Enantioselective Michael additions of aldehydes to nitroalkenes catalyzed with ionically tagged organocatalyst

Article abstract of DOI:10.2478/s11532-013-0391-4

Enantioselective organocatalytic Michael additions affords useful building blocks for many biologically and medicinally relevant compounds. Ionically-tagged diphenylprolinol silyl ether efficiently catalyzes several Michael additions of aldehydes to nitro

Full text of DOI:10.2478/s11532-013-0391-4

Cent. Eur. J. Chem. • 12(3) • 2014 • 416-425
DOI: 10.2478/s11532-013-0391-4
Central European Journal of Chemistry
Enantioselective Michael additions
of aldehydes to nitroalkenes catalyzed
with ionically tagged organocatalyst
Research Article
Radovan Šebesta1*, Attila Latika2
1Department of Organic Chemistry,
Faculty of Natural Sciences, Comenius University in Bratislava,
84215 Bratislava, Slovakia
2Synkola, 84215 Bratislava, Slovakia
Received 18 September 2013; Accepted 24 November 2013
Abstract:
Enantioselective organocatalytic Michael additions affords useful building blocks for many biologically and medicinally relevant
compounds. Ionically-tagged diphenylprolinol silyl ether efficiently catalyzes several Michael additions of aldehydes to nitroalkenes in
ionic liquids. The Michael additions work well in ionic liquids; yields up to 95% and enantioselectivities up to 95% ee were achieved.
Furthermore, in some cases, the catalytic system was reusable.
Keywords: Organocatalysis • Ionic liquid • Ionic tag • Michael addition • Oseltamivir
© Versita Sp. z o.o.
1. Introduction
Stereoselective organocatalytic Michael additions are
important C-C [14-19] and C-heteroatom [20,21] bond
formingreactions. Michaelacceptorssuchasunsaturated
carbonyl compounds, sulfones, phosphonates, and
nitroalkenes react with enolizable aldehydes and
ketones, nitroalkanes and other C-acids. Practicality of
organocatalytic Michael addition is demonstrated also
in the fact that they are part of a number of domino or
one-pot reactions [22-25]. Such reactions lead to highly
functionalized compounds, which often have interesting
biological activities [26,27].
Diarylprolinol silyl ethers, initially developed
independently by Jorgensen [28] and Hayashi [29],
belong among the most effective organocatalysts [30,31].
These compounds are also highly effective catalysts
for enantioselective Michael additions of aldehydes to
a variety of Michael acceptors, such as nitroalkenes
[29,32-37], vinyl sulfones [38,39] and unsaturated
thioesters [40]. Given the high catalytic activity of diaryl
silyl ether in a range of reactions, it is understandable
that several immobilizations have been described with
Asymmetric organocatalysis provides access to
a
broad range of important chiral compounds [1-4].
One of the possible ways to increase efficiency of an
organocatalytic reaction is to immobilize a catalyst. From
among a large variety of immobilization strategies, an
immobilization within a liquid phase offers several useful
properties. Homogeneous immobilized catalysts attempt
to combine positive features of both homogeneous as
well as heterogeneous catalysis [5]. Thus, a catalyst
having an ionic tag appended is supposed to behave
similarly to analogous homogeneous catalyst. At the
same time, it should be amenable to facile isolation and
possible recycling. Introduction of an ionic tag into the
organocatalyst structure enables use of such catalyst in
ionic liquids [6-7]. There have been a number of reports
of efficient organocatalytic reactions performed in ionic
liquids [8-12]. Furthermore, introduction of an ionic
tag into a catalyst structure can influence its catalytic
properties [13].
* E-mail: radovan.sebesta@fns.uniba.sk
416

R. Šebesta, A. Latika
this organocatalyst. Zlotin and coworkers attached an
imidazolium ion through an O-acyl group on position 4 in
the 4-hydroxyproline [41]. The resulting organocatalyst
was efficient in the Michael addition of malonates to
α,β-unsaturated aldehydes. The catalyst was recycled
six times in ethanol. On the other hand, Lombardo and
coworkers used the silyl group of Jorgensen-Hayashi
catalyst to attach the ionic moeity [42]. This catalyst was
then used for catalyzing Michael addition of enolizable
aldehydes to nitroalkenes. Although Lombardo also
used his catalyst in an ionic liquid, recycling was not
evaluated. Yet another successful way of immobilizing
diarylprolinol silyl ether was developed by Headley, Ni
and coworkers. They attached quaternary ammonium
moieties onto the aryl groups of the catalyst [43-44].
These organocatalysts were also not used in ionic
liquids, but in aqueous media.
Inthiscontext,wedecidedtoemploy4-hydroxyproline-
type catalyst for organocatalytic Michael additions in
ionic liquids. The use of ionically-tagged catalyst in
connection with ionic liquids constitutes a primary sense
of the notion of catalyst ionic tagging. Furthermore, we
have selected several useful Michael additions, which
are applicable in the synthesis of biologically relevant
molecules such as oseltamivir and its analogues.
Attention was paid to recycling of the catalyst while
retaining its high catalytic activity and practicality of the
procedure.
