Integrated soluble polymer and mesoporous silica as a double–type support to immobilize tertiary amine–Ru/diamine–bifunctionality for aza–addition/reduction cascade reaction

Article abstract of DOI:10.1016/j.jcat.2019.07.005

Exploiting advantages of a double–type support to create an active site–isolated heterobifunctional catalyst is beneficial to an efficiently sequential organic transformation. Herein, an integrated soluble polymer and mesoporous silica as a double–type support to immobilize the tertiary amine–Ru/diamine–bifunctionality for the construction of an active site–isolated catalyst is developed, where the tertiary amine–functionality is tethered in the outer soluble polymer and chiral ruthenium/diamine–functionality is anchored within the inner mesoporous silica. Electron microscopy images, together with analyses of solid–state NMR spectra, disclose that catalyst possesses the uniformly distributive morphology with well–defined single–site ruthenium/diamine active centers. As envisaged, the heterobifunctional catalyst performs a highly efficient aza–Michael addition/asymmetric transfer hydrogenation enantioselective cascade reaction, where the outer tertiary amine–functionality enables a high reactivity to afford β–secondary amino ketones via an aza–Michael addition reaction of enones and amines, and the inner chiral ruthenium/diamine–functionality guarantees a high enantioselectivity to chiral γ–secondary amino alcohols via an asymmetric transfer hydrogenation of β–secondary amino ketones. Furthermore, this catalyst can also be recovered easily and recycled for six runs, showing a practical preparation of aryl–substituted γ–secondary amino alcohols.

Full text of DOI:10.1016/j.jcat.2019.07.005

Journal of Catalysis 376 (2019) 191–197
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Journal of Catalysis
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Integrated soluble polymer and mesoporous silica as a double–type
support to immobilize tertiary amine–Ru/diamine–bifunctionality for
aza–addition/reduction cascade reaction
⇑
Ming Gao, Fengwei Chang, Shitong Wang, Zeyang Liu, Zhitong Zhao, Guohua Liu
Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Exploiting advantages of a double–type support to create an active site–isolated heterobifunctional
catalyst is beneficial to an efficiently sequential organic transformation. Herein, an integrated soluble
polymer and mesoporous silica as a double–type support to immobilize the tertiary amine–Ru/dia
mine–bifunctionality for the construction of an active site–isolated catalyst is developed, where the ter-
tiary amine–functionality is tethered in the outer soluble polymer and chiral ruthenium/diamine–func
tionality is anchored within the inner mesoporous silica. Electron microscopy images, together with anal-
yses of solid–state NMR spectra, disclose that catalyst possesses the uniformly distributive morphology
with well–defined single–site ruthenium/diamine active centers. As envisaged, the heterobifunctional cat-
alyst performs a highly efficient aza–Michael addition/asymmetric transfer hydrogenation enantioselec-
tive cascade reaction, where the outer tertiary amine–functionality enables a high reactivity to afford
b–secondary amino ketones via an aza–Michael addition reaction of enones and amines, and the inner chi-
Received 3 May 2019
Revised 24 June 2019
Accepted 1 July 2019
Keywords:
Heterogeneous catalysis
Supported catalysts
Asymmetric transfer hydrogenation
Michael addition
Immobilization
Mesoporous materials
ral ruthenium/diamine–functionality guarantees a high enantioselectivity to chiral c–secondary amino
alcohols via an asymmetric transfer hydrogenation of b–secondary amino ketones. Furthermore, this
catalyst can also be recovered easily and recycled for six runs, showing a practical preparation of
aryl–substituted c–secondary amino alcohols.
Ó 2019 Elsevier Inc. All rights reserved.
