Recyclable Merrifield resin-supported thiourea organocatalysts derived from l-proline for direct asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2011.03.016

Four Merrifield resin-supported thiourea organocatalysts derived from l-proline were synthesized and found to be efficient catalysts for the direct asymmetric aldol reaction between ketone and aromatic aldehydes. The catalysts exhibited high catalytic activity, diastereoselectivity and excellent enantioselectivity at room temperature with a low loading (only 2 mol %). They also retained unchanged enantioselectivities even after being reused for at least four cycles.

Full text of DOI:10.1016/j.tetasy.2011.03.016

Tetrahedron: Asymmetry 22 (2011) 613–618
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Recyclable Merrifield resin-supported thiourea organocatalysts derived
from L-proline for direct asymmetric aldol reaction
a,b
b
b
b
a,
⇑
Jia Li , Gengxu Yang , Yanyan Qin , Xinran Yang , Yuanchen Cui
a
Key Laboratory of Ministry of Education for Special Functional Materials, Henan University, Kaifeng 475004, China
School of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Four Merrifield resin-supported thiourea organocatalysts derived from L-proline were synthesized and
Received 27 January 2011
Accepted 10 March 2011
Available online 4 May 2011
found to be efficient catalysts for the direct asymmetric aldol reaction between ketone and aromatic alde-
hydes. The catalysts exhibited high catalytic activity, diastereoselectivity and excellent enantioselectivity
at room temperature with a low loading (only 2 mol %). They also retained unchanged enantioselectivi-
ties even after being reused for at least four cycles.
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
1
. Introduction
mer-supported catalysts for direct aldol reactions with good effi-
ciency and performance in an aqueous medium.
1
3,16
Organocatalysts, small-molecule chiral hydrogen-bond donors
We noticed that there are only a few reports
currently avail-
capable of promoting a reaction in a substoichiometric amount,
have received increasing interest in recent years. Organocatalytic
able with regards to aldol reactions catalyzed by polymer-sup-
ported catalysts at a small dosage of less than 5 mol %. As a
result, we turned our attention to the development of chiral organ-
ocatalysts with high efficiency and enantioselectivity as well as
good recyclability. Thanks to the ability of the thiourea group being
a weak Brønsted acid able to activate the electrophilic substrate via
double-hydrogen-bonding, we envisioned that the combination of
1
processes are generally considered as operationally simple and
environmentally friendly because the use of metals is avoided.
However, their catalytic efficiency, in terms of turnover number,
is usually lower than that of metal-catalyzed processes. To circum-
vent this disadvantage, organic chemists have made great efforts to
2
develop immobilized, easily recoverable and reusable catalysts.
L-proline with a thiourea motif and a functionalized Merrifield re-
Polymeric materials are widely used in organic synthesis and catal-
sin could constitute a new type of recyclable and bifunctional
organocatalyst. Therefore, Merrifield resin-supported thiourea
ysis as the supports of catalysts.3
Asymmetric aldol reactions have been found to be extremely
powerful for constructing carbon–carbon bonds and are used to
generate many valuable biologically optically active b-hydroxyl
organocatalysts derived from L-proline were prepared. The resul-
tant products were used to catalyze highly enantioselective aldol
reactions in an aqueous medium and were found to offer good
efficiency even at a low loading of 2 mol %. These results hopefully
broaden the application and scope of chiral thioureas as
4
carbonyl compounds. Proline and its analogues bearing secondary
5
6
7
8
9
amides, thioamides, sulfonamides, dipeptides and tetrazole as
H-bond donors have been extensively investigated as catalysts for
aldol reactions; much effort has been dedicated to the immobiliza-
1
7
organocatalysts.
