Stereoselective michael addition of carbonyl compounds to (E)-β-nitrostyrene catalysed by N-toluensulfonyl-l-proline amide in ionic liquids

Article abstract of DOI:10.1007/s00706-007-0732-0

N-Toluensulfonyl-l-prolin amide was tested as catalyst in the enantioselective Michael addition of carbonyl compounds to (E)-β- nitrostyrene in nine ionic liquids under different reaction conditions. The reaction rates and enantioselectivities were strong

Full text of DOI:10.1007/s00706-007-0732-0

Monatshefte f u¨ r Chemie 138, 1181–1186 (2007)
DOI 10.1007/s00706-007-0732-0
Printed in The Netherlands
Stereoselective Michael Addition of Carbonyl Compounds
to (E)-b-Nitrostyrene Catalysed by N-Toluensulfonyl-L-proline
Amide in Ionic Liquids
M a´ ria Me cˇ iarov a´ 1 , Katar ´ı na Hubinsk a´ , Stefan Toma , Burkhard Koch , and Albrecht Berkessel
;ꢀ
1 ˇ
1
2
2
1
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic
2
Institut f u¨ r Organische Chemie der Universit a¨ t zu K o¨ ln, K o¨ ln, Germany
Received May 2, 2007; accepted May 24, 2007; published online August 27, 2007
#
Springer-Verlag 2007
Summary. N-Toluensulfonyl-L-prolin amide was tested as
catalyst in the enantioselective Michael addition of carbonyl
compounds to (E)-ꢀ-nitrostyrene in nine ionic liquids under
different reaction conditions. The reaction rates and enan-
tioselectivities were strongly dependent on the ionic liquids.
Change of enantioselectivity was observed too and it is attrib-
uted to both the cation and the anion of ionic liquid. The best
yields (up to 98%) and enantioselectivity (70% ee) of product
lective Diels-Alder reactions, 1,3-dipolar cycloaddi-
tions, epoxidations, cyclopropanations, etc. [1].
L-Proline is a very attractive and useful organo-
catalyst. It is nontoxic, inexpensive, no stringent
to special reaction conditions (temperature, inert
atmosphere . . .), and it is available in both enantiomer-
ic forms. On the other hand, fine-tuning of its catalytic
properties by derivatization is difficult. N-Sulfonyla-
tion of proline amide has resulted in an organocatalyst
having comparable NH acidity as L-proline. The ad-
vantage of such a sulfonamide catalyst is the possibil-
ity of electronic and steric fine-tuning of the catalyst
by variation of substituents on the aryl residue [2].
N-Arylsulfonyl derivatives of L-proline amide
have been applied to enantioselective aldol reactions
of aromatic aldehydes with acetone in DMSO. Com-
pared to L-proline, the enantioselectivity was im-
proved while maintaining high activity at low
catalyst loadings [2]. Both the chemical yields and
the enantioselectivities of the aldol reactions cata-
lysed by N-toluenesulfonyl-L-proline amide in 1-bu-
tyl-3-methylimidazolium hexafluorophosphate and
were obtained in a basic ionic liquid [bmim]BF at room
4
temperature.
Keywords. Ionic liquids; Michael addition; Enantioselecti-
vity; Organocatalysis.
Introduction
The asymmetric transformations of carbonyl com-
pounds by chiral amines as are ꢁ-amino acids, espe-
cially L-proline and its derivatives as organocatalysts
are well known. The crucial intermediate is an en-
amine formed from the ketone. Enamine catalysis has
been applied to both intramolecular and intermo-
lecular aldol reactions, Mannich reactions, addition
to azodicarboxylates as well as to nitrosobenzene,
Michael additions, ꢁ-alkylations of aldehydes, etc.
Using the MacMillan’s chiral amines as the organo-
catalysts the crucial intermediate is an minimum salt.
Such catalysis has been used for highly enantiose-
1-butyl-1-methylpyrrolidinium tris(pentafluoroethyl)
trifluorophosphate ionic liquids were comparable to
those in DMSO. The undoubted advantage is that the
ionic liquid containing the catalyst is recyclable and
the chemical yield as well as the enantiopurity of the
product remained at a comparable level as in the
case of fresh catalyst [3].
ꢀ Corresponding author. E-mail: mmeciarova@fns.uniba.sk

