Basic chiral ionic liquids: A novel strategy for acid-free organocatalysis

Article abstract of DOI:10.1016/j.cattod.2012.07.002

We present design, synthesis and application of basic chiral ionic liquids based on commercially available (S)-proline. This new set of chiral ionic liquids was specifically designed to replace trifluoroacetic acid in enamine-based organocatalysis for asy

Full text of DOI:10.1016/j.cattod.2012.07.002

Catalysis Today 200 (2013) 80–86
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Catalysis Today
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Basic chiral ionic liquids: A novel strategy for acid-free organocatalysis
Maria Vasiloiua, Daniel Rainera, Peter Gaertnera, Christian Reichelb,
Christian Schröderc, Katharina Bicaa,∗
a Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
b Seibersdorf Labor GmbH, 2444 Seibersdorf, Austria
c Institute of Computational Biological Chemistry, University of Vienna, Währingerstr. 17, A-1090 Wien, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
We present design, synthesis and application of basic chiral ionic liquids based on commercially avail-
able (S)-proline. This new set of chiral ionic liquids was specifically designed to replace trifluoroacetic
acid in enamine-based organocatalysis for asymmetric C C bond formation. Based on their permanent
charge, these chiral ionic liquids could be applied as organocatalysts in asymmetric aldol reaction of 4-
nitrobenzaldehyde and acetone, and good yields and selectivities up to 80%ee could be obtained without
additional acid.
Received 31 March 2012
Received in revised form 19 June 2012
Accepted 2 July 2012
Available online 10 August 2012
Keywords:
Ionic liquids
© 2012 Elsevier B.V. All rights reserved.
Organocatalysis
Chirality
Aldol reaction
Asymmetric synthesis
1. Introduction
areas such as chiral solvents or (organo-)catalysts [4]. Since the first
example of a chiral ionic liquids was reported in 1997 by Howarth
Enantioselective reactions catalyzed by small organic molecules
provide a unique and booming methodology in asymmetric C
et al. the number of publications dealing with chiral ionic liquids
grew rapidly, and nowadays a large pool of chiral ionic liquids bear-
ing either chiral cations, anions or seldom both and a wide variety
of functionalities is available [5]. Although the hydrogen bonded
supramolecular network inherent to the structure of chiral ionic
liquids was early identified as novel aspect for asymmetric syn-
thesis, this potential could not be immediately translated into the
development of real applications. Successful applications in asym-
metric synthesis remained limited for some time, and it took 9
years after the first chiral ionic liquid was published that a highly
enantioselective synthesis with an enantiomeric excess >90% was
reported [6]. While the original idea of chiral ionic liquids was based
on the use of novel chiral solvents it was soon realized that chiral
ionic liquids can equally serve as (liquid-phase supported-) chiral
catalysts. It was particularly the wide field of organocatalysis that
gave access to highly enantionselective reactions catalyzed by chi-
ral ionic liquids, with the special benefits of a simple recyclation of
the chiral catalyst [7]. However, while some issues in organocatal-
ysis, e.g. catalyst activity and recycling could be solved using ionic
liquid-based strategies, most chiral ionic liquids in organocatalysis
still require a substantial amount of toxic and corrosive trifluo-
roacetic acid, which raises not only environmental concerns, but
also drastically limits the reaction range to acid-stable substrates.
The replacement of trifluoroacetic acid or, in general, protonated
catalysts in organocatalysis, motivated us to develop novel basic
chiral ionic liquids that, based on its permanent charge can function
C
bond forming reactions [1]. Proline-like cyclic five-membered
secondary amine structures have been recognized as privileged
organocatalysts and can catalyze many reactions under mild condi-
tions without requiring expensive and often toxic transition metals
[2]. However, despite being readily accessible and inexpensive,
chiral amino acids and their derivatives suffer from a number of
drawbacks: Low rates and selectivities often require substantial
quantities of organocatalyst (5–30 mol%), but also highly polar sol-
vents, e.g. DMSO making work-up and catalyst recycling difficult.
Another drawback is the necessity of strongly acidic additives to
provide a protonated ammonium moiety as essential H-bonding
unit, which is characteristic for enamine-based organocatalysis
[3]. Trifluoroacetic acid or other strong acids have to be added
to observe high diastereo- and enantioselectivities, and hence the
development of new, effective catalysts is still desired.
Chiral ionic liquids have been recognized for years as an alter-
native strategy to carry out chiral transformations, especially in
∗
Corresponding author. Tel.: +43 1 58801 163601; fax: +43 1 58801 16399.
E-mail addresses: mvasiloiu@ias.tuwien.ac.at (M. Vasiloiu),
daniel.rainer@aon.at (D. Rainer), peter.gaertner@tuwien.ac.at
(P. Gaertner), christian.reichel@seibersdorf-laboratories.at (C. Reichel),
christian@mdy.unvie.ac.at (C. Schröder), kbica@ias.tuwien.ac.at (K. Bica).
