Catalytic performance of silica supported cinchona alkaloids as heterogeneous catalysts for asymmetric michael reaction

Article abstract of DOI:10.1007/s10562-014-1322-5

Silica supported cinchona alkaloids were prepared by thio-ene coupled reaction so as to develop novel highly efficient heterogeneous organocatalysts for asymmetric Michael reaction. As-prepared supported cinchona alkaloids were used as heterogeneous catal

Full text of DOI:10.1007/s10562-014-1322-5

Catal Lett (2014) 144:1681–1688
DOI 10.1007/s10562-014-1322-5
Catalytic Performance of Silica Supported Cinchona Alkaloids
as Heterogeneous Catalysts for Asymmetric Michael Reaction
•
Wenshan Zhao Yanli Zhang Chengke Qu
•
•
•
Lei Zhang Jing Wang Yuanchen Cui
•
Received: 5 February 2014 / Accepted: 20 July 2014 / Published online: 21 August 2014
Ó Springer Science+Business Media New York 2014
Abstract Silica supported cinchona alkaloids were pre-
pared by thio-ene coupled reaction so as to develop novel
highly efficient heterogeneous organocatalysts for asym-
metric Michael reaction. As-prepared supported cinchona
alkaloids were used as heterogeneous catalysts to catalyze
the asymmetric Michael reaction between 1,3-dicarbonyl
compounds and N-benzylmaleimide, and their catalytic
performance was evaluated. It was found that, when tolu-
ene is employed as the solvent, silica supported cinchona
alkaloid catalysts can catalyze the aforementioned Michael
reaction with medium enantiomeric excess (ee) values (up
to 87 %) and significant diastereo ratio (dr) values (up to
96:4). In the meantime, they can be recovered and reused
for at least five cycles while their stereo-selectivity remains
almost unchanged. This means that the title catalysts could
be highly efficient organocatalysts for the investigated
Michael reaction.
1 Introduction
Asymmetric Michael reaction is one of the most effective
approaches for constructing of stereo-selective C–C bond
[1, 2]. Kinds of optically active compounds, which are
important intermediates of medical compounds and natural
product, can be synthesized by Michael addition Reaction
easily (like 1,5-dicarbonyl compounds). This can well
explain why scholars pay more and more attention to
asymmetric Michael reaction [3–5].
Among various efficient asymmetric catalysts for
Michael reaction [6–10] and many other reactions [11–13],
Cinchona alkaloids and their derivatives are of special sig-
nificance, because of their high efficiency and hypotoxicity.
Unfortunately, the utility of Cinchona alkaloids and their
derivatives is often limited by the difficulty of separating
them from the reaction system. In order to overcome this
drawback, researchers have tried to graft cinchona alkaloid-
type organocatalysts with suitable supports thereby acquir-
ing improved recyclability, simplified reaction set-up plus
easy experimental procedure, and reduced toxicity [14–16].
Frequently-used supports for such a purpose are polymers,
such as polystyrene [17–20], polyethyleneglycol [21, 22],
copolymer [23], and even nature polymers [24, 25]. Never-
theless, few reports are currently available about grafting
cinchona alkaloid-type organocatalysts with silica, although
silica as an inorganic support exhibits high surface area, good
thermal and mechanical stabilities, and good chemical
inertness [26, 27].
Keywords Silica supported cinchona alkaloids Á
Asymmetric michael reaction Á Heterogeneous catalyst Á
Catalytic performance
W. Zhao Á C. Qu Á L. Zhang Á J. Wang Á Y. Cui (&)
College of Chemistry and Chemical Engineering, Henan
University, Kaifeng 475004, China
e-mail: yuanchencui@126.com
Bearing those perspectives in mind and noticing that
cinchona alkaloids are considered as active and highly ste-
reo-selective catalysts for asymmetric Michael reaction, in
the present research we choose quinine and cinchonine as
original small catalysts to synthesize silica-supported cin-
chona alkaloid heterogeneous catalysts via thermal induced
Y. Zhang
School of Materials and Chemical Engineering, Zhongyuan
University of Technology, Zhengzhou 451191, China
Y. Cui
Key Laboratory of Ministry of Education for Special Functional
Materials, Henan University, Kaifeng 475004, China
123

1682
W. Zhao et al.
Scheme 1 Routes to synthesis
of silica supported Cinchona
Alkaloids catalysts (Me refers to
methyl)
thiol–ene coupling [28]. The present approach is facile and
competitive, and it could be utilized to synthesize organo-
catalysts possessing high catalytic activity while the cata-
lytic centre of cinchona alkaloids is maintained. This paper
reports the synthesis of silica supported cinchona alkaloids
and the evaluation of their catalytic performance for asym-
metric Michael reaction between 1,3-dicarbonyl compounds
and N-benzylmaleimide. Moreover, the recyclability of the
catalyst was also evaluated carefully.