2.1. Synthesis of catalyst C1
(3R,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)
pyrrolidin-3-ol (2)
Into a solution of ester 1 (4.0 g, 17 mmol) in
anhydrous THF (100 mL), PhMgBr (102 mL, 102 mmol,
18% in THF) was added over 1 h at -78°C. The reaction
mixture was stirred without adding additional cooling
agent for 18 h. The reaction was quenched by adding
saturated NH4Cl solution (35 mL) at 0°C. Layers were
separated and aqueous layer was extracted with Et2O
(3×30 mL). The combined organic exctracts were
washed with saturated NH4Cl solution (2×50 mL), dried
(Na2SO4) and concentrated. The residue was dissolved
in a mixture hexanes/EtOAc and activated charcoal was
added. After filtration, the filtrate was concentrated and
crystallized from hexane/EtOAc 2:3 (25 mL). The pure
product 2 was obtained (2.0 g, 33%) as white crystals.
The supernatant was concentrated and purified by flash
chromatography (SiO2, 250 g; hexanes/EtOAc 7:3. In
this way another batch of product 2 was obtained (1.9 g,
31%). Combined yield was 64%.
1H NMR (300 MHz, CDCl3) δ: 7.77 (td, J=1.6Hz,
J=8.4Hz, 2H), 7.60 (td, J=1.7Hz, J=8.4Hz, 2H) 7.17
(m, 11H) 4.95 (s, 1H) 4.41 (t, J=7.9Hz, 1H) 4.28 (dq,
J=8.6Hz, J=4.2Hz, 1H) 3.31 (d, J=2.6Hz, 2H) 3.09 (dd,
J=11.2Hz, J=4.6Hz, 1H) 2.53 (ddd, J=1.1Hz, J=4.0Hz,
J=11.2Hz, 1H) 1.88 (m, 2H) 1.41 (d, J=3.2Hz, 1H)
ppm. 13C NMR (75MHz, CDCl3) δ: 38.7 , 61.2, 62.1,
70.4, 70.8, 76.8, 125.4, 125.6, 126.4, 126.6, 126.9,
128.1, 128.2, 128.3, 128.5, 139.5, 146.0, 147.6 ppm,
[α]D20 = +44.7 (c=1.01,CHCl3), Lit.[41] [α]D20 + 41.6 (c=1,
CHCl3). HRMS: m/z [M+H]+ calcd: 360.1958, found:
360.1962. Spectral data are in agreement with those in
the literature [41].
2. Experimental procedure
All reactions were carried out in an inert atmosphere of
N2 or Ar. Solvents were dried and purified by standard
methods before use. NMR spectra were recorded on
Varian Mercury plus instrument (300 MHz for 1H, 75 MHz
(3R,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)
pyrrolidin-3-yl 5-bromopentanoate (3)
1
for 13C) and Varian NMR System 600 (600 MHz for H,
Into a solution of DCC (1.8 g, 4.7 mmol) and DMAP
(90 mg, 0.71 mmol) in CH2Cl2 (50 mL) at 0°C,
5-bromopentanoic acid (1.5 g, 4.7 mmol) was added.
Then, compound 2 (2.55 g, 7.1 mmol) in CH2Cl2 was
added. The reaction mixture was stirred for 1 h at 0°C.
Then another portion of DCC (0.9 g, 2.4 mmol) and
5–bromopentanoic acid (0.8 g, 2.4 mmol) was added
and the reaction mixture was refluxed for 30 min. After
cooling, the mixture was filtered and collected solid
was washed with CH2Cl2 (3x15 mL). The combined
organic extracts were washed with concetrated HCl
(2.5 mL), saturated NaHCO3 solution (25 mL) and H2O
(25 mL). Organic layer was dried (Na2SO4), concentrated
and purified by column chromatography (SiO2, 200 g,
hexanes/EtOAc 85:15). Pure product 3 (3.23 g, 87%)
was obtained as yellow oil.
150 MHz for 13C). Chemical shifts (δ) are given in ppm
relative to tetramethylsilane. Specific optical rotations
were measured on Jasco instrument and are given in
deg cm−3 g−1 dm−1. Flash chromatography was performed
on Merck silica gel 60. Thin-layer chromatography was
performed on Merck TLC-plates silica gel 60, F-254.
Diastereomeric ratios were determined by 1H NMR and
GC (Agilent Technologies 6850). Enantiomeric ratios
were determined by HPLC on Chiralpak, OD-H and IC
(Daicel Chemical Industries), column using hexane/
iPrOH as a mobile phase and detection with UV-
detector at 211-259 nm. Catalyst C2 was synthesized
according to literature procedure [42]. Relative and
absolute configurations of products 7, 10, 12, and 14
were assigned by comparison to their retention time
from enantioselective HPLC with literature values.
417

Enantioselective Michael additions of aldehydes
to nitroalkenes catalyzed with ionically tagged organocatalyst
1H NMR (300 MHz, CDCl3) δ: 7.78 (td, J=1.7Hz, at 60°C. The product 4 (3.76 g, 99%) was obtained as
J=8.5Hz, 2H), 7.60 (td, J=1.7Hz, J=8.4Hz, 2H), 7.18 white crystalline solid. Overal yield from 3 was 75%.