tion and recycling of
L-proline or hydroxyproline with the
2
. Results and discussion
3d,10
11
assistance of either linear polyethyleneglycol
/polystyrene
or cross-linked polystyrene-based supports.12 Recently, Hansen
et al. reported an interesting approach for the preparation of
The procedures for preparing Merrifield resin-supported organ-
ocatalysts 1a–d are outlined in Scheme 1. First, commercially avail-
able Merrifield resin was modified by tetraethylenepentamine
1
3
polymer-supported proline via acrylic copolymerization. These
functionalized polymer systems have proven to be very efficient
for asymmetric aldol reactions and offer an advantageous recycla-
bility. We have also made attempts to immobilize proline on
(
TEPA) or diamine as the linker between the polymer backbone
and organic molecule, to give the functionalized resin 4. Resin 4
was then allowed to react with N-9-fluorenylmethyloxy-carbonyl
1
4
15
chitosan and polyvinyl chloride (PVC) so as to prepare poly-
(
Fmoc)-
CH Cl to generate Fmoc-protected thiourea derivatives 2. After
the N-Fmoc protecting group was removed with aqueous NH , de-
2 4
L-proline 3 derived isothiocyanate (SOCl and NH SCN) in
2
2
3
⇑
Corresponding author. Tel./fax: +86 378 3881358.
E-mail address: yccui@henu.edu.cn (Y. Cui).
sired Merrifield resin-supported thiourea organocatalysts 1a–d
were finally obtained.
0
957-4166/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.016

6
14
J. Li et al. / Tetrahedron: Asymmetry 22 (2011) 613–618
H2N
R
NH2
Cl
NH
R NH2
4
O
S
1
2
.SOCl2,CH2Cl2
.NH4SCN,PEG-400
R
N
H
N
H
N
H
N
COOH
N
3
. 4, r.t., 24 h
Fmoc
Fmoc
3
2
O
S
Aqueous NH3
r.t., 24 h
R
N
H
N
H
N
H
a: R=(CH2CH2NH)3CH2CH2
b: R=(CH2)6
c: R=(CH2)10
d: R=(CH2)12
N
H
1
Scheme 1. Synthetic route to the Merrifield resin-supported thiourea organocatalysts 1a–d.
For the evaluation of the catalytic properties of Merrifield resin-
supported thiourea organocatalysts 1a–d derived from -proline,
O
S
L
N
H
N
H
NH2
10
the aldol reaction between 4-nitrobenzaldehyde and cyclohexa-
none served as a model reaction. While screening catalysts for
the reaction, we found that the aldol reaction proceeded smoothly
at room temperature in the presence of Merrifield resin-supported
organocatalysts under neat reaction conditions or in an aqueous
medium, generating the corresponding products with moderate
to good yields and good to high enantioselectivities (Table 1). Cat-
alyst 1a possessed good catalytic performance under neat reaction
conditions, while 1b, 1c, and 1d showed good catalytic perfor-
mance in an aqueous medium (Table 1, entries 1–6). When the
reaction was performed in an aqueous medium, it proceeded effi-
ciently and had excellent enantioselectivities (96–97% ee; Table 1,
entries 4–6). Compared with the corresponding resin-free homoge-
neous catalyst 1e (Fig. 1), the supported catalyst 1d exhibited bet-
ter enantioselectivity but less activity and diastereoselectivity in
the model reaction (Table 1, entry 6 vs 7). In addition, when the
N
H
1e
Figure 1. Structure of the corresponding resin-free homogeneous catalyst 1e.
Table 2. It is noteworthy that regardless of the reaction conditions,
the introduction of a larger amount (10 mol %) of catalyst acceler-
ated the reaction but lowered the stereoselectivity. When organo-
catalysts 1a–d were used at a decreased loading of 2 mol %, the
anti-aldol products were obtained with high to excellent enanti-
oselectivities (91–97% ee; Table 2, entries 3, 6, 8 and 10) and mod-
erate diastereoselectivities. To the best of our knowledge, such a
highly enantioselective aldol reaction catalyzed by supported cat-
alysts at such a low loading (2 mol %), the same as that of small-
1
8
molecule organocatalysts, has rarely been reported.
2 5
reactions were carried out in DMSO, hexane, C H OH or petroleum
ether, only low yields and fair ee values were obtained (Table 1, en-
tries 8–11).
Table 2
Effect of the amount of catalyst on the aldol reaction between cyclohexanone and p-
nitrobenzaldehyde catalyzed by 1a–d
a
Table 1
O
O
OH
Screening catalyst and solvent for the asymmetric aldol reaction between cyclohex-
OHC
anone and p-nitrobenzaldehydea
Cat.
