A novel (S)-proline-modified task-specific chiral ionic liquid-an amphiphilic recoverable catalyst for direct asymmetric aldol reactions in water

Article abstract of DOI:10.1016/j.tetlet.2007.12.044

A novel chiral (S)-proline-modified task-specific ionic liquid has been designed and synthesized as an efficient recoverable organocatalyst for the direct asymmetric aldol reaction between cycloalkanones and aromatic aldehydes in the presence of water. The catalyst retains its activity and selectivity over at least five reaction cycles.

Full text of DOI:10.1016/j.tetlet.2007.12.044

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1212–1216
A novel (S)-proline-modified task-specific chiral ionic
liquid—an amphiphilic recoverable catalyst for direct
asymmetric aldol reactions in water
Dmitriy E. Siyutkin, Alexander S. Kucherenko, Marina I. Struchkova, Sergei G. Zlotin *
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky Prospect, 119991 Moscow, Russia
Received 30 October 2007; revised 27 November 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
A novel chiral (S)-proline-modified task-specific ionic liquid has been designed and synthesized as an efficient recoverable organo-
catalyst for the direct asymmetric aldol reaction between cycloalkanones and aromatic aldehydes in the presence of water. The catalyst
retains its activity and selectivity over at least five reaction cycles.
Ó 2007 Published by Elsevier Ltd.
Keywords: Direct asymmetric aldol reaction; Water; Chiral ionic liquid; Organocalatyst; Recycle
The direct asymmetric aldol reaction between unmodi-
fied ketones and aldehydes is a convenient method for
the synthesis of chiral organic compounds. In Nature this
reaction is catalyzed by native aldolase ferments.1 In the
laboratory, small organic molecules, which simulate aldol-
ase action, in particular amino acids2 and their derivatives,3
low-molecular weight peptides4 and substituted pyrrol-
idines,5 are used as the catalysts. Aldol reactions run with
an excess of the ketone,3a,6 in dipolar organic sol-
vents,2a,b,3d,5b,6d,7 or in ionic liquids, have become popular
in recent years.8
A few examples of asymmetric aldol reactions in the
presence of water, which is the most cost-effective and envi-
ronment-friendly reaction medium, have been pub-
lished.3f,h,9,10 High conversions and selectivity were
achieved in reactions catalyzed by water-insoluble organo-
catalysts bearing hydrophobic fragments, in particular
long-chained hydrocarbon moieties CnH2n+2 (n P 10),10a
binaphthyl10h or trialkyl(aryl)silyl groups,3g,10f,g polysty-
rene10c,d or dendritic fragments.10b Reactions in hetero-
geneous aqueous systems containing hydrophobic
catalysts and reagents were characterized by Sharpless as
‘reactions on water’.11a Thus, organic molecules react with
each other inside or on the surface of concentrated organic
associates (micelles) where efficient stereo-control in the
transition state is ensured by hydrogen bonds between
the reagents and catalysts.10a,11b,12 The important role of
the organic associations at the organic/water interfacial
region is consistent with the moderate rate and enantiose-
lectivity of aldol reactions catalyzed by water-soluble
amino acids10e,f and with the favorable influence of organic
acids10a,e,h–j,13a and/or surfactants13b,c on heterogeneous
aldol reactions ‘on water’.
In spite of the impressive results obtained during the last
decade in implementing aqueous media in organic synthe-
sis,14 the development of efficient recoverable catalysts for
the asymmetric aldol reaction ‘on water’ has so far
remained challenging. Indeed, the syntheses of recoverable
4-hydroxyproline and proline amide derivatives bearing
polymer10c,d or dendritic moieties10b are rather complicated
and/or require expensive starting compounds. The catalytic
activity of more readily available hydroxyl amino acid
*
Corresponding author. Tel.: +7 499 137 13 53; fax: +7 499 135 53 28.