(m, 11H), 5.06 (m, 1H), 4.84 (s, 1H), 4.35 (t, J=8.0Hz,
1H NMR (300 MHz, CDCl3) δ: 8.84 (s, 1H), 7.77 (dd,
1H), 3.40 (m, 3H), 3.21 (m, 2H), 2.62 (ddd, J=1.0Hz, J=1.1Hz, J=8.4Hz, 2H), 7.59 (dd, J=1.1Hz, J=8.3Hz,
J=3.4Hz, J=12.0Hz, 1H) 2.33 (td, J=2.4Hz, J=8.2Hz, 2H), 7.20 (m, 11H), 6.99 (dd, J=1.7Hz, J=7.5Hz, 2H),
2H), 1.86 (m, 6H) ppm. 13C NMR (75MHz, CDCl3) δ: 5.01 (dd, J=4.8Hz, J=9.6Hz, 1H), 4.82 (s, 1H), 4.35 (t,
23.5, 31.8, 33.0, 33.6, 35.6, 59.4, 61.0, 70.4, 73.7, 76.7, J=7.9Hz, 1H), 4.18 (t, J=7.3Hz, 2H), 3.90 (s, 3H), 3.33
125.3, 125.6, 126.5, 126.7, 127.1, 128.2, 128.3, 128.5, (d, J=12.8Hz, 1H), 3.19 (m, 2H), 2.58 (dd, J=3.8Hz,
20
139.1, 145.7, 147.4, 172.5 ppm. [α]D = +21.4, (c=1, J=11.6Hz, 1H), 2.36 (dt, J=1.7Hz, J=7.1Hz, 2H), 1.92
MeOH); Lit.[41] [α]D20 = +17.9 (c=1, MeOH). HRMS: m/z (m, 4H), 1.60 (m, 2H) ppm. 13C NMR (75MHz, CDCl3)
[M+H]+ calcd: 522.1638, found: 522.1646. Spectral data δ: 21.0, 29.1, 33.0, 35.5, 36.4, 49.8, 59.2, 60.9, 70.1,
are in agreement with those in the literature [41].
3 - ( 5 - ( ( 3 R , 5 S ) - 1 - b e n z y l - 5 - 125.4, 125.6, 126.5, 126.7, 127.1, 128.2, 128.3, 128.4,
(hydroxydiphenylmethyl)
pyrrolidin-3-yloxy)-5- 128.5, 136.5, 139.0, 145.7, 147.3, 172.5 ppm, [α]D20 = +
oxopentyl)-1-methyl -1H-
(trifluoromethylsulfonyl)amide (4)
The ester 3 (3.23 g, 6.18 mmol) was mixed with
1-metyl-1H-imidazol (2.54 g, 6.18 mmol) and the methyl) pyrrolidin-3-yloxy)-5-oxopentyl)-1-methyl-
73.6, 76.8, 119.8 (q, J=321Hz, 2C, CF3), 122.1, 123.4,
imidazol-3-ium
bis 7.1 (c=1.0, CHCl3). HRMS: m/z [M+H]+ calcd: 524.2913,
found: 524.2904.
3-(5-((3R,5S)-5-(diphenyl(trimethylsilyloxy)
resulting mixture was stirred for 10 min at 100°C. After 1H-imidazol-3-ium
cooling, the mixture was washed with Et2O (5×5 mL) at amide (C1)
bis(trifluoromethylsulfonyl)
room temperature and with hot Et2O (reflux, 2×5mL).
Into a solution of alcohol 4 (3.76 g, 4.67 mmol)
The residue was dissolved in MeOH (3 mL) and into this in CH2Cl2 (80 mL), Et3N (1.04 mL, 7.47 mmol)
solution again Et2O (20 mL) was added and the mixture and TMSOTf (1.66 g, 7.47 mmol) were added over
was stirred for 5 min. Upper layer was separated and 20 min at 0°C. The reaction mixture was stirred for 18 h
the rest was again washed with Et2O (3 mL). Then and temperature was let to rise to r.t. Then H2O (100 mL)
the residue was purified by column chromatography was added and layers were separated. Aqueous phase
(SiO2, 200 g, CH2Cl2/MeOH = 9:1). 3-(5-((3R,5S)-1- was extracted with CH2Cl2 (3×50 mL). Combined organic
benzyl-5-(hydroxydiphenylmethyl)pyrrolidin-3-yloxy)- extracts were vigorously stirred with NaHCO3 for 15 min,
5-oxopentyl)-1-methyl-1H-imidazol-3-ium
(2.82 g, 76%) was obtained as white solid.
bromide then it was washed with H2O (3x), dried (Na2SO4) and
concentrated. Drying under reduced pressure afforded
1H NMR (300 MHz, CDCl3) δ: 10.86 (s, 1H), 7.79 3-(5-((3R,5S)-1-benzyl-5-(diphenyl(trimethylsilyloxy)
(d, J=7.5Hz, 2H), 7.61 (dd, J=2.3Hz, J=6.2Hz, 2H), methyl) pyrrolidin-3-yloxy)-5-oxopentyl)-1-methyl-
7.23 (m, 11H), 7.01 (d, J=6.2Hz, 2H), 5.03 (td, J=4.4Hz, 1H-imidazol-3-ium bis (trifluoromethylsulfonyl)amide
J=9.0Hz, 1H), 4.83 (s, 1H), 4.38 (t, J=7.2Hz, 3H), 4.06 (3.97 g, 97%) as pale yellow viscous oil.
