Copolymer-supported heterogeneous organocatalyst for asymmetric aldol addition in aqueous medium

Article abstract of DOI:10.1039/c2ob25106j

In the current study, a convenient and simple way is presented to synthesize a novel type of supported heterogeneous organocatalyst in 21-81% yield by the copolymerization of 9-amino-9-deoxy-epi-cinchonine organocatalyst with acrylonitrile using AIBN as r

Full text of DOI:10.1039/c2ob25106j

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PAPER
Copolymer-supported heterogeneous organocatalyst for asymmetric aldol
addition in aqueous medium†
Jinqing Zhou, Jinwei Wan, Xuebing Ma* and Wei Wang
Received 14th January 2012, Accepted 30th March 2012
DOI: 10.1039/c2ob25106j
In the current study, a convenient and simple way is presented to synthesize a novel type of supported
heterogeneous organocatalyst in 21–81% yield by the copolymerization of 9-amino-9-deoxy-epi-
cinchonine organocatalyst with acrylonitrile using AIBN as radical initiator. The chemical compositions
(x/y) and weight-average molecular weights of copolymers 1a–d were determined by 1H NMR and GPC
analysis respectively. Their porous and layered structure, and surface morphology were characterized by
nitrogen adsorption–desorption, XRD and TEM. In the asymmetric aldol addition of p-nitrobenzaldehyde
to cyclohexanone and 1-hydroxy-2-propanone in water, all the supported organocatalysts 1a–d afforded
excellent isolated yields (90.2–94.7%) and stereoselectivities (96.8–97.8%ee anti, anti/syn = 91/9). The
highest catalytic property (96% yield, anti/syn = 90/10 and 99%ee anti) in water as the sole solvent was
achieved under the optimized conditions. Compared with cyclohexanone, cyclopentanone and acetone
showed the less desired enantioselectivities in the same aldol reactions. At the end of the aldol reaction,
the copolymer-supported organocatalyst 1a was readily recovered in 95–98% yield from reaction mixture
by simple filtration using an organic membrane. Even in the fifth run, there was no significant loss in
catalytic activity and stereocontrol (94.3% yield, 97.2%ee anti, anti/syn = 90/10). After continuous reuse
five times, there was some drop in catalytic activity and stereoselectivity.
an environmentally friendly and safe medium, which avoids the
Introduction
problem of pollution that is inherent with organic solvents.7
It is clear by now that modern asymmetric catalysis is built on
three rather than two pillars, namely biocatalysis, metal catalysis
and organocatalysis. The last two decades have witnessed a spec-
tacular advancement in new catalytic methods based on organic
molecules. In many cases, these small organic compounds result
in extremely high enantioselectivities. Chiral organocatalysts1
are stable to moisture and air, and free from toxic, rare, and
expensive metals. However, some of them are expensive owing
to the cost of the chemical transformations in the synthetic pro-
cedure. Thus, the development of recyclable chiral organocata-
lysts is currently a highly sought after goal in green chemistry.
One of the strategies is heterogenizing homogeneous organocata-
lysts,2 including the attachment to porous silica gel,3 organic
polymer4 and biopolymer,5 and magnetic nanoparticles.6 On the
other hand, chemical reactions in which water is used as the sole
solvent have attracted a great deal of attention because water is
Therefore, from a concept of green chemistry, both the easy,
complete separation and subsequent recycling of homogeneous
organocatalysts from reaction media and catalytic reactions in
water are urgently desired.
The aldol condensation is one of the most important carbon–
carbon bond-forming reactions, which creates the β-hydroxy car-
bonyl structural unit found in many natural products and drugs.