1. Introduction
promote catalytic efficiency [13]. Despite these significant achieve-
ments, the only use of mesoporous silica and soluble polymer as
single–type supports has still some limitations, especially their
applications in multi–step enantioselective organic transforma-
tions [15]. A general restriction comes from single–type support
itself. Rigid silica–supported catalysts have the diffused shortcom-
ing of mass transfers that lead to the decreased reaction rates,
whereas flexible polymer–supported catalysts have the swelling
disadvantage of soluble polymers that result in the poor enantios-
electivities. A special restriction lies in a strict and subtle demand
of chiral catalytic environment in an enantioselective cascade reac-
tion because dual functionality in a single–type support must pos-
sess an ability to differentiate two possible enantiomers and more
intermediates during a complicated catalysis process. However,
due to the drawback of cross interference, dual functionality in a
single–type support is quite difficult to work together well. Thus,
utilization of a double–type support to immobilize two species
has a significant superiority in a multi–step sequential enantiose-
lective organic transformation as shown in Scheme 1, which not
only exploits the respective advantages of a double–type support
Development of supported dual molecule catalysts for multi–
step sequential enantioselective reactions has been attracting
extensive interest, where some reviews are well–documented
recently [1–4]. So far, the common strategy for immobilization of
dual functionality is through single–type supports, where numer-
ous supported bifunctional catalysts have successfully applied to
various cascade reactions, especially the use of single–type meso-
porous silica–supported [5–11] and soluble polymer–supported
chiral bifunctional catalysts [12–14]. Outstanding feature of
silica–supported bifunctional catalysts is their orderly mesoporous
structures with adjustable channels and highly mechanical stabil-
ities, and some designed and explored synergistic effects enhance
reactivity and enantioselectivity [7,8] Prominent contributions of
soluble polymer–supported bifunctional catalysts are attributed
to the high–dispersibility in reaction systems because a mimic
homo–like catalytic environment benefits the mass transfer to
⇑
Corresponding author.
E-mail address: ghliu@shnu.edu.cn (G. Liu).
https://doi.org/10.1016/j.jcat.2019.07.005
0021-9517/Ó 2019 Elsevier Inc. All rights reserved.

192
M. Gao et al. / Journal of Catalysis 376 (2019) 191–197
for two hours at 80 °C. After cooling to room temperature, the
solids were collected by centrifugation and washed repeatedly
with excess distilled water. The collected solids (1.36 g) were sus-
pended in 20.0 mL of dry toluene and 0.45 g (2.14 mmol) of tri-
ethoxy(vinyl)silane in 2 mL of dry toluene was added, and the
mixture was stirred overnight at ambient temperature. The surfac-
tant template was removed by refluxing in a solution (80.0 mg of
ammonium nitrate in 120 mL of ethanol) at 60 °C for 12 h. The
solids were filtered and washed with excess ethanol, and dried at
ambient temperature under vacuum overnight to afford Viny-
l@ArDPEN@MSN (2) (1.52 g) as a white powder. (The second step
for the synthesis of 4) 1.0 g of 2, 0.25 g (2.95 mmol) of N,N–dimethyl
prop–2–en–1 were weighed into a 100 mL nitrogen flask and dis-
solved in 20 mL of distilled DMSO. Then, 65.5 mg (2% mol) of
2,2–azobisisobutyronitrile (AIBN) was added at room temperature.
After a degassed period by three freeze–pump–thaw cycles, the
flask was placed into the oil to polymerize at 60 °C for 6.0 h. After
cooling to room temperature, the solids were filtered and washed
with excess ethanol, and dried at ambient temperature under vac-
uum overnight to afford P@ArDPEN@MSN (4) as a white powder
(0.11 g). (The third step for the synthesis of 5) The collected solids
(0.50 g) was suspended in 20.0 mL of dry CH2Cl2, 50.0 mg of
(MesRuCl2)2 (0.086 mmol) was added at room temperature, and
the resulting mixture was stirred at 25 °C for 12 h. The mixture
was filtered and rinsed with excess CH2Cl2. After Soxhlet extraction
for 4 h in CH2Cl2, the solid was dried at ambient temperature under
vacuum overnight to afford P@MesRuArDPEN@MSN (5) (0.51 g)
light–red powder. TG analysis showed that the tertiary amine–
loadings were 1.02% (1.6414 mg, 0.1172 mmol of N-loadings per
gram of catalyst), and Ru–loadings were 1.81% (11.8610 mg,
0.1164 mmol of the Ru–loadings per gram of catalyst) that was
consistent with the Ru loadings (11.9103 mg, 0.1167 mmol) per
gram of catalyst detected by an inductively coupled plasma optical
emission spectrometer (ICP–OES) analysis. 13C CP/MAS NMR
Scheme 1. Construction of a supported dual molecule catalyst via a double–type
support for the aza–Michael addition/reduction cascade reaction.
and complements the drawbacks of a single–type support but also
benefits to create site–isolation–featured catalysts.