anhydrous toluene (30 mL) were sequentially added into
three-necked flask (50 mL). Resultant reaction system was
saturated with N2 and heated to 70 °C with a water bath,
followed by magnetic stirring at 70 °C for 24 h to allow
generation of yellow powder. The yellow powder was
collected by leaching and washing sequentially with tolu-
ene and chloroform, followed by drying in a vacuum oven
until its weight remained unchanged to afford target
product, silica-supported quinine catalyst (denoted as
Cat.I). Silica-supported cinchonine catalyst (denoted as
Cat.II) was prepared in the same manners while chloroform
rather than anhydrous toluene was used as the solvent and
the reaction temperature was kept around 61 °C (Reflux).
As-synthesized catalysts were characterized by FT-IR. It
could be seen from Fig. 1 (b, c) that the broad band at
around 3100 cm-1 was assigned to hydroxyl and amino
group, the absorption of 1600 cm-1 was caused by the
aromatic rings of cinchona alkaloid. The catalyst load of
as-prepared heterogeneous catalysts was also confirmed by
elemental analysis (Ratio of S to N; Cat.I: 0.27 mmol/g;
Cat.II: 0.23 mmol/g).
2 Experiment
2.1 General
Commercial grade reagents and solvents were used as-
received except that specific purification procedure was
recommended. Thin layer chromatography (TLC) was
conducted with GF254 silica gel plates. Silica and (3-
Mercaptopropyl)trimethoxysilane were bought from
Changzhou Chemistry Company. Infrared spectra were
recorded with an Avatar360 Fourier transform infrared
spectrometer (FTIR; Nicolet Company, USA). Nuclear
magnetic resonance (NMR) spectra were obtained from
Bruker Avance 400 M system, and the chemical shifts of
1H NMR spectra were reported in relation to tetramethyl
silane (d = 0). Analytical high performance liquid chro-
matography (HPLC) was performed with an Agilent 1100
system with a diode array ultraviolet detector and Daicel
Chiralpak AD-H chiral columns.
2.3 General Procedure for Michael Reaction
1,3-dicarbonyl compound (0.2 mmol), N-benzylmaleimide
(0.24 mmol), and a proper amount of as-synthesized cata-
lyst were added into solvent (1 mL). Resultant mixture was
heated at pre-set temperature under magnetic stirring, and
the reaction system was detected by TLC [ethyl acetate/
petroleum ether = 1:2 (volume ratio)]. Upon completion
of the reaction, the product was filtered and extracted with
ethyl acetate, and then the organic layer was dried with
anhydrous Na2SO4, filtered, concentrated and purified by
TLC on a silica gel (ethyl acetate/petroleum ether) to
afford desired target products.
2.2 Preparation of the Catalysts
Silica-thiol was prepared according to the literature [29]
and was characterized by FT-IR and elemental analysis (S
0.51 mmol%/g). SEM showed that silica–thiol appeared as
random power-like, while this kind of silica was imporous.
