Polystyrene-immobilized pyrrolidine as a highly stereoselective and recyclable organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2008.01.026

Polystyrene-immobilized pyrrolidine 4 has been developed as a highly efficient, reusable, and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of trifluoroacetic acid, 4 catalyzed the rea

Full text of DOI:10.1016/j.tetlet.2008.01.026

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2173–2176
Polystyrene-immobilized pyrrolidine as a highly stereoselective
and recyclable organocatalyst for asymmetric Michael addition
of cyclohexanone to nitroolefins
Tao Miao a, Lei Wang a,b,
*
a Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
Received 1 November 2007; revised 23 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract
Polystyrene-immobilized pyrrolidine 4 has been developed as a highly efficient, reusable, and stereoselective organocatalyst for the
asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of trifluoroacetic acid, 4 catalyzed the reaction of cyclo-
hexanone to a variety of nitroolefins with high yields (up to >99%) and excellent diastereoselectivities (up to >99:1 dr), and enantio-
selectivities (up to >99% ee). Furthermore, 4 could be recovered and recycled by a simple filtration of the reaction solution and used
for more than 10 consecutive trials without significant loss of its catalytic activity.
Ó 2008 Published by Elsevier Ltd.
Keywords: Polystyrene-immobilized pyrrolidine; Organocatalyst; Asymmetric Michael addition; Cyclohexanone; Nitroolefins
The Michael addition is one of the most important
carbon–carbon bond-formation reactions in organic syn-
thesis, and thus, it is absolutely necessary to develop the
enantioselective catalytic protocols for this cornerstone
reaction.1 Asymmetric organocatalytic Michael addition
has attracted much attention in the recent few years due
to its environmental friendliness and the generation of mul-
tiple stereogenic centers in a single step. So far quite a num-
ber of chiral small organic molecules have been developed
as stereoselective catalysts for this transformation.2–4
L-Proline was first used to catalyze the intermolecular
Michael addition of carbon nucleophiles to nitroolefins.
However, it afforded the adducts with poor enantioselectiv-
ity, albeit with good diastereoselectivity.2 Recently, various
catalysts were designed and synthesized based on proline
and applied to this reaction, and significantly improved
efficiencies, diastereoselectivities, and enantioselectivities
were obtained.3,4 Most of these catalysts take advantage
of the carboxylic acid function of proline to install steric
shielding substrate-orienting functional groups. Barbas5
and Alexakis6 have shown that aminomethylpyrrolidine
and 2,20-bipyrrolidine derivatives could serve as useful
asymmetric catalysts for the Michael addition reactions.
Furthermore, Jorgensen and co-workers7 reported an
asymmetric Michael addition reaction catalyzed by chiral
imidazoline catalysts.
Although these catalytic processes provide a unique
methodology in asymmetric Michael addition reactions,
development of new, effective catalysts is still desirable.8
Recently, there are some reports on the asymmetric reac-
tions using immobilized proline and its derivatives on
PEG, mesoporous support, and ionic liquid.9,10 To develop
highly enantioselective and efficient chiral organocatalysts
with broad substrate applicability and easy recyclability
in this field is essential.11
Herein, we wish to report a new catalyst 4, a polysty-
rene-immobilized pyrrolidine unit for achieving high
stereoselectivity in the asymmetric Michael addition of
*
Corresponding author. Tel.: +86 561 380 2069; fax: +86 561 309 0518.
E-mail address: leiwang@hbcnc.edu.cn (L. Wang).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.01.026