Chiral c–secondary amino alcohols and analogues are important
pharmaceutical intermediates for the synthesis of the highly value–
added antidepressants [16–21]. General preparations of chiral
c–secondary amino alcohols is through a single-step asymmetric
hydrogenation of prochiral b–amino ketones under homogeneous
conditions [22–28], where the main works employ the Rh–bispho
sphine–complexes, Rh–Duanphos complex and analogues as chiral
catalysts to convert various b–amino ketones into chiral
c–sec-
ondary amino alcohols. Recently, we also report an asymmetric
transfer hydrogenation (ATH) method to enable the preparation of
optically pure c–secondary amino alcohols [29]. However, due to
the problems of environmentally unfriendly solvents, expensive
transition–metal recycling and poor catalysis efficiency, their appli-
cations are still greatly limited. Therefore, based on the considera-
tion of green catalysis, development of an atom–economic,
environmentally friendly cascade process for highly efficient prepa-
ration of optically pure
desirable.
c–secondary amino alcohols is highly
(161.9 MHz): 157.8–119.1 (C of pH and Ar groups), 106.8, 103.3
(C of mesitylene), 78.3–74.6 (CH of ANCHPh), 63.5, 57.3 (C of
CH3NA and ACH2NA), 39.9–25.6 (ACH2CH2A), 21.9 (CH3 of mesi-
In this contribution based on our efforts in the cascade reactions
[30–32], we integrate thesoluble polymer and mesoporous silica as a
double–type support to construct a supported dual molecular cata-
lyst (Scheme 1), where the tertiary amine–functionality is tethered
in the outer soluble polymer and the chiral ruthenium/diamine–func
tionality is anchored within the inner mesoporous silica. The advan-
tage ofthisheterobifunctionalcatalystis thecatalytically active site–
isolated, where theouter tertiary amine–functionality enables a high
reactivity in aza–Michael addition reaction due to the highly dis-
persed benefit of soluble polymer in an aqueous medium whereas
the inner chiral ruthenium/diamine–functionality in silica network
guarantees high enantioselectivity in asymmetric transfer hydro-
genation owing to the maintainable chiral catalytic environment.
As we envisaged, this heterobifunctional performs an efficiently
enantioselective cascade reaction in an environmentally friendly
tylene), 17.6 (CH2 of ACH2Ar), 12.5 (CH2 of ACH2Si) ppm.
29Si MAS/NMR (79.4 MHz): T3 (d = À58.4 ppm), T3 (d = À68.9 ppm),
Q2 (d = À92.9 ppm), Q3 (d = À102.8 ppm), Q4 (d = À112.1 ppm).
2.2. General procedure for the cascade reaction
In a typical procedure, catalyst 5 (8.59 mg, 1.0
lmol of Ru based
on ICP analysis, and 1.01 mol of N based on TG analysis), enones
l
(0.10 mmol), amines (0.11 mmol), HCOONa (1.0 mmol), and 2.0 mL
of iPrOH/H2O (v/v = 1:1) were added sequentially to a 10.0 mL
round–bottom flask. The mixture was then stirred at 40 °C for
2.5–12 h. After completion of the reaction, the catalyst was sepa-
rated by centrifugation (10,000 rpm) for the recycling experiment.
The aqueous solution was extracted with ethyl ether (3 Â 3.0 mL).
The combined ethyl ether extracts were washed with aqueous
Na2CO3 and brine, and dehydrated with Na2SO4. After evaporation
of ethyl ether, the residue was purified by silica gel flash column
chromatography to afford the desired product. The ee values were
determined by an HPLC analysis using a UV–Vis detector and a Dai-
medium, affording chiral aryl–substituted
c–secondary amino
alcohols with high yields and enantioselectivities.
2. Experimental
2.1. Preparation of catalyst 5
cel chiralcel column (
U
0.46 Â 25 cm).