1
182
M. Me cˇ iarov a´ et al.
Michael addition of carbonyl compounds to (E)-
-nitrostyrene catalysed by chiral amines in classical
organic solvents are well known [4–10]. Additions
have been performed with high diastereoselectivity
Since the addition of 3-methylbutanal (2) to (E)-
ꢀ-nitrostyrene (1) in IL4 was sluggish and after five
day reaction at room temperature we isolated only
40% of the product 3, we tried to improve the reac-
tion course by increasing the reaction temperature.
ꢀ
(
syn=anti up to 95=5), but with very different enan-
ꢁ
tioselectivity (20–99% ee). Stereoselectivity of the
additions was strongly dependent on the catalyst as
well as on the solvent. The best results have been
obtained with polar nonprotic solvents, such as DMF
and NMP [9].
Michael additions of different carbonyl com-
pounds to (E)-ꢀ-nitrostyrene and 2-(ꢀ-nitrovinyl)-
thiophene catalysed by various organocatalysts in
ionic liquids were described for the first time by
Kotrusz et al. [11]. The ionic liquids were shown
to be good solvents for additions of various donors
to (ꢀ-nitrovinyl)arenes. L-Proline was found to be
the best among seven catalysts tested. Just 5 mol%
of this catalyst were necessary to reach reasonable
to high yields. Aldehydes proved to be much better
donors than ketones.
The good solubility of L-proline in ionic liquids
could be likely the reason for better enantioselectiv-
ity than that obtained in classical organic solvents.
The catalytic activity of L-proline was strongly depen-
dent on the nature of the ionic liquids. The structure
of ionic liquids influenced the yield and selectivity
of the process [12].
The main aim of this work was to examine the
course of the Michael addition of carbonyl com-
pounds to (E)-ꢀ-nitrostyrene catalysed by N-toluene-
sulfonyl-L-proline amide in various ionic liquids.
Reaction performed at 60 C gave after 1 day 44% of
3 and the enantioselectivity did not change (Entries 1
and 2). This observation is in accordance with those
observed at organocatalytic enantioselective aziridi-
nation of ꢁ,ꢀ-unsaturated aldehydes [13] and asym-
metric ꢁ-aminomethylation of cyclohexanones [14],
which were thermally accelerated, but the enantio-
selectivity did not drop.
Increasing the Michael donor amount from 1.5
equiv. to 5 equiv. resulted in slight rate enhancement,
but the enantioselectivity dropped from 32 to 20%
ee (Entry 3).
The beneficial effect of water addition in proline-
catalyzed aldol reactions is well known. Water might
help to increase the solubility of the catalyst in reaction
media and it might also assist in the hydrolysis of the
oxazolidinones that might be forming from carbonyl
compounds and catalyst [15]. Addition of 5 equiv. of
water to the reaction mixture of 1 and 2 in IL4 accel-
erated the reaction. We isolated 64% of 3 after 2 days
instead of 40% after 5 days, when the reaction pro-
ceeded without water. On the other hand the enantio-
selectivity dropped from 32 to 18% ee (Entry 4).
Increasing the amount of water to 10 equiv. resulted
in further acceleration, 83% of 3 was isolated after one
day reaction. The enantioselectivity slightly increased
to 24% ee (Entry 5). Addition of 20 equiv. water slo-
wed down the reaction rate as well as the enantiose-
lectivity. The product 3 was isolated after 2 days in
Results and Discussion
41% yield with 12% ee (Entry 7). This observation
We started our work with a study of Michael addition
of 3-methylbutanal (2) to (E)-ꢀ-nitrostyrene (1) ca-
talysed by N-toluenesulfonyl-L-proline amide (Fig. 1)
was probably due to formation of a two-phase reaction
system after addition of 20 equiv. of water.
Organocatalysts in ionic liquids can be reused in
several reaction cycles without significant changes
of the reaction course [11]. Therefore we tried to
(5 mol%) in IL4 under different reaction conditions
(Scheme 1). The results are given in Table 1.
Scheme 1