E-mail address: zlotin@ioc.ac.ru (S. G. Zlotin).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.12.044

D. E. Siyutkin et al. / Tetrahedron Letters 49 (2008) 1212–1216
1213
trialkyl(aryl)silyl esters was reduced noticeably in the 2nd
or 3rd runs10f probably due to the gradual hydrolysis of
the Si–O bond. Multi-component catalytic systems con-
taining organic acids or surfactants could normally be used
successfully only once per run.
Recoverability is a characteristic feature of amphiphilic
organocatalysts containing ionic liquid fragments. Yet, the
aldol reactions catalyzed by a pyrrolidine derivative modi-
fied with an imidazolium cation proceed with poor diaste-
reo- and enantioselectivity.9g In addition, we have found
that (S)-proline-containing ionic liquid 1, being an efficient
organocatalyst of asymmetric aldol reactions in organic
solution,15 is completely inactive in an aqueous
environment.
It might be expected that hydrophobic structural ana-
logs of catalyst 1 bearing long-chain hydrocarbon groups
at the imidazolium nitrogen atoms and being poorly solu-
ble in aqueous media would possess a much higher activity
in asymmetric aldol reactions in water (Scheme 1).
To verify this hypothesis, we synthesized new amphi-
philic chiral imidazolium salts 2 and 3 bearing hydrophilic
ðBF4ꢀÞ and hydrophobic ðPF6ꢀÞ anions, respectively. The
synthetic scheme included esterification of (2S,4S)-N-Cbz-
4-hydroxylproline benzyl ester (4)16 under the action of
5-bromovaleric acid and DCC/DMAP,17 subsequent reac-
tion of ester 5 with n-dodecyl imidazole18,19 followed by
deprotection of the resulting salt 620 and metathesis of
the anion in the product amino acid 721,22 (Scheme 2).
Salts 2 and 3 melt at 119 °C and 158 °C, respectively,
and can be described as ionic liquids. They have quite dif-
ferent solubility in water. Tetrafluoroborate 2 gave a clear
5% aqueous solution at 20 °C, whereas hexafluorophos-
phate 3/water mixture was a suspension under the same
conditions.
We studied the catalytic activity of chiral salts 2 and 3 in
the model aldol reaction between cyclohexanone 8a
(3 equiv) and p-nitrobenzaldehyde 9a in the presence of
water at 20 °C. The amount of organocatalyst was
30 mol % with respect to aldehyde 9a. The reaction did
not occur in the presence of the water-soluble compound
2. However, with salt 3/water suspension, it proceeded with
high conversion to afford chiral aldol 10a with extremely
high diastereo- and enantioselectivity (Table 1, entry 1).
Next, we applied catalyst 3 in the asymmetric aldol reac-
tions between cycloalkanones 8a,b and aromatic aldehydes
9a–d.23 In all the cases, the corresponding aldols 10b–e
were obtained. High conversions (P86%) were achieved
after 10 h in the reactions of aldehydes 9a,b bearing elec-
tron-withdrawing groups on the aromatic ring (Table 1,
entries 2 and 5). p-Methoxybenzaldehyde (9d) was found
to be less active under the conditions studied: about 80%
of the starting compound remained intact after 64 h.
H3C
BF4
An
H3C
N
N
11N
N
4
O
O
O
O
COOH
COOH
N
H
N
H
An = BF4 (2), PF6 (3)
1
Scheme 1. Synthetic strategy.
O
O
IL
Br
HO
O
4
O
4
Br
COOBn
H
IL
Br(CH2)4COOH
DCC/DMAP
COOBn
IL
COOBn
N
Z
N
N
Z
5
6
4
Z
O
O
IL
O
4
O
4
X
Br
COOH
AgX (for 2), HX (for 3)
H2, Pd/C
CH3OH
COOH
N
N
H
X = BF4 (2), PF6 (3)
7
H
N
C12H25-n
IL
N
=
Scheme 2. Synthesis of amphiphilic (S)-proline-modified chiral salts 2 and 3.