Neat or H2O, r.t.
+
O
O
OH
NO2
NO2
eec (%)
OHC
Cat. (2 mol%)
Yieldb
(%)
drc (syn/
anti)
+
Entry Catalyst
(mol %)
Solvent Time
(d)
Solvent, r.t.
NO2
(anti)
NO2
eec (%)
1d
1a (10)
1a (5)
1a (2)
1b (10)
1b (5)
1b (2)
1c (5)
1c (2)
1d (5)
1d (2)
Neat
Neat
Neat
O
O
O
O
O
O
O
3
6
6
4
6
6
6
6
6
6
85
72
68
85
82
80
84
83
88
84
60:40
39:61
28:72
30:70
25:75
26:74
42:58
34:66
49:51
30:70
80
88
91
90
95
96
94
97
87
97
Entry Catalyst Solvent
Time
d)
Yieldb
(%)
drc (syn/
anti)
d
2
3
(
(anti)
d
1d
2
1a
1a
1b
1b
1c
1d
1e
1a
1a
1a
1a
Neat
6
6
6
6
6
6
2
8
8
8
8
68
80
76
80
83
84
84
15
67
28
81
28:72
45:55
47:53
26:74
34:66
30:70
19:81
18:82
53:47
37:63
55:45
91
61
85
96
97
97
96
82
69
53
73
4
5
6
7
8
9
10
H
H
H
H
H
H
H
2
2
2
2
2
2
2
H
2
O
d
3
Neat
4
5
6
7
8
9
H
H
H
H
2
O
2
O
2
O
2
O
DMSO
Hexane
a
Reaction was performed with 0.5 mmol of aldehyde, 4 equiv of ketone and
0 equiv of H O in the presence of catalyst.
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
0 equiv of ketone were used.
1
2
1
1
0
1
2 5
C H OH
Petroleum
ether
b
c
d
1
a
Reaction was performed with 0.5 mmol of aldehyde, 4 equiv of ketone and
0 equiv of H O in the presence of 2 mol % of catalyst.
1
2
In order to optimize the reaction conditions, we also examined
b
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
the effect of the amount of cyclohexanone on the aldol reaction
under investigation. As shown in Table 3, when the amount of
cyclohexanone was reduced to 8 equiv, catalyst 1a exhibited good
activity and high enantioselectivity (Table 3, entry 2). Catalysts 1b–
d gave a high yield and stereoselectivity even in the presence of
c
d
1
0 equiv of ketone were used.
The influence of catalyst loading on the yield and stereoselectiv-
ities of the aldol reaction under investigation is summarized in

J. Li et al. / Tetrahedron: Asymmetry 22 (2011) 613–618
615
only 4 equiv of ketone (Table 3, entries 6–8). The optimized reac-
tion conditions for the aldol reaction were considered to be a cat-
alyst dosage of 2 mol %, 4 equiv of cyclohexanone, a water medium,
and room temperature, at which the highest yield and stereoselec-
tivities were obtained for catalyst 1d.
The recyclability of the Merrifield resin-supported thiourea
organocatalysts derived from -proline, 1b–d, was also investi-
gated under the optimized reaction conditions. The results are
summarized in Table 5. It can be seen that catalysts 1b–d can be
readily recycled and reused, with stereoselectivity remaining al-
most unchanged after four cycles.