Stereoselective Michael Addition
1183
Table 1. Results of Michael addition of 2 to 1 catalysed by N-
toluenesulfonyl-L-proline amide in IL4 under different reac-
tion conditions
c
Yield =
d
ee =
Entry
Water=
eq.
Time=
days
Temp.=
ꢁ
e
% ( )
C
%
Fig. 1. Structure of the catalyst N-toluenesulfonyl-L-pro-
line amide
1
2
3
4
5
6
7
0
0
0
5
10
5
1
4
2
1
1
2
20
60
20
20
20
20
20
40
44
65
64
83
70
41
32 (ꢂ)
34 (ꢂ)
20 (ꢂ)
18 (ꢂ)
24 (ꢂ)
24 (ꢂ)
12 (ꢂ)
a
perform the addition of 3-methylbutanal (2) to
(
E)-ꢀ-nitrostyrene (1) in the recycled catalyst in
IL4 with 10 equiv. of water (Entry 6). Yield of 3
obtained in the recycled IL-water-catalyst reaction
system dropped from 83% to 70%, while the en-
antioselectivity remained unchanged (24%).
It has been described [9] that the stereoselectivity
of additions of ketones to (E)-ꢀ-nitrostyrene cata-
lyzed by 1,2-amino-alcohol-derived prolineamides
were strongly dependent on the solvent. The cata-
lysts exhibited the highest activity in polar aprotic
solvents such as DMF and NMP. These literature
data inspired us to study the Michael addition of
b
10
20
a
Reaction was performed with 5 equiv. 2
b
c
1
d
e
Reaction was performed in recycled IL-catalyst system
dr (syn=anti) values (90=10–95=5) were determined using
H NMR spectra
ee values were determined by HPLC
Sign of optical rotation
Ionic liquids are known to be not only solvents, but
3-methylbutanal to (E)-ꢀ-nitrostyrene catalysed by
N-toluenesulfonyl-L-proline amide in various ionic
liquids (Fig. 2).
they can play also a role as catalyst. Many reactions
in acidic and basic ionic liquids as reaction media
with catalytic activity have been described [16]. Such
Fig. 2. Structures of ionic liquids

1
184
M. Me cˇ iarov a´ et al.
Table 2. Results of Michael addition of 2 to 1 in various ionic liquids under different conditions
a
Yield =%
b
ee =% ( )
c
IL
pH IL
Water=eq.
Catalyst=mol%
Time=days
ꢁ
IL1
1.58 (22.8 C)
0
5
5
7
7
traces
traces
–
–
1
0
ꢁ
IL2
IL3
IL4
IL5
IL6
2.58 (23.2 C)
0
0
0
5
5
15
6
6
6
traces
50
68
–
1
18 (ꢂ)
d
36 (ꢂ)
ꢁ
3.09 (22.9 C)
0
0
0
5
5
15
7
5
6
traces
38
62
–
1
1
1
1
20 (ꢂ)
36 (ꢂ)
ꢁ
4.33 (22.2 C)
0
0
0
5
5
15
5
1
2
40
83
80
32 (ꢂ)
42 (ꢂ)
38 (ꢂ)
ꢁ
7.01 (22.7 C)
0
0
0
5
5
15
1
1
1
traces
95
92
–
28 (þ)
30 (þ)
ꢁ
7.09 (23.1 C)
0
0
0
5
5
15
2
1
2
94
89
96
34 (þ)
20 (þ)
42 (þ)
ꢁ
IL7
IL8
7.09 (23.1 C)
ꢁ
0
15
1
98
28 (þ)
18 (þ)
7.89 (22.8 C)
0
0
0
5
5
15
2
1
1
95
86
98
e
1
1
30 (þ)
42 (þ)
ꢁ
IL9
8.32 (22.8 C)
0
0
5
5
1
1
98
98
32 (þ)
70 (þ)
a
1
dr (syn=anti) values (90=10–95=5) were determined using H NMR spectra
ee values were determined by HPLC
Sign of optical rotation
b
c
d
e
3
ꢂ1
ꢂ1
[
[
ꢁ] ¼ ꢂ15.2 cm g dm (c ¼ 0.77, CHCl , ee ¼ 36%)
ꢂ1 ꢂ1
D 3
D
3
3
ꢁ] ¼ þ16.5 cm g dm (c ¼ 0.77, CHCl , ee ¼ 30%)
ionic liquids usually have a basic or acidic function
attached to the alkyl chain. Some non-functionalized
ionic liquids are claimed to be acidic or basic, but no
pH values for them are available. We decided there-
fore to estimate the pH values of ionic liquids used in
this paper (IL1–IL7) as from their 10 vol% solution
in water. From the data given in Table 2 it is possible
to see that the pH values of used ionic liquids varied
under these conditions from 1.58 to 8.32.
and IL3 (pH 3.09) reaction did not proceed using
5 mol% of the catalyst without water. Addition of
10 equiv. of water improved the reaction course
and 50% (IL2) or 38% (IL3) of the product 3 were
isolated. Performing the reaction with 15 mol% of
the catalyst improved the chemical yield to 50% in
IL2 and to 62% in IL3. The enantioselectivity in-
creased to 36% for both IL2 and IL3.
Reaction in IL4 (pH 4.33) with 5 mol% of catalyst
without water gave after 5 days 40% of the product 3
with 32% ee. Addition of water enhanced the rate,
yield, and enantioselectivity. Product 3 was isolated
in 83% yield with 42% ee after 1 day at room tem-
perature. Very similar results were obtained when
the addition of 2 to 1 was performed with 15 mol%
of the catalyst for 2 days. Product 3 was isolated in
80% yield with 38% ee. A positive effect of water on
the addition of 2 to 1 was observed also in the neutral
IL5 (pH 7.01). When the reaction was performed for
1 day with 5 mol% of the catalyst with 10 equiv. of
The diastereoselectivities of all reactions described
in this work have been very high. For the syn=anti
ratio values of 90=10–95=5 were achieved.
Results of Michael addition of 3-methylbutanal to
E)-ꢀ-nitrostyrene catalysed by N-toluenesulfonyl-L-
(
proline amide in various ionic liquids are given in
Table 2. Michael addition of 2 to 1 did not proceed
in acidic IL1 (pH 1.58) not even after addition of 10
equiv. water to the reaction mixture. Only traces of
the product 3 were detected in the reaction mixture
(TLC) after 7 days. In ionic liquids IL2 (pH 2.58)