1214
D. E. Siyutkin et al. / Tetrahedron Letters 49 (2008) 1212–1216
Table 1
The catalytic asymmetric aldol reaction between compounds 8 and 9 in the presence of water catalyzed by amphiphilic organocatalyst 3
O
O
OH
O
3 (30 mol %)
H2O, 20 oC
2
+
R
1
H
R
n
n
10a-e
9a-d
8a,b
n=3 (a), 2 (b)
Entry
8
9 (R)
10
Timea (h)
Conversiona (%)
>95 (86,25 939g
dra [anti:syn]
ee, anti-isomera,b (%)
1
2
3
4
5
a
a
a
a
a
b
a (p-NO2C6H4)
b (p-CH3O2CC6H4)
c (C6H5)
d (p-CH3OC6H4)
a (p-NO2C6H4)
a
b
c
d
e
10 (5,25 209g
10
)
)
97:3 (20:1,25 1:19g
97:3
)
>99 (>99,25 109g
>99
)
86
36 (18,25 809g
)
67 (78,25 669g
)
93:7 (13:1,25 1.3:19g
)
88 (>99,25 99g
)
64 (5025
)
20 (2125
)
84:16 (5:125
85:15 (1:2.89g
)
80 (9625
91 (59g
)
10 (69g
)
>95 (879g
)
)
)
Reported data are given in brackets.
b
HPLC, chiral phase: Chiralcel OD-H, OJ-H.
lyst activity and widening the reaction scope is currently
underway.
Table 2
Recycling of catalyst 3 in the asymmetric aldol reaction (10 h) between
compounds 8a and 9b ‘on water’
Cycle
Conversiona
(%)
dr of aldol 10ba
[anti:syn]
ee of aldol
10bb (%)
Acknowledgments
1
2
3
4
5
a
86
88
86
85
83
97:3
96:4
96:4
97:3
97:3
>99
99
98
99
99
This work was partially supported by the Russian Foun-
dation of Basic Research (Grant 06-03-32603) and the Rus-
sian Academy of Sciences.
References and notes
Determined by 1H NMR.
Determined by HPLC.
b
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JH1–H2 syn < 2.4 Hz) the anti/syn diastereomeric ratio (dr)
of aldols 10b–e was high (P84:16) irrespective of the alde-
hyde structure. Moreover, the ee’s of the major anti-iso-
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influence of the pyrrolidine-derived amphiphilic catalyst9g
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tions ‘on water’ catalyzed by the most efficient 4-siloxy-(S)-
proline derivatives.25
The recyclability of the catalytic system 3/H2O was
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with fresh starting mixtures 8a and 9b. Catalyst 3 retained
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In conclusion, we have synthesized novel (S)-proline-
modified task-specific chiral ionic liquid 3 and demon-
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asymmetric aldol reactions in the presence of water. Ionic
liquid structure optimization aimed at improving the cata-
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It is worth mentioning that the syn-diastereomer was the major
component of aldol 10e obtained from compounds 8b and 9a under the
action of (S)-proline in an excess of ketone24 or 1-(pyrrolidyl-2-methyl)-3-
butylimidazolium tetrafluoroborate in water.9g

D. E. Siyutkin et al. / Tetrahedron Letters 49 (2008) 1212–1216
1215
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18. de Savignac, A.; Roques, C.; Hinedi, M.; Michel, G.; Lattes, A. Eur.