(s, 3H), 3.38 (m, 1H), 3.24 (m, 2H), 2.60 (m, 1H), 2.39
1H NMR (300 MHz, CDCl3) δ: 9.08 (s, 1H) 7.57 (m,
(ddd, J=6.8Hz, J=10.2Hz, J=16.7Hz, 2H), 1.99 (m, 4H), 4H), 7.21 (m, 13H) 4.46 (m, 1H), 4.20 (m, 4H), 3.94 (s,
1.64 (m, 2H) ppm. 13C NMR (75MHz, CDCl3) δ: 21.2, 3H), 3.59 (m, 1H), 2.61 (m, 1H), 2.31 (m, 3H), 2.10 (m,
29.4, 33.2, 35.5, 36.7, 49.7, 59.2, 60.9, 70.3, 73.6, 2H), 1.90 (m, 2H), 1.57 (m, 2H), -0.18 (s, 9H) ppm. 13C
76.8 122.0, 123.1, 125.4, 125.6, 126.5, 126.7, 127.1, NMR (75MHz, CDCl3) δ: 1.9, 21.0, 29.1, 33.0, 35.2, 36.4,
128.2, 128.3, 128.4, 128.6, 137.8, 138.9, 145. 7, 147.2, 49.8, 58.0, 62.2, 71.5, 74.4, 84.4, 119.8 (q, J=321,2 Hz,
20
172.5 ppm, [α]D20 = +5.7 (c=0.99,CHCl3); Lit.[41] [α]D
=
2C, CF3), 122.2, 123.4, 127.2, 127.3, 127.4, 128.1,
+1.8 (c=1, CHCl3). HRMS: m/z [M+H]+ calcd: 524.2913, 128.27, 128.33, 128.6, 128.5, 129.4, 129.5, 136.4,
found: 524.2907. Spectral data are in agreement with 143.2, 143.6, 172.8 ppm. [α]D20 = - 24.8 (c=1.01, CHCl3).
those in the literature [41].
To solution of 3-(5-((3R,5S)-1-benzyl-5-
(hydroxydiphenylmethyl)pyrrolidin-3-yloxy)-5- (diphenyl(trimethylsilyloxy)methyl)pyrrolidin-3-
oxopentyl)-1-methyl-1H-imidazol-3-ium bromide yloxy)-5-oxopentyl)-1-methyl-1H-imidazol-3-ium bis
HRMS: m/z [M+H]+ calcd: 596.3308, found: 596.3331.
a
A
solution 3-(5-((3R,5S)-1-benzyl-5-
(2.82 g, 4.67 mmol) in distilled H2O (80 mL), a solution of (trifluoromethylsulfonyl)amide (4.96 g, 4.52 mmol)
LiNTf2 (2.68 g, 9.34 mmol) in distilled H2O (80 mL) was in MeOH (70 mL) was stirred under H2 atmosphere
added over 10 min at 20°C. Separated solid material was (balloon) in the presence Pd/C (5%, 770 mg,
decanted and washed with distilled H2O (3×300 mL). 0.36 mmol) for 20 h. Then the Pd/C was filtered off with
The solid material was dried under reduced pressure the help of Celite. Filtrate was concentrated and dried
418

R. Šebesta, A. Latika
under reduced pressure. Catalyst C1 (3.3 g, 90%) was (syn, minor), 17.41 (syn, maJor) min. Spectroscopic
obtained as a yellow honey-like material.
data are in agreement with those in the literature [45].
(2R,3S)-2-benzyl-4-nitro-3-phenylbutanal (10)
Chromatography hexanes/EtOAc 1:1.
1H NMR (300 MHz, CDCl3) δ: 8.88 (s, 1H), 7.45
(td, J=2.3Hz, J=8.7Hz, 2H), 7.28 (m, 10H), 4.97 (td,
J=3.5Hz, J=5.9Hz, 1H), 4.34 (dd, J=6.8Hz, J=9.1Hz,
1
syn-10: Colorless oil. H-NMR (300 MHz, CDCl3) δ
1H), 4.20 (t, J=7.3Hz, 2H) 3.93 (s, 3H), 2.93 (m, 2H), 9.72 (d, J = 2.3Hz, 1H), 7.38-7.11 (m, 8H), 7.03 (dd,
2.36 (dt, J=1.8Hz, J=7.0Hz, 2H), 2.15 (m, 1H), 1.90 (m, J = 7.9, 1.5 Hz, 2H), 4.73-4.70 (m, 2H), 3.87-3.79 (m,
3H), 1.63 (m, 3H), -0.10 (s, 9H) ppm. 13C NMR (75MHz, 1H), 3.16-2.98 (m, 1H), 2.78-2.75 (m, 2H). 13C NMR
CDCl3) δ: 2.01, 20.98, 29.07, 33.00, 34.42, 36.45, 49.76, (75MHz, CDCl3): δ 203.02, 137.13, 136.64, 129.27,
52.94, 64.58, 75.05, 82.60, 119.70 (q, J=321,0 Hz, 2C, 128.81, 128.75, 128.34, 128.07, 126.95, 78.02, 55.28,
CF3), 122.21, 123.44, 127.39, 127.53, 127.57, 127.93, 44.44, 34.24. MS: neg. mode (M-H) 282.2. HPLC:
128.00, 128.34, 136.40, 144.22, 145.00, 172.71 ppm. (Chiralcel OD-H, hexane/iPrOH=9:1,
1
mL min-1,
20
[α]D
= -12.8 (c = 0.99, CHCl3). HRMS: m/z [M+H]+ λ=220 nm: tR= 50.41 (syn, minor), 55.17 syn, maJor)
calcd: 506.2839, found: 506.2834.
min. Spectroscopic data are in agreement with those in
the literature [46].
