Recyclable merrifield resin-supported organocatalysts containing pyrrolidine unit through A3-coupling reaction linkage for asymmetric michael addition

Article abstract of DOI:10.1002/chir.20759

Merrifield resin-supported pyrrolidine-based chiral organocatalysts A2D through A³-coupling reaction linkage have been developed and found to be highly effective catalysts for the Michael addition reaction of ketones with nitrostyrenes. The rea

Full text of DOI:10.1002/chir.20759

CHIRALITY 22:432–441 (2010)
Recyclable Merrifield Resin-Supported Organocatalysts
Containing Pyrrolidine Unit through A3-Coupling Reaction
Linkage for Asymmetric Michael Addition
JIE LIU,1 PINHUA LI,1 YICHENG ZHANG,1 KAI REN,1 LEI WANG,1,2 AND GUANWU WANG
3
*
*
1Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui, People’s Republic of China
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai, People’s Republic of China
3Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
ABSTRACT
Merrifield resin-supported pyrrolidine-based chiral organocatalysts
A2D through A3-coupling reaction linkage have been developed and found to be highly
effective catalysts for the Michael addition reaction of ketones with nitrostyrenes. The
reactions generated the corresponding products in good yields (up to 92%), excellent
enantioselectivities (up to 98% ee), and high diastereoselectivities (up to 99:1 dr). In
addition, the catalysts can be reused at least five times without a significant loss of cata-
C
VV
lytic activity and stereoselectivity. Chirality 22:432–441, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: asymmetric Michael additions; Merrifield resin; supported
organocatalysis; A3-coupling reaction linkage; pyrrolidine unit
mesoporous support, and ionic liquids.48–62 The
development of highly enantioselective and efficient chiral
organocatalysts with broad substrate applicability and easy
recyclability is essential in this field.63,64
We have focused our attention on a general immobiliza-
tion strategy for organocatalysis for Michael addition of
ketones to nitrostyrenes. In this article, we wish to report
a class of newly designed, facile, Merrifield resin-sup-
ported organocatalysts, A2D containing pyrrolidine unit
through A3-coupling reaction linkage (three-component
coupling of aldehyde, alkyne, and amine), which gave
excellent diastereoselectivity (syn/anti up to 99:1) and
high enantioselectivity (up to 98% ee) for the Michael
addition of ketones to nitrostyrenes (Scheme 1).
INTRODUCTION
As List et al.1 and Barbas and coworkers2 reported the
enantioselective Michael additions of unmodified ketones
using L-proline and (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine
as organocatalysts, respectively, some new chiral-type
amines have been developed for promoting the efficiency
of the process.3–10 Recently, small chiral amines have
become attractive and powerful catalysts for CꢀꢀC bond
forming reactions.11,12 Michael addition reactions of
aldehydes or ketones to nitroolefins13–16 occupy a central
position in the playground of organic synthesis and play
an important role in CꢀꢀC bond forming reactions17 due to
the versatility of the nitrofunctionality which can be easily
transformed into, for example, amine, nitrile oxide, ketone,
carboxylic acid, or hydrogen.18
Asymmetric organocatalysis has attracted intense inter-
ests in recent years for its environmental friendliness and
the generation of multiple stereogenic centers in a single
step.19–30 Various effective organocatalysts for Michael
reaction have been developed, such as modified pro-
lines,31–33 pyrrolidine-based diamines,34,35 chiral dia-
mines,36,37 chiral guanidines,38 cinchona alkaloid-based
bifunctional organocatalysts,39,40 urea(thiourea)-based
bifunctional organocatalysts.41–44 Organocatalytic proc-
esses are generally considered as environmentally benign
because the use of metals is avoided. However, their cata-
lytic efficiency is usually lower than in metal-catalyzed
processes in terms of turnover number. To circumvent
this difficulty, the development of immobilized, easily
recoverable, and reusable catalysts appears as one of the
most promising strategies.45–47 Recently, there are some
reports on the asymmetric reactions using immobilized
EXPERIMENTAL
General Remarks
Melting points were recorded on a WRS-2 B melting
1
point apparatus and are uncorrected. All H nuclear mag-
netic resonance (NMR) and 13C NMR spectra were
recorded on a 400 MHz Bruker FT-NMR spectrometers.
All chemical shifts are given as d value (ppm) with refer-
ence to tetramethylsilane (TMS) as an internal standard.
Infrared (IR) spectra were obtained on a Nicolet NEXUS
*Correspondence to: Lei Wang, Department of Chemistry, Huaibei Coal
Teachers College, Huaibei, Anhui 235000, People’s Republic of China.
E-mail: leiwang@hbcnc.edu.cn or Guanwu Wang, Department of Chemis-
try, University of Science and Technology of China, Hefei, Anhui 230026,
People’s Republic of China. E-mail: gwang@ustc.edu.cn
Received for publication 24 January 2009; Accepted 9 June 2009
DOI: 10.1002/chir.20759
Published online 17 July 2009 in Wiley InterScience
proline and its derivatives on poly(ethylene glycol) (PEG), (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

MERRIFIELD RESIN-SUPPORTED ORGANOCATALYSTS
433
Scheme 1. Merrifield resin-supported organocatalysts and their application in asymmetric Michael addition.