Routes to synthesis of silica supported Cinchona Alkaloids
catalysts are outlined in Scheme 1. Silica–thiol (0.50 g,
0.25 mmol), quinine (0.24 g, 0.75 mmol), 2,2-azobisi-
sobutyronitrile (denoted as AIBN; 0.08 g, 0.50 mmol), and
2.3.1 Ethyl 1-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-
oxocyclopentanecarboxylate, 3a
Colourless foam. [Daicel Chiralpak AD-H, hexane/i-PrOH =
85/15, 0.75 mL/min,
k 214 nm, major diastereomer:
123

Catalytic Performance of Silica Supported Cinchona Alkaloids
1683
Table 1 Screening reaction conditions for the organocatalytic
asymmetric conjugate addition of 1a to maleimide 2 catalyzed by
Cat.I and Cat.II
Entry Solvent
T (d) Catalyst Yield dr
(%)a
ee
(%)
(syn)b
(syn/
anti)b
1
Toluene
CH2Cl2
4
4
4
4
4
4
4
5
4
4
4
4
4
4
CatI
CatI
CatI
CatI
CatI
CatI
CatI
CatI
CatI
CatII
CatII
CatII
CatII
CatII
83
86
82
74
93
52
71
61
87
87
86
82
74
93
82:18
80:20
78:22
77:23
64:36
49:51
45:55
84:16
75:25
75:25
63:37
68:32
63:37
62:38
84
80
74
78
71
45
45
80
75
78
70
71
69
67
2
3
Pseudocumene
CHCl3
4
5
CH3CN
Fig. 1 FT-IR spectra of silica-SH (a), silica-supported quinine
catalyst (b) and silica-supported cinchonine catalyst (c)
6
NMP
7
MeOH
8
Toluenec
Toluened
Toluene
CH2Cl2
smajor = 17.2 min, sminor = 20.1 min; minor diastereomer:
1
9
smajor = 21.8 min, sminor = 24.2 min]. H NMR(CDCl3):
10
11
12
13
14
d = 1.22 (t, J = 7.2, 3H), 1.93–2.03 (m, 2H), 2.08–2.20 (m,
1H), 2.35–2.50 (m, 3H), 2.60 (dd, J = 6.0, 18.0, 1H), 2.80 (dd,
J = 9.2, 18.0, 1H), 3.46 (dd, J = 6.0, 9.2, 1H), 4.17 (q, J = 7.2,
2H), 4.57 (AB, J = 14.2, 2H), 7.18–7.35 (m, 5H). 13C NMR
(CDCl3): d = 13.9 (CH3), 19.1 (CH2), 31.6 (CH2), 32.6 (CH2),
37.9 (CH2), 42.1 (CH), 42.2(CH2), 60.6 (C), 62.0 (CH2), 127.7
(CH), 128.3 (CH, 2C), 128.5 (CH, 2C), 135.4 (C), 169.5 (C),
175.0 (C), 177.0 (C), 213.5 (C). HRMS: m/z calcd for
C19H21NO5: 343.14197; found: 343.14173.
Pseudocumene
CHCl3
CH3CN
Experimental conditions (0.2 mmol scale): The reactions were stirred
at ambient temperature in 1 mL undistilled solvent with a 1:1.2 ratio
of 1a–2 and a certain amount of catalyst
a
Isolated yield
b
Determined by HPLC analysis
c
Reaction is performed in the presence of 5 mol% catalyst
2.3.2 3-(3-acetyl-2-oxotetrahydrofuran-3-yl)-1-
d
Reaction is performed in the presence of 20 mol% catalyst
benzylpyrrolidine-2,5-dione, 3b
White solid. [Daicel ChiralpakAD-H, hexane/i-PrOH = 80/
20, 0.75 mL/min, k 214 nm, major diastereomer: smi-
nor = 27.9 min, smajor = 33.2 min; minor diastereomer:
smajor = 20.0 min, sminor = 23.8 min]. 1H NMR
(CDCl3): d = 2.27 (s, 3H), 2.40–2.49 (m, 1H), 2.53 (dd,
J = 6.4, 18.4, 1H), 2.68–2.75 (m, 1H), 2.81 (dd, J = 9.2,
18.4, 1H), 3.35 (dd, J = 6.4, 9.2, 1H), 4.27–4.34 (m, 2H),
4.64 (AB, J = 14.4, 2H), 7.23–7.33 (m, 3H), 7.32–7.36 (m,
2H). 13C NMR (CDCl3): d = 25.9 (CH3), 28.7 (CH2), 31.7
(CH2), 42.1 (CH), 42.6 (CH2), 61.6 (C), 65.9 (CH2), 127.9
(CH), 128.5 (CH, 2C), 128.6 (CH, 2C), 135.3 (C), 173.6 (C),
174.4 (C), 176.1 (C), 200.7 (C). HRMS: m/z calcd for
C17H17NO5: 315.11067; found: 315.11085.