In a typical synthesis, (The first step for the synthesis of 2) 0.25 g
(0.17 mmol) of cetyltrimethylammonium bromide (CTAB) was
added to an aqueous solution (120 mL) of NaOH (0.88 mL, 2.0 M)
at 70 °C. After the dissolution of CTAB, 2.0 g of (9.62 mmol) of
tetraethoxysilane (TEOS) was added, and the mixture was stirred
for 5–10 min. After that, 0.10 g (0.20 mmol) of ArDPEN–siloxane
(1) was added to the system by dropwise, the mixture was stirred
for another 5–10 min. Finally, the mixture was stirred vigorously
3. Results and discussions
3.1. Synthesis and structural characterization of the heterobifunctional
catalyst 5
A
simple three–step procedure for the assembly of the
tertiary amine–functionalized polymer onto the MesRuArDPEN–

M. Gao et al. / Journal of Catalysis 376 (2019) 191–197
193
functionalized mesoporous silicate nanoparticles (MSNs) provided
4
the bifunctional catalyst, abbreviated as P@MesRuArDPEN@MSN
(5), (MesRuArDPEN: [33–36] Mes = Mesitylene: 1,3,5–trimethyl-
benzene and ArDPEN: (S,S)–4–((trimethoxysilyl)ethyl)phenylsulfo
nyl–1,2–diphenylethylene–diamine), as shown in Scheme 2. In
the first step, the co–condensation of tetraethoxysilane (TEOS)
and (S,S)–ArDPEN–siloxane (1) using cetyltrimethylammonium
bromide (CTAB) as a template [37,38], followed by the postgrafting
of triethoxy(vinyl)silane, led to a vinyl/ArDPEN–functionalized
nanoparticles, Vinyl@ArDPEN@MSN (2). Next, the direct complex-
ation of 2 and (MesRuCl2)2 gave a parallel catalyst 3, abbreviated as
MesRuArDPEN@MSN (3), as a light–red powder. In the second step,
the free radical polymerization [39–41] of 2 and N,N–dimethyl
prop–2–en–1–amine produced P@ArDPEN@MSN (4) as a white
powder. In the third step, catalyst 5 as a light–red powder could
Catalyst 5
g
c
b
*
*
e
d
a
f
*
*
300
250
200
150
100
50
0
-50 ppm
be steadily obtained by
a similar complexation of 4 with
(MesRuCl2)2 (see SI in Experiments and in Figs. S1 and S2).
Fig. 1. Solid–state 13C CP/MAS NMR spectra of 4 and catalyst 5.
Fig. 1 showed the solid–state 13C cross–polarization (CP)/magic
angle spinning (MAS) NMR spectra of catalyst 5, disclosing its
well–defined single–site MesRuArDPEN–functionality within its
mesoporous silica network. It was found that catalyst 5 and its par-
ent material 4 presented general carbon signals between d = 70 and
4
Q3
Catalyst 5
75 ppm for the carbon atoms of the ANCHPh moiety and between
d = 121 and 168 ppm for the aromatic carbon atoms in the ArDPEN
groups, suggesting the successful incorporation of chiral ligand
within the silica network. Catalyst 5 exhibited characteristic peaks
at 107.7 and 104.2 ppm for the carbon atoms of the aromatic ring,
and at 22.5 ppm for the attached methyl carbon atoms in mesity-
lene, which were absent in the spectrum of 4. This finding demon-
Q4
Q2
T3
ppm
-200
50
0
-50
-100
-150
strated that catalyst
5 possessed the similar well–defined
Fig. 2. Solid-state 29Si CP/MAS NMR spectra of 4 and catalyst 5.
