored organocatalysts can be
removed by precipitation and centrifugation. As supported
carriers, magnetic nanoparticles (MNPs) have been attracted
much attention for their simple and easy recover from the
liquid-phase reaction by magnetically derived separation.20–27
Moreover, MNPs supported catalyst can rapidly disperse in
reaction solvent. Thus, MNPs have been applied in traditional
Introduction
In addition to organometallic and bio-catalytic catalysts, as
small organic molecules, organocatalysts are capable of
promoting asymmetric synthesis and have rapidly gained much
attention due to their relatively easy operation and environ-
mentally friendly nature. Thus, for the asymmetric reduction of
imine, an organocatalytic approach is an attractive alternative
method to obtain chiral amine. Moreover, the Lewis-basic
organocatalytic reduction with trichlorosilane is an emerging
organocatalytic methodology. Aer Matsumura et al. rstly
reported the N-formyl-L-proline anilide as a Lewis-basic orga-
nocatalyst to catalyze the reduction of imines with tri-
chlorosilane in moderate enantioselectivity,1 some highly
effective Lewis-basic organocatalysts were developed to catalyze
the asymmetric reduction of imines. Besides N-formyl-L-proline
anilide, some other L-proline-derived organocatalysts, such as
aKey Laboratory of Biomass Chemical Engineering of Ministry of Education, College of
Chemical and Biological Engineering, Zhejiang University, P.R China. E-mail:
xzchen@zju.edu.cn; Tel: +86-571-87951615
bSchool of Chemical and Material Engineering, Jiangnan University, P.R China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra08516k
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metal catalysts, organocatalysts, and even enzyme. Recently, was obtained. CuAAC reaction was used as an anchored bridge
MNPs supported chiral organocatalysts and ionic liquid have (Scheme 1).
been successfully prepared to catalyze Michael addition,28,29
The XRD patterns of SiO2@Fe3O4 and MNPs-supported
ammoximation,30 Suzuki–Miyaura coupling reaction31 and so organocatalyst 5 were shown in Fig. 1 and matched well with
on. To the best of our knowledge, N-formyl-L-valine derived the date of the standard sample.30 It exhibits diffraction peaks
organocatalyst immobilized onto magnetic nano-Fe3O4 was not of crystal planes (220), (311), (400), (422), (511), (440) and rela-
reported. Herein, we present magnetic nano-Fe3O4-supported tive intensity. Comparing with the XRD patterns of SiO2@Fe3O4
N-formyl-L-valine derived organocatalyst by click reaction and and MNPs-supported organocatalyst 5, there is no signicant
its application in asymmetric reduction of imines with inuence on the structure of Fe3O4 nanoparticles in the
trichlorosilane.
immobilization of valine-derived formamide catalyzed by
CuAAC click chemistry. However, the broad peak of amorphous
silica phase in the shell of the silica-coated Fe3O4 from 2q ¼ 20ꢀ
to 30ꢀ is not obvious.22 Moreover, the transmission electron
microscopy (TEM) images of SiO2@Fe3O4, azide@MNPs and
MNPs-supported organocatalyst 5 are shown in Fig. 2. The
thickness of the silica shell surrounding the bare nano-Fe3O4
particles is about 3–5 nm and the average particle diameter is
20–30 nm (in Fig. 2a). The TEM morphologies of azide@MNPs
Results and discussion
Preparation and characterization of the catalyst
The synthesis of the precursor N-formyl-L-valine derived orga-
nocatalyst 4 was commenced with the methylation of N-BOC-L-
valine with iodomethane in presence of neat sodium
hydride,32,33 which afforded the corresponding N-methylated
product 1. Then the precursor N-formyl-L-valine derived orga-
nocatalyst 4 was prepared by the condensation of the BOC-
protected N-methyl valine 1 with respective aniline derivative
2, followed by BOC-deprotection with CF3COOH and
N-formylation.34
Magnetic nano-Fe3O4 particles was prepared via the copre-
cipitation of ferric chloride hexahydrate and ferrous chloride
tetrahydrate in an alkaline medium.35 Considering the aggre-
gation of magnetic nano-Fe3O4 particles (MNPs) and further
modication on the surface, it is a good solution that the
magnetic nanoparticles was coated with silica and the silica-
coated Fe3O4 (SiO2@Fe3O4) was prepared according to the
literature procedures.26,36 The abundant surface hydroxyl groups
of MNPs (SiO2@Fe3O4) were used as carriers to gra 3-azido-
propyl moiety onto surface with 3-azidopropyltrimethox-
ysilane.21 Finally, the catalytically active species
4 was
immobilized onto azide@MNPs using CuI-catalyzed azide-
alkyne 1,3-dipolar cycloaddition (CuAAC) “click chem-
Fig. 1 XRD patterns of SiO2@Fe3O4 (a) and MNPs-supported orga-
istry”33,37–40 and the desired MNPs-supported organocatalyst 5 nocatalyst 5 (b).