0920-5861/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.cattod.2012.07.002

M. Vasiloiu et al. / Catalysis Today 200 (2013) 80–86
81
temperature the reaction mixture was diluted with H2Odest and
repeatedly extracted with diethyl ether. The combined organic
layers were washed once with brine, dried over Na2SO4 and the
solvent was removed under reduced pressure. The crude prod-
uct was purified via chromatography (CH2Cl2/MeOH) to obtain
benzyl (S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate 2
as light yellow oil. Yield: 0.42 g, 87%. Rf = 0.7 (CH2Cl2/MeOH
4:1). [␣]58920 = + 51.5 (EtOH, c = 1.03). 1H NMR (400 MHz, CDCl3):
ı = 1.69–2.00 (m, 8H), 2.41–2.62 (m, 6H), 3.40 (s, 2H), 3.96 (br s, 1H),
5.08–5.17 (m, 2H), 7.29–7.34 (m, 5H). 13C NMR (100 MHz, CDCl3):
ı = 23.5, 29.3, 46.5, 54.6, 56.7, 59.1, 66.6, 127.9, 137.0, 155.0. ATR-
IR: ꢀ = 2961, 2881, 2789, 1699, 1410, 1358, 1104, 698 cm−1. HR-MS:
m/z (calculated) = 288.1838, m/z (found) = 289.1911 (M++H).
Fig. 1. Proposed ionic liquid strategy for acid replacement based on the example of
the common organocatalyst (S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidin 1.
without additional acid. We anticipated that a protic intermediate
in organocatalysis can be replaced by a permantly alkylated species.
The incorporation of a bulky quaternary ammonium cation might
enhance chiral induction via electrophilic activation, although the
H-bonding property would be sacrificed (Fig. 1) [8,9].
2.2.2. (S)-1-Methyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
methyl sulfate 3
Compound 2 (0.85 g, 3 mmol) was dissolved in 10 ml anhydrous
CH2Cl2 under argon atmosphere. Dimethylsulfate (0.49 g, 4 mmol)
was added dropwise at 0 ◦C and the solution was stirred for 20 min
at room temperature. After complete reaction the solvent was evap-
orated under reduced pressure and the crude product was dissolved
in MeOH. Palladium on charcoal (5 wt.%) (0.3 mmol) was added,
and the solution was hydrogenated for 30 min at 4 bar in a Parr-
apparatus. Filtration over celite and evaporation of the solvent gave
(S)-1-methyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium methyl
sulfate 3 as light yellow oil. Yield: 0.58 g, 97%. [␣]58920 = +1.9
(EtOH, c = 0.53). 1H NMR (400 MHz, d3-MeOD): 1.64–1.74 (m, 1H),
1.85–2.05 (m, 2H), 2.25–2.40 (m, 5H), 3.17 (s, 2H), 3.27 (m, 1H),
3.29–3.30 (m, 1H), 3.55–3.72 (m, 10H), 3.92–3.96 (m, 1H). 13C
NMR (100 MHz, MeOD): 20.9, 21.1, 23.6, 30.6, 46.3, 47.7, 53.9, 64.6,
65.0, 65.4. ATR-IR: ꢀ = 2956, 1463, 1216, 1058, 1004, 937, 738,
659, 609 cm−1. HR-MS: m/z (M+ calculated) = 169.1699, m/z (M+
found) = 169.1694. Tg = −46 ◦C, T5%onset = 109 ◦C.
2. Experimental
2.1. General
All chemicals unless otherwise stated were purchased from
commercial suppliers and used without further purification. Anhy-
drous solvents were obtained from a Puresolv unit from It
Innovative, Inc. (S)-1-[(Pyrrolidin-2-yl)methyl]pyrrolidin 1 was
prepared from (S)-pyrogluthaminic acid or from (S)-proline follow-
ing literature methods [10]. Chromatography was done on a Büchi
SepacoreTM MPLC system with silica 60 from Merck (40–63 ␮m).
1H and 13C NMR spectra were recorded on a Bruker AC 200 at 200
and 50 MHz, resp., using the solvent peak as reference. J values are
given in Hz. 13C NMR spectra were run in proton-decoupled mode.
IR spectra were recorded against an air background with 32 scans
on a Biorad FTS 135 FT-IR spectrometer equipped with a specac
ATR-unit. High resolution mass spectroscopy was performed on a
Thermo Electron LTQ Orbitrap Hybrid Mass Spectrometer with a
Finnigan nanospray ionization (NSI) source. Optical rotation was
measured on an Anton Paar MCP500 polarimeter. Thermogravimet-
ric analysis was performed on a Netzsch TGA/DSC under helium.