single–site active centers to its homogeneous MesRuTsDPEN [33]
due to their same chemical shift values, which could be further
confirmed by the XPS investigations since catalyst 5 and its homo-
geneous MesRuTsDPEN had the similar Ru 3d5/2 electron binding
energy (281.68 eV versus 281.62 eV) (see SI in Fig. S3). In addition,
the observed peaks denoted by asterisks were attributed to the
rotational sidebands that often appeared in the MAS high–speed
rotation process. Solid–state 29Si magic angle spinning (MAS)
NMR spectra further demonstrated that catalyst 5 was composed
of inorganic and organic silica compositions owing to the presence
of two groups of typical silica signals (Q–series signals for inor-
ganic silica and T–series signals for organic silica), as shown in
Fig. 2. It was found that their chemical shift values were similar
to those reported in the literature (T–series: À58.5 and
À67.5 ppm for T2 of [R(HO)Si(OSi)2] and T3 of [RSi(OSi)3]. Q–series:
À91.5, À101.5, and À110.0 ppm for Q2 of [(HO)2Si(OSi)2], Q3 of
[(HO)Si(OSi)3], and Q4 of [Si(OSi)4], respectively) [42]. Notably,
the contents of inorganic Q–series signals were higher than those
of organic T–series signals, suggesting that catalyst 5 mainly pos-
sessed the inorganic silicate RASi(OSi)3 species as its main silica
network with a small part of organic silicate RASi(OSi)3 species
(R = alkyl–linked chiral functionalities and polymers) tethered in
its silica wall.
The structural morphology from the scanning electron micro-
scopy (SEM) showed that catalyst 5 was uniformly distributed,
where the average size of nanoparticles was about 45 nm
(Fig. 3a). Furthermore, the transmission electron microscopy
(TEM) also disclosed its mesoporous structure (Fig. 3b), which
could be confirmed by its nitrogen adsorption–desorption iso-
therm (Fig. 4) owing to a similar typical IV character with an H1
hysteresis loop to a pure MSNS material [37].
3.2. Catalytic performance of the heterobifunctional catalyst
3.2.1. Catalytic property
With the well–established heterobifunctional catalyst 5 in
hand, we chose the cascade reaction of 1–phenylprop–2–enone
and aniline as a model reaction to examine its catalytic property
in the aza–Michael addition/ATH one–pot cascade process. Owing
to the environmentally friendly cosolvent system of water and
alcohols could be used in the single–step aza–Michael addition
reaction [43] and in the single–step asymmetric transfer hydro-
genation [35,44–49], the tested reaction was carried out in the
iPrOH/H2O (1:1, v/v) cosolvent system with 1.0 mol% of ruthenium
loadings and 1.02 mol% the tertiary amine loadings in 5 as a cata-
lyst and sodium formate as a hydrogen resource at 40 °C according
to the optimal conditions [30]. The result showed that the 5–cat-
alyzed aza–Michael addition/ATH one–pot enantioselective
cascade reaction could produce the targeting products of
(S)–1–phenyl–3–(phenylamino)propanol in 96% yield with 96%
ee, which was slightly better than that (95% yield with 95% ee)
Scheme 2. Preparation of the heterobifunctional catalyst 5.

194
M. Gao et al. / Journal of Catalysis 376 (2019) 191–197
without the polymer–coating layer [30], further confirming the
superiority of catalyst 5 equipped with the outer soluble poly-
mer–coating layer. Also, it was found that this result was markedly
better than that obtained with the physically mixed N,N–dimethyl
prop–2–en–1–amine and homogeneous MesRuTsDPEN as dual
catalysts (Table 1, entry 1 versus entry 3). This observation sug-
gested that the active site–isolation–featured catalyst 5 efficiently
overcame the shortage of their interactions under the homoge-
neous catalysis conditions.
On the basis of this efficient aza–Michael addition/ATH cascade
reaction, the 5–catalyzed cascade reactions with a series of aryl–
substituted enones and arylamines were further tested for the
investigation of its general feasibility, as shown in Table 1. The
results showed that all of the tested reactions could steadily pro-
ceed, producing the corresponding
c–secondary amino alcohols
with high yields and enantioselectivities. Also, it was found that
the yields and enantioselectivities were not significantly affected
by the structures and electronic properties on the aromatic rings
of Ar2 group in the reaction of 1–phenylprop–2–enone and aro-
matic amines bearing electron–withdrawing and –donating sub-
stituents (Entries 4–12). However, in the case of the reactions of
different aryl–substituted enone and aniline, the yields and enan-
tioselectivities has an obvious changes, where the electron–with-
drawing substituents on the aromatic rings of Ar1 group had
higher yields and lower ee values than those with electron–donat-
ing substituents (entries 13–20 versus entries 21–22).