Scheme 1 Synthese of N-formyl-L-valine derived organocatalyst supported onto MNPs.
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of azido was determined to be 0.28 mmol gꢁ1 by elemental
analysis. Aer the successful functionalization of azi-
de@MNPs with valine-derived formamide catalyzed by CuAAC
click chemistry, the strong adsorption peak of azido group was
weakened. Moreover, new band at 1560 cmꢁ1 (C]N and C]C
vibrations) emerged in the formation of the 1,2,3-triazole
linker. The loading of the N-formyl-L-valine derived organo-
catalyst was determined to be 0.24 mmol gꢁ1 by elemental
analysis.
The magnetism of SiO2@Fe3O4 and MNPs-supported orga-
nocatalyst 5 was investigated at room temperature. As shown in
Fig. 4, the two samples can be completely saturated at high
elds of up to 2.0 T. When active species 4 was graed on the
surface of SiO2@Fe3O4, the saturated magnetism was decreased
from the 59.7 to 24.5 emu gꢁ1. Thus, the efficient magnetization
of MNPs-supported organocatalyst 5 could guarantee simple
separation with an external magnet.
Fig. 2 TEM images of SiO2@Fe3O4 (a), azide@MNPs (b), MNPs-sup-
ported organocatalyst 5 (c) and MNPs-supported organocatalyst 5
after being reused five times (d).
The stability of the MNPs-supported organocatalyst 5 was
investigated by the thermogravimetric (TG) analysis. As the
ꢀ
Fig. 5 shown, an initial weight loss up to 160 C was detected
and MNPs-supported organocatalyst 5 were similar to that of
the SiO2@Fe3O4 and the core–shell structures were obvious (in
Fig. 2b–c).
owing to the remove of adsorbed water on the support. Thermal
degradation of MNPs-supported organocatalyst 5 occurred from
160 ꢀC to 575 ꢀC, which resulted into the weight loss of 13%. It
revealed that the catalyst exhibited the excellent stability.
Moreover, the decomposition of the organocatalyst was mainly
occurred from 500 ꢀC to 575 ꢀC. Thus, the MNPs-supported
In order to make sure whether the functionalization of
azide@MNPs with valine-derived formamide catalyzed by
CuAAC click chemistry is successful, the Fourier transform
infrared spectroscopy (FT-IR) analysis was employed to
further investigate. As shown in Fig. 3, the spectrum of all the
ꢀ
organocatalyst 5 is stable around or below 160 C.
samples exhibited broad peaks at around 3400 and 1640 cmꢁ1
,
which were attributed to the OH group on the silica surface
and adsorbed water, respectively. Meanwhile, the peaks at
1080 and 575 cmꢁ1 should be due to Si–O–Si stretch vibration
and Fe–O vibration modes, respectively. For azide@MNPs,
azido group was introduced into SiO2@Fe3O4 and led to a
characteristic peak at 2100 cmꢁ1, following the appearance of
typical bands at 2940, 2850 and 1390 cmꢁ1 (alkyl chain
stretching and deformation vibrations). The loading amount
Catalytic activity of MNPs-supported organocatalyst in
asymmetric reduction of imines with trichlorosilane
With the MNPs-supported organocatalyst 5 in hand, we evalu-
ated its catalytic activity in enantioselective reduction of imines
with trichlorosilane. The asymmetric reduction of imine 6a with
trichlorosilane was selected as model reaction. Initially, the
reaction conditions were optimized and the results were shown
in Table 1. We rst attempted the active species 4 to catalyze
Fig. 3 FI-IR spectrum of SiO2@Fe3O4 (a), azide@MNPs (b) and MNPs- Fig. 4 Magnetic curves of SiO2@Fe3O4 (a) and MNPs-supported
supported organocatalyst 5 (c).
organocatalyst 5 (b).
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Table 2 Asymmetric reduction of imine 6 with catalyst 5a
Entry
Imine
R1
R2
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
C6H5
C6H5
C6H5
C6H5
C6H5
94
95
97
94
72
94
93
84
92
81
67
85
88
91
92
67
81
83
74
86
52
25
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-CH3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-ClC6H4
3-ClC6H4
3-BrC6H4
4-CH3C6H4
2-CH3C6H4
Fig. 5 TG-DTG analysis for azide@MNPs.