Among the successful strategies, chiral organocatalysts have
been seen as a simplified version of enzymes. Several prominent
chiral organocatalysts have been developed for the aldol reaction,
and some of them provided aldol-adducts excellently and stereo-
selectively, even in aqueous medium.8 9-Amino-9-deoxy-epi-
cinchonine, one of the cinchona derived primary amines, is
regarded as an outstanding representative of these organocata-
lysts, and has been employed as an efficient organocatalyst with
excellent catalytic properties in asymmetric aldol addition,9
Diels–Alder reaction,10 Friedel–Crafts reaction,11 Henry reac-
tion,12 Mannich reaction,13 Michael addition,14 hydrogenation,15
epoxidation,16 1,3-dipolar cycloaddition,17 decarboxylation,18
and methanolytic desymmetrization.19 Due to the virtue of its
excellent catalytic performance and the defect of its being
expensive, it is necessary that amino-9-deoxy-epi-cinchonine
should be easily separated from the reaction mixture and reused
after the completion of catalytic reaction. Unfortunately, very
College of Chemistry and Chemical Engineering, Southwest University,
Chongqing, 400715, P.R. China. E-mail: zcj123@swu.edu.cn;
Fax: (+86)23-68253237; Tel: (+86)23-68253237
†Electronic supplementary information (ESI) available: XRD of 1a–d;
IR spectra of 1a–d; thermogravimetric curves of 1a–d; N2 adsorption–
desorption analysis of 1a–d; some of the HPLC spectra. See DOI:
10.1039/c2ob25106j
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Scheme 1 The synthetic route to the supported organocatalysts 1a–d.
little research work focused on the theme of recycling amino-9-
deoxy-epi-cinchonine and its derivatives has been reported.20
In this paper, by the simple copolymerization of 9-amino-9-
deoxy-epi-cinchonine organocatalyst with acrylonitrile in the
presence of AIBN as radical initiator,21 copolymer-supported
organocatalysts 1a–d with different chemical compositions (x/y)
of 9-amino-9-deoxy-epi-cinchonine were prepared for the first
time in one synthetic step under mild conditions (Scheme 1). In
the asymmetric direct aldol addition of p-nitrobenzaldehyde to
cyclohexanone, the high catalytic properties (96% yield, anti/syn
= 90/10 and 99%ee anti) and reusability for five times without
significant loss in catalytic properties were achieved using water
as a sole reaction medium.
Fig. 1 1H NMR spectra of copolymer-supported organocatalyst 1d.
4000–400 cm−1 shown in ESI.† The broad, strong and wide
absorption band extending from 3700 to 2500 cm−1 and centered
at 3450 cm−1 was assigned to the O–H stretching vibration,
which was indicative of the presence of hydrogen bonds
between adsorbed water on the internal surface. With the
increase of y values from 14 to 25, the stretching vibrations of
–CuN at 2244 cm−1 and C–H at 2940 and 2890 cm−1 were
strengthened in turn from 1d to 1a. The moderate absorption
bands at 1651 and 619 cm−1 were attributed to the stretching
vibration mode and flexural vibration of the quinoline moiety,
respectively.
Results and discussion
The thermal stabilities of the copolymer-supported organoca-
talysts 1a–d were investigated by using TGA. From the DTG
and TG curves, it can be deduced from the weight loss below
150 °C that 3.4–4.3% of the surface-bound or intercalated water
was absorbed in the internal pores, and the process was
endothermic, verified by DSC curves. Accompanied by the
exothermic peaks in the DSC curves, the sharp and slow weight
losses in the temperature range of 150–550 °C and 550–800 °C
corresponded to the initial and deep decompositions of the
appended organic fragments, respectively. The total weight
losses of supported organocatalysts 1a–d in the temperature
range of 150–800 °C were 46.4, 53.3, 51.3 and 49.9%
respectively.
Characterization of copolymer-supported organocatalyst
Chemical composition. The novel analogues, copolymer-sup-
ported organocatalysts 1a–d, which possessed different loading
amounts of 9-amino-9-deoxy-epi-cinchonine, were prepared
under different molar ratios of 9-amino-9-deoxy-epi-cinchonine
and acrylonitrile in DMF at 80 °C for 48 h in the presence of
AIBN as radical initiator. The chemical compositions (x/y) in the
1
copolymers 1a–d could be determined by the H NMR method.