2.2. Typical procedure for the Michael addition
N-[(2R,3S)-1-nitro-4-oxo-3-benzyloxybutan-2-yl]
Organocatalyst (0.025 mmol, 10 mol%) and nitroalkene acetamide (12)
(0.25 mmol) were dissolved in a solvent (0.5 mL for
Mixture of two diastereomers. Colorless oil. 1H NMR
each 0.25 mmol of nitroalkene) and chloroacetic (300 MHz, CDCl3) δ: 9.61(s, 1H) and 9.60 (d, J = 2.5
acid (0.05 mmol, 20 mol%). After 10 min stirring, Hz, 1H), 7.41-7.21(m, 5H+5H), 6.03-5.91(m, 1H + 1H),
aldehyde (0.375 mmol) was added and the resulting 5.21-5.13 (m, 1H), 4.87-4.69 (m, 5H), 4.58-4.49 (m,
mixture was stirred at 20°C for 24 h. The mixture was 2H+2H), 4.15 (d, J=2.7 Hz, 1H), 3.93 (dd, J=7.6, 2.5 Hz,
then extracted with Et2O (4×1.5 mL). The combined 1H), 1.97 (s, 3H), 1.94 (s, 3H). 13C NMR (75MHz, CDCl3)
extracts were concentrated and the residue was δ: 199.75 and 199.10, 170.32 and 170.16, 135.93 and
purified by column chromatography (25 g of silica gel, 135.83, 129.6-127.85, 81.58 and 81.03, 74.32 and
hexanes/EtOAc).
74.08, 73.68, 46.97 and 46.85, 22.99 and 22.94. MS:
(M+H) 281.1. HPLC for triphenylphosphoranylidene
derivative (Chiralpak IC column, hexane/iPrOH = 82:18,
, λ=254 nm: tR= 14.99 (anti), 19.45 (syn),
23.00 (anti), 35.52 (syn) min. Spectroscopic data are in
agreement with those in the literature [45].
2.3. Recycling
The residue after extracting the reaction mixture with 1.2 mL min-1
Et2O was charged with a new batch of nitroalkene and
aldehyde, and the reaction was repeated.
(2R,3S)-tert-butyl
2-(nitromethyl)-4-oxo-3-
2.4. Characterisation data
(pentan-3-yloxy)butanoate (14)
1
N-[(2R,3S)-1-nitro-4-oxo-3-(pentan-3-yloxy)butan-2-
yl]acetamide (7)
syn-14: Colorless oil. H NMR (300 MHz, CDCl3) δ:
9.74 (s, 1H), 4.86 (dd, J = 14.3, 7.7 Hz, 1H), 4.47 (dd, J
= 14.3, 6.2 Hz, 1H), 4.00 (d, J = 3.1 Hz, 1H), 3.79-3.73
(m, 1H), 3.39-3.31 (m, 1H), 1.62-1.48 (m, 4H), 1.44 (s,
9H), 0.96(t, J = 7.3Hz, 3H) 0.90 (t, J = 7.4 Hz, 3H). 13C
NMR (75MHz, CDCl3) δ: 201.92, 167.01, 83.65, 83.39,
79.42, 72.24, 46.51, 27.82, 26.09, 25.12, 9.31.
Chromatography hexanes/EtOAc 1:1.
1
syn-7: Colorless oil. H NMR (300 MHz, CDCl3) δ:
9.65 (s, 1H), 6.03 (d, J = 8.7 Hz, 1H), 5.12-5.02 (m,
1H), 4.58 (d, J = 6.6 Hz, 2H), 4.09 (d, J = 3.3 Hz, 1H),
3.41(q, J = 5.8 Hz, 1H) 1.99 (s, 3H), 1.63-1.48 (m, 4H),
0.98-0.84 (m, 6H). 13C NMR (75 MHz, CDCl3) δ: 201.01,
170.05, 83.60, 79.52, 74.05, 48.03, 25.93, 24.99, 23.07,
9.38, 9.29. MS: neg. mode (M-H) 259.
anti-7: Colorless oil.1H NMR (300 MHz, CDCl3) δ:
9.61(d, J = 3.1Hz, 1H), 6.10 (d, J = 8.5 Hz, 1H), 4.84-
4.52 (m, 3H), 3.93 (dd, J = 8.0, 3.1Hz, 1H), 3.31-3.23
(m, 1H), 2.00 (s, 3H), 1.57-1.42 (m, 4H), 0.95-0.84 (m,
6H). 13C NMR (75MHz, CDCl3) δ: 201.07, 170.27, 83.19,
80.31, 74.05, 47.08, 26.05, 24.83, 23.09, 9.47, 9.13.
MS: neg. mode (M-H) 259.
1
anti-14: Colorless oil. H NMR (300 MHz, CDCl3) δ
9.69 (d, J = 1.4Hz, 1H), 4.79 (dd, J = 15.0, 8.7 Hz, 2H),
4.45 (dd, J=15.0, 4.2 Hz, 1H), 4.24 (dd, J = 4.9, 1.5 Hz,
1H), 3.66-3.58 (m, 1H), 3.36-3.28 (m, 1H), 1.62-1.48 (m,
4H), 1.46 (s, 9H), 0.91(t, J = 7.5 Hz, 3H) 0.87 (t, J = 7.5
Hz, 3H). 13C NMR (75MHz, CDCl3) δ 200.50, 168.26,
83.60, 83.15, 79.52, 71.33, 45.13, 27.82, 25.88, 25.09,
9.49. HPLC for ethyl(triphenyl-phosphoranylidene)
acetate derivative (Chiralpak IC column, hexane/iPrOH
= 200:1, 1mL min-1, λ=211 nm: tR= 55.97 (syn, major),
58.23 (anti, major), 105.60 (syn, minor), 146.80 (anti,
minor) min. Spectroscopic data are in agreement with
those in the literature [47].