9
10
11
6j
6k
Table 1 Asymmetric reduction of imine 6–22aa
C6H5
a
The reactions were carried out with 10 mol% catalyst 5 and 1.5 equiv.
b
of SiHCl3 on a 0.5 mmol scale in 2.0 mL of toluene for 24 h. Isolated
yield based on the imine. c Determined by chiral HPLC.
model reaction, the product was obtained in 94% yield and 85%
ee (Table 2, entry 1). For aromatic N-Ph imines 6b–6e, satis-
factory yields and enantioselectivities were affording (Table 2,
entry 2–5). The imines 6e with electron-donating group showed
lower catalytic activity than that of 6a, affording 72% yield and
67% ee. The aromatic N-Ph imines 6b–6d with electron-
withdrawing groups exhibited more excellent asymmetric
reduction.
Entry
Catalyst (mol%)
Solvent
Yieldb (%)
eec,d (%) (cong)
1
2
3
4
5
4 (10)
5 (10)
5 (10)
5 (10)
5 (10)
Toluene
Toluene
CH2Cl2
CHCl3
95
94
93
91
89
89 (S)
85 (S)
74 (S)
81 (S)
24 (S)
CH3CN
a
The reactions were carried out with catalyst and 1.5 equiv. of SiHCl3 on
The effect of the imine N-substituent (R2) is similar to that of
R1, affording the 25–86% ee value (Table 2, entries 6–12). The
electron-poor N-substituent imines exhibited higher catalytic
activity than electron-rich imines. The electron-poor N-substit-
uent imines 6f–6i could be reduced in 84–94% yield and 74–
86% ee (Table 2, entries 6–9). For electron-rich N-substituent
imines 6j–6k, the yields and enantioselectivities were 67–81%
and 25–52% separately (Table 2, entries 10 and 11).
a 0.5 mmol scale in 2.0 mL of solvent for 24 h. b Isolated yield based on
c
d
the imine. Determined by chiral HPLC. The absolute conguration
was determined by HPLC via comparison with authentic samples.6,12
asymmetric reduction of imine 6a, which affording 95% yield
and 89% ee separately with the (S)-enantiomer (Table 1, entry 1).
When the MNPs-supported organocatalyst 5 was used for this
reduction, 94% yield and 85% ee could be obtained (Table 1,
entry 2). By contrast, it was obvious that the catalytic activity did
not decline. The reactivity of the immobilized catalyst in
different solvent was studied (Table 1, entries 2–5). In the
asymmetric reduction of imines catalyzed by N-formyl-L-valine
derived organocatalyst, the hydrogen bonding and the p–p
interactions inuenced the enantioselectivity.33 Thus, toluene is
the best solvent, which takes both in consideration. When the
reaction was carried out in chloroform and dichloromethane,
the catalytic activity declined slightly. Moreover, in acetonitrile,
the ee value is only 24%.
Having testing the activity of the MNPs-supported organo-
catalyst 5 for the reduction of imine 6a, the substrate scope of
MNPs-supported organocatalyst 5 was explored further. The
results were summarized in Table 2. As the substrate 6a of the
Fig. 6 Recycling and reuse of catalyst 5. a The reactions were carried
out with 10 mol% catalyst 5 and 1.5 equiv. of SiHCl3 on a 0.5 mmol
scale in 2.0 mL of toluene for 24 h. b Isolated yield based on the imine. c
ee value was determined by chiral HPLC.
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The main advantage of MNPs is easy recover from the liquid-
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asymmetric reduction. The catalyst 5 could be readily dispersed
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was easily recovered from the reaction system by external
magnet, then washed by ethanol and dried under vacuum. The
recovered catalyst could be reused and easily redispersed in
reaction medium. Generally, the recycling catalyst was less than
the previous (see in the ESI†). The slight loss of catalyst led to
slight decrease of the yield and enantioselectivity. Aer ve
cycles, the catalyst had not an obvious loss of catalytic activity
(Fig. 6). As shown in Fig. 2d, a TEM of the recovered catalyst was
observed. The morphology and size have no obvious changes. It
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Conclusion
In sum, we achieved successfully the immobilization of valine-
derived formamide organocatalyst onto magnetic nano-Fe3O4
by click reaction. The obtained catalyst exhibited high catalytic
activity in the asymmetric reduction of imines with tri-
chlorosilane. Furthermore, the catalyst could be readily recov-
ered by an external magnet and reused ve times without an
obvious activity decline.
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Acknowledgements
The authors are grateful for the nancial support from the
Natural Science Foundation of China (21376213, 21476194), the
Research Fund for the Doctoral Program of Higher Education of
China (20120101110062) and the Zhejiang Provincial Public
Technology Research of China (2014C31123).
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