L
Table 3
Effect of the amount of cyclohexanone on the aldol reaction between cyclohexanone
and p-nitrobenzaldehyde catalyzed by 1a–d
Table 5
a
a
Recyclability of catalysts under the optimized conditions
O
O
OH
O
O
OH
OHC
Cat.(2 mol%)
OHC
Cat. (2 mol%)
+
+
Neat or H2O, r.t.,6 d
NO2
H2O, r.t.,6 d
NO2
eec (%)
NO2
NO2
Entry Catalyst Cyclohexanone Solvent
equiv)
Yieldb drc
Yieldb (%)
drc (syn/anti)
eec (%) (anti)
Entry
Catalyst
(
(%)
(syn/anti) (anti)
1
2
3
4
5
6
7
8
9
1b (cycle 1)
1b (cycle 2)
1b (cycle 3)
1b (cycle 4)
1c (cycle 1)
1c (cycle 2)
1c (cycle 3)
1c (cycle 4)
1d (cycle 1)
1d (cycle 2)
1d (cycle 3)
1d (cycle 4)
80
75
65
66
70
80
73
60
82
85
75
63
28:72
30:70
31:69
14:86
22:78
35:65
25:75
19:81
34:66
39:61
20:80
22:78
95
92
90
96
93
90
90
93
95
91
95
96
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1c
1d
10
8
Neat
Neat
Neat
Neat
68
78
60
73
80
80
83
84
28:72
38:62
37:63
38:62
52:48
26:74
34:66
30:70
91
93
71
80
77
96
97
97
6
4
8
4
4
4
H
H
H
H
2
O
2
O
2
O
2
O
a
10
Reaction was performed with 0.5 mmol of aldehyde, a certain amount of ketone
and 10 equiv of H
11
2
O in the presence of 2 mol % of catalyst.
b
12
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
c
a
Reaction was performed with 0.5 mmol of aldehyde, 4 equiv of ketone and
0 equiv of H O in the presence of 2 mol % of catalyst.
Isolated yield.
1
2
b
c
Under the optimized reaction conditions, a set of benzaldehydes
with different substituents were examined (Table 4). As shown in
Table 4, catalyst 1d in an aqueous medium possessed a better cat-
alytic performance than catalyst 1a under neat reaction conditions.
Aldehydes with strong electron-withdrawing substituents acceler-
ated the reaction and afforded good enantioselectivities and mod-
erate diastereoselectivities; however, a phenyl ring substituent
with a weak electron-withdrawing group, such as a halogen, slo-
wed down the asymmetric aldol reaction and resulted in greatly
decreased yields and slightly decreased enantioselectivities and
diastereoselectivities. Moreover, when cyclopentanone was used
as the aldol donor, good yield (87%) and enantioselectivity (74%
ee) were obtained (Table 4, entry 14).
Determined by chiral HPLC analysis (Chiralpak AD-H).
Based on the experimental results, we supposed the catalytic
procedure in a plausible bifunctional catalytic mechanism. The
double hydrogen-bonding interaction between the aldehyde car-
bonyl and the thiourea moiety should be favorable in activating
the aldehyde acceptor and facilitating the aldol reaction, while
the pyrrolidine activated the ketone by the formation of an enam-
ine intermediate. When the reaction was carried out under neat
reaction conditions, the proposed transition state model is de-
picted as TS 1 (Fig. 2). On the other hand, when the reaction was
carried out in an aqueous medium, the water molecules might
form hydrogen bonds with the nitro group in the transition state
1
9
model (TS 2, Fig. 2). The Merrifield resin could provide a hydro-
Table 4
Asymmetric aldol reaction between cyclohexanone and various benzaldehydes catalyzed by catalysts 1a–da
O
O
OH
OHC
Cat. (2 mol%)
+
R
R
Neat or H2O r.t.
Entry
R
Catalyst
Solvent
Neat
Time (d)
Yieldb (%)
drc (syn/anti)
eec (%) (anti)
1d
2
3
3-NO
3-NO
3-NO
3-NO
2,4-Dinitro
2,4-Dinitro
2,4-Dinitro
2,4-Dinitro
2-NO
4-CN
4-F
4-Cl
4-Br
4-NO
1a
1b
1c
1d
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
7
7
7
7
7
7
7
7
7
9
9
9
9
2
61
61
67
70
62
62
67
81
44
70
23
40
53
87
35:65
36:64
31:69
26:74
35:65
30:70
32:68
26:74
40:60
25:75
37:63
37:63
35:65
62:38
40
32
48
58
48
54
51
72
60
49
46
52
63
74
2
2
2
2
H
2
H
2
H
2
O
O
O
4
5
d
Neat
6
7
8
9
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
O
O
2
1
1
1
1
1
0
1
2
3
4
e
2
a
b
c
Reaction was performed with 0.5 mmol of aldehyde, 4 equiv of ketone and 10 equiv of H
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
2
O in the presence of 2 mol % of catalyst.
d
e
8
equiv of ketone were used.