HPLC for triphenylphosphoranylidene derivative
(Chiralcel OD-H, hexane/iPrOH=8:2, 0.75 mL min-1,
λ=259 nm: tR= 7.95 (anti, minor), 9.54 (anti, major), 11.44
419

Enantioselective Michael additions of aldehydes
to nitroalkenes catalyzed with ionically tagged organocatalyst
Scheme 1. Synthesis of catalyst C1, structure of catalyst C2 and C3.
chloroacetic acid as additive and 0°C as reaction
temperature.
Ionically-tagged catalyst C1 affords in the Michael
addition of aldehyde 5 to alkene 6 mainly syn-7 isomer.
The absolute configuration of product syn-7 is (S,R)
that is the same as obtained with catalyst C3. With
ionically-tagged catalyst C1, we again evaluated some
of the reaction parameters, such as solvent, additive,
temperature and reaction time. The results of condition
screening in non-ionic solvents are summarized in
Scheme 2. The reaction of aldehyde 5 with alkene 6.
3. Results and discussion
Organocatalyst C1 can be synthesized by known Table 1. Several notable features can be observed.
methods from simple starting materials by a sequence The best solvent was again chloroform/water mixture.
developed by Zlotin and coworkers [41]. When we Longer reaction times seem to be detrimental to the
repeated the procedure, however, this synthesis did yield of the product as well as its stereochemical integrity
not afford pure product. Therefore, we interchanged (Table 1, cf. entries 3 and 4). We also attempted to use
the order of reaction steps in the later stage of the recycled catalyst C1, but no product 7 was isolated from
synthesis (Scheme 1). In addition, we have prepared this experiment (Table 1, entry 7). With catalyst C2,
catalyst C1 with bis(trifluormethylsulfonyl)imide (NTf2) comparable results were obtained as with catalyst C1
anion instead of hexafluorophosphate, because NTf2 is (Table 1, entry 12).
considered to be more stable and does not release HF
Although, there are examples in the literature in which
upon decomposition. We have also employed ionically ionically-tagged catalysts were used and even recycled
tagged catalyst developed by Lombardo and coworkers in non-ionic media, catalyst C1 could not be recycled
(C2) [42] (Scheme 1). For comparison, we also used in the Michael reaction of aldehyde 5 with nitroalkene
non-tagged Jorgensen-Hayashi catalyst (C2).
6 in CHCl3/water mixture. Catalyst C1 was designed
With ionically-tagged catalyst C1 in hand, we for use in ionic liquid media. We evaluated both neat
started to assess its performance in enantioselective ionic liquids and their mixtures with chloroform because
1,4-additions. For the first Michael addition, we chose a chloroform seems to have a beneficial effect on the
reaction of aldehyde 5 with nitroalkene 6, which affords reaction. The results of experiments in ionic liquids are
compound 7 (Scheme 2). Compound 7 is a valuable summarized in Table 2. The Michael addition of aldehyde
intermediate in the short organocatalytic synthesis of 5 with nitroalkene 6 was evaluated at two different
oseltamivir [45,48,49]. From our previous studies of temperatures, 0 and 20°C. The differences were mostly
this reaction with non-tagged catalyst C3, we knew that small with a predictable outcome. Lower temperature
the best conditions comprised CHCl3/H2O as solvent, slowed down the reaction, but enantioselectivities were
420

R. Šebesta, A. Latika
Table 1. Screening for optimal reaction condition on the addition of 5 to 6.a
Entry
Solvent/condition
Time (h)
Yield (%)
d.r.b
ee (%)c
1
CHCl3/No additive/C1
CHCl3/Cl-AcOH/C1
70
40
18
70
5
43
81
72
48
61
72
0
52:48d
58:42d
66:34d
50:50d
72:28
63:37
-
66/44
72/54
76/43
63/48
85/10
68/20
-
2
3
CHCl3/ Cl-AcOH/C1
4
CHCl3/ Cl-AcOH/C1e
5
CHCl3/ Cl-AcOH,0°C/C1
CHCl3/PhCO2H, -5°C/C1
CHCl3/recycled C1/Cl-AcOH
DMF/ Cl-AcOH /C1
6
17
20
40
40
70
5
7
8
49
55
13
71
79e
65
71
62:38d
55:45d
62:38d
58:42
68:32
57:43d
80:20
50/43
21/4
9
DMSO/ Cl-AcOH /C1
10
11
12
13
14
CHCl3/H2O/No additive/C1
CHCl3/H2O (3:2)/Cl-AcOH,0°C/C1
CDCl3/H2O, Cl-AcOH/C2
CHCl3/H2O/C3 /Cl-AcOH
CHCl3/H2O/C3/Cl-AcOH, 0°C
40/30
81/-5
85/20
72/52
93/17
18
18
5
aConditions: nitroalkene 6 (0.25 mmol), aldehyde 5 (0.375 mmol), C1 (0.025 mmol), CHCl3 (0.5 mL), H2O (0.5 mL), 20°C, ClCH2CO2H (0.05 mmol);
bRatio of syn-7/anti-7, determined by 1H NMR of the crude reaction mixture;
cee syn-7/anti-7, determined by enantioselective HPLC;
dd.r. of chromatographically purified product;
e0.1 mmol (40 mol%) of ClCH2CO2H was used and conversion determined by 1H NMR.