sminor = 32.7 min, smajor = 38.3 min]. 1H NMR (CDCl3):
d = 1.22 (t, J = 7.2, 3H), 1.50 (s, 3H), 2.24 (s, 3H), 2.44 (dd,
J = 6.0, 18.4, 1H), 2.85 (dd, J = 9.2, 18.4, 1H), 3.37 (dd,
J = 6.0, 9.2, 1H), 4.18 (q, J = 7.2, 2H), 4.64 (AB,
J = 14.0, 2H), 7.23-7.40 (m, 5H). 13C NMR (CDCl3):
d = 13.9 (CH3), 18.9 (CH3), 26.8 (CH3), 32.4 (CH2), 42.4
(CH2), 44.9(CH), 61.2 (C), 62.2 (CH2), 127.8 (CH), 128.5
(CH, 2C), 128.7 (CH, 2C), 135.6 (C), 170.7 (C), 175.2 (C),
177.0 (C), 204.2(C). HRMS: m/z calcd for C18H21NO5:
331.14197; found: 331.14163.
2.3.4 3-(1-acetyl-2-oxocyclopentyl)-1-benzylpyrrolidine-
2,5-dione, 3d
2.3.3 Ethyl 2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-
White foam. [Daicel Chiralpak AD-H, hexane/i-
PrOH = 75/25, 0.75 mL/min, k 214 nm, major diastereo-
mer: sminor = 15.2 min, smajor = 22.7 min; minor dia-
stereomer: sminor = 11.4 min, smajor = 13.8 min]. 1H
NMR (CDCl3): d = 1.80–2.00 (m, 3H), 2.19 (s, 3H), 2.35
(dd, J = 6.4, 18.4, 1H), 2.40–2.57 (m, 3H), 2.74 (dd,
methyl-3-oxobutanoate, 3c
White foam. [Daicel Chiralpak AS-H column, hexane/i-
PrOH = 80/20, 0.75 mL/min, k 214 nm, major diastereomer:
sminor = 21.3 min, smajor = 26.2 min; minor diastereomer:
123

1684
W. Zhao et al.
Table 2 Highly stereo-selective conjugate addition of 1,3-dicarbonyl compounds 1–2 catalyzed by CatI
Entry
1
Temperature (°C)
Time (h)
Yield (%)a
dr (syn/anti)b
ee (syn) (%)b
1
2
Ambient temperature
0
96
93
87
82:18
80:20
84
84
1a
144
3
4
Ambient temperature
0
96
94
90
85:15
89:11
73
72
144
1b
5
6
Ambient temperature
0
96
80
82
90:10
92:8
83
86
144
1c
7
8
Ambient temperature
0
96
83
80
92:8
91:9
57
73
144
1d
9
Ambient temperature
0
96
72
71
93:7
96:4
75
83
10
144
1e
11c
12c
Ambient temperature
0
48
48
89
76
78:22
80:20
83
91
1a
Experimental conditions (0.2 mmol scale): The reactions were stirred in 1 mL Toluene with a 1:1.2 ratio of 1a–e to 2 and 10 mol% of the
catalyst
a
Isolated yield
b
Determined by HPLC analysis
c
The reaction was catalyzed by 10 mol% of the quinine as catalyst
J = 9.2, 18.4, 1H), 3.55 (dd, J = 6.4, 9.2, 1H), 4.63 (AB,
J = 14.0, 2H), 7.24-7.39 (m, 5H). 13C NMR (CDCl3):
d = 19.4 (CH2), 26.2 (CH3), 28.8 (CH2), 31.8 (CH2), 38.4
(CH2), 42.5 (CH2), 43.6 (CH), 68.7 (C), 128.0 (CH), 128.6
(CH, 2C), 128.7 (CH, 2C), 135.4 (C), 174.7 (C), 176.5 (C),
202.0 (C), 213.4 (C). HRMS: m/z calcd for C18H19NO4:
313.13141; found: 313.13121.
