Ionic liquid-supported (ILS) (S)-pyrrolidine sulfonamide, a recyclable organocatalyst for the highly enantioselective Michael addition to nitroolefins

Article abstract of DOI:10.1021/ol900003e

A new class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst has been developed and shown to be a very effective catalyst for the asymmetric Michael addition reactions of ketones and aldehyde to nitroolefins with high enantio- an

Full text of DOI:10.1021/ol900003e

ORGANIC
LETTERS
2009
Vol. 11, No. 4
1037-1040
Ionic Liquid-Supported (ILS)
(S)-Pyrrolidine Sulfonamide, a
Recyclable Organocatalyst for the
Highly Enantioselective Michael Addition
to Nitroolefins
Bukuo Ni,* Qianying Zhang, Kritanjali Dhungana, and Allan D. Headley*
Department of Chemistry, Texas A&M UniVersity-Commerce, Commerce, Texas
75429-3011
bukuo_ni@tamu-commerce.edu; allan_headley@tamu-commerce.edu
Received January 1, 2009
ABSTRACT
A new class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst has been developed and shown to be a very effective
catalyst for the asymmetric Michael addition reactions of ketones and aldehyde to nitroolefins with high enantio- and diastereoselectivities.
This ILS organocatalyst is also easily recycled and could be reused at least five times without significant loss of its ability to affect the
outcome of the asymmetric reactions.
Over the past few years, there has been a tremendous increase
in research activities on the development of organocatalysts
for asymmetric carbon-carbon bond-forming reactions,1
especially for the Michael addition reaction.2 The conjugate
addition of ketones to nitroolefins is of particular importance
since it represents an efficient method for the preparation of
γ-nitrocarbonyl compounds with two contiguous stereo-
centers in a single step. These compounds are versatile
synthetic building blocks since the nitro and carbonyl groups
can be transformed easily into other useful functional
groups.3 As a result, much effort has been devoted toward
developing efficient asymmetric catalysts, especially envi-
ronmentally friendly organocatalysts that are also metal-free
for these and similar asymmetric reactions. Proline and its
pyrrolidine-based derivatives have been investigated and
shown to be effective asymmetric catalysts for the Michael
addition of aldehydes and ketones to nitroolefins;4-6 how-
ever, these organocatalysts still have some drawbacks in that
(1) For reviews, see: (a) Dalko, P. L.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719. (c) Berkessel, A.; Groger, H. Asymmetric Organocatalysis-From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH
Verlag GmbH & Co. KGaA: Weihei, Germany, 2005. (d) Special Issue on
Asymmetric Organocatalysis. Acc. Chem. Res. 2004, 37, 487.
(2) For reviews, see: (a) Sulzer-Mosse, S.; Alexakis, A. Chem. Comm.
2007, 30, 3123. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481.
(3) For recent reviews, see: (a) Krause, N.; Hoffmann-Roder, A.
Synthesis 2001, 171. (b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. (d) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688.
(4) Proline-catalyzed Michael addition reactions see: (a) Hanessian, S.;
Pham, V. Org. Lett. 2000, 2, 2975. (b) List, B.; Pojarliev, P.; Martin, H. J.
Org. Lett. 2001, 3, 2423. (c) Enders, D.; Seki, A. Synlett 2002, 26. (d) Chi,
Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (e) Mosse´, S.; Alexakis, A.
Org. Lett. 2005, 7, 4361. (f) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V.
Synlett 2005, 611. (g) Planas, L.; Perand-Viret, J.; Royer, J. Tetrahedron:
Asymmetry 2004, 15, 2399. (h) Betancort, J. M.; Sakthivel, K.; Thayumana-
van, R.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441. (i) Betancort,
J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737
.
10.1021/ol900003e CCC: $40.75
Published on Web 01/29/2009
2009 American Chemical Society

