Ionic liquid-supported (ILS) (S)-pyrrolidine sulfonamide for asymmetric Michael addition reactions of aldehydes with nitroolefins

Article abstract of DOI:10.2174/157017811795038395

A class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst (1c), which was developed earlier in our lab, has been applied to a wider range of Michael addition reaction, involving various aryl-substituted nitroolefins and a series of aldehydes. Catalyst 1c catalyzes Michael additions in which only 2 equivalents of aldehydes to each equivalent of nitroolefin are required. With 10 mol% of ILS catalyst 1c loading, moderate to excellent yields (51-98%) with moderate enantioselectivities (28-83% ee) and high diastereoselectivities (syn/anti ratio up to 97/3) were obtained. Moreover, the catalyst 1c could be easily recycled and reused for at least 5 times with slightly reduced activities.

Full text of DOI:10.2174/157017811795038395

170
Letters in Organic Chemistry, 2011, 8, 170-175
Ionic Liquid-Supported (ILS) (S)-Pyrrolidine Sulfonamide for Asymmetric
Michael Addition Reactions of Aldehydes with Nitroolefins
Emmy M. Omarb, Kritanjali Dhunganaa, Allan D. Headley*,a and Mohd Basyaruddin Abdul
Rahmanb
aDepartment of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
bDepartment of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Received May 27, 2010: Revised September 21, 2010: Accepted October 14, 2010
Abstract: A class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst (1c), which was developed
earlier in our lab, has been applied to a wider range of Michael addition reaction, involving various aryl-substituted
nitroolefins and a series of aldehydes. Catalyst 1c catalyzes Michael additions in which only 2 equivalents of aldehydes to
each equivalent of nitroolefin are required. With 10 mol% of ILS catalyst 1c loading, moderate to excellent yields (51-
98%) with moderate enantioselectivities (28-83% ee) and high diastereoselectivities (syn/anti ratio up to 97/3) were
obtained. Moreover, the catalyst 1c could be easily recycled and reused for at least 5 times with slightly reduced activities.
Keywords: Aldehydes, asymmetric catalysis, ionic liquid, michael addition, nitroolefins.
INTRODUCTION
and the catalyst was easily separated and could be recycled
[6b]. A large excess of the Michael donor, up to 20
equivalents, is required in order to increase the reaction
conversion, this becomes a serious limitation for reactions
where Michael donors that are not commercially available.
The group of Wang has described fluorous (S)-pyrrolidine
sulfonamide promoted enantioselective Michael addition of
ketones and aldehydes to nitroolefins [6a]. Again, the same
drawback is that 10 equivalents of Michael donor source are
needed, and the expensive fluorous silica gel is required for
catalyst recovery. Therefore, the development of the high
catalytic activity of catalysts, which integrate the advantages
of homogeneous and heterogeneous catalysis with easy
separation and convenience of recycling the catalysts from
the reaction mixture, as well as with low Michael donors
loading, are of tremendous importance.
The organocatalytic asymmetric Michael reaction has
been one of the most powerful synthetic methodologies in
modern chemistry for the construction of C-C bonds with
simultaneous generation of two contiguous stereocenters in a
single step [1]. The products of the Michael reaction are
versatile synthetic building blocks for a wide variety of
important biological and pharmaceutical compounds [2].
Since the pioneering work of List and Barbas in 2001 [3], a
great deal of effort has been devoted to the development of
more selective and catalytic protocols for this cornerstone
type transformation, and significant progress has been made
in recent years [4]. A major problem associated with this
reaction however, is that most organocatalytic systems that
are typically used require high loadings (normally 10-30
mol%) and a large excess of Michael donor sources
(normally 5-20 equivalents) to complete the reactions in
reasonable timescales and give good stereoselectivity. As a
result, there are high costs associated with these reactions
and their applications are limited. Such limitations are of
practical significance, especially in the pharmaceutical
industry. Despite the effort invested in the development of
highly effective organocatalysts aimed at lowering catalyst
loading and reducing the quantity of donor sources, only
limited success has been achieved [5].