J = 6.0, 9.2, 1H), 4.73 (AB, J = 14.4, 2H), 7.22–7.37 (m,
5H), 7.39–7.45 (m, 2H), 7.52 (t, J = 7.6, 9.2, 1H), 8.07 (d,
J = 7.6, 9.2, 1H). 13C NMR (CDCl3, T = 50 °C):
d = 25.6 (CH2), 29.1 (CH3), 31.1 (CH2), 31.9 (CH2), 42.6
(CH2), 44.2 (CH), 65.5 (C), 127.4 (CH), 127.7 (CH), 128.1
(CH), 128.5 (CH, 2C), 128.6 (CH, 2C), 129.0 (CH), 132.1
(CH), 134.4 (C), 135.9 (C), 142.9 (C), 175.0 (C), 177.1 (C),
196.1 (C), 205.6 (C). HRMS: m/z calcd for C23H21NO4:
375.14706; found: 375.14643.
2.3.5 3-(2-acetyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-
yl)-1-benzylpyrrolidine-2,5-dione, 3e
2.3.6 (S)-(?)-Methyl 2-carbomethoxy-4-nitro-3-phenyl-
butyrate, 4a
White solid. [Daicel Chiralpak AD-H, hexane/i-
PrOH = 75/25, 0.75 mL/min, k 214 nm, major diastereo-
mer: sminor = 24.0 min, smajor = 22.8 min; minor dia-
stereomer: sminor = 25.8 min, smajor = 20.3 min]. 1H
NMR (CDCl3): d = 2.19 (s,3H), 2.37–2.54 (m, 3H), 2.63
(dd, J = 6.0, 18.4, 1H), 2.98–3.03 (m, 2H), 3.30 (dd,
White solid. [Daicel chiralcel AD-H, hexane/i-PrOH = 95/5,
1.0 ml/min,
k
254 nm,
smajor = 26.2 min,
smi-
nor = 40.8 min]. 1H NMR (400 MHz, CDCl3): d = 7.34–7.22
(m, 5H), 4.95–4.85 (m, 2H), 4.25 (dt, J = 5.2 Hz, 8.8 Hz, 1H),
123

Catalytic Performance of Silica Supported Cinchona Alkaloids
1685
Table 3 Highly stereoselective conjugate addition of 1,3-dicarbonyl compounds 1 to 2 catalyzed by Cat II
Entry
1
Temperature (°C)
Time (h)
Yield (%)a
dr (syn/anti)b
ee (syn) (%)b
1
2
Ambient temperature
0
96
73
69
75:25
74:26
78
82
1a
144
3
4
Ambient temperature
0
96
87
71
94:6
93:7
82
87
1b
144
5
6
Ambient temperature
0
96
83
85
87:13
85:15
81
86
144
1c
7
8
Ambient temperature
0
96
72
61
51:49
72:28
74
80
1d
144
9
Ambient temperature
0
96
86
89
90:10
93:7
66
80
10
144
1e
11c
12c
Ambient temperature
0
48
48
87
76
74:26
74:26
76
83
1a
Experimental conditions (0.2 mmol scale): The reactions were stirred in 1 mL Toluene with a 1:1.2 ratio of 1a–e to 2 and 10 mol% of the
catalyst
a
Isolated yield
b
Determined by HPLC analysis
c
The reaction was catalyzed by 10 mol% of the cinchonine as catalyst
3.86 (d, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 3H). 13C NMR
2.3.8 (?)-Methyl 2-carbomethoxy-4-nitro-3-(4-methoxy-
phenyl)-butyrate, 4c
(100 MHz, CDCl3): d = 167.8, 167.2, 136.1, 128.9, 128.3,
127.8, 77.3, 54.7, 52.9, 52.7, 42.9. HRMS: m/z calcd for
(C13H15NO6 ? H?) 282.0964, found 282.0969.
Colorless foam. [Chiralpak AD-H, hexane/i-PrOH = 60:40,
1.0 ml/min,
k 220 nm, sminor = 7.6 min, smajor =
1
11.9 min]. H NMR (400 MHz, CDCl3): d 7.14 (d, J =
9.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.89 (dd, J = 4.8 Hz,
12.8 Hz, 1H), 4.83 (dd, J = 8.8 Hz, 13.6 Hz, 1H), 4.19 (dt,
J = 4.8 Hz, 13.2 Hz, 1H), 3.82 (d, J = 9.2 Hz, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 3.58(s, 3H). 13C NMR (100 MHz, CDCl3):
d 167.9, 167.3, 159.4, 129.0, 127.8, 114.3, 77.6, 55.2, 54.8,
52.9, 52.8, 42.2. HRMS: m/z calcd for (C14H17NO7 ? H?)