2174
T. Miao, L. Wang / Tetrahedron Letters 49 (2008) 2173–2176
cyclohexanone to nitroolefins. 4 and its analogs were not
rene-immobilized pyrrolidine 4 was obtained in a nearly
quantitative yield.
only reported by our group in the abstract of Chinese Jour-
nal of Organic Chemistry,12 but also reported by Pericas’s
´
In our initial screening experiments, the asymmetric
Michael addition of cyclohexanone to nitrostyrene cata-
lyzed by polystyrene-immobilized pyrrolidine 4 was chosen
as the model reaction. When we searched for a Michael
addition protocol of cyclohexanone and nitrostyrene, we
observed that cyclohexanone could react with nitrostyrene
in the presence of polystyrene-immobilized pyrrolidine 4
(10 mol % of catalyst active unit loading) in ethanol at
room temperature for 72 h to afford the desired product
in 85% yield with good stereoselectivity (87% ee and 90%
dr). Encouraged by this result, we continued our research
to improve the yield of product and the stereoselectivity
by the optimization of reaction conditions.
The solvent played an important role in the asymmetric
Michael addition of cyclohexanone to nitrostyrene. In the
presence of trifluoroacetic acid, when the reactions were
conducted in EtOH, THF, toluene, CH2Cl2, and CH3CN,
products with good enantioselectivities and diastereoselec-
tivities were isolated (Table 1, entries 1–5). When excess
amount of cyclohexanone was added to the reaction mix-
ture as solvent and substrate instead of additional solvents,
excellent yield of desired product (97%) was obtained with
very high ee (>99%) and dr (>99:1) (Table 1, entry 7).
However, a lower yield (85%) and ee (92%) were observed
in the absence of TFA (Table 1, entry 6).
group.13 In the presence of trifluoroacetic acid, 4 catalyzed
the reaction of cyclohexanone and a variety of nitroolefins
with high yields (up to >99%) and excellent diastereoselec-
tivities (up to >99:1 dr) and enantioselectivities (up to
>99% ee). Furthermore, 4 could be recovered and recycled
by a simple filtration of the reaction solution and used for
more than 10 consecutive trials without significant loss of
its catalytic activity (Scheme 1).
Polystyrene-immobilized pyrrolidine 4 was easily pre-
pared starting from the commercially available Merrifield
resin (2% DBV, loading 2.0 mmol/g active Cl from Aldrich
Company) according to Scheme 1. Merrifield resin reacted
with propargyl alcohol in the presence of sodium hydride
in anhydrous THF under reflux condition for 12 h to gen-
erate functionalized resin 1. Then, 1 reacted with an
organic azide 2 in the presence of cuprous iodide and
DIPEA in DMF/THF co-solvents at room temperature
via click chemistry to give the corresponding 1,2,3-triazole
3. After the removal of the N-Boc protecting group using
trifluoroacetic acid (TFA) in CH2Cl2, the desired polysty-
P
Cl
The effect of reaction temperature and time on the
Michael reaction was also investigated. The results were
listed in Table 2. At room temperature (25 °C), the reaction
took place smoothly with excellent isolated yield, good
enantioselectivity, and high diastereoselectivity (Table 2,
entry 1). An excellent enantioselectivity (>99% ee) was
obtained along with excellent yield and dr when the reac-
tion was performed at 10 °C. Meanwhile, a lower yield
was observed when the reaction was performed at 0 °C.
It is interesting to note that isolated yields, both of ee
OH
NaH, THF, reflux
P
O
1
N3
CuI, DIPEA
DMF/THF, RT
N
2
Boc
N
N
P
O
Table 1
N
Effect of solvent on the Michael reactiona
3
N
O
O
C6H5
TFA/CH2Cl2
Boc
NO2
4 (10 mol%)
Solvent
NO2
+
C6H5
N
Entry
Solvent
Yieldb (%)
eec (%)
drd
P
O
N
1
2
3
4
5
6
7
a
EtOH
THF
70
68
55
62
65
85
97
92
72
56
70
83
99:1
99:1
95:5
95:5
97:3
N
4
Toluene
CH2Cl2
CH3CN
Cyclohexanonee
Cyclohexanone
N
H
O
Ar
O
92
>99
99:1
>99:1
NO2
4 (10 mol%)
NO2
+
Ar
°
2.5 mol%TFA, 3d, 10 C
Nitrostyrene (1.00 mmol), cyclohexanone (4.00 mmol), catalyst
4
(10 mol %), TFA (2.5 mol %) in solvent (2 mL) at 10 °C for 72 h.
Yield: up to 99%
ee: up to >99%
d.r. up to >99:1
b
Isolated yields.
c
Determined by HPLC using chiral column.
Diastereomeric ratio, dr (syn/anti), determined by 1H NMR.
d
e
Scheme 1.
In the absence of TFA.