Recently, the use of ionic liquids (ILs) as supports for
homogeneous catalyst has attracted much attention due to
their attractive physical properties; they include lack of
measurable vapor pressure, have high chemical and thermal
stability, and they exhibit high ionic conductivity [7]. Most
important, the solubility of ionic liquids can be fine-tuned by
modification of their cation and anion so that they can be
separated easily from organic solvents as well as aqueous
media due to solubility differences. ILS chiral pyrrolidine
organocatalysts have been used recently to promote the
direct asymmetric Michael addition of ketones to nitroolefins
with high stereoselectivity. However, a large excess of
ketones or aldehydes (10-20 equivalents) is still required to
drive the reaction to completion in reasonable timescales
[6d-e]. As a result, it is desirable to design and develop
efficient ILS organocatalysts, which catalyze Michael
reactions with low Michael donor source loading. We have
developed a series of ILS pyrrolidine sulfonamide, shown in
Fig. (1), and it was shown that 1c served as a recyclable
organocatalyst for Michael reactions of ketones to
nitroolefins in i-PrOH at room temperature affording
An alternative strategy is to develop recyclable and
reusable chiral organocatalysts. Methods for immobilizing
homogeneous organocatalysts have only been developed in
recent years [6]. For example, insoluble polymer supported
proline was used as organocatalyst for the asymmetric
Michael addition of ketones and aldehydes to nitroolefins
*Address correspondence to this author at the Department of Chemistry,
Texas A&M University-Commerce, Commerce, TX 75429-3011, USA; Tel:
903/886-5159; Fax: 903/886-5165;
E-mail: allan_headley@tamu-commerce.edu
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Ionic Liquid-Supported (ILS) (S)-Pyrrolidine Sulfonamide
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
171
BF4
O
S
O
O
N
+
+
N
N
S
N
H
S
N
N
N
N
H
-
O
H
NTf2
N
O
NH
-
O
NH
NTf2
NH
1a
1b
1c
O
S
IL
N
H
O
O
Ar
O
O
N
NO2
H
NO2
O
+
Ar
N
H
R
R
R
Ar
Fig. (1). ILS pyrrolidine sulfonamide organocatalysts used for Michael addition.
Michael adducts in high levels of enantioselectivities (up to
99% ee) and diastereoselectivities (syn/anti ratio from 92/8
to 99/1) [6i].
enantioselectivities. It was observed that the long chain of
the linear aldehydes gave the Michael adducts with relatively
higher enantioselectivities and diastereoselectivities,
compared to the short chain (Table 1, entries 1-5). However,
Herein, we report the results of studies aimed at
exploring the use of ILS organocatalyst 1c for a wide scope
of Michael reactions involving aldehydes. Based on the
mechanism proposed for Michael addition to nitroolefins
involving the pyrrolidine sulfonamide organocatalysts shown
in Fig. (1), the acidic N-H hydrogen is believed to stabilize
the transition state through hydrogen bonds that allow the
preferential enamine addition to the less hindered face of the
nitroolefins to induce the outcome of the stereoselectivity.
Therefore, subtle changes that affect the acidity of N-H of
the catalyst can be utilized to improve catalytic activity and
selectivity in a dramatic way.
for the case of 3-phenylpropionaldehyde,
enantioselectivity and reaction rate was observed (Table 1,
entry 6).