slightly higher (Table 2, cf. entries 3 and 9, 6 and 7). by flash chromatography. An alternative procedure for
On the other hand, structure of ionic liquid had a much isolating product 7 was to subject the whole reaction
larger influence on the Michael addition of 5 with 6. mixture to column chromatography. However, recycling
Three ionic liquids stand out in terms of isolated yield of is not possible in this way.
product 7 and its enantiomeric purity. The best results
were obtained in [bmpyr]BF4, [bmim]NTf2, and [bdmim] 6, we tested recyclability of the catalyst C1. For recycling
NTf2 (Table 2, entries 7, 9-10, and 14). experiments, we have selected [bdmim]NTf2, one of the
In the Michael addition of aldehyde 5 with nitroalkene
Contrary to the commonly perceived notion that ionic liquids, in which the reaction worked best. The
organic compounds are easily extracted from ionic catalyst can be used repeatedly, but reduction of yield
liquids with non-polar organic solvents, we have and enantiomeric purity of product 7 was observed. The
encountered difficulties in isolating product 7 from ionic main reason for decreased performance was probably
liquids by extraction with Et2O. To test extractability of catalyst decomposition. This was evidenced by 1H
the product, we dissolved a fixed amount of compound 7 NMR analysis of the catalyst C1 after the reaction,
in ionic liquid ([bdmim]NTf2) and extracted it with various which showed its decomposition. The notion was
solvents and procedures. Surprisingly, even when also supported by the fact that yield and enantiomeric
repeating extractions, we were not able to fully recover purity of product 7 increased in the fourth run, in which
compound 7 from ionic liquids. Taking into account 10 mol% of fresh catalyst C1 was added to the reaction
solubility of compound 7 and miscibility of the ionic liquid mixture. The decomposition of prolinol silyl ethers in
with organic solvents, only Et2O, tBuOMe, toluene and polar and acidic media was also described by Zeitler,
cyclohexane were suitable. After 10 extractions, 45% of Gschwind and co-workers [50]. Another practical issue
product 7 was obtained with Et2O and 44% with toluene. is that quality of Et2O, used for extracting product
However, substantial amounts of ionic liquid was also 7 from the ionic liquid, affecting the recyclability of
extracted. A continual extraction was more effective in catalyst C1. Using distilled and dried Et2O led to
obtaining product 7, where it was recovered in almost considerably improved recyclability of the catalyst
quantitative yield after 5 h with Et2O. However, similarly C1. Probably, removal of reactive organic peroxide
to batch extraction, substantial quantities of ionic liquid from technical Et2O was responsible for this fact.
was extracted and contaminated the product. The The results of the C1 recycling are summarized in
extracted ionic liquid could be separated from the product Table 3.
421

Enantioselective Michael additions of aldehydes
to nitroalkenes catalyzed with ionically tagged organocatalyst
Table 2. Addition of aldehyde 5 to nitroalkene 6 catalyzed by C1 in ionic liquidsa.
Entry
Solvent/conditions
Yield (%)
d.r. (syn:anti)b
ee (syn/anti)c
1
CHCl3/[bmim]BF4/A
CHCl3/[bmim]PF6/A
CHCl3/[bmim]NTf2/A
CHCl3/[bmim]N(CN)2/A
CHCl3/[bmim]MeCO3/A
CHCl3/[bmpyr]BF4/A
CHCl3/[bmpyr]BF4/B
CHCl3/[bmim]BF4/B
CHCl3/[bmim]NTf2/B
CHCl3/[bdmim]NTf2/B
CHCl3/[bmim]OTs/B
CHCl3/[bmim]OTf/B
[bdmim]NTf2/B
23
67
2:1
1:1.2
2.3:1
1:1
84/43
40/-45
85/67
38/37
-
2
3
61
4
11
5
0
-
6
32
1.9 : 1
1.3 :1d
1:1.3d
1.6:1d
1.4:1d
1.3:1d
-
83/25
73/47
78/67
75/55
86/68
73/26
-
7
76f(48)e
52
8
9
74
10
11
12
13
14
15
16
17
67
60
0
38
1.2:1d
1.3:1d
1.3:1d
1.4:1d
1.3:1d
78/78
69/32
27/-20
78/6
[bdmim]NTf2/C
95
[bdmim]NTf2/H2O/C
[bdmim]NTf2/CHCl3/H2O/B
[bdmim]NTf2/CHCl3/H2O/C
65
14
41
21/25
aConditions: nitroalkene 6 (0.25 mmol), aldehyde 5 (0.375 mmol), C1 (0.025 mmol), ionic liquid (0.5 mL), 20°C, ClCH2CO2H (0.05 mmol), time
22-24 h;
bDetermined by 1H NMR of the crude reaction mixture;
cDetermined by enantioselective HPLC;
ddr of isolated product;
eproduct was isolated by extraction with Et2O;
fAverage of two experiments. A: ClCH2CO2H, 0°C; B: ClCH2CO2H, 20°C; C: no additive, 20°C.
Table 3. Recycling of C1 in the reaction of 5 with 6 in [bdmim]NTf2a.
The catalyst C1 was evaluated also in the reaction
of 3-phenylpropanal (8) with β-nitrostyrene (9). The
resulting product 10 was isolated as a mixture of two
diastereomers. Usually dominant isomer syn-10 had
high enantiomeric purity. Interestingly, the product 10
was isolated in higher yield and with higher enantiomer
purity in ionic liquid [bmim]NTf2 than in toluene
(Scheme 3).