By the comparative investigation of 1H NMR of 9-amino-9-
deoxy-epi-cinchonine, acrylonitrile and the copolymers 1a–d, it
was found that the five hydrogens neighboured on the nitrogen
atom in 9-amino-9-deoxy-epi-cinchonine moiety and one hydro-
gen neighboured on the cyano group were in the range of
2.5–3.5 ppm, and the absorption peaks in 7.3–9.2 ppm range
were attributed to the six aromatic hydrogens in the quinoline
Porous and layered structure. In Table 1 were listed, for all
the as-synthesized copolymers 1a–d, BET-specific surface areas,
average pore diameters and pore volumes by BJH analysis. Due
to the winding round each other of cyano resin chains and the
supporting pillar of 9-amino-9-deoxy-epi-cinchonine, the sup-
ported organocatalysts 1a–d possessed porous structures with the
surface area (20–41.2 m2 g−1), average pore diameters
(8.2–10.1 Å) and pore volumes (8.4–20.7 cc g−1) shown in
Table 1. However, it was found that the surface areas, average
pore diameters and pore volumes decreased successively with
the increase of immobilized 9-amino-9-deoxy-epi-cinchonine,
which showed that the more 9-amino-9-deoxy-epi-cinchonine
was immobilized, the more space was occupied. In addition, the
layered structures of the copolymer-supported organocatalysts
1a–d (d = 5.3 Å at 2θ = 17°), which can be determined from the
00n peaks in the powder XRD pattern (via the Bragg equation,
nλ = 2d sin θ), were observed unexpectedly owing to the ordered
overlapping of cyano resin chains.
1
moiety (Fig. 1). Therefore, according to the H NMR principle
that peak area is directly proportional to the number of hydrogen,
the molar ratios of x to y in the co-polymers 1a–d could be cal-
culated to be 1/25, 1/22, 1/20 and 1/14 respectively. Unfortu-
nately, similar chemical compositions in the copolymers 1a–d
were obtained, even at high initial molar ratios (10 : 1) of acrylo-
nitrile to 9-amino-9-deoxy-epi-cinchonine. GPC analysis showed
that weight-average molecular weights of the polymers 1a–d
were between 0.7 and 1.2 kDa and PDI values between 1.7 and
2.2, which may be not accurate since linear polyacrylonitrile
standards were used for calibration while the supported organo-
catalysts 1a–d were brush polymers.
The covalent attachment of chiral 9-amino-9-deoxy-epi-cinch-
onine on the frame of the copolymers 1a–d was also success-
fully corroborated and verified by infrared spectra in the range of
4180 | Org. Biomol. Chem., 2012, 10, 4179–4185
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Table 1 Porous properties of the synthesized copolymers 1a–da
Surface
areab
Pore
Average pore volumed
Interlayer
distance [Å]
Cat.
[m2 g−1
]
diameterc [Å] [cc g−1
]
1a (y = 25) 41.2
1b (y = 22) 35.9
1c (y = 20) 30.3
1d (y = 14) 20.5
10.1
8.4
10.0
8.2
20.7
15.1
15.2
8.4
5.4
5.3
5.3
5.3
5.4
1a (7th)
38.6
9.5
18.9
a Degassed at 80 °C for 12 h. b Based on the multipoint BET method.
c Based on the desorption data using BJH method. d Based on the
desorption data of BJH method.
Fig. 3 The SEM images of copolymer-supported organocatalysts 1a–
d.
“true” states of the catalysts 1a–d in the asymmetric aldol
addition in water. The SEM images with aggregates larger than
5 μm in size, which were observed in the solid state, could be
considered to mirror surface morphologies of catalysts 1a–d in
the solid state (Fig. 3).