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19. 1-(5-((1,5-Bis((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)-5-oxopentyl)-
3-dodecyl-1H-imidazol-3-ium bromide (6). A mixture of compound 5
(1.10 g, 2.12 mmol) and 1-(n-dodecyl)imidazole (0.60 g, 2.54 mmol)
was heated at 90 °C for 10 min, cooled to 20 °C and washed with Et2O
(6 ꢁ 15 ml). The residue was dissolved in MeOH (3 ml), and Et2O
(15 ml) was gradually added to the stirred solution. The separated oil
was dried in vacuo (0.5 Torr) for 2 h to afford compound 6 (1.13 g,
19
1
71%) as a yellow viscous oil; ½aꢂD ꢀ17.1 (c 1.33, CH3OH); H NMR
(300 MHz, CDCl3), d: 10.72 (1H, s, NCHN), 7.16–7.39 (12H, m, Ph,
NCHCHN), 5.27 (1H, s, CHO), 4.98–5.23 (4H, m, CH2Ph), 4.24–4.54
(5H, m, CH2CH2N, CH2CHN), 3.61–3.82 (2H, m, CHCH2N), 2.40
(2H, t, J = 7.3 Hz, CH2CH2COO), 2.17–2.51 (2H, m, CH2CHN),
1.84–2.02 (4H, m, CH2CH2N), 1.59–2.71 (2H, m, CH2CH2COO),
1.21–1.38 (18H, m, CH3(CH2)9), 0.88 (3H, t, J = 6.8 Hz, CH3) ppm;
13C NMR (75 MHz, CDCl3), d: 172.13, 171.58, 154.28, 136.61,
136.01, 135.08, 128.40, 128.31, 128.18, 127.98, 127.90, 127.63, 122.27,
121.83, 72.13, 67.14, 66.86, 57.67, 52.19, 49.93, 49.31, 35.78, 32.94,
31.68, 30.08, 29.47, 29.39, 29.31, 29.19, 29.12, 28.81, 26.07, 22.47,
21.04, 13.94 ppm. Anal. Calcd for C40H56BrN3O6: C, 63.65; H, 7.48;
N, 5.57; Br, 10.59. Found: C, 63.82; H, 7.41; N, 5.69; Br, 10.48.
20. 4-((5-(3-Dodecyl-1H-imidazol-3-ium-1-yl)pentanoyl)oxy)proline bromide
(7). A mixture of compound 6 (1.13 g, 1.50 mmol), Pd/C (5%)
(0.11 mg), and dry CH3OH (35 ml) was stirred under H2 (760 Torr) at
ambient temperature for 2 h. The resulting precipitate was filtered off,
and the filtrate was evaporated in vacuo. The residue was dissolved in
MeOH (2.5 ml), and Et2O (12 ml) was gradually added to the stirred
solution. The separated oil was dried in vacuo (0.5 Torr) for 2 h to
19
afford amino acid 7 (0.70 g, 87%) as a pale yellow oil; ½aꢂD ꢀ13.2 (c
1.22, CH3OH); 1H NMR (300 MHz, DMSO-d6) d: 9.26 (1H, s,
NCHN), 7.82 (2H, s, NCHCHN), 5.18–5.23 (1H, m, CHO), 4.11–4.22
(4H, m, CH2CH2N), 3.80 (1H, t, J = 8.9 Hz, CH2CHN), 3.08–3.50
(2H, m, CHCH2N), 2.37 (2H, t, J = 6.6 Hz, CH2CH2COO), 2.04–2.23
(2H, m, CH2CHN), 1.72–1.88 (4H, m, CH2CH2N), 1.43–1.55 (2H, m,
CH2CH2COO), 1.22 (18H, s, CH3(CH2)9), 0.85 (3H, t, J = 6.1 Hz,
CH3) ppm; 13C NMR (75 MHz, DMSO-d6), d: 172.07, 169.90, 136.04,
122.49, 122.44, 73.25, 59.37, 49.91, 48.88, 48.49, 35.06, 32.58, 31.32,
29.34, 29.04, 28.96, 28.85, 28.74, 28.68, 28.38, 25.53, 22.11, 20.72,
13.93 ppm. Anal. Calcd for C25H44BrN3O4: C, 56.60; H, 8.36; N, 7.92;
Br, 15.06. Found: C, 56.79; H, 8.29; N, 8.03; Br, 14.91.