a
low
Next, the reactions of various substituted nitroolefins and
the linear aldehyde n-pentanal were studied. Generally, the
nature of the substituents on the aryl group has a slight
influence on the yields and enatioselectivities. For
nitroolefins with electron-rich groups (methyl and methoxy),
the reaction proceeded smoothly to afford Michael adduct
4g-i in excellent yields with enantio- (38-46% ee) and
diastereoselectivities (syn/anti up to 93/7) (Table 1, entries
7-9). For nitroolefins with electron-deficient groups, the
Michael adducts 4j-n were also obtained in moderate to high
yields (70-98%) with moderate enantioselectivities (35-
44%), but relative low reaction rate for the NO2 and CF3
substituted compounds (Table 1, entries 10-14). The
branched aldehyde isovaleraldehyde was also found to be a
suitable substrate as Michael donor affording the product 4o
in high yield with 69% ee and excellent diastereoselectivity
(syn/anti: 97/3) (Table 1, entry 15). In addition, ꢀ,ꢀ-
RESULTS AND DISCUSSION
Earlier, we reported on the Michael addition of aldehydes
to nitroolefins catalyzed by ILS catalysts 1a and 1b, and it
was shown that the catalytic activity of 1b is higher,
compared to that of 1a [6g]. Under the optimized reaction
conditions, the conjugate addition reaction of aldehydes (6
equiv) to nitroolefins catalyzed by 20 mol% of 1a afforded
the product in moderate yields (29-70%) with 54-84% ee
after 6 days, whereas the reaction is complete within 2-3
days by using 1b (20 mol%) in excellent yields (82-99%)
with 41-85% ee. Since ILS catalyst 1c was found to exhibit
superior catalytic activity for the Michael addition of ketones
to nitroolefins, compared to catalyst 1a and 1b [6i], we
tested it as a catalyst for the Michael addition of aldehydes to
nitroolefins; this should result in the use of reduced
aldehydes, with respect to the nitroolefin. To test this
hypothesis, we used only 2 equivalents of the aldehydes and
carried out the reaction in i-PrOH at room temperature with
10 mol% of ILS catalyst 1c loading, the results are
summarized in Table 1 [8]. From these results, it is obvious
that all aldehydes tested can efficiently undergo Michael
addition reactions with a wide range of aryl-substituted
nitroolefins to afford the Michael adducts 4a-q in moderate
to excellent yields (51-98%) with moderate enantio- (28-
83% ee) and high diastereoselectivities (syn/anti ratio up to
97/3). As demonstrated in Table 1, the length of the chain
attached to the aldehydes can influence the yields and
disubstituted
aldehydes,
isobutyraldehyde
and
cyclopentanecarboxaldehyde, are also suitable Michael
donors and afforded adducts 4p-q, which simultaneously
generated quaternary carbon centers, in 51-65% yields with
good enantioselectivities (75-83%) (Table 1, entries 16-17).
Since the best results for the Michael reaction were
obtained using catalyst ILS 1c (20 mol% of 1c was used), we
chose that reaction to examine the recyclability of the
catalyst. We decided to use the reaction of trans-ꢁ-
nitrostyrene and isovaleraldehyde, under standard reaction
conditions, as the model reaction. When the first run of the
reaction was completed, the reaction mixture was
concentrated and the residue was diluted with ethyl acetate to
precipitate the catalyst, which was easily recovered (> 90%)
by simple phase separation. The ethyl acetate phase was
combined, concentrated and further purified by flash silica
gel column to give the Michael adduct 4o. The catalyst was
recovered, dried and reused for the next run of the reaction.
As shown in Table 2, catalyst 1c could be recycled and
reused for at least 5 times without significant loss of

172 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Omar et al.
Table 1. Michael Addition of Aldehydes to Nitroolefins Catalyzed by ILS 1ca
O
O
Ar
Ar
NO2
1c (10 mol%)
H
*
H
*
+
R2
R2
2
NO2
i-PrOH, r.t.
4
3
Yield (%)b
ee (%)c
dr (syn/anti)d
Product
Entry
Time (h)
O
Ph
NO2
1
4
95
38
81/19
91/9
H
4a
O
Ph
NO2
2
3
93
44
H
n-Pr
4b
O
Ph
NO2
3
4
5
2
2
3
97
96
98
48
49
50
94/6
95/5
96/4
H
n-Bu
4c
O
Ph
NO2
H
4d
n-C5H11
O
Ph
NO2
H
4e
n-C7H11
O
Ph
NO2
6
24
85
28
87/13
H
4f
CH2Ph
O
C6H4-p-Me
NO2
7
8
4
5
5
4
3
91
93
98
91
98
46
40
38
43
44
91/9
93/7
H
4g
n-Pr
O
C6H4-p-OMe
NO2
H
4h
n-Pr
O
C6H4-m-OMe
NO2
9
89/11
84/16
89/11
H
4i
n-Pr
O
C6H4-p-Br
NO2
10
11
H
4j
n-Pr
C6H4-o-Cl
NO2
O
H
4k
n-Pr

Ionic Liquid-Supported (ILS) (S)-Pyrrolidine Sulfonamide
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
173
(Table 1). Contd…..