Stereoselective Michael Addition
1185
Scheme 2
water, we obtained 3 in 95% yield with 28% ee. The
same results were achieved when the reaction was
performed with 15mol% of the catalyst without wa-
ter. On the other hand, the reaction did not proceed
with 5 mol% of the catalyst, but without water.
observed reversal of enantioselectivity of Michael ad-
dition of dimethyl malonate to chalkone in [bmim]PF6,
[bmim]BF (ꢂ), and [bpy]BF (þ). According to this
4
4
study, the reversal of the enantioselectivity might be
attributed to the cation associated with the anion of the
ionic liquid.
Reaction rate as well as enantioselectivity of the
addition of 2 to 1 catalysed by N-toluenesulfonyl-L-
proline amide were the best in basic ionic liquids.
Very similar results were achieved in IL6 (pH 7.09)
and IL8 (pH 7.89). Using 5 mol% of the catalyst
without water we obtained product 3 after 2 days
in 94% yield with 34% ee (IL6) and 95% yield
with 18% ee (IL8), respectively. Addition of water
decreased the enantioselectivity in IL6 from 34
to 20% ee and on the other hand, increased the
enantioselectivity in IL8 from 18 to 30% ee. Enan-
tioselectivity of the process increased to 42% (IL6)
and 48% (IL8), respectively, when 15 mol% of the
catalyst were used in the reaction. Quantitative yield
of 3 with 28% ee was obtained in IL7 (pH 7.09)
when the addition was performed with 15 mol%
of the catalyst. The highest enantioselectivity was
achieved when the studied reaction was performed
in IL9 (pH 8.32). Addition of water to the reaction
mixture improved the enantioselectivity to 70%.
Without water we obtained the product 3 with only
We also studied the Michael addition of cyclohex-
anone (4) to (E)-ꢀ-nitrostyrene (1) in three different
ionic liquids with 10 equiv. of water (Scheme 2). As
it follows from Table 3 the reactions proceeded
with moderate yields. The reaction rate was lower
in acidic ionic liquid IL4 (pH 4.33) than in IL6
(pH 7.09) and IL8 (pH 7.89). On the other hand,
the highest enantioselectivity was observed in IL4.
Product 3 was isolated from IL4 after 2 days in
44% yield with 60% ee. The best yield (63%) was
achieved in IL8, but only 16% ee was determined.
Product 3 was isolated after 1 day from IL6 in 53%
yield, but no enantioselectivity was observed.
In contrast to addition of 3-methylbutanal, Michael
0
addition of 4 to 1 gave (2S,1 R)-(ꢂ)-2-(1-phenyl-2-
nitroethyl)cyclohexanone as the major enantiomer
both in acidic and basic ionic liquids.
Michael addition of different carbonyl compounds
to (E)-ꢀ-nitrostyrene catalysed by N-arylsulfonyl-L-
proline amide in ionic liquids is under investigation
3
2% ee.
From the results given in Table 2 it follows,
Table 3. Results of Michael addition of 4 to 1 catalysed by
5 mol% of N-toluenesulfonyl-L-proline amide in various ionic
liquids with 10 equiv. of water
that ionic liquids play an active role in organocata-
lyzed Michael addition of 2 to 1. Very different re-
action rates and yields were achieved in various
ionic liquids, but interestingly the enantioselectivity
was reversed in the reactions in acidic and neutral
and basic ionic liquids. While (2R,3S)-(þ)-2-isopro-
pyl-4-nitro-3-phenylbutanal was the major enantio-
mer isolated from neutral and basic ionic liquids,
a
b
c
Time=days Yield =% ee =% ( )
IL
pH IL
ꢁ
ꢁ
ꢁ
IL4 4.33 (22.2 C)
IL6 7.09 (22.8 C)
2
1
1
44
53
63
60 (ꢂ)
2 (n.d.)
16 (ꢂ)
IL8 7.89 (22.8 C)
a
dr (syn=anti) values (90=10–95=5) were determined using
H NMR spectra
ee values were determined by HPLC
Sign of optical rotation
(2S,3R)-(ꢂ)-2-isopropyl-4-nitro-3-phenylbutanal was
1
b
c
isolated as the mayor enantiomer from acidic ionic
liquids. Similar results described Dere et al. [17]. They