T. Miao, L. Wang / Tetrahedron Letters 49 (2008) 2173–2176
2175
Table 2
Table 3
Effect of reaction temperature and time on the Michael reactiona
Polystyrene-immobilized pyrrolidine catalyzed Michael addition of cyclo-
hexanone to nitrostyrenesa
O
O
C6H5
NO2
4 (10 mol%)
R
NO2
+
C6H5
O
O
NO2
NO2
4 (10 mol%)
Entry
T (°C)
t (h)
Yieldb (%)
eec (%)
drd
+
1
2
3
4
25
0
72
72
72
48
96
72
72
99
74
97
88
97
90
98
95
>99
>99
>99
>99
>99
>99
99:1
TFA (2.5 mol%)
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
R
10
10
10
10
10
Entry
1
Nitrostyrene
Yieldb (%)
97
eec (%)
drd
5
NO2
6e
7f
a
>99
92
>99:1
NO2
Nitrostyrene (1.00 mmol), cyclohexanone (2 mL), catalyst 4 (10 mol %
active unit loading), TFA (2.5 mol %) at the reaction temperature and
time indicated in the table.
2
3
4
5
6
7
94
90
92
88
91
>99:1
98:2
F
b
Isolated yields.
c
NO2
Determined by HPLC using chiral column.
Diastereomeric ratio, dr (syn/anti), determined by 1H NMR.
In the presence of 4 (5 mol %).
In the presence of 4 (20 mol %).
d
>99
99
e
Br
f
NO2
>99:1
99:1
Cl
and dr, were maintained up to >99% when 10 mol % of
polystyrene-immobilized pyrrolidine 4 active unit loading
was added to the reaction mixture. A lower yield of the
Michael addition reaction product was isolated when less
than 10 mol % of 4 loading was used in the reaction. It
was found that the reaction was accomplished more than
72 h.
We have investigated the reactions using a variety of
nitrostyrenes as the substrates under the standard reaction
conditions and the results are summarized in Table 3. As
shown in Table 3, high isolated yields were obtained for
all the selected nitroolefins regardless of the electronic nat-
ure of the aromatic substituent R. Most of the nitroolefins,
especially para substitution ones, were obtained in nearly
optically pure form (>99% ee) and with excellent dr (99:1
to >99:1) in most of the cases examined (Table 3, entries
1, 4, 5, and 7). This addition was also tolerant of ortho
or meta substitution in nitroolefins and led to good yields
with good enantioselectivities and diastereoselectivities
(90% ee, 98:2 dr and 88% ee, 97:3 dr, respectively, for
entries 8 and 9, Table 3).
The recyclability of polystyrene-immobilized pyrrolidine
4 was also surveyed. After carrying out the reaction, the
reaction solution was vacuum filtered using a sintered glass
funnel and washed with CH2Cl2 (2 mL), Et2O (2 mL),
C2H5OH (2 mL), and hexane (2 mL), respectively. It can
be reused directly without further purification. The 4 could
be recovered, recycled and used for 10 consecutive trials
without loss of activity (Table 4).
Typical procedure for the asymmetric Michael addi-
tion of cyclohexanone to nitroolefins: An oven-dried
round-bottomed flask was charged with polystyrene-
immobilized pyrrolidine 4 (150 mg, f = 0.697 mmol/g, con-
tains 0.10 mmol of active pyrrolidine unit), nitroolefin
(1.0 mmol), TFA (0.025 mmol), and cyclohexanone
NO2
>99
96
H3C
F3C
H3CO
NO2
99:1
NO2
85
92
>99
>99:1
NO2
NO2
8
9
90
98:2
Cl
95
89
88
96
97:3
99:1
NO2
NO2
10
O
a
Nitrostyrene (1.00 mmol), cyclohexanone (2 mL), catalyst 4 (10 mol %
active unit loading), TFA (2.5 mol %) at 10 °C for 72 h.
b
Isolated yields.
c
Determined by HPLC using chiral column.
Diastereomeric ratio, dr (syn/anti), determined by 1H NMR.
d
(2 mL) (Note: bulk solution of TFA in cyclohexanone
was freshly prepared and employed in the reaction, 40 lL
of TFA in 100 mL of cyclohexanone). The reaction mixture
was stirred at 10 °C for 72 h. After the reaction mixture
was vacuum filtered using a sintered glass funnel and
washed with CH2Cl2 (2 ꢀ 2 mL), the combined organics
were dried over Na2SO4, filtered, concentrated, and the res-
idue was purified by flash chromatography on silica gel to
give the desired asymmetric Michael addition product.

2176
T. Miao, L. Wang / Tetrahedron Letters 49 (2008) 2173–2176
Table 4
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Successive trials by using recoverable catalyst 4a
O
O
C6H5
NO2
Reused 4
NO2
+
C6H5
Trial
Yieldb (%)
eec (%)
drd
1
2
3
4
5
6
7
8
97
95
96
93
95
94
93
90
88
89
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
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9e
10e
a
Nitrostyrene (1.00 mmol), cyclohexanone (2 mL), reused catalyst 4
(10 mol %), TFA (2.5 mol %) at 10 °C for 72 h.
b
Isolated yields.
c
Determined by HPLC using chiral column.
Diastereomeric ratio, dr (syn/anti), determined by 1H NMR.
10 °C for 96 h.
d
e
8. For other types of organocatalytic Michael addition reactions, see: (a)
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Synthesis 2006, 3795–3800.
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analogous, see: (a) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth.
Catal. 2001, 343, 171–173; (b) Benaglia, M.; Cinquini, M.; Cozzi, F.;
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H. Adv. Synth. Catal. 2006, 348, 1711–1718; (e) Zhou, L.; Wang, L.
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In conclusion, we have developed polystyrene-immobi-
lized pyrrolidine as a highly stereoselective and recyclable
organocatalyst for the asymmetric Michael addition of
cyclohexanone to nitroolefins. Polystyrene-immobilized
pyrrolidine 4 catalyzed the reaction of cyclohexanone to
a variety of nitroolefins with high yields (up to >99%)
and excellent diastereoselectivities (up to >99:1 dr) and
enantioselectivities (up to >99% ee) in the presence of tri-
fluoroacetic acid. Furthermore, 4 could be recovered and
recycled by a simple filtration and used for more than 10
consecutive trials without significant loss of its catalytic
activity.
Acknowledgment
We gratefully acknowledge financial support by the
National Natural Science Foundation of China (Nos.
20572031, 20772043).
References and notes
`
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