Yield (%)b
ee (%)c
dr (syn/anti)d
Product
Entry
Time (h)
O
O
O
O
C6H4-o,p-Cl2
NO2
12
13
14
15
16
17
3
91
35
93/7
H
H
H
H
4l
n-Pr
C6H4-o-NO2
NO2
30
24
15
50
50
70
82
96
65
51
37
40
69
75
83
75/25
86/14
97/3
-
4m
n-Pr
C6H4-o-CF3
NO2
4n
n-Pr
Ph
NO2
4o
O
Ph
NO2
H
4p
O
Ph
NO2
-
H
4q
a2 equiv of aldehydes was used. bIsolated yield. cDetermined by chiral HPLC. dDetermined by 1HNMR.
stereoselectivity (ee > 68%; syn/anti > 96/4) despite some
slight decreasing of activity observed in cycles 3-5.
substituted nitroolefins and a series of aldehydes. We have
demonstrated that catalyst 1c catalyzes Michael additions of
aldehydes to nitroolefins using only 2 equivalents of
aldehydes and low catalyst loading. Moderate to excellent
yields (51-98%) with moderate enantio- (28-83% ee) and
high diastereoselectivities (syn/anti ratio up to 97/3) were
obtained. Moreover, the catalyst 1c could be easily recycled
and reused for at least 5 times with slightly reduced
activities.
CONCLUSION
In conclusion, a class of ionic liquid supported (ILS) (S)-
pyrrolidine suflonamide organocatalyst (1c), which was
developed earlier in our lab, has been applied to a wider
range of Michael addition reaction involving various aryl-
Table 2. Recycling Studies of ILS 1c Catalyzed Michael Addition of Isovaleraldehyde to trans-ꢀ-Nitrostyrenea
O
O
Ph
Ph
NO2
1c (20 mol%)
rt, i-PrOH
+
NO2
4o
cycle
time (h)
yield (%)b
ee (%)c
syn/antid
1
2
3
4
5
10
10
12
20
36
97
95
95
90
86
69
68
69
69
68
97/3
97/3
96/4
97/3
96/4
a2 equiv of aldehydes was used. bIsolated yield. cDetermined by chiral HPLC. dDetermined by 1HNMR.

174 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Omar et al.
Cordova, A. Simple highly modular acyclic amine-catalyzed direct
enantioselective addition of ketones to nitro-olefins. Chem.
Commun., 2006, (4), 460-462. (n) Kotrusz, P.; Toma, S.; Schmalz,
H.-G.; Adler, A. Michael additions of aldehydes and ketones to ꢁ-
nitrostyrenes in an ionic liquid. Eur. J. Org. Chem., 2004, 7, 1577-
1583; (o) Mase, N.; Watanabe, K.; Yoda, Takabe, K.; Tanaka, F.;
Barbas, C.F., III. Organocatalytic direct michael reaction of
ketones and aldehydes with ꢁ-nitrostyrene in brine. J. Am. Chem.
Soc., 2006, 128(15), 4966-4967; (p) Pansare, S.; Pandya, K. Simple
diamine- and triamine- protonic acid catalysts for the
enantioselective michael addition of cyclic ketones to nitroalkenes.
J. Am. Chem. Soc., 2006, 128(30), 9624-9625; (q) Vishnumaya;
Singh, V.K. Highly enantioselective water- compatible
organocatalyst for michael reaction of ketones to nitroolefins. Org.
Lett., 2007, 9(6), 1117-1119; (r) Ni, B.; Zhang, Q.; Headley, A.D.
Highly enantioselective michael addition of ketones to nitroolefins
catalyzed by (s)-pyrrolidine arenesulfonamide. Tetrahedron
Asymmetry, 2007, 18(12), 1443-1447; (s) Belot, S.; Massaro, A.;
Tenti, A.; Mordini, A.; Alexakis, A. Enantioselective
organocatalytic conjugate addition of aldehydes to nitrodienes.
Org. Lett. 2008, 10(20), 4557-4560.