Asymmetric aldol reaction
We first examined the copolymer-supported organocatalyst 1a in
a model reaction, the asymmetric aldol addition of p-nitrobenzal-
dehyde to cyclohexanone, which was conducted in different sol-
vents for 48 h at room temperature. As shown in Table 2, the
solvent played an important role in the catalytic activity, diaster-
eoselectivities and enantioselectivity of aldol adducts and a
series of solvents were screened. Taking the solubility of copoly-
mer-supported organocatalyst 1a in various solvents into
account, the aldol additions could be carried out homogeneously
in DMF, DMSO and CH3CN, and heterogeneously in other sol-
vents such as H2O, toluene and THF. In nonpolar or less polar
solvents, the aldol product was apparently retarded with low
yields (18.3–37.4%) and poor stereocontrol (0–15.7%ee anti,
Table 2, entries 1–5). However, the reaction proceeded smoothly
in polar solvents such as H2O, DMF and ethanol in the moderate
to high yields (49.4–94.7%) and with the excellent stereocontrol
(86.8–97.6%ee anti, anti/syn = 94–71/6–29, Table 2, entries
6–14). To our delight, the excellent yield and stereoselectivity
(94.7% yield, anti/syn = 89/11, and 97.6%ee anti) could be
obtained, although the aldol reaction was carried out heteroge-
neously in water (Table 2, entry 7). Predicated on these data, the
influence of solvents on the stereoselectivities was related to the
different conformations of 9-amino-9-deoxy-epi-cinchonine in
different solvents.22
Fig. 2 The TEM images of copolymer-supported organocatalysts 1a–
d.
Surface morphology. Taking into account the intimate
relationship between physical surface property of supported
organocatalyst and its catalytic performance, it was necessary
that the copolymer-supported organocatalysts 1a–d should be
well clarified by TEM and SEM to understand the surface mor-
phology and particle size in water. After being well-dispersed in
water (5 mg sample in 1 mL of H2O) for 30 min under ultrasonic
radiation, sputtered over copper wire, and evaporated under
infrared radiation for 10 min, the TEM images were observed
under an accelerating rate voltage of 200 keV. From Fig. 2, it can
be seen that the filiform structures were produced with widths of
20–30 nm and lengths up to hundreds of micrometers. Based on
the interlayer d-spacings of the copolymer-supported organocata-
lysts 1a–d (d = 5.3 Å) determined by XRD, it can be deduced
that each filiform chain consisted of ordered stacks of 40–60
cyano resin chains. Due to being well-dispersed in water, the
TEM images could be identified as efficiently elaborating the
surface morphologies of the copolymer-supported organocata-
lysts 1a–d in aqueous solution, which seemed to simulate the
The influence of catalyst loading, used amount and reaction
time on catalytic performance was further examined. As men-
tioned above, by the copolymerization using different initial
molar ratios of organocatalyst 9-amino-9-deoxy-epi-cinchonine
to acrylonitrile, different incorporation levels (x/y = 1/25, 1/22,
1/20 and 1/14) of 9-amino-9-deoxy-epi-cinchonine in 1a–d were
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Table 2 The effect of various solvents in the yields,
Table 3 The effect of catalyst loading, used amount, reaction time and
diastereoselectivities and enantioselectivities of aldol adductsa
temperature on the catalytic performancea
Entry Variable
Yieldc [%] %ee antid %ee synd Dr (anti/syn)
Yieldb
[%]
%ee
%ee
Dr
Entry Solvent
antic
sync
(anti/syn)d
1
2
1a
1b
94.7
93.5
90.2
91.8
55.0
78.3
94.6
95.6
97.8
97.8
97.2
96.8
90.0
95.0
98.1
97.9
95.5
95.0
96.0
97.8
99.0
97.0
93.5
95.6
99.0
96.4
91.3
73.4
74.2
70.2
72.0
45.3
68.0
61.1
69.7
66.1
57.5
60.1
61.5
61.2
60.0
44.0
66.5
61.2
59.7
55.1
91/9
91/9
1
2
Et2O
PhMe
21.4
27.3
26.9
37.4
18.3
49.4
94.7
64.3
51.8
0.0
14.4
3.6
15.7
0.0
91.4
97.6
86.8
95.1
94.2
97.0
92.4
90.0
92.5
21.3
19.7
8.6
11.5
3.4
51.3
73.0
15.0
61.7
58.1
2.3
37.7
27.7
35.2
52/48
58/42
43/57
57/43
58/42
89/11
89/11
71/29
82/18
79/21
94/6
3
1c
1d
1.0 mol%
2.5 mol%
5.0 mol%
7.5 mol%
90/10
90/10
78/22
85/15
90/10
90/10
90/10
90/10
91/9
4
3
4
5
6
CH3CO2C2H5
CHCl3
CH2Cl2
EtOH
5b
6b
7b
8b
7
8
H2O
THF
9b
10.0 mol% 96.8
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
12 h
24 h
36 h
48 h
63.6
74.7
85.3
96.1
96.6
77.3
95.5
96.1
93.5
87.8
9
DMSO
10
11
12
13
14
DMSO/H2O = 5/1 55.2
MeCN 56.5
MeCN/H2O = 5/1 62.2
91/9
90/10
91/9
81/19
90/10
90/10
89/11
80/20
86/14
81/19
91/9
72 h
DMF
DMF/H2O = 5/1
51.7
57.2
10 °C
20 °C
25 °C
30 °C
40 °C
a Reaction conditions: p-nitrobenzaldehyde (37.3 mg, 0.25 mmol),
cyclohexanone (473.5 mg, 4.8 mmol, 0.5 mL), 5 mol% 1a, 10 mol%
TfOH, 25 °C, 2 mL of solvent, 48 h. b Isolated yield. c Determined by
chiral HPLC using Daicel Chiralpak AD-H chiral column. d Determined
by 1H NMR.