Cyclopentanone instead of cyclohexanone was used.

6
16
J. Li et al. / Tetrahedron: Asymmetry 22 (2011) 613–618
O
S
by drying in a vacuum for 12 h, allowing the generation of a series
of light yellow polystyrene-amide resin 4.
O
S
N
H
N
H
N
H
N
H
N
H
N
H
10
10
N
N
4
.2.2. Synthesis of N-Fmoc-
At first, -proline (1.5 g) was dissolved in 30 mL of aqueous
CO (mass fraction 10%) and mixed with 4.3 g of N-(9-fluore-
L-proline, 3
O
O
L
H
H
Na
2
3
O
N
O
nylmethoxycarbonyloxy)succinimide (Fmoc-Osu) dissolved in
THF (30 mL), followed by stirring for 48 h. The mixture was added
to water (50 mL) and extracted with ether (3 ꢀ 50 mL). The pH va-
lue of the aqueous phase was adjusted to 2–3 with aqueous HCl
and extracted with ethyl acetate (3 ꢀ 50 mL), while the organic
O2N
H
O
hydrophobic region
H
O
TS 1
H2O
TS 2
2 4
layer was dried over Na SO and evaporated to remove the solvent
Figure 2. Proposed transition state models for the asymmetric aldol reaction
carried out under neat reaction conditions TS 1 and in aqueous medium TS 2.
to give 4.0 g of a white solid product with a yield of 91%. mp 102–
2
D
0
1
1
(
04 °C. ½
aꢁ
¼ ꢂ34 (c 1.01, DMF). H NMR (400 MHz, CDCl
3
) d: 9.7
‘protuberance’ s, 1H), 7.78–7.76 (m, 1H), 7.62–7.58 (m, 1H), 7.43–
7
1
.38 (m, 1H), 7.36–7.27 (m, 1H), 4.49–4.39 (m, 1H), 4.27–4.29 (d,
H), 3.60 (s, 1H), 3.49 (m, 2H), 2.0–1.97 (m, 2H), 1.89 (m, 2H).
C NMR (100 MHz, CDCl ) d: 178.13, 176.5, 155.72, 154.43,
3
phobic microenvironment for the substrates and catalytic sites
(
pyrrolidine and thiourea moiety) to be in close contact. The high
1
3
efficiency of the thiourea catalysts could be attributed to the dou-
ble activation, water-compatibility and hydrophobicity.
1
5
43.83, 141.2, 127.62, 127.03, 124.99, 119.9, 67.80, 67.46, 59.23,
8.47, 47.1, 46.74, 30.94, 29.28, 24.30, 23.27. Mass spectrometry
+
(
MS) (EI, m/z): C20
H19NO
4
[M+Na] calcd 360.36, found 360.2.
3
. Conclusion
A group of novel Merrifield resin-supported thiourea organocat-
4.2.3. Synthesis of compound 2
alysts derived from
L
-proline, 1a–d, have been obtained via a sim-
2 2
Compound 3 (1.687 g, 5 mmol) was dissolved in CH Cl (20 mL)
and mixed with dripping SOCl (1 mL, 3 equiv). The mixture was
2
stirred at room temperature for 30 min and decompressed at
40 °C to remove HCl formed during the reaction, as well as the sol-
ple synthesis. The catalytic performance of the resultant synthetic
products for the direct asymmetric aldol reactions of ketones and
aromatic aldehydes has been evaluated. It has been found that all
four resin-supported thiourea organocatalysts are efficient for the
aldol reactions under investigation, and they have excellent
enantioselectivities, high yields and moderate diastereoselectivi-
ties even at small dosages of 2 mol % in the absence of additives.