470 spectrophotometer. The CHN analysis was performed
Preparation of N-Boc-(S)-2-aminomethylpyrroli-
on a Vario El III elementary analyzer. Enantiomeric dine, 7. N-Boc-(S)-2-azidomethylpyrrolidine, 6 (2.53 g,
excesses were determined on Agilent 1100 HPLC using 11.2 mmol) was dissolved in anhydrous tetrahydrofuran
Daicel Chiralpak AS-H, OJ-H and AD-H columns with race- (THF) (95 ml), and triphenylphosphine (6.2 g, 22.96
mic products as standards. Products were purified by flash mmol) and H2O (0.45 ml) were added to it. The reaction
chromatography on 230–400 mesh silica gel, SiO2.
mixture was heated to reflux temperature for 24 h until all
The chemicals and solvents were purchased from com- starting material had been consumed (TLC monitoring).
mercial suppliers (Aldrich, Fluka, Fisher Scientific, and The organic solvent was then removed under reduced
Novabiochem, USA, or Shanghai Chemical Company, pressure and the remaining oil was dissolved in diethyl
China) and were used without purification before use.
ether (200 ml). The pH of solution was adjusted to around
2 by using 1.0 mol/L HCl with vigorous stirring, and the
aqueous phase was washed with diethyl ether (2 3 40
ml). The pH of the aqueous phase was adjusted to 13 by
using 2.0 mol/L NaOH and extracted with CH2Cl2 (6 3 30
ml). The organic phase was dried with Na2SO4 and con-
centrated under reduced pressure to afford the crude
product 7, which was not further purified (1.57 g, 78%
yield) for the further procedure.65 1H NMR (400 MHz,
CDCl3): d 1.40 (s, 9H), 1.49 (m, 2H), 1.75 (m, 4H), 2.62
(m, 1H), 2.77 (b, 1H), 3.26 (m, 2H), 3.75 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 22.1, 22.7, 27.5, 44.2, 45.7,
46.0, 58.7.
Preparation of Merrifield Resin-Supported
Organocatalysts A, B, C, and D
Preparation of N-Boc-(S)-2-(4-toluenesulfonyloxy)-
methylpyrrolidine, 5. To an ice-cold solution of N-Boc-
(S)-prolinol, 4 (2.95 g, 14.7 mmol) in pyridine (23 ml) was
added 4-toluenesulfonyl chloride (4.94 g, 25.9 mmol). The
reaction mixture was stirred for 6 h and then diluted with
diethyl ether (200 ml). The organic phase was washed
with 10% HCl (3 3 75 ml), NaHCO3 (3 3 75 ml), and NaCl
(2 3 75 ml), respectively. The organic phase was dried
over Na2SO4 and the solvent was evaporated under
reduced pressure. The crude product was subjected to
flash chromatography on silica gel (eluent:pentane/EtOAc
3/2) to obtain 4.38 g of compound 5 (84% yield).22 1H
NMR (400 MHz, CDCl3): d 1.37 (s, 9H), 1.84 (br, 4H),
2.44 (s, 3H), 3.28 (br, 2H), 3.93 (br, 2H), 7.33 (br, 2H),
7.76 (d, J 5 8.18 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.9, 28.5, 47.1, 55.8, 69.9, 128.1, 130.0.
General procedure for the preparation of 8. N-Boc-
(S)-2-aminomethylpyrrolidine 7 (1.57 g, 8.77 mmol) was
dissolved in anhydrous MeOH (5.0 ml) and was heated to
reflux temperature for 0.5 h. Aldehyde (8.77 mmol), such
as para-formaldehyde, phenylacetaldehyde, and n-hexalde-
hyde, respectively, was added dropwise over a period of 5
min and the mixture was stirred at reflux temperature for
Preparation of N-Boc-(S)-2-azidomethylpyrrolidine, 30 min. The solution was allowed to cool to room tempera-
6. N-Boc-(S)-2-(4-toluenesulfonyloxy)methylpyrrolidine, ture and sodium borohydride (700 mg, 18.4 mmol) was
5 (4.38 g, 12.3 mmol) was dissolved in dry dimethyl sulf- added in one portion. After the vigorous effervescence had
oxide (DMSO; 130 ml) and sodium azide (4.81 g, 74.0 stopped, the mixture was heated to reflux temperature for
mmol) was added. The reaction mixture was heated to 15 min. The reaction was then quenched by the addition
648C for 19 h, allowed to cool to room temperature, and of water (5 ml) and the aqueous phase extracted with
diluted with diethyl ether (250 ml). The organic phase was dichloromethane (DCM) (3 3 10 ml). The separated or-
washed with H2O (3 3 200 ml) and NaCl (sat. aq. 100 ml), ganic phase was dried over potassium carbonate, filtered,
dried with Na2SO4, and the solvent was evaporated. The and the solvent evaporated to give the corresponding 8a,
1
crude product 6 (2.53 g, 90% yield) was not further puri- 8b, and 8c, respectively. 8a: 1.86 g (99% yield), H NMR
fied and was stored in the refrigerator until it was further (400 MHz, CDCl3): d 1.39 (s, 9H), 1.43 (m, 2H), 2.10 (b,
used.65 1H NMR (400 MHz, CDCl3) d 1.47 (s, 9H), 1.86 1H), 2.93 (m, 4H), 3.29 (m, 4H), 3.62 (m, 2H). 8b: 2.52 g
1
(m, 4H), 3.37 (m, 4H), 3.8024.00 (b, 1H); 13C NMR(100 (99% yield), H NMR (400 MHz, CDCl3): d 1.42 (s, 9H),
MHz, CDCl3): d 22.3, 27.6, 28.1, 45.9, 52.7, 55.7.
1.92 (m, 4H), 2.15 (s, 1H), 2.76 (m, 1H), 3.29 (m, 2H), 3.82
Chirality DOI 10.1002/chir

434
LIU ET AL.