a Reaction conditions: p-nitrobenzaldehyde (37.3 mg, 0.25 mmol),
cyclohexanone (473.5 mg, 4.8 mmol, 0.5 mL), 5 mol% 1a, 10 mol%
TfOH, 25 °C, 2 mL of solvent. b Cat. 1a. c Isolated yield. d Determined
by chiral HPLC using Daicel Chiralpak AD-H chiral column.
obtained. In the direct aldol addition of p-nitrobenzaldehyde to
cyclohexanone, all the supported organocatalysts 1a–d possessed
excellent isolated yields (90.2–94.7%) and stereoselectivities
(96.8–97.8%ee anti, 70.2–74.2%ee syn, anti/syn = 91/9) without
significant difference (Table 3, entries 1–4). However, due to the
larger specific surface area, pore diameter and pore volume of 1a
than that of the others (Table 1), better catalytic performance
(94.7%, 97.8%ee anti, 73.4%ee syn, anti/syn = 91/9) was
observed, although the supported organocatalysts 1a contained a
relatively low incorporation of 9-amino-9-deoxy-epi-cinchonine.
Therefore, using supported organocatalyst 1a as an example, the
optimized catalytic conditions were investigated in detail to be
7.5 mol% of catalyst in combination with 10 mol% triflic acid as
an additive, water as sole solvent and 48 h at room temperature
(Table 3, entries 5–19).
The optimized protocol was then expanded to a wide variety
of aldehydes, cyclic and open-chain ketones to investigate cata-
lytic performances. The results indicated that the aldol reaction
catalyzed by supported organocatalyst 1a was dramatically
dependent on the electronic effect of the substituent as that of its
parent 9-amino-9-deoxy-epi-cinchonine in homogeneous cataly-
sis. For example, o-, m- and p-nitrobenzaldehydes smoothly
underwent the aldol reaction with cyclohexanone in good to
excellent yields (81.0–95.8%) and excellent stereoselectivities
(96.6–98.7%ee anti, anti/syn = 90–98/10–2) (Table 4, entries
1–3). Compared with their corresponding “blank” reaction using
9-amino-9-deoxy-epi-cinchonine as catalyst (Table 4, entries
21–23), supported organocatalyst 1a was found to be less reac-
tive (48 h) to obtain similar yields, for o-, m- and p-nitrobenzal-
dehydes. In general, homogeneous organocatalyst 9-amino-9-
deoxy-epi-cinchonine only needed 6–9 h to obtain good yield
(>90%) at room temperature. The excellent stereoselectivity
(97.2%ee anti) and good yield (87.2%) were also obtained for
the electron-withdrawing cyano group (Table 4, entry 4). Unsub-
stituted aromatic aldehyde, benzaldehyde, was less reactive in
59.6% yield with good enantioselectivity (92.3%ee anti) and
moderate anti/syn = 72/28 (Table 4, entry 10). Unfortunately, the
substrates with electron-donating groups at the aromatic ring
were not suitable for aldol reaction. For example, 4-methoxyben-
zaldehyde reacted with cyclohexanone for 48 h yielding the corre-
sponding product in only 22.2% yield and 91.4%ee anti (Table 4,
entry 9). The other substituted groups such as CH3, F, Cl, Br
showed the same results (Table 4, entries 5–8). It was worth notice
that, under the same catalytic conditions, o-, m- and p-nitrobenzal-
dehydes catalyzed by 1a afforded the same (2S,1′R)-configuration
as their corresponding homogeneous catalysis.23 However, the het-
erogeneous catalyst system gave improved diastereoselectivities
(Table 4, entries 2, 3) and enantioselectivity (Table 4, entry 1).