Samples between 5 and 10 mg were placed in open alumina pans
and were heated from 25 ◦C to 500 ◦C with a heating rate of
10 ◦C/min. Decomposition temperatures (T5%onset) were reported
from onset to 5 wt.% mass loss. Differential scanning calorimetry
(DSC) was performed on a Netzsch TGA/DSC under helium. Sam-
ples between 5 and 10 mg were heated from 25 ◦C to 110 ◦C at a
heating rate of 10 ◦C/min followed by a 10 min isotherm. A cooling
rate of 10 ◦C/min to −100 ◦C was followed by a 10 min isotherm at
−100 ◦C, and the cycle was repeated twice.
2.2.3. (S)-1-Butyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bromide 4
Butyl bromide (0.164 g, 1.2 mmol) was added to benzyl (S)-
2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate 2 (0.288 mg,
1 mmol) and the reaction mixture was stirred for 48 h at 80 ◦C.
Remaining butyl bromide was removed under vacuum, and the
crude product was dissolved in MeOH. Palladium on charcoal
(5 wt.%) (0.1 mmol) was added, and the solution was hydrogenated
for 30 min at 4 bar in a Parr-apparatus. Filtration over celite
and evaporation of the solvent gave (S)-1-butyl-1-[(pyrrolidin-2-
yl)methyl]pyrrolidin-1-ium bromide 4 as light yellow oil. Yield:
0.283 g, 97%. [␣]58920 = +12.0 (EtOH, c = 0.98). 1H NMR (400 MHz,
CDCl3): 0.99 (t, J = 7.44 Hz, 3H), 1.45 (sext, J = 7.48 Hz, 2H), 1.92–1.48
(m, 4H), 2.20 (m, 5H), 2.98 (m, 1H), 3.10 (m, 1H), 3.58 (m,
2H), 3.66 (m, 2H), 3.81 (m, 4H), 4.17 (m, 1H), 4.46 (br s, 1H).
13C NMR (100 MHz, CDCl3): 13.67, 19.66, 21.48, 21.86, 25.03,
25.40, 31.24, 46.97, 54.09, 59, 76, 62.51, 63.30, 63.35. ATR-IR:
ꢀ = 3423, 2958, 2685, 1631, 1457, 1380, 109, 912, 617 cm−1. HR-MS:
m/z (M+ calculated) = 211.2169, m/z (found) = 211.2169. Tg = +3 ◦C,
T5%onset = 196 ◦C.
HPLC analysis was performed on a Thermo Finnigan Surveyor
chromatograph equipped with a PDA plus (190–360 nm) detector.
For analysis of 4-hydroxy-4-(4-nitrophenyl)butan-2-one 12, a Dai-
cel CHIRALPAK AS-H column was used as stationary phase with
heptane/isopropanol = 85/15 as solvent and a flow of 1 ml/min;
detection was done at 280 nm (Method A). For the determination
of 2-[1-hydroxy-1-(4-nitrophenyl)methyl]cyclohexan-1-one 13, a
Daicel CHIRALPAK IA column was used as stationary phase with
heptan/isopropanol = 80/20 as solvent and a flow of 0.5 ml/min;
detection was done at 280 nm (Method B).
2.2.4. (S)-1-Octyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bromide 5
Prepared according to Section 2.2.2 from benzyl (S)-2-
2.2. Synthesis of chiral ionic liquids
[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate
2
(0.288 g,
1 mmol) and n-octyl bromide (0.193 g, 1.2 mmol) to give chiral
ionic liquid 5 as brown solid. Yield: 0.306 g, 88%. [␣]58920 = +6.8
(EtOH, c = 1.01). 1H NMR (400 MHz, CDCl3): 0.79 (t, J = 6.84 Hz, 3H),
1.26 (m, 10H), 1.39 (m, 1H), 1.58 (m, 2H), 1.74 (m, 2H), 2.15 (m,
5H), 2.82 (m, 1H), 2.97 (m, 1H), 3.43 (m, 2H), 3.53 (m, 2H), 3.74
(m, 4H), 3.85 (br s, 1H), 4.09 (m,1H). 13C NMR (100 MHz, CDCl3):
13.93, 21.46, 21.77, 22.43, 23.51, 25.31, 26.25, 28.89, 29.01, 31.27,
2.2.1. Benzyl
(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate 2
Benzyl chloroformate (0.39 g, 2.3 mmol) was added dropwise
to a suspension of (S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine 1
(0.25 g, 1.6 mmol) and K2CO3 (0.46 g, 3.3 mmol) in anhydrous
CH3CN at 0 ◦C under argon. After stirring overnight at room

82
M. Vasiloiu et al. / Catalysis Today 200 (2013) 80–86
31.48, 47.07, 53.89, 60.01, 62.91, 63.22, 63.31. ATR-IR: ꢀ = 3416,
2925, 2855, 1456, 1377, 981, 911, 725, 648 cm−1. HR-MS: m/z
(M+ calculated) = 267.2795, m/z (found) = 267.2795. Tg = −6 ◦C,
T5%onset = 187 ◦C.