high catalyst loading (10-30 mol %) is typically required,
which will raise the cost and limit its application in the
pharmaceutical industry. In addition, low temperature and a
large excess of ketone (normally 10-20 equiv) are also
generally required to achieve good enantioselection.7 There-
fore, the design and development of highly active organo-
catalysts aimed at overcoming these limitations have proven
to be a significant challenging task and limited success has
only been achieved quite recently.8,9
One aspect of our research is aimed at the development
of recyclable ionic liquid supported (ILS) organocatalysts
for asymmetric organic reactions, and we have recently
shown that imidazolium ILS pyrrolidine sulfonamides 1a-b
(Figure 1) serve as recyclable catalysts for Michael addition
is more electronegative than C-4 or C-5; in addition, the
imidazolium cation which serves as an electron-withdrawing
group will result in a fairly acidic N-H. The increased
acidity will result in stronger hydrogen bonds that are formed
in the transition states of these reactions. We believe that
such modifications, even though slight, will result in dramatic
enhancement of the catalytic activity and selectivity and will
avoid the need for an acidic additive. Also, this substitution
of imidazolium cation introduces more steric bulk closer to
the catalytic site and may improve the stereoselectivity.
Herein, we report the synthesis of this new and novel
organocatalyst, 1c (Scheme 1) and the results of the studies
Scheme 1
.
Synthesis of ILS (S)-Pyrrolidine Sulfonamide
Organocatalyst 1c
Figure 1. ILS (S)-pyrrolidine sulfonamide organocatalysts.
of aldehydes with nitroolefins;8a,b these ILS catalysts,
however, resulted in moderate reaction rate when cyclohex-
anone was used as the substrate (see Table 1, entries 6-8).
using 1c as a recyclable organocatalyst to promote highly
enantio- and diastereoselective Michael addition reactions
of ketones and aldehyde to nitroolefins.
Table 1. Optimization of the Reaction Conditionsa
(5) For selected reports of pyrrolidine-based organocatalysts, see: (a)
Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004,
126, 9558. (b) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III
Org. Lett. 2004, 6, 2527. (c) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Tanaka, F.; Barbas, C. F., III Synthesis 2004, 1509. (d) Alexakis, A.;
Andrey, O. Org. Lett. 2002, 4, 3611. (e) Andrey, O.; Alexakis, A.;
Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147. (f)
Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem.
Commun. 2004, 1808. (g) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.;
Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (h) Reyes, E.;
Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett. 2006, 8, 6135. (i) Cao,
C-L.; Ye, M-C.; Sun, X-L.; Tang, Y. Org. Lett. 2006, 8, 2901. (j) Wang,
W.; Wang, J.; Li, H. Angew. Chem. Int. Ed. 2005, 44, 1369. (k) Wang, J.;
Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.-Eur. J. 2006, 12, 4321.
(l) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624. (m)
Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F.,
III J. Am. Chem. Soc. 2006, 128, 4966. (n) Vishnumaya; Singh, V. K. Org.
Lett. 2007, 9, 1117. (o) Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron:
Asymmetry 2007, 18, 1443. (p) Xu, D.-Q.; Wang, L.-P.; Luo, S.-P.; Wang,
Y.-F.; Zhang, S.; Xu, Z.-Y. Eur. J. Org. Chem. 2008, 1049.
yieldb eec
entry catalyst
solvent
MeOH
i-PrOH
CH3CN
neat
[BMIM][PF6]
CH3CN
i-PrOH
MeOH
time (h)
(%)
(%) syn/antid
1
1c
1c
1c
1c
1c
1a
1a
1b
19
16
17
14
17
144
120
144
95
91
81
92
<10
38
73
90
86
95/5
95/5
95/5
2
3
4
85
99/1
5e
6g
7g
f
f
88
95/5
f
f
<10
40
8g h
90
94/6
,
(6) For selected other organocatalytic Michael addition reactions, see:
(a) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
8331. (b) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 4955. (c) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem.
2003, 68, 4151. (e) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 1272. (f) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2001, 123, 4370. (g) Li, H.; Wang, Y.; Tang, L.; Deng,
L. J. Am. Chem. Soc. 2004, 126, 9906. (h) Okino, T.; Hoashi, Y.; Takemoto,
Y. J. Am. Chem. Soc. 2003, 125, 12672.
a Ketone (5 equiv) was used. b Isolated yield. c Determined by chiral
HPLC. d Determined by 1H NMR. e [BMIM][PF6] ) 1-Butyl-3-methyl
imidazolium hexafluorophosphate. f Not determined. g Catalyst (20 mol %)
was used. h Trifluoroacetic acid (5 mol %) was used.
For Michael addition reactions involving sulfonamide orga-
nocatalysts of this type, it is believed that the acidic N-H
hydrogen plays an important role in the stabilization of the
transition state via hydrogen bonding.5k,8a,b Based on this
knowledge, we have designed a new type of ILS pyrrolidine
sulfonamide organocatalyst based on subtle structural modi-
fications to catalysts 1a and 1b in order to increase the N-H
acidity. This new design is based on introducing the sulfonyl
group into the C-2 position of the imidazolium cation, which
(7) Only the diamine- and triamine-protonic acid catalysts (ref 5l using
5 equiv of ketone and ref 5m using 2 equiv of ketone) provide good ee for
a few substrates at room temperature.
(8) For examples reported recyclable organocatalysts for Michael
addition reactions using ionic liquid as support, see: (a) Ni, B.; Zhang, Q.;
Headley, A. D. Green Chem. 2007, 9, 737. (b) Zhang, Q.; Ni, B.; Headley,
A. D. Tetrahedron 2008, 64, 5091. (c) Ni, B.; Zhang, Q.; Headley, A. D.
Tetrahedron Lett. 2008, 49, 1249. (d) Wu, L.-Y.; Yan, Z.-Y.; Xie, Y.-X.;
Niu, Y.-N.; Liang, Y.-M. Tetradedron: Asymmetry 2007, 18, 2086. (e) Luo,
S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed.
2006, 45, 3093.
1038
Org. Lett., Vol. 11, No. 4, 2009