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Asymmetry 2006, 17, 1493; (b) Peng, Y.-Y.; Ding, Q.-P.; Li, Z.; Wang,
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21. 4-((5-(3-Dodecyl-1H-imidazol-3-ium-1-yl)pentanoyl)oxy)proline tetra-
fluoroborate (2). A solution of AgBF4 (0.24 g, 1.23 mmol) in CH3OH
(5 ml) was gradually added to a stirred solution of amino acid 7
(0.65 g, 1.23 mmol) in the same solvent (5 ml). The resulting precip-
itate was filtered off and washed with CH3OH (5 ml). The combined
organic extracts were evaporated, and the residue was dried in vacuo
(0.5 Torr) for 2 h to afford tetrafluoroborate 2 (0.64 g, 98%) as
14. Li, C.-J. Chem. Rev. 2005, 105, 3095.
15. Miao, W.; Chan, T. H. Adv. Synth. Catal. 2006, 348, 1711.
16. Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66, 1038.
17. Dibenzyl 4-((5-bromopentanoyl)oxy)pyrrolidine-1,2-dicarboxylate (5).
A mixture of compound 416 (4.01 g, 11.30 mmol), 5-bromovaleric acid
(2.09 g, 11.55 mmol), DCC (2.38 g, 11.55 mmol), DMAP (20 mg,
0.16 mmol), and CH2Cl2 (60 ml) was stirred at 5 °C for 3 h. The
resulting precipitate was filtered off and washed with CH2Cl2
(3 ꢁ 10 ml). The combined organic extracts were washed successively
with 35% HCl (2 ꢁ 15 ml) and distilled water (2 ꢁ 20 ml). The solvent
was evaporated in vacuo, and the residue was purified by column
19
colorless hydroscopic crystals, mp 117–119 °C; ½aꢂD ꢀ11.8 (c 1,
CH3OH); 1H NMR (300 MHz, DMSO-d6), d: 9.19 (1H, s, NCHN),
7.79 (2H, s, NCHCHN), 5.17–5.23 (1H, m, CHO), 4.11–4.21 (4H, m,
CH2CH2N), 3.81 (1H, t, J = 8.9 Hz, CH2CHN), 3.08–3.50 (2H, m,
CHCH2N), 2.36 (2H, t, J = 6.6 Hz, CH2CH2COO), 2.05–2.23 (2H, m,
CH2CHN), 1.73–1.86 (4H, m, CH2CH2N), 1.43–1.54 (2H, m,
CH2CH2COO), 1.23 (18H, s, CH3(CH2)9), 0.85 (3H, t, J = 6.1 Hz,
CH3) ppm; 13C NMR (75 MHz, DMSO-d6), d: 172.07, 169.90, 136.04,
122.49, 122.44, 73.25, 59.37, 49.91, 48.88, 48.49, 35.06, 32.58, 31.32,
29.34, 29.04, 28.96, 28.85, 28.74, 28.68, 28.38, 25.53, 22.11, 20.72,
13.93 ppm; 11B NMR (64.21 MHz, DMSO-d6), d: ꢀ1.08 ppm; 19F
NMR (188.31 MHz, DMSO-d6), d: ꢀ147.6 ppm. Anal. Calcd for
˚
chromatography on silica gel (Acros, 60–200 lm, 60 A, eluent
n-hexane/EtOAc 4:1) to afford compound 5 (4.73 g, 80%) as a
23
colorless viscous oil; ½aꢂD ꢀ30.2 (c 1, CHCl3); 1H NMR (300 MHz,
CDCl3), d: 7.18–7.43 (10H, m, Ph), 5.30 (1H, s, CHO), 4.98–5.27 (4H,
m, PhCH2), 4.52 (1H, dt, J = 19.5, 7.7 Hz, CHCOO), 3.62–3.85 (2H,
m, CH2N), 3.41 (2H, t, J = 6.4 Hz, BrCH2), 2.15–2.49 (2H, m,
CHCH2CH), 2.33 (2H, t, J = 6.4 Hz, CH2CH2COO), 1.68–1.93 (4H,
m, BrCH2CH2CH2) ppm; 13C NMR (75 MHz, CDCl3), d: 172.32,
171.78, 154.34, 136.13, 135.22, 128.58, 128.54, 128.46, 128.27, 128.00,
127.83, 72.13, 67.25, 66.96, 57.77, 52.32, 36.51, 35.47, 33.07, 31.73,
23.20 ppm. Anal. Calcd for C25H28BrNO6: C, 57.92; H, 5.44; N, 2.70;
Br, 15.41. Found: C, 58.14; H, 5.31; N, 2.74; Br, 15.27. Rf = 0.35 (n-
hexane/ethyl acetate 3:1).