(100 MHz, MeOD): 12.5, 19.3, 21.1, 21.2, 24.6, 24.8, 31.1, 46.4, 53.8,
59.9, 62.4, 62.9, 63.2, 119.8 (q, J = 320.4 Hz). ATR-IR: ꢀ = 2973, 1352,
1190, 1138, 1057 cm−1. HR-MS: m/z (calculated) = 211.2169, m/z
(found) = 211.2162. Tg = −50 ◦C, T5%onset = 228 ◦C.
2.2.5.
2.2.8. (S)-1-Octyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bis(trifluormethylsulfonyl)imide 9
(S)-1-Dodecyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bromide 6
Prepared according to Section 2.2.2 from benzyl (S)-2-
[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate
Prepared according to Section 2.2.7 from benzyl (S)-2-
[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate
2 (0.288 mg,
2
(0.288 g,
1 mmol) to obtain chiral ionic liquid 9 as light brown oil. Yield:
0.438 g, 80%. [␣]58920 = +6.9 (EtOH, c = 1.00). 1H NMR (400 MHz, d3-
MeOD): 0.93 (t, J = 6.96 Hz, 3H), 1.30–1.46 (m, 11H), 1.72 (m, 2H),
2.10 (m, 1H), 2.20 (m, 4H), 2.90 (m, 1H), 2.98 (m, 1H), 3.24 (dd,
J1 = 13.90 Hz, J2 = 8.96 Hz, 1H), 3.39(m, 3H), 3.56 (m, 4H), 3.83 (m,
1H). 13C NMR (100 MHz, MeOD): 14.39, 22.44, 22.63, 23.66, 24.29,
26.41, 27.42, 30.16, 30.21, 32.41, 47.93, 55.00, 61.48, 64.21, 64.42,
64.54. ATR-IR: ꢀ = 2931, 2860, 1468, 1349, 1225, 1179, 1134, 1053,
740, 653, 614 cm−1. HR-MS: m/z (M+ calculated) = 267.2795, m/z
(found) = 267.2795. Tg = −61 ◦C, T5%onset = 205 ◦C.
1 mmol) and n-dodecyl bromide (0.299 g, 1.2 mmol) to give chiral
ionic liquid 6 as brown oil. Yield: 0.272 g, 84%. [␣]58920 = +1.9
(EtOH, c = 0.99). 1H NMR (400 MHz, CDCl3): 10.86 (t, J = 6.89 Hz,
3H), 1.31 (m, 18 H), 1.50 (m, 1H), 1.58–1.90 (m, 4H), 2.10–2.38
(m, 5H), 2.96 (m, 1H), 3.09 (m, 1H), 3.61 (m, 4H), 3.82 (m, 4H),
4.10 (br s, 1H), 4.18 (m, 1H). 13C NMR (100 MHz, CDCl3): 14.16,
21.62, 21.98, 22.71, 23.68, 25.29, 26.45, 29.28, 29.35, 29.44, 29.51,
29.63, 31.43, 31.92, 47.20, 54.23, 60.09, 62.74, 63.39, 63.47. ATR-IR:
ꢀ = 2922, 2853, 1738, 1465, 1377, 913, 656, 624 cm−1. HR-MS:
m/z (M+ calculated) = 323.3421, m/z (found) = 323.3420. Tg = −9 ◦C,
T5%onset = 186 ◦C.
2.2.9. (S)-1-Dodecyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-
1-ium bis(trifluoromethylsulfonyl)imide 10
2.2.6. (S)-1-Methyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bis(trifluoromethylsulfonyl)imide 7
Prepared according to Section 2.2.6 from benzyl (S)-2-
Compound 2 (3.68 g, 13 mmol) was dissolved in 20 ml anhy-
drous CH2Cl2 under argon atmosphere and cooled to 0 ◦C. Dimethyl
sulfate (1.6 g, 13 mmol) was added dropwise and the solution
was stirred for 20 min at room temperature. After completed
reaction the solvent was evaporated under reduced pressure
[(pyrrolidin-1-yl)methyl]pyrrolidine-1-carboxylate
2 (0.432 mg,
1.5 mmol) to obtain chiral ionic liquid 10 as light brown oil. Yield:
0.832 g, 92%. [␣]58920 = =5.7 (EtOH, c = 1.06). 1H NMR (400 MHz, d3-
MeOD): 0.91 (t, J = 7.04 Hz, 3H), 1.27–1.41 (m, 19H), 1.70 (m, 2H),
1.83 (m, 2H), 2.08 (m, 1H), 2.18 (m, 4H), 2.88 (m, 1H), 2.95 (m, 1H),
3.21–3.44 (m, 4H), 3.55 (m, 4H), 3.81 (m, 1H). 13C NMR (100 MHz,
MeOD): 14.42, 22.44, 22.63, 23.73, 24.29, 26.43, 27.43, 30.20, 30.46,
30.53, 30.61, 30.73, 32.42, 33.06, 47.95, 55.0, 61.47, 64.20, 64.41,
64.55. ATR-IR: ꢀ = 2926, 2856, 1659, 1466, 1349, 1183, 1135, 1055,
739, 654, 616 cm−1. HR-MS: m/z (M+ calculated) = 323.3421, m/z
(found) = 323.3421. Tg = −59 ◦C, T5%onset = 206 ◦C.