Catalyst 1c was readily prepared from 1-methyl-2- sufonyl
chloride imidazole and (S)-2-amino-1-N-Boc-pyrrolidine in
three steps with 82% overall yield (Scheme 1).
we next investigated the scope of the Michael reaction for
which catalyst 1c is effective with a series of ketones and
nitroolefins in i-PrOH as the solvent, and the results are
shown in Table 2. From these results, it is obvious that all
6-membered ring ketones can efficiently undergo Michael
reactions with different aryl-substituted nitroolefins in the
presence of 10 mol % of catalyst 1c in i-PrOH at room
Initially, the Michael reaction of cyclohexanone and trans-
ꢀ-nitrostyrene in various solvents was examined at room
temperature using ILS pyrrolidine sulfonamide 1a-c as
organocatalysts. As shown in Table 1, the catalyst 1c
displayed excellent catalytic efficiency in protic solvent
MeOH at room temperature for 19 h, affording Michael
adduct 4a in 95% yield with moderate enantioselectivity
(73% ee) and high diastereoselectivity (syn/anti 95/5) (Table
1, entry 1). The enantioselectivity dramatically improved
when the solvent i-PrOH was used (Table 1, entry 2). When
the reaction was carried out in CH3CN or a neat condition,
slightly decreased enantioselectivities were observed (Table
1, entries 3-4). However, using ionic liquid [BMIM][PF6]
as solvent only resulted in low yield (Table 1, entry 5).
Noteworthy, catalyst 1c exhibited superior catalytic activity,
compared to catalysts 1a-b (Table 1, entries 6-8). These
results are a strong indication that the introduction of the
sulfonyl group into the C-2 position of the electron-
withdrawing imidazolium cation enhances the acidity of the
N-H proton of catalyst 1c and thus provide a stronger
hydrogen-bonding interaction with substrate in the transition
state, which results in enhanced catalytic activity and
stereochemical control.
Table 3. Michael Reaction of Ketones to Nitroolefinsa
Next, we chose the reaction of trans-ꢀ-nitrostyrene and
cyclohexanone as the model under standard reaction condi-
tions to examine the recyclability of catalysts ILS 1c (20
mol % was used). After 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 the simple phase separation.
The catalyst was dried and reused for the next run of the
reaction. As shown in Table 2, catalyst 1c could be recycled
Table 2. Recycling Studies of ILS 1c Catalyzed Michael
Addition of Cyclohexanone to trans-ꢀ-Nitrostyrenea
cycle
time (h)
yieldb (%)
eec (%)
syn/antid
1
2
3
4
5
12
16
18
24
40
92
90
93
86
80
90
90
90
89
88
95/5
95/5
94/6
95/5
93/7
a Ketone (5 equiv) was used. b Isolated yield. c Determined by chiral
d
1
HPLC. Determined by H NMR.
and reused for at least 5 times without significant loss of
stereoselectivity (ee > 88%; syn/anti > 93/7) despite some
slight decreasing of activity observed in cycles 2-5.
Having established the standard reaction conditions for
Michael addition of cyclohexanone with trans-ꢀ-nitrostyrene,
a Ketone (5 equiv) was used. b Isolated yield. c Determined by chiral
HPLC. d Determined by 1H NMR. e Ketone (3 equiv) was used. f Not
determined.
Org. Lett., Vol. 11, No. 4, 2009
1039