3.2.2. Investigations of the factors affecting catalytic performance
To eliminate the affecting factors that the catalytic performance
possibly comes from the contributions of the homogeneous Mes-
RuTsDPEN via the noncovalent physical adsorption, one parallel
experiment was performed, where this aza–Michael addition/
ATH cascade reaction catalyzed by the physical mixture of 4 and
homogeneous MesRuTsDPEN was carried out under the optimal
reaction conditions. The result showed that the cascade reaction
also yielded the corresponding (S)–1–phenyl–3–(phenylamino)pro
panol in 88% yield with 91% ee that was similar to that attained
with the physically mixed N,N–dimethylprop–2–en–1–amine and
homogeneous MesRuTsDPEN as dual catalysts (entry 3). However,
the recycled catalyst 5 via a treatment of the Soxhlet extraction
only produced tiny targeting products with the unconverted inter-
mediate 1–phenyl–3–(phenylamino)propanone detected by the 1H
NMR analysis. A similar result was also observed via a parallel hot-
filtrate experiment. In this case, this cascade reaction proceeded for
2 h at first. Subsequently, after a hot-filtration, the reaction was
continued for a further 2.0 h. It was found that there was no appre-
ciable change in either conversion or ee value of the targeting prod-
ucts. These findings disclosed that the contributions coming from
the homogeneous MesRuTsDPEN via the noncovalent physical
adsorption had been eliminated owing to the synthetic procedure
via a strict Soxhlet extraction during the preparation process of
catalyst 5.
Fig. 3. (a) SEM images of 5, (b) TEM image of 5.
500
400
300
200
100
4
Catalyst 5
5
10
15
20
25
30
35
Pore diameter (nm)
0.0
0.2
0.4
0.6
0.8
1.0
Relative Pressure (P/P0
)
Fig. 4. Nitrogen adsorptionÀdesorption isotherms of 4 and catalyst 5.
To demonstrate the catalytic nature of the aza–Michael addi-
tion/ATH cascade reaction, the time course in the reaction of 1–phe
nylprop–2–enone and aniline was also investigated, as shown in
Fig. 5. Firstly, we found that the aza–Michael addition of 1–phenyl
prop–2–enone (6a) and aniline (7a) proceeds rapidly, and give
intermediate 1–phenyl–3–(phenylamino)propanone (A) with 88%
of maximum conversion within 10 min. In the next ten minutes,
the conversion of 6a is completed, the ATH of 1–phenyl–3–(pheny
lamino)propanone (A) occurred. Subsequently, the target product
of (S)–1–phenyl–3–(phenylamino)propanol (8a) increased quickly
from 20 min to 60 min that is concomitant with the gradual
decrease of the intermediates A. Finally, the ATH of 1–phenyl–3–
(phenylamino)propanone proceeds smoothly with a completed
disappearance of A in 150 min, providing 8a in 96% yield. Notably,
attained with the inorganic Na2CO3 as an aza–Michael catalyst and
homogeneous MesRuTsDPEN as an ATH catalyst in one-pot cascade
reaction under the homogeneous conditions. In particular, such a
result was obviously higher than that attained with the physically
mixed N,N–dimethylprop–2–en–1–amine and the parallel catalyst
3 as dual catalysts (Table 1, entry 1 versus entry 2) because the lat-
ter needed 12 h to reach its catalytic completion. This finding
revealed the benefit of the outer polymeric parts in the catalyst 5
because of the obviously enhanced reaction rate. It was worth
mentioning that this reaction rate in the 5–catalyzed aza–Michael
addition/ATH cascade reaction was nearly five times that in the
previously reported yolk–shell–structured heterogeneous catalyst

M. Gao et al. / Journal of Catalysis 376 (2019) 191–197
195
Table 1
The aza–Michael addition/ATH enantioselective cascade reactions of aryl–substituted enones and amines.a
Entry
Ar1, Ar2 (8)
Time (h)
%Yieldb
%eec
1
2
3
4
5
6
7
8
Ph, Ph (8a)
Ph, Ph (8a)
Ph, Ph (8a)
2.5
12
12
4
3
3
5
4
4
4
4
3
2
2
2
3
3
3
96
92
86
91
92
91
88
93
95
92
91
90
91
95
90
89
87
91
92
94
73
76
96
96d
91e
96
95
97
95
96
96
95
96
96
93
93
90
84
94
93
80
93
97
95
Ph, 4–ClPh (8b)
Ph, 3–ClPh (8c)
Ph, 4–BrPh (8d)
Ph, 3–NO2Ph (8e)
Ph, 4–CH3Ph (8f)
Ph, 3,4–Me2Ph (8g)
Ph, 3,5–Me2Ph (8h)
Ph, 3–Cl–4–MePh (8i)
Ph, 3–CH3OPh (8j)
4–FPh, Ph (8k)
3–FPh, Ph (8l)
2–FPh, Ph (8m)
4–ClPh, Ph (8n)
4–BrPh, Ph (8o)
4–IPh, Ph (8p)
4–NO2Ph, Ph (8q)
4–CNPh, Ph (8r)
4–CH3Ph, Ph (8s)
4–CH3OPh, Ph (8t)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4
2
10
10
a
Reaction conditions: catalyst 5 (8.59 mg, 1.0 lmol of Ru based on ICP analysis, and 1.01 lmol of N based on TG analysis), enones (0.10 mmol), amines (0.11 mmol),
i
HCOONa (1.0 mmol), 2.0 mL of PrOH/H2O (v/v = 1:1), and reaction time (2.5–12 h).