This can be considered as an interesting result since in several
cases supported catalysts were used in higher amounts (10–
vent and superfluous SOCl
the yellow oil were added NH
ene glycol (PEG)-400 (0.053 mL, 0.15 mmol) and CH
2
, generating a yellow oil product. Into
SCN (0.570 g, 7.5 mmol), polyethyl-
Cl (25 mL) at
4
2
2
room temperature within 1 h to give isothiocyanate. A certain
amount of resin 4 was then added to the mixture with isothiocya-
nate and stirred at room temperature. After being stirred for 24 h,
water was added to dissolve the salt formed during the reaction,
and ethanol was used to precipitate the product. Compound 2,
either a yellow or light yellow solid, was obtained after filtering,
1
2
2
0 mol %). Merrifield resin-supported catalysts can be recovered
and reused for at least four cycles, with high enantioselectivities
and yields only slightly decreasing. Further studies on similar types
of polymer-supported thiourea organocatalysts and reaction
mechanisms are currently underway.
and then washing with water, CH
a vacuum.
2 2
Cl and acetone, and drying in
4
4
. Experimental
4.2.4. Synthesis of catalysts 1a–d
Compound 2 (1 g) was added into a 50 mL round-bottomed
flask filled with saturated aqueous NH (25 mL) and stirred at room
.1. General
3
temperature for 24 h. Then ethanol was added to precipitate the
products. After being filtered, washed with water and acetone,
and dried in vacuo, catalysts 1a–d were obtained as either a yellow
or light yellow solids. The products were characterized by means of
Fourier transformation infrared (FTIR) spectrometry. The final tar-
get products, catalysts 1a–d, were used as novel catalysts for direct
asymmetric aldol reactions. Proline loading of 1a–d was deter-
mined, by weight gain, to be 0.88, 0.50, 0.50 and 0.63 mmol/g,
respectively.
All reagents and solvents were purchased from commercial
suppliers and used without further purification. Thin layer chro-
matography (TLC) was conducted on GF254 silica gel plates. Infra-
red (IR) spectra were recorded with an Avatar360 Fourier
transformation infrared spectrometer (Nicolet Company, USA). Nu-
clear magnetic resonance (NMR) spectra were obtained from Bru-
ker Avance 300 M system, and the chemical shifts of 1H NMR
spectra were reported in relation to tetramethyl silane (d = 0).
Melting points were measured with an X-6 melting point appara-
tus. High performance liquid chromatographic (HPLC) analysis
was carried out on Agilent 1100 equipped with a diode array ultra-
violet (UV) detector; and Daicel Chiralpak AD columns were used
for the HPLC analysis.
4
.3. Preparation of resin-free homogeneous catalyst 1e
To a solution of compound 3 (1.687 g, 5 mmol), derived isothi-
2 4 2 2
ocyanate (SOCl and NH SCN) in CH Cl , 1,12-dodecanediamine
(
2.00 g, 10 mmol) was added and stirred at room temperature.
4
1
.2. Preparation of Merrifield resin-supported organocatalysts
a–d
After being stirred for 1.5 h, the dichloromethane solution was
washed with water (2 ꢀ 30 mL). The organic phase was dried over
2 4
Na SO and concentrated under reduced pressure. The residue was
4
.2.1. Modification of resin 4
Into a round-bottomed flask filled with 10 mmol of amine were
purified by column chromatography on silica gel (ethanol). The
protecting group (Fmoc) was removed by saturated aqueous NH3
within 24 h. To the mixture was added hydrochloric acid, and then
extracted with dichloromethane (2 ꢀ 30 mL). The aqueous phase
was adjusted to be basic with aqueous NaOH (40 wt %), and then
added 2.0 g of Merrifield resin (1.23 mmol/g Cl). After being stirred
at 70–90 °C for 24 h, the reaction mixture was cooled to room tem-
perature, filtered and fully washed with H O and ethanol, followed
2

J. Li et al. / Tetrahedron: Asymmetry 22 (2011) 613–618
617
extracted with dichloromethane (2 ꢀ 30 mL). The organic phase
was dried over Na SO and concentrated under reduced pressure.
4.5.5. (S)-2-[(R)-Hydroxy(4-cyanophenyl)methyl]cyclohexanone
2
2
2
4
White powder; mp 82–83 °C; ½
a
ꢁ
D
¼ þ23:3 (c 1.55, CHCl
3
).