1
Representative Experimental Procedure for Michael
Addition Reaction in the Presence of Catalyst
C in Toluene
(m, 2H), 7.25 (m, 5H). 8c: 2.35 g (90% yield), H NMR
(400 MHz, CDCl3): d 0.89 (t, 3H), 1.29 (m, 4H), 1.31 (m,
2H), 1.38 (m, 2H), 1.46 (s, 9H), 1.46 (m, 4H), 2.12 (m, 1H),
2.56 (m, 2H), 2.95 (m, 2H), 3.32 (m, 2H), 3.58 (b, 1H).
Under an atmosphere of nitrogen, an oven-dried round-
bottomed flask was charged with trans-b-nitrostyrene (0.5
mmol), cyclohexanone (1.0 ml), catalyst C (21 mg), and
toluene (2.0 ml). The mixture was stirred at room tempera-
ture (258C) for 72 h, then washed with ethyl acetate (3 3
3 ml), the combined ethyl acetate was concentrated. Flash
chromatography (hexane:ethyl acetate 5 3:1, V/V) fur-
nished the corresponding g-nitroketone as colorless crys-
tals (112.3 mg, 91% yield).
Preparation of Merrifield resin-supported azide,
9. A Merrifield resin (2.5 mmol/g, 3.0 g) was treated
with propargyl alcohol (560 mg) under basic conditions
for 24 h at 708C (NaH 400 mg in THF 50 ml) to provide
the Merrifield resin-supported azide, 9 (2.96 g). IR (film,
cm21): 3298, 3058, 3024, 2918, 2848, 1600, 1492, 1451; the
loading of Merrifield resin-supported azide 9 was quanti-
fied via CHN microanalysis and found to be 2.12 mmol/g.
Representative Experimental Procedure for Michael
Addition Reaction in the Presence of Catalyst A Under
Neat Reaction Conditions
Preparation of Merrifield resin-supported organoca-
talysts A, B, C and D. para-Formaldehyde (5.0 mmol)
and amine 7, 8a, 8b, or 8c (5.0 mmol) were added to a
mixture of the Merrifield resin-supported azide 9 (2.0 g,
2.12 mmol/g) and anhydrous acetonitrile (10 ml) con-
tained in a clean, dry, 25 ml round-bottomed flask under
nitrogen atmosphere. The mixture was stirred at 808C for
24 h in oil bath. After the reaction was completed and
cooled to the room temperature, the solid catalyst was
flushed by anhydrous acetonitrile (3 3 25 ml) and
dichloromethane (3 3 25 ml) in a sintered glass funnel, at
last it was dried to ensure removal of the solvent from the
surface of catalyst in a vacuum desiccators to afford the N-
Boc protected Merrifield resin-supported organocatalysts,
which was not further purified before deprotection.
Trifluoroacetic acid (TFA, 5 ml) was added to suspen-
sions of the above N-Boc protected Merrifield resin-sup-
ported organocatalysts swelled with 5 ml of dichlorome-
thane and the mixture was shaken at 08C for 2 h, then at
room temperature for 2 h. After complete deprotection of
N-Boc group in catalysts, the catalysts were filtered and
washed sequentially with Et3N solution (3 3 25 ml),
CH2Cl2 (3 3 25 ml), and EtOEt (3 3 25 ml). The obtained
solid was dried under vacuum for 24 h at 408C to generate
the corresponding Merrifield resin-supported organocata-
lysts A, B, C, and D in good yields, respectively. Catalyst
A: 1.98 g, IR (film, cm21): 3548, 3059, 2922, 2200, 1389,
699; The loading of catalyst A was quantified via CHN
microanalysis and found to be 0.55 mmol/g. Catalyst B:
2.00 g, IR (film, cm21): 3547, 3299, 2852, 2109, 1397, 624;
the loading of catalyst B was quantified via CHN micro-
analysis and found to be 1.11 mmol/g. Catalyst C: 2.01 g,
IR (film, cm21): 3542, 3176, 2870, 2115, 1394, 689; the
loading of catalyst C was quantified via CHN microanalysis
and found to be 1.16 mmol/g. Catalyst D: 1.97 g, IR (film,
cm21): 3547, 3299, 2923, 2852, 2116, 1452, 1349, 699; the
loading of catalyst D was quantified via CHN microanaly-
sis and found to be 0.71 mmol/g.
Under an atmosphere of nitrogen, an oven-dried round-
bottomed flask was charged with trans-b-nitrostyrene (0.5
mmol), cyclohexanone (1.0 ml), and catalyst A (45 mg).
The mixture was stirred at room temperature (258C) for
72 h, then washed with ethyl acetate (3 3 3 ml), the com-
bined ethyl acetate was concentrated. Flash chromatogra-
phy (hexane:ethyl acetate 5 3:1, V/V) furnished the corre-
sponding g-nitroketone as colorless crystals (86 mg, 70%
yield).
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone,
3A.34 1H NMR (400 MHz, CDCl3): d 7.34–7.24 (m, 3H,
ArH), 7.16 (d, J 5 7.3 Hz, 2H, ArH), 4.93 (dd, J 5 4.5, 12.3
Hz, 1H, CH), 4.63 (dd, J 5 9.9, 12.0 Hz, 1H, CH), 3.76 (dt,
J 5 4.5, 9.9 Hz, 1H, CH), 2.70–2.68 (m, 1H, CH), 2.50–2.47
(m, 1H, CH), 2.43–2.38 (m, 1H, CH), 2.14–2.07 (m, 1H,
CH), 1.77–1.59 (m, 4H, 23 CH2), 1.28–1.22 (m, 1H, CH);
13C NMR (100MHz, CDCl3): d 211.8, 137.7, 128.9, 128.1,
127.7, 78.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0. HPLC (Chi-
ralpak AD-H, i-propanol/hexane 5 10:90, flow rate 1.0 ml/
min, k 5 254 nm): tminor 5 10.34 min, tmajor 5 12.94 min;
ee 5 98%.