C
25H44BF4N3O4: C, 55.87; H, 8.25; N, 7.82; F, 14.14. Found: C,
56.05; H, 8.17; N, 7.68; F, 13.99.
22. 4-((5-(3-Dodecyl-1H-imidazol-3-ium-1-yl)pentanoyl)oxy)proline
hexafluorophosphate (3).
A solution of amino acid 7 (0.10 g,
0.19 mmol) in water (5 ml) was adjusted to pH ꢃ 2–3 with 60%
HPF6 (0.06 ml, 0.38 mmol) at 20 °C. The reaction mixture was then
adjusted to pH ꢃ 8–9 with 25% NH3. The resulting precipitate was
filtered off, and washed with water until the washings became neutral

1216
D. E. Siyutkin et al. / Tetrahedron Letters 49 (2008) 1212–1216
and then dried in vacuo (0.5 Torr) for 2 h to afford hexafluoropho-
23. Typical procedure for the aldol reaction: A mixture of organocatalyst 3
(23.2 mg, 0.039 mmol), ketone (0.40 mmol), aldehyde
19
phate 3 (0.11 g, 95%) as a colorless powder, mp 156–158 °C; ½aꢂD
ꢀ10.8 (c 1, CH3OH); 1H NMR (300 MHz, DMSO-d6), d: 9.20 (1H, s,
NCHN), 7.79 (2H, s, NCHCHN), 5.18–5.22 (1H, m, CHO), 4.11–4.22
(4H, m, CH2CH2N), 3.79 (1H, t, J = 8.9 Hz, CH2CHN), 3.06–3.49
(2H, m, CHCH2N), 2.37 (2H, t, J = 6.6 Hz, CH2CH2COO), 2.03–2.23
(2H, m, CH2CHN), 1.71–1.88 (4H, m, CH2CH2N), 1.42–1.55 (2H, m,
CH2CH2COO), 1.22 (18H, s, CH3(CH2)9), 0.85 (3H, t, J = 6.1 Hz,
CH3) ppm; 13C NMR (75 MHz, DMSO-d6), d: 172.07, 169.90, 136.04,
122.49, 122.44, 73.25, 59.37, 49.91, 48.88, 48.49, 35.06, 32.58, 31.32,
29.34, 29.04, 28.96, 28.85, 28.74, 28.68, 28.38, 25.53, 22.11, 20.72,
13.93 ppm; 19F NMR (188.31 MHz, DMSO-d6), d: ꢀ67.4,
ꢀ71.1 ppm; 31P NMR (81.02 MHz, DMSO-d6), d: ꢀ42.46 (hp,
J = 8.8 Hz) ppm. Anal. Calcd for C25H44F6N3O4P: C, 50.41; H,
7.45; N, 7.06; F, 19.14. Found: C, 50.59; H, 7.37; N, 6.95; F, 18.97.
8
9
(0.13 mmol), and distilled water (0.5 ml) was stirred at 20 °C for the
period given in Tables 1 and 2. Aldol 10 and the remaining starting
compounds were extracted with Et2O (3 ꢁ 5 ml), the combined
extracts were dried over anhydrous NaSO4, the solvent was evapo-
rated in vacuo (15 Torr) and the residue was purified by column
˚
chromatography on silica gel (Acros, 40–60 lm, 60 A, eluent n-
hexane/EtOAc 3:1). Conversions and dr’s of aldols 10 were measured
by 1H NMR of the crude reaction mixture, ee’s of the anti-isomers of
10 were determined by HPLC, chiral phase: Chiralcel OD-H, OJ-H.
24. Kucherenko, A. S.; Struchkova, M. I.; Zlotin, S. G. Eur. J. Org.
Chem. 2006, 2000.
25. Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.;
Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958.