312.1070, found 312.1076.
2.3.7 (?)-Methyl 2-carbomethoxy-4-nitro-3-(4-chloro-
phenyl)-butyrate, 4b
White solid. [Daicel chiralcel AD-H, hexane/i-PrOH =
70:30, 1.0 ml/min, k 220 nm, smajor = 10.5 min, smi-
1
nor = 15.6 min]. H NMR (400 MHz, CDCl3): d 7.31 (d,
J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 4.91 (dd,
J = 4.8 Hz, 12.8 Hz, 1H), 4.85 (dd, J = 8.4 Hz, 13.6 Hz,
1H), 4.23 (dt, J = 4.8 Hz, 9.2 Hz, 1H), 8.83 (d, J =
9.2 Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 167.6, 167.0, 134.6, 134.4, 129.3,
129.2, 77.1, 54.4, 53.0, 52.9, 42.3. HRMS: m/z calcd for
(C13H14ClNO6 ? H?) 316.0583, found 316.0582.
2.4 Evaluation of Recyclability of Catalyst
At the end of the Michael reaction, the used catalyst
was recollected by filtering in vacuum, followed by
123

1686
W. Zhao et al.
Table 4 Asymmetric Michael reaction between b-nitrostyrolene compounds 4 and dimethyl malonate 5 catalyzed by silica-supported cinchona
alkaloid heterogeneous catalysts
Entry
1
Catalyst
R
Time (h)
Yield (%)a
ee (%)b
CatI
CatII
CatI
CatII
CatI
CatII
QN
4-H (4a)
120
120
168
120
168
120
48
87
65
86
47
89
75
83
76
31
6
2
4-Cl (4b)
4-OMe (4c)
4-H (4a)
26
9
3
25
-2
25
19
4c
CN
48
Experimental conditions (0.2 mmol scale): The reactions were stirred at ambient temperature in 1 mL Toluene with a 1:1.2 ratio of 4–5 and
10 mol% of the catalyst
a
Isolated yield
b
Determined by HPLC analysis
c
The reaction was catalyzed by 10 mol% of the quinine (QN) or cinchonine (CN) as catalyst
Table 5 The reusability of the CatI in the reaction of ethyl-2-cyclopentanonecarboxylate 1a to n –benzylmaleimide 2
Entry
Cycle
T (d)
Yield (%)a
dr (syn/anti)b
ee (%) (syn)b
1
1
2
3
4
5
–
–
4
4
4
4
6
6
9
83
86
82
74
93
trace
–
82:18
80:20
78:22
83:17
82:18
59:41
–
84
80
74
76
77
37
–
2
3
4
5
6c
7d
Experimental conditions (0.2 mmol scale): The reactions were stirred at ambient temperature in 1 mL Toluene with a 1:1.2 ratio of 1a–2 and
10 mol% of the catalyst
a
Isolated yield
b
Determined by HPLC analysis
c
The CatI was stirred at ambient temperature in 1 mL Toluene in 4 days, then the filtered toluene was used as solvent for the reaction
d
The CatI was stirred at ambient temperature in 1 mL Toluene in 4 days, and the CatI was obtained by filtration and dried, then the obtained
CatI was stirred at ambient temperature in another 1 mL again in 4 days. The filtered toluene was used as solvent for the reaction
123

Catalytic Performance of Silica Supported Cinchona Alkaloids
1687
washing with dichloromethane and drying in an oven for
24 h to afford recycled catalyst. As-obtained recycled cata-
lyst was reused directly without further purification.
catalyze the Michael reaction between b-alkenylstyrene
and dimethyl malonate [30, 31]. As shown in Table 4,
target Michael reaction products can successfully be
obtained with a medium yield but a quite poor stereo-
selectivity (the highest ee value is only about 30 %). But,
by comparing with non-supported catalysts (Entries 11 and
12), we could draw a conclusion that the low stereoselec-
tivity of Cat.I and Cat.II inherited from cinchona alkaloids.