and the product was immediately dissolved in 10 ml H2Odest
.
LiN(Tf)2 (4.00 g, 14 mmol) in 15 ml H2Odest was added dropwise
and the solution was stirred for 30 min. The ionic liquid was
extracted with CH2Cl2 and dried over Na2SO4. After evaporation
of the solvent under reduced pressure, the intermediate (2.25 g,
4 mmol) was dissolved in MeOH and Pd/C (5 wt.%) (1.3 mmol)
was added. The supension was hydrogenated for 30 min at 4 bar
on a Parr-apparatus. Filtration over celite and evaporation of the
solvent gave (S)-1-methyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-
1-ium bis(trifluoromethylsulfonyl)imide 7 as light yellow oil. Yield:
1.69 g, 98%. [␣]58920 = +10.5 (EtOH, c = 0.48). 1H NMR (400 MHz, d3-
MeOD): 1.57 (m, J1 = 12.74 Hz, J2 = 8.70 Hz, 1H), 1.90–2.00 (m, 1H),
1.79–1.88 (m, 1H), 2.24–2.25 (m, 5H), 3.08–3.13 (m, 2H), 3.15 (s,
3H), 3.30 (br s, 1H), 3.47–3.65 (m, 6H), 3.92–3.75 (m, 1H). 13C
NMR (100 MHz, MeOD): 20.77, 21.08, 30.77, 46.26, 47.69, 54.29,
64.92, 66.41, 119.80. ATR-IR: ꢀ = 2973, 1464, 1350, 1333, 1178,
1135, 1053, 937, 741 cm−1. HR-MS: m/z (calculated) = 169.1699,
m/z (found) = 169.1694. Tg = −59 ◦C, T5%onset = 246 ◦C.
2.2.10. General procedure for the chiral ionic liquid-catalyzed
aldol reaction
The catalyst was dissolved in ketone (7 mmol) and a solution of
4-nitrobenzaldehyde 11 (0.15 g, 1 mmol) in ketone (7 mmol) was
added dropwise and stirring of the mixture was continued at dif-
ferent conditions. For isolation of the product, diethyl ether was
added and the upper layer containing the product was decanted
off. The insoluble catalyst remained at the bottom of the flask and
the procedure was repeated for several times. After evaporation of
the solvent the product was purified by column chromatography
(PE/EE).
2.2.7. (S)-1-Butyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-1-ium
bis(trifluoromethylsulfonyl)imide 8
2.2.11. 4-Hydroxy-4-(4-nitrophenyl)butan-2-one 12
Butyl bromide (0.77 g, 6 mmol) was added to compound 2
(1.08 g, 4 mmol) and the reaction mixture was stirred for 48 h at
80 ◦C. Remaining butyl bromide was removed under vacuum and
the crude product was dissolved in 10 ml H2Odest. LiN(Tf)2 (0.59 g,
2 mmol) in 15 ml H2Odest was added dropwise and the solution
was stirred for 30 min. The ionic liquid was extracted with CH2Cl2
and dried over Na2SO4. After evaporation of the solvent under
reduced pressure, the intermediate (2.25 g, 4 mmol) was dissolved
in methanol and Pd/C (5 wt.%) (0.50 g, 5 mmol) was added. The solu-
tion was hydrogenated for 30 min at 4 bar on a Parr-apparatus. After
Celite-filtration (S)-1-butyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidin-
1-ium bis(trifluoromethylsulfonyl)imide 8 could be isolated as
light yellow oil. Yield: 0.56 g, 80%. [␣]58920 = +13.7 (EtOH, c = 0.59).
1H NMR (400 MHz, d3-MeOD): 1.01 (t, J = 7.4 Hz, 3H), 1.38–1.53
(m, 3H), 1.65–1.91 (m, 4H), 2.13–2.19 (m, 5H), 2.94–3.07 (m, 2H),
3.31–3.42 (m, 6H), 3.56–3.64 (m, 3H), 3.74–3.78 (m, 1H). 13C NMR
Prepared according to Section 2.2.10 from acetone.