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclo-
hexanone, 3B.66 1H NMR (400 MHz, CDCl3): d 7.31
(d, J 5 8.3 Hz, 2H, ArH), 7.17 (d, J 5 8.4 Hz, 2H, ArH),
4.94 (dd, J 5 4.6, 12.5 Hz, 1H, CH), 4.63 (dd, J 5 10.0, 12.6
Hz, 1H, CH), 3.79–3.73 (m, 1H, CH), 2.71–2.64 (m, 1H,
CH), 2.47–2.38 (m, 2H, CH2), 2.12–2.05 (m, 1H, CH),
1.78–1.55 (m, 4H, 23 CH2), 1.26–1.22 (m, 1H, CH); 13C
NMR (100 MHz, CDCl3): d 211.6, 136.3, 133.5, 129.6,
129.1, 122.9, 78.5, 52.4, 43.4, 42.6, 33.2, 29.5, 28.3, 25.1.
HPLC (Chiralpak AD-H, i-propanol/hexane 5 10:90, flow
rate 1.0 ml/min, k 5 254 nm): tminor 5 17.41 min, tmajor
27.86 min; ee 5 98%.
5
(S)-2-((R)-1-(4-Methylphenyl)-2-nitroethyl)cyclo-
hexanone, 3C.17 1H NMR (400 MHz, CDCl3): d 7.12
(d, J 5 8.2 Hz, 2H, ArH), 7.04 (d, J 5 8.0 Hz, 2H, ArH),
The Recyclability of the Merrifield Resin-Supported
Organocatalysts
After carrying out the reaction, the mixture was vacuum 4.92 (dd, J 5 4.7, 12.0 Hz, 1H, CH), 4.60 (dd, J 5 9.3, 11.9
filtered using a sintered glass funnel and washed with Hz, 1H, CH), 3.71 (dt, J 5 4.6, 10.0 Hz, 1H, CH), 2.66–2.58
CH2Cl2 (3 ml), Et2O (3 ml), C2H5OH (3 ml), and hexane (m, 1H, CH), 2.47–2.40 (m, 1H, CH), 2.39–2.34 (m, 1H,
(3 ml), respectively. After drying in an oven, the Merrifield CH) 2.31 (s, 3H, CH3), 1.78–1.76 (m, 1H, CH), 1.76–1.57
resin-supported organocatalysts can be reused directly (m, 4H, 23 CH2), 1.24–1.21(m, 1H, CH); 13C NMR (100
without further purification.
MHz, CDCl3): d 212.0, 137.4, 134.6, 129.7, 128.0, 79.0,
Chirality DOI 10.1002/chir

MERRIFIELD RESIN-SUPPORTED ORGANOCATALYSTS
435
52.6, 43.6, 42.6, 33.2, 28.5, 25.0, 21.0. HPLC (Chiralpak
(S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)cyclo-
AD-H, i-propanol/hexane 5 10:90, flow rate 1.0 ml/min, hexanone, 3F.19 1H NMR (400 Hz, CDCl3): d 7.15 (d,
k 5 254 nm): tminor 5 8.99 min, tmajor 5 11.54 min; ee 5 J 5 8.2 Hz, 2H, ArH), 7.01 (d, J 5 8.5 Hz, 2H, ArH), 4.94
80%.
(dd, J 5 4.5, 12.6 Hz, 1H, CH), 4.58 (dd, J 5 10.0, 12.4 Hz,
1H, CH), 3.80–3.74 (m, 1H, CH), 2.65–2.61 (m, 1H, CH),
2.49–2.37 (m, 2H, CH2), 2.09–2.07 (m, 1H, CH), 1.79–1.59
(m, 4H, 23 CH2), 1.25–1.21 (m, 1H, CH); 13C NMR (100
MHz, CDCl3): d 211.7, 133.4, 129.7, 129.5, 124.6, 124.4,
116.0, 115.7, 78.8, 52.4, 43.2, 42.7, 33.2, 28.4, 25.0. HPLC
(Chiralpak AD-H, i-propanol/hexane 5 10:90, flow rate 1.0
ml/min, k 5 254 nm): tminor 5 11.45 min, tmajor 5 15.57
min; ee 5 81%.
(S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)cyclo-
hexanone, 3D.56 1H NMR (400 MHz, CDCl3): d 7.37
(d, J 5 8.0 Hz, 1H, ArH), 7.26–7.20 (m, 3H, ArH), 4.95–
4.87 (m, 2H, CH2), 4.32–4.26 (m, 1H, CH), 2.94–2.90 (m,
1H, CH), 2.47–2.38 (m, 2H, CH2), 2.13–2.09 (m, 1H, CH),
1.81–1.58 (m, 4H, 23 CH2), 1.28–1.22 (m, 1H, CH); 13C
NMR (100 MHz, CDCl3): d 211.6, 135.4, 134.5, 130.3,
129.4, 128.9, 127.3, 77.2, 51.7, 42.8, 41.0, 33.0, 28.5, 25.2.