1
186
M. Me cˇ iarov a´ et al.: Stereoselective Michael Addition
0
in our laboratory. The change of the stereoselec-
tivity by acidity of the ionic liquids will be scruti-
nized also.
(2S,1 R)-(ꢂ)-2-(1-Phenyl-2-nitroethyl)cyclohexanone (5)
1
H NMR data were found to be identical with the data
ꢂ1
3
ꢂ1
3
described in Ref. [19]. [ꢁ] ¼ ꢂ12.5cm g dm (c ¼ 0.77,
D
ꢂ1
ꢂ1
CHCl , ee¼ 60%) (Ref. [19] [ꢁ] ¼ þ26.8cm g dm
3
D
(
c ¼ 1, CHCl )) Retention time of the major enantiomer was
3
Experimental
9.5 min, retention time of the minor enantiomer was 8.2min
HPLC, Daicel Chiralpac AD-H, n-hexane=iPrOH 70=30,
(
0
Starting materials, that is (E)-ꢀ-nitrostyrene and carbonyl
compounds were commercially available (Aldrich, Fluka,
Acros) and purified by standard methods. Ionic liquids were
obtained from Merck (IL2, IL6, IL7, IL9) and Solvent
Innovation (IL1, IL3, IL4, IL5, IL8). The catalyst N-toluene-
sulfonyl-L-proline amide was prepared according to the pro-
cedure described in Ref. [2]. Column chromatography was
performed on Merck silica gel 65=40. Thin-layer chromatog-
3
.75cm =min, 3.8 MPa).
Acknowledgements
NMR measurements were performed on the equipment
supported by the Slovak State Program Project No.
2003SP200280203. Our thanks are due to Slovak Grant
Agency VEGA (grant No. 1=3569=06) for the financial
support.
raphy was performed on Merck TLC-plates silica gel 60, F-
1
54. H NMR spectra were recorded at 300 MHz on a Varian
2
Gemini spectrometer in CDCl with TMS as an internal stan-
3
dard. The pH of ionic liquids (10% aq. solutions) were mea-
sured on a WTW inoLab pH 720 instrument using a SenTix 81
electrode. Optical rotations were measured on a Perkin-Elmer
References
2
41 instrument. Enantiomeric excesses were determined by
[
[
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1
141
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N-Toluenesulfonyl-L-proline amide catalyst (40.25 mg,
5
liquid. In some cases, water (5–20 equiv.) was added to the
ionic liquids. This mixture was stirred at room temperature for
2
[
[
[
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[
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[
[
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5ꢃ3 cm ether. The combined organic extracts were concen-
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2
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1
H NMR data were found to be identical with the data
ꢂ1
3
ꢂ1
ꢂ1
described in Ref. [5]. [ꢁ] ¼ þ16.5cm g dm (c ¼ 0.77,
D
3
ꢂ1
CHCl , ee¼ 30%) (Ref. [18] [ꢁ] ¼ þ53.1 cm g dm (c ¼
3
D
0
antiomer was 7.0 min (HPLC, Daicel Chiralpac AD-H, n-
.77, CHCl , ee ¼ 99% ) Retention time of the major en-
3
3
hexane=iPrOH 70=30, 0.75cm =min, 3.8 MPa).
[
6
(
2S,3R)-(ꢂ)-2-Isopropyl-4-nitro-3-phenylbutanal (3)
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T, Simsom T, Seebach D (1993) Synthesis 1271
1
H NMR data were found to be identical with the data
ꢂ1
3
ꢂ1
described in Ref. [5]. [ꢁ] ¼ ꢂ15.2cm g dm (c ¼ 0.77,
D
CHCl , ee¼ 36%). Retention time of the major enantiomer
3
was 7.5 min (HPLC, Daicel Chiralpac AD-H, n-hexane=
iPrOH 70=30, 0.75cm =min, 3.8 MPa).
3