Rf = 0.26 (PE:EE = 2:1). Tm 59–62 ◦C. 1H NMR (200 MHz, CDCl3):
2.20 (s, 3H), 2.82 (m, 2H), 3.28 (br s, 1H), 5.24 (m, 1H), 7.50 (d,
J = 8.9 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H). 13C NMR (50 MHz, CDCl3):
30.7, 51.50, 68.9, 123.7, 126.4, 147.26, 150.1, 208.5.
2.2.12. 2-[1-Hydroxy-1-(4-nitrophenyl)methyl]cyclohexan-
1-one 13
Prepared according to Section 2.2.10 from cyclohexanone.
Rf = 0.40/0.50 (PE:EE = 2:1), Tm 157–159 ◦C. 1H NMR (200 MHz,
CDCl3): 1.23–1.86 (m, 10H), 2.05–2.15 (m), 2.27–2.67 (m, 6H,), 3.25
(br s, 1H), 4.09 (br s, 1H), 4.89 (d, J = 8.4 Hz), 5.46 (s, 1H), 7.75 (dd,
J1 = 8.8 Hz, J2 = 3.8 Hz, 4H,), 8.18 (d, J = 7.9 Hz). 13C NMR (50 MHz,
CDCl3): 24.7, 25.9, 27.8, 30.7, 42.6, 56.8, 57.1, 70.1, 73.9, 123.5,
126.6, 127.9, 147.0, 147.5, 148.4, 149.2, 214.0, 214.8.

M. Vasiloiu et al. / Catalysis Today 200 (2013) 80–86
83
Scheme 1. Synthetic strategy for basic chiral ionic liquids 3–10 starting from commercially available (S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine 2.
3. Results and discussion
sulfate anions. Thermogravimetrical analysis revealed good ther-
mal stabilities of >200 ◦C for all bistriflimide-based ionic liquids,
and the best values were obtained for bistriflimide ionic liquids
with a short alkyl chain.
Our synthetic strategy is based on commercially available
(S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine 1 that could be easily
obtained in a three-step sequence starting from cheap and chiral-
pool derived (S)-pyroglutaminic acid or (S)-proline (Scheme 1) [10].
Chiral diamine 1 is a well-established organocatalyst for stereos-
elective C C bond formation including aldol reaction and Michael
addition; however, stoichiometric amounts of trifluoroacetic acid
are typically essential for H-bonding and to achieve satisfying
enantio- and diasteroselectivity [11].
Protection of the secondary amine as benzyl carbamate gave
Cbz-intermediate 2 that was further alkylated to obtain a set of chi-
ral quaternary ammonium salts with an alkyl chain length varying
from n = 2–12. Except for methylated derivatives 3 and 7, alky-
lation was best performed under solvent-free conditions with a
small excess of the corresponding bromoalkane and gave interme-
diate salts in quantitative yield after 24–48 h at 80 ◦C. Alternatively,
the alkylation step was performed under microwave conditions,
and the reaction time could be dramatically shortened as we
have previously shown for camphor-based chiral ionic liquids [12].
In contrast, methylation of intermediate 2 was performed with
dimethyl sulfate according to literature protocols, and complete
conversion was obtained in 30 min reaction time only at 0 ◦C. The
intermediate N-protected ammonium salts were directly subjected
to the final deprotection step via catalytic hydrogenation using
H2/Pd-C to give hydrophilic chiral ionic liquids 3–6. Alternatively,
we performed an additional ion exchange step with LiNTf2 prior
to hydrogenation to obtain the corresponding hydrophobic chiral
ionic liquids 7–10.
In order to test our hypothesis, we investigated the aldol reac-
tion of 4-nitrobenzene 11 with acetone and compared activity
and selectivity of the basic chiral ionic liquid 7 with the tradi-
tional organocatalyst (S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine 1
in the presence of different acids (Scheme 2). Organocatalytic aldol
reactions are a very powerful way for enantioselective C C bond
formation and are typically catalyzed by chiral organic molecules
containing a primary or secondary amino group. However, the rates
and selectivities of the aldol reactions are usually relatively low
thus requiring waste amounts of catalyst and considerable excess
of the ketone.
As expected from literature data, the aldol reaction between
4-nitrobenzaldehyde 11 and acetone gave only low selectivity of
27%ee [15]. The addition of acid significantly improved the selec-
tivity, thus highlighting the importance of a charged catalytically
active species. With increasing acid strength (AcOH < TFA < HNTf2)
enantioselectivities are increasing as well, indicating incomplete
proton transfer with weaker acids (Table 2) [16]. Given the large
pKa difference between (S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine
1 and the super-acidic H(NTf)2, complete ionization – comparable
to a fully ionized protic ionic liquid – can be expected [17].