Furthermore, the Michael reaction between ethyl
2-oxocyclopentanecarboxylate and N-benzylmaleimide
was adopted as a model reaction to evaluate the recycla-
bility of as-synthesized silica-supported cinchona alkaloid
Cat.I (Table 5). It can be seen that as the recycle times
rises, the reaction proceeds with slightly reduced stereo-
selectivity and catalytic activity as well. Reactions which
used filtered toluene as reaction solvent (Entries 6 and 7)
implied that, although stirring might cause detachment of
the alkaloid from the supporter during the aforementioned
asymmetric Michael reactions, the detached catalyst was
few and could not show catalytic effect. After all, silica-
supported cinchona alkaloids as heterogeneous catalysts
possess good catalytic activity and reusability.
3 Results and Discussions
The catalytic performances of as-synthesized catalysts in
different solvents are listed in Table 1. It can be seen that
Cat.I possesses good stereo-selectivity and catalytic activity
in low polar aprotic solvents such as toluene, dichloro-
methane, and chloroform (Entries 1–4), but it exhibits lower
stereo-selectivity in polar aprotic solvents (Entries 5 and 6).
Unsurprisingly, silica supported cinchona alkaloids do not
adapt to protic solvent (Entry 7), due to the formation of
hydrogen bonds via either the catalysts or the substrates. The
effects of catalyst load on the stereo-selectivity and yield are
also summarized in Table 1. It can be seen that decreasing
catalyst load to 5 mol% leads to lower yield but has no effect
on the stereo-selectivity (Entries 8 and 9). The suitability of
Cat.II for different solvents was also explored, and it was
found that Cat.II exhibits similar suitability for various sol-
vents as Cat.I does. Summarizing the results listed in
Table 1, we can conclude that toluene is the optimal solvent
for the Michael reaction under investigation, and the optimal
catalyst dosage is 10 mol%.
4 Conclusion
We further examined the conjugate addition of a variety
of trisubstituted carbon Michael donors to N-benzylmalei-
mide in the presence of Cat.I (Table 2). It can be seen that
Cat.I can catalyze the aforementioned Michael reaction
successfully. Namely, when cyclic b-ketoesters (Entries 3
and 4) or acyclic b-ketoesters (Entries 5 and 6) are used as
Michael donors, reactions proceed with moderate stereo-
selectivity. When b-diketones, much more challenging
substrates, are used as Michael donors, high diastereo-
selectivity is obtained, but fair enantio-selectivity is
acquired. Moreover, we carried out relevant reactions at
ambient temperature and 0 °C and found that the catalyst
possesses higher stereo-selectivity but lower catalytic
activity at 0 °C (Table 2). The reaction between aimethyl
malonate and N-benzylmaleimide was also been explored,
but the Michael production was not obtained. Moreover, by
comparing with quinine (Entries 11 and 12), we could draw
a conclusion that the supported catalyst possessed similar
stereoselectivity but lower catalytic activity.
Silica supported cinchona alkaloid catalysts have been
successfully prepared by thio–ene coupled reaction. As-
prepared silica supported cinchona alkaloids as heteroge-
neous catalysts exhibit desired performances for the
asymmetric Michael reaction between 1,3-dicarbonyl
compounds and N-benzylmaleimide, and both their cata-
lytic activity and stereo-selectivity vary with varying
reaction conditions such as the type of solvent, catalyst
dosage, and reaction temperature. Particularly, they can
well catalyze the title Michael reaction with medium ee
values (up to 87 %) and significant dr values (up to 96:4) in
the presence of toluene as the solvent. Besides, as-prepared
silica supported cinchona alkaloids retain almost unchan-
ged stereo-selectivity even after five cycle of recovery and
reuse, showing promising potential as highly efficient or-
ganocatalysts for the aforementioned Michael reaction.
Studies on the immobilization of 9-amino-9-deoxy-epi-
cinchonine are underway in order to further improve the
performance of the title catalysts.
The catalytic performances of Cat.II for different kinds of
Michael reactions were also explored (Table 3). It is worth
emphasizing that Cat.II allows access to the opposite enan-
tiomer of the 1,4-adduct with a medium stereo-selectivity.
Besides, Cat.II provides similar ee values as Cat.I does
(Table 2), but the former exhibits greatly reduced dr values.
To broaden the scope of the methodology, we also
adopted silica-supported cinchona alkaloid catalysts to
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