Enantiomeric excess was determined by HPLC with a Chiralpak
4
.4. Recyclability of the Merrifield resin-supported thiourea
AD-H column (n-hexane/isopropanol = 92:8), flow rate 1.0 mL/
catalysts
min, k = 267 nm; t
R R
(anti) = 40.88 min (major) and 31.98 min, t
1
(syn) = 23.20 and 27.33 min (major); H NMR (300 MHz, CDCl ): d
3
At the end of the aldol reaction between cyclohexanone and p-
nitrobenzaldehyde, the catalysts were filtered in vacuum and
washed with C H OH and CH Cl . After being dried in an oven
2 5 2 2
7.65 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 4.84 (d, J = 8.4 Hz,
1H), 4.07 (s, 1H), 2.47–2.62 (m, 2H), 2.31–2.41 (m, 1H), 2.08–2.15
(m, 1H), 1.81–1.83 (m, 1H), 1.49–1.73 (m, 3H), 1.32–1.41 (m, 1H).
for 24 h, the Merrifield resin-supported catalysts could be reused
directly without further purification.
4.5.6. (S)-2-[(R)-Hydroxy(4-fluorophenyl)methyl]cyclo-
hexanone
2
D
4
4
.5. General procedure for direct aldol reaction
½
aꢁ
¼ þ27:5 (c 0.35, CHCl
3
). Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (n-hexane/isopro-
panol = 90:10), flow rate 0.3 mL/min; k = 208 nm; t (anti) = 49.15
and 44.19 min (major), (syn) = 29.38 min (major) and
33.28 min; H NMR (300 MHz, CDCl ): d 1.41–1.87 (m, 5H), 1.91–
Substituted benzaldehyde (0.5 mmol) was added into a mixture
R
of cyclohexanone, a certain amount of catalyst and H
2
O or solvent
t
R
1
(
3 mL). The mixture was stirred at room temperature, and the reac-
3
tion system was followed by TLC (ethyl acetate/petroleum
ether = 1:2.5). Upon completion of the reaction, the products were
filtered and extracted with ethyl acetate; then the organic layer
2.21 (m, 1H), 2.26–2.49 (m, 3H), 3.01–3.20 (br s, 1H), 3.88–3.92
(br s, 1H), 4.70–4.73 (d, J = 9 Hz, 1H), 5.29 (s, 1H), 6.96–7.00 (m,
2H), 7.20–7.23 (br s, 2H).
2 4
was dried over Na SO , filtered, concentrated and purified by thin
layer chromatography on a silica gel (ethyl acetate /petroleum
ether) to give pure aldol products.
4.5.7. (S)-2-[(R)-Hydroxy(4-chlorophenyl)methyl]cyclo-
hexanone
2
D
45
½aꢁ
¼ þ21:7 (c 1.00, CHCl
mined by HPLC with a Chiralpak AD-H column (n-hexane/isopro-
panol = 90:10), flow rate 0.3 mL/min; k = 224 nm; t (anti) = 52.77
(syn) = 29.96 min (major) and
, 300 MHz): d 1.55–1.87 (m, 5H),
3
). Enantiomeric excess was deter-
4
.5.1. (S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclohexanone
25
White powder; mp 129–130 °C; ½
aꢁ
¼ þ12:8 (c 1.85, CHCl
3
).
R
D
Enantiomeric excess was determined by HPLC with a Chiralpak
and 45.71 min (major),
t
R
1
AD-H column (n-hexane/isopropanol = 92:8), flow rate 1.0 mL/
34.61 min,; H NMR (CDCl
3
min, k = 268 nm; t
syn) = 22.99 and 26.25 min (major); H NMR (300 MHz, CDCl
d 8.20–8.24 (m, 2H), 7.48–7.54 (m, 2H), 4.90 (d, J = 8.1 Hz, 1H),
R
(anti) = 40.25 min (major) and 29.86 min, t
R
1.98–2.09 (m, 1H), 2.33–2.55 (m, 3H), 3.00 (br s, 1H), 3.91 (br s,
1H), 4.71–4.74 (d, J = 9 Hz, 1H), 5.33 (s, 1H), 7.20–7.30 (m, 4H).