(a) Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Highly
efficient asymmetric michael addition of aldehydes to nitroalkenes
catalyzed by a simple tans-4-hydroxyprolylamide. Angew. Chem.
Int. Ed., 2006, 45(36), 5984-5987; (b) Wiesner, M.; Revell, J. F.;
Wennemers, H. tripeptides as efficient asymmetric catalysts for
1,4-addition reactions of aldehydes to nitroolefins – a rational
approach. Angew. Chem. Int. Ed., 2008, 47(10), 1871-1874; (c)
Zhu, S.; Yu, S.; Ma, D. Highly efficient catalytic system for
enantioselective michael addition of aldehydes to nitroalkenes in
water. Angew. Chem., Int. Ed., 2008, 47(3), 545-548.
For examples reporting recyclable organocatalysts for Michael
addition reactions using fluorous support, (a) Zu, L.; Wang, J.; Li,
H.; Wang, W. A recycle fluoroes (s)-pyrrolidine sulfonamide
promoted direct, highly enantioselective michael addition of
ketones and aldehydes to nitroolefins in water. Org. Lett., 2006,
8(14), 3077-3079. Polymer support, (b) Alza, E.; Camberiro, X. C.;
Jimeno, C.; Pericàs, M. A. highly enantioselective michael
additions in water catalyzed by a ps-supported pyrrolidine. Org.
Lett., 2007, 9(19), 3717-3720; (c) Gu, L.; Wu, Y.; Zhang, Y.; Zhao,
G. A new class of efficent poly(ethylene-glcol)- supported catalyst
based on proline for the asymmetric michael addition of ketone to
nitrostyrenes. J. Mol. Catal. A, 2007, 263(1-2), 186-194. Ionic
liquid support from other groups and our research group, see: (d)
Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, Jin-Pei.
Functionalized chiral ionic liquids as highly efficient asymmetric
organocatalysts for michael addition to nitroolefins. J. Angew.
Chem. Int. Ed., 2006, 45(19), 3093-3097; (e) Kotrusz, P.; Toma, S.;
Schmalz, H.; Adler, A. Michael Additions of aldehydes and
ketones to ꢁ-nitrostyrenes in an ionic liquid. Eur. J. Org. Chem.,
2004, 7, 1577-1583; (f) Ni, B.; Zhang, Q.; Headley, A.D.
Funtionalized chiral ionic liquid as recyclable organocatalyst for
asymmetric michael addition to nitrostyrenes. Green Chem., 2007,
9(7), 737-739; (g) Zhang, Q.; Ni, B.; Headley, A.D. Asymmetric
michael addition reactions of aldehydes with nitrostyrenes
catalyzed by functionalized chiral ionic liquids. Tetrahedron, 2008,
64(22), 5091-5097; (h) Ni, B. Zhang, Q.; Headley, A.D.
Pyrrolidine-based chiral pyridinium ionic liquids(ils) as recyclable
and highly efficient organocatalysts for the asymmetric michael
addition reactions. Tetrahedron Lett., 2008, 49(7), 1249-1252; (i)
Ni, B.; Zhang, Q.; Dhungana, K.; Headley, A.D. Ionic liquid-
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support of this
research by the Robert A. Welch Foundation (T-1460).
REFERENCES AND NOTES
[1]
For selected reviews on organocatalytic asymmetric Michael
addition, see: (a) Tsogoeva, S.B. Recent advances in asymmetric
organocatalytic 1,4-conjugate additions. Eur. J. Org. Chem., 2007,
11, 1701-1716; (b) Almasi, D.; Alonso, D.A.; Nájera, C.
Organocatalytic asymmetric conjugate additions. Tetrahedron
Asymmetry, 2007, 18, 299-365; (c) Sulzer-Mossé, S.; Alexakis, A.
Chiral amines as organocatalysts for asymmetric conjugate addition
to nitroolefins and vinyl sulfones via enamine activation. Chem.