HPLC (Chiralpak AD-H, i-propanol/hexane 5 10/90, flow
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclo-
hexanone, 3G.3 1H NMR (400 MHz, CDCl3): d 7.07 (d,
J 5 8.3 Hz, 2H, ArH), 6.84 (d, J 5 8.9 Hz, 2H, ArH), 4.92
(dd, J 5 4.5, 12.2 Hz, 1H, CH), 4.58 (dd, J 5 10.2, 12.3 Hz,
1H, CH), 3.78 (s, 3H, OCH3), 3.71 (dt, J 5 4.8, 10.4 Hz,
1H, CH), 2.65–2.63 (m, 1H, CH), 2.54–2.43 (m, 1H, CH),
2.44–2.38 (m, 1H, CH), 2.11–2.07 (m, 1H, CH), 1.80–1.55
(m, 4H, 23 CH2), 1.25–1.21 (m, 1H, CH); 13C NMR (100
MHz, CDCl3): d 212.1, 137.4, 134.6, 129.6, 128.0, 79.0,
52.6, 43.6, 42.7, 33.2, 28.5, 25.0, 21.0. HPLC (Chiralpak
AD-H, i-propanol/hexane 5 10:90, flow rate 1.0 ml/min,
k 5 254 nm): tminor 5 11.99 min, tmajor 5 14.86 min; ee 5
94%.
rate 1.0 ml/min, k 5 254 nm): tminor 5 9.34 min, tmajor
15.13 min; ee 5 86%.
5
(S)-2-((R)-1-(2-Bromophenyl)-2-nitroethyl)cyclo-
hexanone, 3E.44 1H NMR (400 MHz, CDCl3): d 7.58
(d, J 5 8.2 Hz, 1H, ArH), 7.30–7.21 (m, 2H, ArH), 7.15–
7.11 (m, 1H, ArH), 4.89 (d, J 5 8.0 Hz, 2H, CH2), 4.30 (dd,
J 5 6.3, 6.8 Hz, 1H, CH), 2.91–2.86 (m, 1H, CH), 2.47–2.34
(m, 2H, CH2), 2.11–2.08 (m, 1H, CH), 1.81–1.58 (m, 4H,
23 CH2), 1.40–1.21 (m, 1H, CH); 13C NMR (100 MHz,
CDCl3): d 211.6, 137.2, 133.6, 129.0, 127.9, 77.3, 52.1, 43.0,
42.6, 41.9, 32.9, 28.5, 25.2. HPLC (Chiralpak AD-H, i-propa-
nol/hexane 5 10:90, flow rate 1.0 ml/min, k 5 254 nm):
tminor 5 10.32 min, tmajor 5 18.07 min; ee 5 98%.
(S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexa-
none, 3H.34 1H NMR (400 MHz, CDCl3): d 7.34 (d, J
Scheme 2. Synthetic route of the Merrifield-supported organocatalysts.
Chirality DOI 10.1002/chir

436
LIU ET AL.
5 1.3 Hz, 1H, ArH), 6.29 (dd, J 5 1.8, 3.3 Hz, 1H, ArH), 78.3, 52.2, 43.6, 42.7, 33.1, 28.4, 25.0. HPLC (Chiralpak
6.18 (d, J 5 3.2 Hz, 1H, ArH), 4.80 (m, 1H, CH), 4.67 (dd, AD-H, i-propanol/hexane 5 10:90, flow rate 1.0 ml/min, k
J 5 8.9, 12.2 Hz, 1H, CH), 3.96 (dt, J 5 9.3 Hz, 1H, CH), 5 254 nm): tminor 5 9.46 min, tmajor 5 10.32 min; ee 5
2.75–2.73 (m, 1H, CH), 2.45–2.36 (m, 2H, CH2), 2.11–2.09 82%.
(m, 1H, CH), 1.84–1.61 (m, 4H, 23 CH2), 1.28–1.26 (m,
1H, CH); 13C NMR (100 MHz, CDCl3): d 210.9, 150.8,
142.3, 110.3, 108.9, 76.6, 51.0, 42.5, 37.5, 32.4, 28.2, 25.0.
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclopentanone,
3M.10 1H NMR (400 MHz, CDCl3): d 7.28–7.20 (m, 3H,
ArH), 7.13–7.08 (m, 2H, ArH), 5.30–5.23 (m, 1H, CH), 4.95
(dd, J 5 9.9, 12.6 Hz, 1H, CH), 3.67–3.60 (m, 1H, CH),
2.34–2.25 (m, 2H, CH2), 2.10–2.06 (m, 1H, CH), 1.87–1.78
(m, 2H, CH2), 1.72–1.65 (m, 1H, CH), 1.53–1.37 (m, 1H,
CH); 13C NMR (100 MHz, CDCl3): d 218.5, 137.7, 137.4,
128.9, 128.5, 127.9, 78.3, 50.5, 44.2, 38.7, 28.3, 25.0. HPLC
(Chiralpak AD-H, i-propanol/hexane 5 10:90, flow rate 1.0
ml/min, k 5 254 nm): syn: tmajor 5 9.96 min, tminor 5 11.42
min, anti: tminor 5 12.90 min, tmajor 5 17.32 min; syn/anti
5 30:70; ee 5 95%.
HPLC (Chiralpak AD-H, i-propanol/hexane 5 10:90, flow
rate 1.0 ml/min, k 5 254 nm): tmajor510.22 min, tminor
12.40 min; ee 5 78%.