1
(
3
):
4
1
.09 (s, 1H), 2.32–2.64 (m, 3H), 2.08–2.16 (m, 1H), 1.82–1.86 (m,
H), 1.35–1.73 (m, 4H).
4.5.8. (S)-2-[(R)-Hydroxy(4-bromophenyl)methyl]cyclo-
hexanone
2
D
4
½
aꢁ
¼ þ22:6 (c 0.70, CHCl
3
). Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (n-hexane/isopro-
panol = 90:10), flow rate 0.3 mL/min; k = 222 nm; t (anti) = 54.91
(syn) = 30.13 min (major) and
, 300 MHz): d 1.50–1.87 (m, 5H),
4
.5.2. (S)-2-[(R)-Hydroxy(2-nitrophenyl)methyl]cyclohexanone
2
D
4
Yellow powder; mp 116–118 °C; ½
aꢁ
¼ þ19:8 (c 1.60, CHCl
3
).
R
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol = 92:8), flow rate 1.0 mL/
and 47.54 min (major),
t
R
1
35.31 min,; H NMR (CDCl
3
1
min, k = 209 nm; t
300 MHz, CDCl
R
(anti) = 24.05 and 22.53 min (major); H NMR
2.05–2.11 (m, 1H), 2.33–2.57 (m, 3H), 3.05 (br s, 1H), 3.93 (br s,
1H), 4.70–4.73 (d, J = 9 Hz, 1H), 5.30 (br s, 1H), 7.14–7.18 (m,
2H), 7.42–7.46 (m, 2H).
(
3
): d 7.84 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz,
H), 7.64 (t, J = 7.2 Hz, 1H), 7.40–7.46 (m, 1H), 5.44 (d, J = 7.2 Hz,
H), 4.11 (br, 1H), 2.73–2.81 (m, 1H), 2.29–2.48 (m, 2H), 2.04–
.14 (m, 1H), 1.55–1.86 (m, 5H).
1
1
2
4.5.9. (S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclopentanone
2
D
2
Light yellow powder; mp 88–90 °C; ½
CHCl ). Enantiomeric excess was determined by HPLC with a Chir-
alpak AD-H column (n-hexane/isopropanol = 90:10), 1.0 mL/min,
k = 254 nm; (anti) = 23.94 min (major) and 23.06 min,
(syn) = 13.95 and 18.04 min (major); H NMR (300 MHz, CDCl
aꢁ
¼ ꢂ30:6 (c 0.56,
4
.5.3. (S)-2-[(R)-Hydroxy(3-nitrophenyl)methyl]cyclohexanone
3
2
D
4
White powder; mp 69–71 °C; ½
aꢁ
¼ þ32:5 (c 1.35, CHCl
3
).
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol = 92:8), flow rate 1.0 mL/
t
R
t
R
3
): d
1
min, k = 263 nm;
t
R
(anti) = 33.94 and 26.05 min (major),
t
R
8.20–8.24 (m, 2H), 7.51–7.56 (m, 2H), 4.78–5.43 (m, 1H), 1.52–
2.62 (m, 7H).
1
(syn) = 23.10 min (major) and 22.08 min; H NMR (300 MHz,
3
CDCl ): d 8.15–8.22 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.53 (t,
J = 7.8 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.14 (d, J = 2.4 Hz, 1H),
Acknowledgment
2
1
.58–2.67 (m, 1H), 2.32–2.54 (m, 2H), 2.09–2.16 (m, 1H), 1.82–
.86 (m, 1H), 1.36–1.71 (m, 4H).
We are grateful for the financial support from the Natural Sci-
ence Foundation of Henan Province (No. 2008A150003).
4
.5.4. (S)-2-[(R)-Hydroxy(2,4-nitrophenyl)methyl]cyclo-
hexanone
Yellow oil. Enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (n-hexane/isopropanol = 92:8), flow rate
.0 mL/min, k = 254 nm; t (anti) = 44.06 and 39.37 min (major),
(syn) = 24.60 and 32.95 min (major); H NMR (400 MHz, CDCl
d 8.74–8.75 (d, J = 2.3 Hz, 1H), 8.45–8.49 (d, J = 8.7 Hz, J = 2.4 Hz,
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