Table 1
Yields and thermal properties of basic chiral ionic liquids 3–10.
b
c
Ionic liquid
Yielda (%)
Tg (◦C)
T5%onset (◦C)
The optimized sequence could be performed in high overall yield
without requiring any chromatographic purification steps and gave
a set of chiral ionic liquids with a free secondary amine structural
motive. DFT-calculations for two different hydrophilic basic ionic
liquids revealed an orthogonal position of the pyrrolidine ring sys-
tems [13,14] (Fig. 2).
All chiral ionic liquids were obtained as viscous liquids with
glass transition temperature between 3 and −61 ◦C (Table 1). As to
be expected, the ion exchange to introduce the bistriflimide anion
resulted in reduced viscosity and a lower glass transition tempera-
ture. Also, we found that the thermal stability of chiral ionic liquids
7–10 based on the bistriflimide anion was significantly higher than
the values obtained for ionic liquids based on bromide or methyl
3
4
5
6
7
8
9
10
97
97
88
84
98
80
80
92
−46
3
109
196
187
186
246
228
205
206
−6
−9
−59
−50
−61
−59
a
Overall yield starting from benzyl (S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine-1-
carboxylate 2.
b
Glass transitions (Tg) determined on a Netzsch TGA/DSC by heating to 110 ◦C at
10 ◦C/min and cooling with 10 ◦C/min to −100 ◦C for 3 cycles.
c
Onset to 5% decomposition temperature (T5%onset) determined on a Netzsch
TGA/DSC from 25 to 500 ◦C with +10 ◦C/min.

84
M. Vasiloiu et al. / Catalysis Today 200 (2013) 80–86
Fig. 2. Optimized geometries of a single ion pair of chiral ionic liquids 7 (left) and 10 (right) via density functional theory with a 6–311 g basis set.
Table 2
Table 3
Comparison between conventional catalyst
organocatalytic aldol reaction of 4-nitrobenzaldehyde 11 and acetone.
1
and basic ionic liquid
7
in the
Different basic chiral ionic liquids 3–10 in the organocatalytic aldol reaction of 4-
nitrobenzaldehyde 11 and acetone to give hydroxyketone 12.
Entry
Catalysta
Additive
Yieldb [%]
ee c [%]
Entry
Catalysta
Yieldb [%]
ee c [%]
1
2
3
4
1
1
1
7
–
TFA
HN(Tf)2
–
76
45
59
67
27
67
78
75
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
10
13
62
41
62
67
77
84
70
70
82
51
58
75
79
72
83
a
Performed with 1 mmol 4-nitrobenzaldehyde, and 14 mmol acetone.
Isolated yield after column chromatography.
Determined via HPLC on a CHIRALPAK AS-H.
b
c
a
Performed with 1 mmol 4-nitrobenzaldehyde, and 14 mmol acetone.
Isolated yield after column chromatography.
Determined via HPLC on a CHIRALPAK AS-H.
b
c
We were pleased to find that yield and enantioselectivity of the
catalyzed aldol reaction was comparable when the combination
(S)-1-[(pyrrolidin-2-yl)methyl]pyrrolidine 1/H(NTf)2 was replaced
with the corresponding chiral ionic liquid 7. Good yield and selec-
tivity of 67% and 75%ee, respectively could be obtained using a
similar catalyst loading. This proves our original assumption that
catalytically active protic intermediates can be replaced by an alky-
lated species for electrophilic activation to avoid acidic additives.
When investigating different ionic liquids, we found that all
ionic liquids could successfully induce chirality (Table 3). While the
hydrophilic methyl sulfate ionic liquid 3 gave only a low yield of
13%, all other chiral ionic liquids could efficiently catalyze the aldol
reaction, and good yields between 64% and 84% were obtained. In
general, hydrophilic bistriflimide salts 7–10 proved to be superior
and gave slightly better yields and selectivities compared to the
hydrophilic bromides 4–6 or the methyl sulfate salt 3. However, it
seems that the steric hindrance obtained from a longer alkyl chain
has only a minor influence on enantioselectivity, and no significant
trend could be observed when increasing the chain length.
We successively modified reactions conditions to investigate
the influence of catalyst loading and temperature (Table 4).