Cyclopentanone was also employed in the same aldol reaction.
Unfortunately, the less desired enantioselectivities compared
with cyclohexanone were found. For example (Table 4, entries
11–13), p-, m- and o-nitrobenzaldehydes afforded the corre-
sponding products in 87.8, 71.4 and 81.6% yields and 85.8, 80.0
and 62.2%ee anti respectively. In almost all cases of cyclopenta-
none, the diastereoselectivity was not high (Table 4, entries
11–20). Furthermore, the aldol addition of p-nitrobenzaldehyde
to an alkyl chain ketone such as acetone and 1-hydroxy-2-propa-
none was preliminarily investigated. Under the optimized con-
ditions, 1-hydroxy-2-propanone gave (3S,4R)-3,4-dihydroxy-4-
(4-nitrophenyl)butan-2-one with the preferable results (91.2%
yield, 98.6%ee syn, syn/anti = 80/20).23a On the other hand, the
aldol reaction between acetone and 4-nitrobenzaldehyde was
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Table 4 The enantioselective direct aldol reactions of aldehydes and
cyclic ketonesa
Yieldb
[%]
%ee
%ee
Dr
Entry
R
X
antic
sync
(anti/syn)d
1
2
3
4
5
6
7
8
o-NO2
m-NO2
p-NO2
p-CN
p-F
p-Cl
p-Br
p-CH3
p-OCH3 CH2 22.2
p-H
p-NO2
m-NO2
o-NO2
p-F
p-Cl
p-Br
p-CH3
p-OCH3
p-H
p-CN
o-NO2
m-NO2
p-NO2
CH2 81.0
CH2 87.6
CH2 95.8
CH2 87.2
CH2 19.8
CH2 35.5
CH2 18.4
CH2 18.3
98.0
96.6
98.7
97.2
96.4
97.0
95.8
92.4
91.4
92.3
85.8
80.0
62.2
81.2
81.4
61.2
81.0
82.0
76.6
89.0
95
39.2
39.0
68.6
67.2
42.6
38.4
7.8
32.6
77.8
35.5
25.2
58.4
24.8
24.8
31.8
26.8
15.8
34.0
10.0
71.0
−44
36
98/2
92/8
90/10
88/12
96/4
99/1
95/5
93/6
67/33
72/28
88/12
67/33
77/23
93/7
81/19
66/34
79/21
94/6
39/61
70/30
98/2
86/16
84/16
Fig. 4 The stability of supported organocatalyst 1a in direct asym-
metric aldol addition of p-nitrobenzaldehyde to cyclohexanone in water.
9
However, it was found that the organic weight loss of organic
moiety in the temperature range of 150–800 °C increased from
46.4 to 49.4%, and the surface area, average pore diameter and
pore volume slightly decreased from 42.1, 10.1 and 20.7 to
38.6 m2 g−1, 9.5 Å and 18.9 cc g−1 respectively. Furthermore,
the aldol addition of p-nitrobenzaldehyde to cyclohexanone
without the addition of recycled 1a was carried out in the filtered
aqueous medium of 7th recycle experiment under the same con-
ditions. As expected, no optically active aldol product was
observed by using HPLC, which was indicative of no leaching
of active component 9-amino-9-deoxy-epi-cinchonine from the
backbone of copolymer. Therefore, considering the increased
organic weight loss (3.0%) by TGA and decreased surface area
and pore volume, it was concluded that the adsorbed reactants,
products, or impurity occupied some pores, covered the catalytic
active sites and resulted in the decrease in catalytic property.