Run
Yield
d.r. (syn:anti)b
ee (syn/anti)c
1
56
22
28
51
1.3 : 1
1.3 : 1
1.2 : 1
1.4 : 1
79/40
36/32
39/29
60/29
2
3
4d
In the reaction of aldehyde 8 with β-nitrostyrene (9),
the catalyst C1 was recycled for seven times without
loss of enantioselectivity. Its catalytic activity decreased
gradually after the fifth run (Table 4). These results also
suggest that stability of catalyst C1 depends on the
structure of reactants. It is therefore possible that the
stability of the intermediate enamine resulting from an
aldehyde and catalyst plays an important role.
aConditions: nitroalkene
6 (0.25 mmol), aldehyde 5 (0.375 mmol),
C1 0.025 mmol), [bdmim]NTf2 (1 mL), 20°C, 20 h, the product was
extracted with Et2O (7×5 mL), the residual solvent was removed under
vacuum and new nitroalkene and aldehyde were added;
bDetermined by 1H NMR of the crude reaction mixture;
cDetermined by enantioselective HPLC;
d0.025 mmol of new C1 was added.
Michael addition of benzyloxyacetaldehyde (11)
with nitroalkene 6 affords product 12, which can lead
to an oseltamivir analogue [45]. This Michael addition
can also be performed with ionically-tagged catalyst C1,
but neither diastereoselectivity or enantioselectivity was
observed in ionic liquid [bdmim]NTf2 (Scheme 4).
Scheme 3. Michael addition of aldehyde 8 to nitrostyrene (9).
422

R. Šebesta, A. Latika
Table 4. C1 recycling in the reaction of 8 with 9 in [bmim]NTf2.
Run
Time
(h)
Yield
of 10 (%)
syn-10/anti-
10
ee
(syn:anti)
1
2
3
4
5
6
7
8
28
45
72
72
96
72
72
72
44
51
69
65
68
47
37
14
79:21
77:23
78:22
79:21
78:22
78:22
78:22
78:22
93/30
89/30
94/26
93/25
94/26
93/27
91/25
91/19
Scheme 4. Michael addition of aldehyde 11 to alkene 6.
Scheme 5. Michael addition of aldehyde 5 to nitroalkene 13.
aConditions: nitroalkene 9 (0.5 mmol), aldehyde 8 (0.75 mmol), C1
(0.025 mmol), [bmim]NTf2 (0.5 mL), 20°C;
bdr of isolated product;
showed that the main reason for low recyclability was
again catalyst decomposition (Table 5, entries 6 and
7). The results of Michael addition of aldehyde 5 with
nitroalkene 13 are summarized in Table 5.
cDetermined by enantioselective HPLC.
Table 5. Michael addition of 5 with 13 in [bdmim]NTf2.
Entry
Conditions
Time Yield
d.r.b
eec
(h)
(%)
4. Conclusions
1
2
3
4
5
6
7
No additive
Cl-AcOH
48
24
22
22
22
24
24
8 %
94 %
71%
6%
-
63:37
57:43
55:45
-
-
Ionically-tagged diphenylprolinol silyl ether is a useful
organocatalyst for enantioselective Michael additions
of aldehydes to nitroalkenes. These reactions can be
performed well in ionic liquids, and, with one exception,
the results obtained in ionic liquids are comparable
to classical solvents. A useful feature of the catalytic
system comprising ionically tagged catalyst in an
ionic liquid is its recyclability, although this depends
95/94
95/91
-
Cl-AcOH, 2nd cycle
Cl-AcOH, 3rd cycle
Cl-AcOH, 4th cycle
Cl-AcOH, 5 mol% C1
Cl-AcOH, 2.5 mol% C1
-
-
95
62:38
52:48
93/90
94/94
37
aConditions: nitroalkene 13 (0.25 mmol), C1 (0.025 mmol), aldehyde
5 (0.375 mmol), ClCH2CO H (0.05 mmol), [bdmim]NTf2 (0.5 mL), 20°C; the on the structure of substrates and is, to some extent,
reaction mixture was extra2cted with Et2O (4x);
limited by inherent instability of silyl ethers in polar
media.
bsyn-14:anti-14 determined by 1H NMR after chromatography;
cee syn-14/anti-14 determined by enantioselective HPLC.
A reaction of aldehyde 5 with nitroacrylate 13
is another useful organocatalytic Michael addition Acknowledgements
(Scheme 5). The product 14 was elaborated by Hayashi
into oseltamivir [47,51]. Ionically-tagged catalyst C1 The European Commission is gratefully acknowledged
was able to efficiently catalyze this reaction as well. for financial support; project FP7-201431 (CATAFLU.
The product 14 was isolated in good yield and with OR). This work was also supported by the Slovak
high enantiomeric purity, although with only a modest Research and Development Agency under the contract
diastereomeric ratio (Table 5, entry 2). The catalyst C1 No. DO7RP-0017-08. This publication is the result of
was recycled at least one time with good results, but, project implementation: 26240120025 supported by the
in subsequent cycles, remarkably little of the product Research & Development Operational Program funded
14 was isolated (Table 5, entries 3-5). Experiments by the ERDF. We also thank Prof. Štefan Toma for
with adding additional catalyst and only 2.5 mol% of C1 valuable discussions.
423

Enantioselective Michael additions of aldehydes
to nitroalkenes catalyzed with ionically tagged organocatalyst
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