5
(S)-2-((R)-1-(3,4-Dimethoxyphenyl)-2-nitroethyl)
cyclohexanone, 3I.22 1H NMR (400 MHz, CDCl3): d
6.81 (d, J 5 8.2 Hz, 1H, ArH), 6.68 (m, 2H, ArH), 4.91 (dd,
J 5 4.6, 7.8 Hz, 1H, CH), 4.60 (dd, J 5 2.4, 9.9 Hz, 1H,
CH), 3.87 (s, 6H, 23 OCH3), 3.70 (m, 1H, CH), 2.66–2.64
(m, 1H, CH), 2.49–2.45 (m, 1H, CH), 2.41–2.38 (m, 1H,
CH), 2.07–2.04 (m, 1H, CH), 1.80–1.60 (m, 4H, 23 CH2),
1.27–1.23 (m, 1H, CH); 13C NMR (100 MHz, CDCl3):
d 212.2, 149.2, 148.6, 130.2, 120.5, 111.5, 79.1, 56.0,
52.7, 43.8, 42.6, 33.3, 28.5, 27.5, 25.1. HPLC (Chiralpak
As-H, i-propanol/hexane 5 30:70, flow rate 1.0 ml/min,
k 5 254 nm): tminor 5 12.31 min, tmajor 5 22.31 min;
ee 5 83%.
TABLE 1. Catalyst and solvent screening in the direct
asymmetric Michael reaction of cyclohexanone with
b-nitrostyrenea
(S)-2-((R)-1-(4-Trifluoromethyl)phenyl)-2-nitroethyl)-
cyclohexanone, 3J.44 1H NMR (400 MHz, CDCl3): d 7.59
(d, J 5 8.1 Hz, 2H, ArH), 7.30 (m, 2H, ArH), 4.98 (dd, J 5
4.5, 12.6 Hz, 1H, CH), 4.67 (dd, J 5 9.8, 12.2 Hz, 1H, CH),
3.86 (m, 1H, CH), 2.72–2.70 (m, 1H, CH), 2.51–2.47 (m,
1H, CH), 2.41–2.38 (m, 1H, CH), 2.11–2.07 (m, 1H, CH),
1.83–1.57 (m, 4H, 23 CH2), 1.27–1.23 (m, 1H, CH); 13C
NMR (100 MHz, CDCl3): d 211.8, 149.1, 136.9, 130.0,
121.7, 121.6, 78.9, 52.9, 42.7, 43.1, 33.6, 28.8, 25.5. HPLC
(Chiralpak AD-H, i-propanol/hexane 5 10:90, flow rate
1.0 ml/min, k 5 254 nm): tminor 5 9.81; tmajor 5 19.25 min;
ee 5 88%.
Yieldb
(%)
eec
(%)
drd
(syn/anti)
Entry
Catalyst
Solvent
Toluene
Neat
Toluene
Neat
Toluene
Neat
Toluene
Neat
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Cyclohexane
DMF
CH3OH
C2H5OH
i-C3H7OH
H2O
1
2
3
4
5
6
7
8
A
A
B
B
C
C
D
D
C
C
C
C
C
C
C
C
C
C
C
C
50
70
57
66
90
69
Trace
45
62
47
44
58
74
40
Trace
Trace
12
Trace
28
91
97
96
94
98
93
2
85
97
98
96
98
98
99
–
91:9
96:4
93:7
92:8
95:5
92:8
2
84:16
95:5
94:6
97:3
95:5
95:5
97:3
–
9e
10f
11g
(S)-2-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)
cyclohexanone, 3K.7 1H NMR (400 MHz, CDCl3): d 6.74
(d, J 5 7.9 Hz, 1H, ArH), 6.64–6.61 (m, 2H, ArH), 5.96 (s,
2H, OCH2O), 4.91 (dd, J 5 4.5, 12.4 Hz, 1H, CH), 4.54 12h
13i
(dd, J 5 4.5, 10.0 Hz, 1H, CH), 3.67 (dt, J 5 4.5, 9.9 Hz,
1H, CH), 2.63–2.58 (m, 1H, CH), 2.51–2.37 (m, 2H, CH2),
14j
15
16
17
2.15–2.07 (m, 1H, CH), 1.79–1.58 (m, 4H, 23 CH2), 1.35–
1.23 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3): d 211.7,
–
94
–
88
96
–
92:8
–
85:15
93:7
148.0, 147.1, 131.2, 121.6, 108.5, 108.0, 101.2,
18
78.9, 52.5, 43.6, 42.6, 33.2, 28.3, 25.1. HPLC (Chiralpak
19
20
AD-H, i-propanol/hexane 5 10:90, flow rate 1.0 ml/min,
k 5 254 nm): tminor 5 16.56 min, tmajor 518.72 min;
ee 5 92%.
13
ab-Nitrostyrene (0.50 mmol), cyclohexanone (1.0 mmol), supported
catalyst A (45 mg, 5 mol % active loading), B (23 mg, 5 mol % active
loading), C (21 mg, 5 mol % active loading), or D (35 mg, 5 mol % active
loading) at room temperature (258C) for 72 h with vigorous stirring.
bIsolated yields.
(S)-2-((R)-1-(3-Bromophenyl)-2-nitroethyl)cyclo-
hexanone, 3L.44 1H NMR (400 MHz, CDCl3): d 7.40 (d,
J 5 7.7 Hz, 1H, ArH), 7.39 (s, 1H, ArH), 7.21 (t, J 5 7.9
Hz, 1H, ArH), 7.10 (d, J 5 7.2 Hz, 1H, ArH), 4.94 (dd, J 5
4.5, 12.7 Hz, 1H, CH), 4.60 (dd, J 5 10.0, 12.7 Hz, 1H,
CH), 3.77–3.71 (m, 1H, CH), 2.65–2.59 (m, 1H, CH), 2.48–
2.38 (m, 2H, CH2), 2.09–2.05 (m, 1H, CH), 1.79–1.56 (m,
4H, 23 CH2), 1.31–1.20 (m, 1H, CH); 13C NMR (100 MHz,
cDetermined by chiral HPLC analysis.
dDetermined by 1H NMR analysis.
eIn the presence of TFA (0.10 mmol).
fIn the presence of citric acid (0.10 mmol).
gIn the presence of TsOH (0.10 mmol).
hIn the presence of benzoic acid (0.10 mmol).
iIn the presence of catalyst C (11 mg, 2.5 mol % active loading).