Commun., 2007, 3123-3135, doi:10.1002/chin.200749254; (d)
Miller, S.J. In search of peptides-based catalysts for asymmetric
organic synthesis. Acc. Chem. Res., 2004, 37, 601-610; (e) Seayad,
J.; List, B. Asymmetric Organocatalysis. Org. Biomol. Chem.,
2005, 3, 719-724; (f) Dalko, P.I.; Moisan, L. In the golden age of
organocatalysis. Angew. Chem. Int. Ed., 2004, 43, 5138-5175; (g)
List, B. Enamine catalysis is a powerful strategy for the catalytic
generation and use of carbanion equivalents. Acc. Chem. Res.,
2004, 37, 548-557; (h) Notz, M.; Tanaka, F.; Barbas, C.F., III.
Enamine- Based organocatalysis with proline and diamines: the
development of direct catalytic assymetric aldol, mannich, michael,
and Diels-Alder reactions. Acc. Chem. Res., 2004, 37, 580-591.
(a) Rosini G. In: Comprehensive Organic Synthesis; Eds.; Trost,
B.M.; Flemming, I.; Heathcock, C.M., Pergamon, New York, 1991,
Vol. 2 pp. 321-340; (b) Ono, N. The Nitro Group in Organic
Synthesis, John Wiley & sons, Inc., New York, USA, 2001.
[5]
[2]
[3]
[6]
(a) List, B.; Pojarlier, P.; Martin, H.J. Efficient proline-catalyzed
michael additions of unmodified ketones to nitro olefins. Org. Lett.,
2001, 3, 2423-2425; (b) Betancort, J.M.; Barbas III, C.F. Catalytic
direct asymmetric michael reactions: taming naked aldehyde donor.
Org. Lett., 2001, 3, 3737-3740.
[4]
For selected examples of Michael additions catalyzed by
organocatalysts, see: (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas,
C.F., III. Amino acid catalyzed direct asymmetric aldol reactions: a
Bioorganic approach to catalytic asymmetric carbon- carbon bond-
forming reactions. J. Am. Chem. Soc., 2001, 123, 5260-5267; (b)
Betancort, J.M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C.F.,
III. Catalytic enantioselective direct michael addition of ketones to
alkylidenemalonates. Tetrahedron Lett., 2001, 42, 4441-4444; (c)
Betancort, J.M.; Barbas III, C.F. Catalytic direct asymmetric
michael reactions: taming naked aldehyde donor. Org. Lett., 2001,
3, 3737-3740; (d) Alexakis, A.; Andrey, O. Diamine-catalyzed
asymmetric michael additions of aldehydes and ketones to
nitrostyrene. Org. Lett., 2002, 4, 3611-3614; (e) Enders, D.; Seki,
A. Proline- catalyzed enantioselective michael additions of ketones
to nitrostyrene. Synlett., 2002, 1, 26-28; (f) Mase, N.;
Thayumanavan, R.; Tanaka, F.; Barbas, C.F., III. Direct
asymmetric organocatalytic michael reactions of ꢀ,ꢀ- disubstituted
aldehydes with ꢁ-nitrostyrenes for the synthesis of quaternary
carbon- containing products. Org. Lett., 2004, 6(15), 2527-2530;
(g) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. A new class of
chiral pyrrolidine- pyridine conjugate base catalysts for use in
asymmetric michael addition reactions. J. Am. Chem. Soc., 2004,
126(31), 9558-9559; (h) Betancort, J.M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C.F., III. Catalytic direct
asymmetric michael reactions: addition of unmodified ketone and
aldehyde donors to alkylidene malonates and nitro olefins.
Synthesis 2004, 9, 1509-1521; (i) Cobb, A.J.A.; Longbottom, D.A.;
Shaw, D.M.; Ley, S.V. 5-Pyrrolidin-2-yltetrazole as an asymmetric
organocatalyst for the addition of ketones to nitro- olefins. Chem.
Commun., 2004, 16, 1808-1809; (j) Wang, W.; Wang, J.; Li, H.
Direct, highly enantioselective pyrrolidine sulfonamide catalyzed
michael addition of aldehydes to nitrostyrenes. Angew. Chem. Int.