b
Isolated yields.
c
The ee determined chiral HPLC analysis (see SI in Figs. S4, S6).
Data were obtained using physically mixed N,N–dimethylprop–2–en–1–amine and 3 as dual catalysts.
Data were obtained using physically mixed N,N–dimethylprop–2–en–1–amine and homogeneous MesRuTsDPEN as dual catalysts.
d
e
this reaction time course discloses a cascade process in this
aza–Michael addition/ATH cascade reaction.
alkylamines since the targeting products were the important phar-
maceutical intermediates for the preparation of optically pure
antidepressants like Fluxetine and Atomoxetine, as shown in
Scheme 3. In this case, three representative alkylamines, methy-
lamine, ethylamine, and butylamine, could steadily react with
1–phenylprop–2–enone in the 5-catalysed aza–Michael addition/
ATH cascade reaction, providing chiral products in moderate yields
with excellent enantioselectivities in environmentally friendly
reaction conditions.
3.2.3. Extension of the aza–Michael addition/ATH cascade reaction
In addition to the general feasibility in the aza–Michael addi-
tion/ATH cascade reaction of enones and arylamines, this cascade
reactions catalyzed by 5 could also be expanded to enones and
3.2.4. Catalyst’s stability and recyclability
Besides general applications in the aza–Michael addition/ATH
enantioselective cascade reaction, the heterobifunctional catalyst
5 also exhibited high recyclability. As shown in Fig. 6, catalyst 5
was recovered by a simple centrifugation and reused repeatedly,
in six consecutive reactions for the aza–Michael addition/ATH of
1–phenylprop–2–enone and aniline, catalyst 5 still afforded 91%
100
80
60
6a
A
40
7a
20
0
0
20
40
60
80
100
120
140
Reaction time (minute)
Fig. 5. Time course of the aza–Michael addition/ATH of 1–phenylprop–2–enone
and aniline to (S)–1–phenyl–3–(phenylamino)propanol (reaction was performed
with 1 equivalent of 1–phenylprop–2–enone, 1.1 equivalent of aniline, 1.0 mol% of
catalyst 5, 10.0 equivalent of HCOONa at 40 °C).
Scheme 3. The 5–catalyzed aza–Michael addition/ATH enantioselective cascade
reactions of 1–phenylprop–2–enone and alkylamines.

196
M. Gao et al. / Journal of Catalysis 376 (2019) 191–197
Fig. 6. Reusability of catalyst 5 using the cascade reduction of 1–phenylprop–2–enone and aniline.
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decreased yield at the seventh recycle (82% yield with 91% ee)
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In conclusions, the integrated soluble polymer and mesoporous
silica as a double–type support for the construction of heterobi-
functional catalyst is developed by tethering tertiary amine–func-
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diamine–functionality within the inner silica. As presented in this
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aza–Michael addition/ATH one–pot enantioselective cascade reac-
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catalytically active site–isolated feature of catalyst, together with
the tertiary amine–functionality for enhanced catalytic activity
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