CDCl3): d 211.2, 140.1, 131.2, 130.9, 130.4, 126.9, 122.8, jAt 08C.
Chirality DOI 10.1002/chir

MERRIFIELD RESIN-SUPPORTED ORGANOCATALYSTS
437
TABLE 2. Catalyst A and C catalyzed asymmetric Michael reactiona
Entry
1a
R
Catalyst
Solvent
Neat
Product
Yieldb (%)
70
eec (%)
97
drd syn/anti
96:4
H
A
1b
C
Toluene
91
98
95:5
2a
2b
4-Cl
A
C
Neat
59
86
96
98
96:4
97:3
Toluene
3a
3b
4-CH3
A
C
Neat
62
90
86
80
98:2
95:5
Toluene
4a
4b
2-Cl
A
C
Neat
57
87
90
86
99:1
97:3
Toluene
5a
5b
2-Br
4-F
A
C
Neat
60
89
88
98
98:2
99:1
Toluene
6a
6b
A
C
Neat
73
84
94
81
98:2
96:4
Toluene
7a
7b
4-CH3O
2-Furyl
A
C
Neat
38
86
87
94
96:4
99:1
Toluene
8a
8b
A
C
Neat
39
92
81
78
98:2
96:4
Toluene
Chirality DOI 10.1002/chir

438
LIU ET AL.
TABLE 2. (Continued)
Entry
9
R
Catalyst
Solvent
Product
Yieldb (%)
80
eec (%)
83
drd syn/anti
92:8
3,4-(CH3O)2
C
Toluene
10
11
4-CF3
C
C
Toluene
Toluene
85
75
88
92
93:7
98:2
3,4-OCH2O-
12
3-Br
C
Toluene
73
82
97:3
ab-Nitrostyrene (0.5 mmol), cyclohexanone (1.0 mmol), catalyst A (45 mg) or C (21 mg), toluene (2.5 mL), or in the absence of solvent at room tempera-
ture for 72 h with vigorous stirring.
bIsolated yields.
cDetermined by chiral HPLC analysis.
dDetermined by 1H NMR analysis.
(R)-5-Nitro-4-phenylpentan-2-one, 3N.26 1H NMR PPh3/THF in 78% isolated yield. The yielded compound 7
(400 MHz, CDCl3): d 7.35–7.21 (m, 5H, ArH), 4.72–4.58 was then reacted with aldehydes, such as para-formalde-
(m, 2H, CH2), 4.03–4.00 (m, 1H, CH), 2.92 (d, J 5 6.8 Hz, hyde, phenylacetaldehyde, and n-hexaldehyde respectively
2H, CH2), 2.12 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): to afford the corresponding imines, and followed by reduc-
d 205.5, 138.8, 129.1, 127.9, 127.4, 79.5, 64.4, 46.1, 39.0, tion with NaBH4/CH3OH to give the corresponding amine
30.4, 25.3. HPLC (Chiralpak AD-H, i-propanol/hexane 5 compounds 8a, 8b, and 8c in good yields. The generated
10:90, flow rate 0.6 ml/min, k 5 254 nm): tminor 5 11.74 7, 8a, 8b, and 8c were then reacted with Merrifield resin-
min, tmajor 5 12.79 min; ee 5 78%.
supported azide 9 and para-formaldehyde in the presence
of catalytic amount CuI via a three-component coupling of
aldehyde, alkyne and amine (Mannich A3-coupling reac-
tion) to generate the corresponding Merrifield resin-sup-
RESULTS AND DISCUSSION
The synthesis of the catalysts A, B, C, and D is illus- ported compounds, and followed by deprotection of N-Boc
trated in Scheme 2. They were readily prepared through a protective group through treatment with TFA in CH2Cl2,
multistep procedure.
N-Boc-(S)-prolinol 4 in anhydrous pyridine was reacted ported organocatalysts A, B, C, and D in good yields.