10
11
12
13
14
15
16
17
18
19
20
21f
22f
23f
CH2 59.6
e
—
—
—
—
—
—
—
—
—
—
87.8
71.4
81.6
26.9
30.4
17.8
41.1
32.7
18.9
92.3
e
e
e
e
e
e
e
e
e
CH2 83
CH2 98
CH2 97
98
99
22
a Reaction conditions: p-nitrobenzaldehyde (37.3 mg, 0.25 mmol),
cyclohexanone (473.5 mg, 4.82 mmol, 0.5 mL), 7.5 mol% 1a, 10 mol%
TfOH, 25 °C, 48 h, 2 mL of water. b Isolated yield. c Determined by
chiral HPLC using Daicel Chiralpak AD-H chiral column. d Determined
by 1H NMR. e Cyclopentanone. f 9-Amino-9-deoxy-epi-cinchonine as
“blank” reaction (25 °C, 6 h).
Conclusions
In conclusion, we have synthesized a novel type of supported
heterogeneous organocatalyst by the simple copolymerization of
the organocatalyst 9-amino-9-deoxy-epi-cinchonine with acrylo-
nitrile in the presence of AIBN as radical initiator. From a
concept of green chemistry, these copolymer-supported hetero-
geneous organocatalysts possessed three virtues: simple synthetic
procedure, the easy, perfect separation and subsequent recycling
from the reaction media, and catalytic aldol reactions in water. In
the asymmetric aldol addition of p-nitrobenzaldehyde to cyclo-
hexanone in water, all the supported-organocatalysts 1a–d pos-
also studied in acetone aqueous solution. However, the aldol
adduct,
(S)-4-hydroxy-4-(4-nitrophenyl)butan-2-one,
was
obtained in moderated yield (78%) and with poor enantioselec-
tivity (44%ee).
The recovery and reuse of catalyst
At the end of aldol reaction, the copolymer-supported organoca-
talyst 1a was readily recovered in 95–98% recovered yields from
reaction mixture by simple filtration using an organic membrane.
The supported organocatalyst 1a was washed with ethyl acetate,
stirred in ammonia water for 2 h, filtered, dried under reduced
pressure and reused in the following recycle experiments. Fig. 4
shows the supported organocatalyst 1a had excellent catalytic
performance and stability. Even in the fifth run, there was no
loss in catalytic activity and stereocontrol. However, after being
continuously reused five times, there were some small drops in
catalytic activity and stereoselectivity. In order to seek the reason
why the catalytic property decreased slightly, TEM, TGA and
nitrogen adsorption–desorption isotherm were used to monitor
the change of surface morphology, weight percent of organic
moiety and pore structure. Compared with fresh catalyst 1a, a
similar surface morphology in the seventh run was observed.
sessed
excellent
isolated
yields
(90.2–94.7%)
and
stereoselectivities (96.8–97.8%ee, anti, anti/syn = 91/9). Further-
more, they could maintain high catalytic performance and stab-
ility in water without
a loss in catalytic activity and
stereocontrol, even in the fifth run.