Although the reaction could be performed with 5 mol% catalyst as
well, a longer reaction time was required to reach only moderate
yields of 48%. Consequently, a higher loading of 25 mol% chiral ionic
liquid resulted in shortened reaction times and a better selectivity,
and a good yield of 87% with 72%ee could be isolated. The reac-
tion could also be accelerated using a higher temperature of 60 ◦C;
however, the increased reaction rate was achieved at the costs of a
lower enantioselectivity. We further expanded the reaction range
to include cyclohexanone as donor to form ␤-hydroxy ketone 13
and found a similar trend for catalyst loading and for the influence
of temperature. Best conditions were present using 10 mol% chiral
ionic liquid at room temperature, and a good yield of up to 80% but
only moderate diastereoselectivity with a syn:anti ratio ∼1:2 was
obtained. Since the tunable solubility of chiral ionic liquids often
Scheme 2. Aldol reaction.

M. Vasiloiu et al. / Catalysis Today 200 (2013) 80–86
85
Table 4
Comparison of different ketones in chiral aldol reactions with the same chiral catalysts.
d
d
Entrya
Ketone
Cat. 7 (mol%)
Conditions
Yieldc
eesyn
69
eeanti
42
syn:antie
1
2
3
Acetone
Cyclohexanone
Acetone
Acetone
Acetone
Acetone
Acetone
Cyclohexanone
Acetone
Cyclohexanone
Acetone
5
5
25 ◦C, 72 h
25 ◦C, 72 h
25 ◦C, 48 h
25 ◦C, 48 h
25 ◦C, 3 days
25 ◦C, 3 days
25 ◦C, 7 days
25 ◦C, 48 h
60 ◦C, 24 h
60 ◦C, 24 h
25 ◦C, 24 h
25 ◦C, 24 h
48
70
67
53
32
15
33
80
71
75
87
73
65
38:62
10
10
10
10
10
10
10
10
25
25
75
77
56
99
97
4b
5b
6b
7b
8
44
43
20
67
44
41
38:62
37:63
37:63
9
58
72
10
11
12
Cyclohexanone
a
Performed with 1 mmol 4-nitrobenzaldehyde, and 14 mmol ketone.
1st, 2nd, 3rd and 4th recylation, respectively.
Isolated yield after column chromatography.
b
c
d
e
Determined via HPLC on a CHIRALPAK AS-H or on a CHIRALPAK IA.
Determined from 1H NMR via integration over the H-4 proton at 5.46 ppm (syn) and 4.88 ppm (anti).
Table 5
replace acidic additive in enamine-based organocatalysis for asym-
metric C C bond formation. Although results for catalyst recycling
remained below our expectations, we could show that catalytically
active protic intermediates can be replaced by alkylated species
without loss of activity, and good yields and selectivities of up to
80%ee could be obtained for the example of organocatalytic aldol
reaction. Hence it seems that for this particular system electrophilic
activation via an inherent quaternary ammoniums structure can
replace the hydrogen bonding properties of protonated ammonium
moieties. We thus envision that this ionic liquid-based strategy can
not only help to reduce the use of toxic and corrosive trifluoroacetic
acid, but opens the substrate scope for organocatalysis toward
acid-sensitive compounds. Further studies to improve catalytic
properties and to extend the scope of this strategy in organocatal-
ysis are ongoing in our group.
Comparison of different chiral catalysts.
Entrya
Catalyst
Yieldb [%]
ee c [%]
1
2
3
4
7
8
9
65
67
41
35
5
66
81
55
10
a
Performed with 1 mmol 4-nitrobenzaldehyde, and 1 mmol acetone in 1 ml H2O.
Isolated yield after column chromatography.
Determined via HPLC on a CHIRALPAK AS-H.
b
c
allows separation and recycling of the catalyst, we were also inter-
ested to recover our catalyst for recycling. After complete reaction,
we could easily separate the product via extraction with diethyl
ether leaving the catalyst as a lower layer behind. After remain-
ing volatile material was removed under vacuum, fresh starting
materials were added and the reaction was repeated. Although we
could maintain a good selectivity of 77%ee, the catalytic activity
was unfortunately dropping to 53% in the second run. We therefore
increased the reaction time up to 7 days in the 4th run; however
the isolated yield was consecutively dropping, although excellent
enantioselectivity was obtained in the last recycling steps. After
four recycling steps we obtained only a disappointing yield of 33%,
and improvements in catalyst recycling are certainly required.
Based on environmental considerations, organocatalysis under
aqueous conditions is currently re-examined, and there is growing
interest in organocatalysts that are capable of efficiently perform-
ing in water [18]. We therefore investigated the aldol reaction of
4-nitrobenzaldehyde and acetone in aqueous solution using only
stoichiometric amounts of acetone and found a significant influence
of the alkyl chain length of the chiral ionic liquids (Table 5). While
the methylated chiral ionic liquid 7 derivative gave good yield but
only neglible selectivity, an increase in chain length resulted in a
gradual decrease of the isolated yield, indicating surface-activity of
the longer-chain basic chiral ionic liquids 8–10 [19].
Acknowledgement
Financial support given by the Hochschuljubiläumsstiftung der
Stadt Wien is gratefully acknowledged.
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