with 4-toluenesulfonyl chloride at 508C for 6 h to give For the evaluation of the catalytic properties of Merri-
respectively, to afford the desired Merrifield resin-sup-
N-Boc-(S)-2-(4-toluenesulfonyloxy)methylpyrrolidine 5 in field resin-supported organocatalysts, A2D containing
84% yield. The obtained 5 in dry DMSO subsequently pyrrolidine unit and optimization of the Michael addition
reacted with sodium azide at 648C for 19 h to generate conditions, the reaction between trans-b-nitrostyrene and
N-Boc-(S)-2-azidomethylpyrrolidine 6 in 90% yield. The cyclohexanone served as a model reaction. The results are
formed compound 6 was then reduced to the correspond- summarized in Table 1. As seen from Table 1, the Michael
ing amine, N-Boc-(S)-2-aminomethylpyrrolidine 7 by using reactions proceeded smoothly at room temperature in the
Chirality DOI 10.1002/chir

MERRIFIELD RESIN-SUPPORTED ORGANOCATALYSTS
439
presence of Merrifield resin-supported organocatalysts
Under the optimized reaction conditions, a variety of
(5 mol % of active loading) in toluene or under neat reac- nitroolefins with different substituents were investigated,
tion conditions to generate the corresponding products in and the results are summarized in Table 2. Various
moderate to good yields and fair to good enantiomeric styrene-type nitroolefins reacted smoothly with cyclo-
excesses. Among A–D tested, the catalytic properties of A hexanone in good yields, high diastereoselectivities,
under neat reaction conditions and C in toluene are supe- and excellent enantioselectivities (Entries 1212, Table
rior to that of A, B, and D in toluene, and B, C, and D 2). As can be seen in Table 2, the results of Michael
under neat reaction conditions (Entries 1–8, Table 1). reactions carried out in the presence of catalyst C in
Fortunately, C was found to be the most efficient for the toluene are superior to that of the results in the pres-
asymmetric Michael reaction in toluene (Entry 5, Table 1, ence of catalyst A under neat reaction conditions. Gen-
90% yield, 98% ee, and 95:5 dr). However, the isolated erally, substituents on aryl groups slightly influenced
yields, enantioselectivities, and diastereoselectivities of the both diastereoselectivities and enantioselectivities as
reaction were not improved when TFA, citric acid, TsOH, well as the yields. For example, nitroolefins with aryl
or benzoic acid (10 mol %) were added to the reactions rings bearing both electron-withdrawing and electron-
(Entries 9–12, Table 1). As shown in Table 1, the reactions donating groups gave the desired products with high
were carried out with 10 mol% of C in a variety of solvents selectivity (dr up to 99:1 and ee up to 98%) in
(Entries 5, 15220, Table 1) to examine the solvent effect. excellent yields (up 90%).
However, when the reactions were carried out in cyclohex-
Moreover, the Michael reactions were evaluated with
ane, DMF, CH3OH, C2H5OH, i-C3H7OH, or H2O, the other ketones and it was found that cyclopentanone and
Michael addition reactions did not proceed very well and acetone were also the suitable substrates as Michael
only trace to 28% yield of the corresponding products were donors (Entries 13 and 14, Table 3). However, acetone
isolated, although good enantioselectivities and diastereo- and cyclopentanone served as Michael donors to produce
selectivities were achieved (Entries 15–20, Table 1). To our the desired adducts with moderate yields, and moderate
delight, when the reactions were carried out in toluene, the to good enantioselectivities and diastereoselectivities in
Michael addition reactions proceeded smoothly and excel- the presence of catalyst A under neat reaction conditions
lent results were obtained (Entry 5, Table 1). Moreover, (Entries 13 and 14, Table 3).
slightly higher enantioselectivity and diastereoselectivity
In addition, the recyclability of the Merrifield resin-
were observed when the reaction temperature was reduced supported organocatalyst containing pyrrolidine unit C
from room temperature (258C) to 08C with a significant was investigated. After carrying out the reaction, the cat-
decrease in the reaction rate (Entry 14, Table 1). During alyst was filtered using a sintered-glass funnel and
the course of our further optimization of the reaction condi- washed with ethyl acetate (3.0 ml) and dichloromethane
tions, we observed that the reactions were generally com- (3.0 ml), respectively. After drying,
C was reused
pleted in 72 h with 5 mol% of C at room temperature (258C, directly without further purification, and it was recov-
Entry 5 vs. 13, Table 1). Thus, the optimized reaction condi- ered, and reused for five repetitive cycles without loss
tions for this Michael reaction are catalyst C (5 mol %) in of its activity, enantioselectivity, and diastereoselectivity
toluene at room temperature (258C) for 72 h.
(Entries 1–5, Table 4).
TABLE 3. Catalyst A and C catalyzed Michael reaction of various ketones with b-nitrostyrenea
Entry
13
R1
R2
Catalyst
Solvent
Neat
T (8C)
Product
Yieldb (%)
46
eec (%)
95
drd
ꢀꢀ(CH2)3ꢀꢀ
A
0
70:30
14a
14b
CH3
H
H
A
C
Neat
Neat
0
43
57
78
28
–
–
CH3
25
ab-Nitrostyrene (0.5 mmol), ketone (1.0 ml), and catalyst A (45 mg) or C (21 mg) was stirred at room temperature for 72 h with vigorous stirring.
bIsolated yields.
cDetermined by chiral HPLC analysis.
dDetermined by 1H NMR analysis (dr: syn/anti).
Chirality DOI 10.1002/chir

440
LIU ET AL.
8. Zu L, Wang J, Li H, Wang W. A recyclable fluorous (S)-pyrrolidine sulfona-
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Yieldb (%)
eec (%)
drd syn/anti
1
2
3
4
5
91
90
89
89
87
98
98
97
97
98
96:4
96:4
96:4
95:5
95:5
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In conclusion, we have developed a novel Merrifield
resin-supported pyrrolidine-based chiral organocatalysts 17. Xu DQ, Wang BT, Luo SP, Yue HD, Wang LP, Xu ZY. Pyrrolidine–
through A3-coupling reaction linkage, which are capable of
catalyzing Michael addition reaction of ketones with nitro-
styrenes in good yields, excellent enantioselectivies, and
high diastereoselectivities. The method is operationally
pyridinium based organocatalysts for highly enantioselective Michael
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simple, the catalyst can be easily recycled, and reused five
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times without loss of catalytic activity and stereoselectivity.
Further investigations of the application of this supported
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our laboratory.
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ACKNOWLEDGMENTS
We gratefully acknowledge financial support by the
National Natural Science Foundation of China (No.
20772043) and the Key Project of Science and Technology
of the Department of Education, Anhui Province, China
(No. ZD2007005-1).
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Chirality DOI 10.1002/chir