temperature to give the Michael adducts 4a-j in high yields
with excellent enantio- (80-99% ee) and diastereoselectivi-
ties (syn/anti ratio up to 99/1). The results in Table 3 also
show that the nature of the substituents on aryl groups slightly
influences the yields and enatioselectivities. For nitroolefins
with electron-rich groups (methyl and methoxy), the reaction
proceeded smoothly to afford Michael adduct 4b-c in
excellent enantio- (98-99% ee) and diastereoselectivities
(syn/anti 99/1) (Table 3, entries 2-3). These results are
superior to those of the experiments by Wang and co-workers
with recyclable fluorous (S)-pyrrolidine sulfonamide catalyst
(ee: 89-91%; syn/anti 16/1-50/1).9a For nitroolefins with
electron-deficient groups, the Michael adducts 4d-g were
also obtained in high yields (87-96%) with excellent
enantio- (90-99% ee) and diastereoselectivities (syn/anti
ratio up to 99/1) (Table 3, entries 4-7). Tetrahydrothio-
pyran-4-one, tetrahydro-4H-pyran-4-one, and 2-(2-nitrovi-
nyl)furan were also suitable substrates as Michael donors
(Table 3, entries 8-10). However, when cyclopentanone was
used as substrate, only poor yield was obtained (Table 3,
entry 11). Acetone worked well to give the desired products
in good yield, but poor enantioselectivity (14% ee) (Table
3, entry 12). The Michael addition of i-butyraldehydes with
trans-ꢀ-nitrostyrene underwent smoothly under catalyst 1c
to afford an adduct containing adjacent quaternary and
tertiary carbon centers (Table 3, entry 13).
The absolute stereochemistry of major product 4a was
determined to be 2S,3R by comparing its optical rotation.5
The absolute stereochemical results can be explained by
related transition state models previous discussed for (S)-
pyrrolidine sulfonamide catalyzed Michael reactions.5k
In conclusion, we have developed a catalytic recyclable
ILS (S)-pyrrolidine sulfonamide organocatalyst 1c, which can
be used to promote highly efficient, asymmetric Michael
addition reactions of ketones and aldehyde to nitroolefins.
The main advantages of this catalyst are the ease of synthesis,
low catalyst loading (10 mol %), and the use of small excess
of ketones (3-5 equiv) for high stereoselectivities (ee up to
99%; syn/anti up to 99/1) at room temperature. Moreover,
the catalyst is readily recovered and reused for at least five
times without significant loss of catalytic activity and
stereoslectivity. Further studies focusing on the scope of this
recyclable catalyst catalyzed asymmetric transformations are
currently under investigation and will be reported in due
course.
Acknowledgment. We are grateful to the Robert A. Welch
Foundation (T-1460) for financial support of this research.
Supporting Information Available: Experimental pro-
cedures, spectral data, HPLC data, and HPLC spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) For examples reported recyclable organocatalysts for Michael
addition reactions using other support, see: (a) Zu, L.; Wang, J.; Li, H.;
Wang, W. Org. Lett. 2006, 8, 3077. (b) Alza, E.; Cambeiro, X. C.; Jimeno,
C.; Perica`s, M. A. Org. Lett. 2007, 9, 3717. (c) Zhao, Y.-B.; Zhang, L.-W.;
Wu, L.-Y.; Zhong, X.; Li, R.; Ma, J.-T. Tetradedron: Asymmetry 2008,
19, 1352. (d) Li, P.; Wang, L.; Wang, M.; Zhang, Y. Eur. J. Org. Chem.
2008, 1157.
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