Experimental section
General remarks
All chemicals were purchased and used without any further
purification. 9-Amino-9-deoxy-epi-cinchonine was synthesized
according to the reference and ascertained by 1H and
13C NMR.24
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Org. Biomol. Chem., 2012, 10, 4179–4185 | 4183

View Article Online
20
D(589)
Instrumentation and methods
24.01; Found: C, 70.83; H, 6.27; N, 22.92. 1c: [α]
= +17.6
(0.5 g 100 mL−1, DMF), anal. calcd for C55.3H58.1N16.1: C,
TLC, where applicable, was performed on pre-coated alu-
minium-backed plates and spots were made visible by quenching
ultraviolet (UV) fluorescence (λ = 254 nm). Fourier transform
infrared spectra were recorded on a Perkin-Elmer Model GX
Spectrometer using a KBr pellet method with polystyrene as a
standard. Thermogravimetric analysis (TGA) was performed on
a SBTQ600 Thermal Analyzer (USA) with a heating rate of
20 °C min−1 over a temperature range of 40–800 °C under
flowing compressed N2 (100 mL min−1). 1H NMR were per-
formed on a Bruker AV-300 NMR instrument at ambient temp-
erature at 300 MHz. All chemical shifts were reported downfield
in ppm relative to the hydrogen resonance of TMS. The inter-
layer spacings were obtained on a DX-1000 automated X-ray
power diffractometer (XRD), using Cu Kα radiation and internal
silicon powder as a standard with all samples. The patterns were
measured between 2.00° and 20.00° (2θ) with a step size of 1°
min−1 and X-ray tube settings of 40 kV and 2.5 mA. The mor-
phologies of as-synthesized samples were determined by a
Hitachi model H-800 transmission electron microscope (TEM).
N2 adsorption–desorption analysis was carried out at 77 K on an
Autosorb-1 apparatus (Quantachrome). The specific surface
areas and pore diameters were calculated by the BET and BJH
model respectively. C, H, and N elemental analysis was obtained
from an EATM 1112 automatic elemental analyzer instrument
(Thermo, USA). Gel permeation chromatography (GPC) was
performed using a 515 HPCC pump and a Waters styragel HT3
column (Mw 500–30 000) with a 2414 refractive index detector
from Waters. Experiments were performed at 35 °C using THF
as fluent, flow rate of 0.7 mL min−1, and molecular weights are
reported versus polyacrylonitrile standards. Optical rotatory
power was measured on Model 341 polarimeter (Perkin Elmer).
70.01; H, 6.13; N, 23.79; Found: C, 72.58; H, 6.39; N, 22.82.
1d: [α]
20
D(589)
= +24.6 (0.5 g 100 mL−1, DMF), anal. calcd for
C
41.5H44.2N11.6: C, 70.74; H, 6.28; N, 22.98; Found: C, 71.97;
H, 6.44; N, 21.54.
Asymmetric aldol reaction in water
In
a 5 mL vial, supported organocatalyst 1a (30 mg,
0.019 mmol) and TfOH (5.6 mg, 0.038 mmol), water (1 mL)
and cyclohexanone (474 mg, 4.8 mmol) were added consecu-
tively. After stirring at room temperature for 5 min in a closed
system, p-nitrobenzaldehyde (37.3 mg, 0.25 mmol) was added
and left under stirring for 48 h at 25 °C (monitored by TLC).
The reaction mixture was centrifuged to recover supported orga-
nocatalyst 1a and extracted with ethyl acetate (15 mL × 3). The
combined organic phases were dried over anhydrous Na2SO4
and evaporated under reduced pressure to recover cyclohexa-
none. The crude products were purified by flash column chrom-
atography eluting with petroleum ether/ethyl acetate (v/v = 10/1)
to remove the unreacted p-nitrobenzaldehyde and then petroleum
ether/ethyl acetate (v/v = 2/1) as an eluent to afford the pure
aldol adduct. The anti/syn ratio and enantioselectivities (%ee)
were determined by 1H NMR and HPLC analysis.
Acknowledgements
The work was financially supported by the National Science
Foundation of China (grants 21071116) and Chongqing Scien-
tific Foundation (CSTC, 2010BB4126).
1
The anti/syn ratio was determined by H NMR of crude product
in CDCl3; CHOH d: syn 5.48 ppm, J = 3.0 Hz; anti: 4.90 ppm, J
= 9.0 Hz. The enantiomeric excess (%ee) was determined on
HPLC with a Daicel Chiralpak AD-H column (n-hexane/2-pro-
panol = 80/20) under 20 °C, 254 nm and 0.5 mL min−1
conditions.
Notes and references
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A dried flask (100 mL) was flushed three times with Ar2 atmos-
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20
D(589)
1a: [α]
= +14.0 (0.5 g mL−1, DMF), anal. calcd for
C
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20
D(589)
H, 6.34; N, 23.02. 1b: [α]
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