Ed., 2005, 44(9), 1369-1371; (k) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Diphenylprolinol silyl ethers as efficient
organocatalyst for the asymmetric michael reaction of aldehydes
and nitroalkenes. Angew. Chem. Int. Ed., 2005, 44(27), 4212-4215;
(l) Terakado, D.; Takano, M.; Oriyama, T. Highly enantioselective
(s)-homoproline- catalyzed michael addition reactions of ketones to
ꢁ-nitostyrenes. Chem. Lett., 2005, 34(7), 962-963; (m) Xu, Y.;
supported (ils) (s)-pyrrolidine sulfonamide,
a
recyclable
organocatalyst for the highly enantioselective michael addition to
nitroolefins. Org. Lett. 2009, 11(4), 1037-1040; (j) Wu, L.-Y.; Yan,
Z.-Y.; Xie, Y.-X.; Niu, Y.-N.; Liang, Y.-M. Ionic-Liquid-supported
organocatalyst for the enantioselective michael addition of ketones
to nitroolefins. Tetradedron Asymmetry, 2007, 18(17), 2086-2090;
(k) Lombardo, M.; Chiarucci, M.; Quintavalla, A.; Trombini, C.
Highly Efficient ion-tagged catalyst for the enantioselective
michael addition of aldehydes to nitroalkenes. Adv. Synth. Catal.,
2009, 351(17), 2801-2806. Using other recyclable organocatalyst,
see: (l) Zheng, Z.; Perkins, B.; Ni, B. diarylprolinol silyl ether salts
as new, efficient, water-soluble, and recyclable organocatalysts for
the asymmetric michael addition on water. J. Am. Chem. Soc.,
2010, 132(1), 50-51.
[7]
For selected reviews, see: (a) Winkel, A.; Reddy, P.V.G.; Wilhelm,
R. Recent advances in the synthesis and application of chiral ionic

Ionic Liquid-Supported (ILS) (S)-Pyrrolidine Sulfonamide
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
175
liquid. Synthesis, 2008, 7, 999-1016; (b) María, P.D. Nonsolvent
applications of ionic liquids in biotransformation and
organocatalysis. Angew. Chem. Int. Ed., 2008, 47(37), 6960-6968;
(c) Toma, ꢀ.; Meꢁiarová, M.; ꢀebsta, R. Are ionic liquids suitable
media for organocatalytic reactions? Eur. J. Org. Chem., 2009, 3,
321-327; (d) Miao, W.; Chan, T.H. Ionic-liquid-supported
synthesis: a novel liquid-phase strategy for organic synthesis. Acc.
Chem. Res., 2006, 39(12), 897-908; (e) Headley, A.D.; Ni, B.
Chiral immidazolium ionic liquids: their synthesis and influence on
the outcome of organic reactions. Aldrichimica Acta, 2007, 40(4),
107-117; (f) Ni, B.; Headley, A.D. Ionic-Liquid-supported (ILS)
Catalysts for asymmetric organic synthesis. Chem. Eur. J., 2010,
16(15), 4426-4436.
4a [4k]. To a solution of catalyst 1c (7 mg, 0.02 mmol, 0.1 equiv)
in i-PrOH (0.5 mL) was added propionaldehyde (23 mg, 0.4
mmol). After stirring for 10 min at room temperature, trans-ß-
nitrostyrene (30 mg, 0.2 mmol) was added and the reaction mixture
was continued to stirring for 4 h. the reaction mixture was
concentrated in vacuum and the residue was diluted with ethyl
acetate (or ether) to precipitate the catalyst. The organic layer was
separated and purified by flash silica gel column (eluent: hexane :
ethyl acetate = 9 : 1) to give the Michael adduct 4a (39 mg, 95%)
1
as a colorless oil. H NMR (400 MHz, CDCl3) ꢂ 9.72 (d, J = 1.6
Hz, 1H), 7.40-7.12 (m, 5H), 4.83-4.64 (m, 2H), 3.87-3.77 (m, 1H),
2.86-2.73 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H); syn/anti: 81/19; ee =
38%. HPLC (Chiralcel OD-H, i-propanol/hexane = 9:91, flow rate
1 mL/min, ꢀ = 237 nm): tminor = 24.7 min, tmajor = 35.8 min.
[8]
Typical experimental procedure for Michael addition of aldehydes
to nitroolefins. Synthesis of (R)-2,2-Dimethyl-4-nitrophenylbutanal