Chiral Imidazolium Ionic Liquids Derived from (S)-Prolinamine as Organocatalysts in the Asymmetric Michael Reaction and Michael-Aldol Cascade Reaction under Solvent-Free Conditions

Article abstract of DOI:10.1002/ejoc.201700133

The synthesis of three new chiral imidazolium ionic liquids (prepared by the combination of one new chiral organic cation with different anions) and their application in the enantioselective Michael reaction between cyclohexanone and substituted nitrostyr

Full text of DOI:10.1002/ejoc.201700133

A Journal of
Accepted Article
Title: Chiral Imidazolium Ionic Liquids derived from (S)-Prolinamine
as Organocatalysts in the Asymmetric Michael Reaction and
Michael-Aldol Cascade Reaction under Solvent-Free Conditions
Authors: Arturo Obregón-Zúñiga, Marco Guerrero-Robles, and Eusebio
Juaristi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700133
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10.1002/ejoc.201700133
European Journal of Organic Chemistry
FULL PAPER
Chiral Imidazolium Ionic Liquids derived from (S)-Prolinamine as
Organocatalysts in the Asymmetric Michael Reaction and
Michael-Aldol Cascade Reaction under Solvent-Free Conditions
Arturo Obregón-Zúñiga,[a] Marco Guerrero-Robles,[a] and Eusebio Juaristi*[a][b]
Abstract: The synthesis of three novel chiral imidazolium ionic
liquids (prepared by the combination of one new chiral organic cation
with different anions) and their application in the enantioselective
Michael reaction between cyclohexanone and substituted
nitrostyrenes under solvent-free conditions is described. In addition,
the first asymmetric cascade Michael-Aldol reaction of
cyclohexanone and benzylidenepyruvate organocatalyzed by chiral
ionic liquids is reported. Recyclability of the catalyst was evaluated
on both reactions observing no loss in stereoselectivity up to the
third cycle.
synthesize chiral ionic liquids derived from (S)-prolinamine,
which was obtained following a synthetic route previously
reported by our group.[7]
Results and Discussion
N-Cbz-protected (S)-prolinamine (S)-1 was treated with
bromoacetyl bromide to afford bromoamide (S)-2 in 76% yield.
Following this, a quaternization reaction with 1-methylimidazole
gave imidazolium derivative (S)-3 in 98% yield. Subsequently,
Pd/C catalyzed hydrogenolysis effectively removed the N-Cbz
protecting group to obtain chiral ionic liquid bromide (S)-4 in
99% of yield. From chiral imidazolium salt (S)-3, anionic
exchange with salts KPF6 and Tf2NLi provided hydrophobic
chiral ionic liquids (S)-5 and (S)-6, in 84% and 89% yield,
respectively. Finally, hydrogenolytic N-Cbz group removal
afforded chiral ionic liquids (S)-7 and (S)-8 in 94% and 98%
yields, respectively (Scheme 1).
Introduction
Ionic liquids (IL) are salts that contain both an organic cation and
an organic or inorganic anion, and that present melting points
below 100 °C. This property enables their use as highly polar,
non-volatile solvents. Some of the most studied and versatile
ionic liquids are those incorporating an imidazolium cation.
These ILs have been used in many different organic
transformations, with excellent results.[1]
With the emergence of asymmetric organocatalysis,[2] several
chiral ionic liquids (CIL) have been developed and employed as
efficient recyclable organocatalysts in enantioselective
transformations.[3] Indeed, the highly polar nature of ILs
facilitates their separation from crude reaction mixtures.
In this context, the asymmetric Michael addition reaction is a
well-studied reaction where ionic liquids derived from (S)-proline
and (S)-prolinamine have been successfully employed as
organocatalysts.[4] The Michael reaction has also provided
access to the synthesis of highly valuable pharmaceutical
drugs,[5] owing to its versatility in the construction of C-C bonds
from readily available substrates. Moreover, several asymmetric
cascade reactions have a Michael addition as their starting
point.[6] With this backgroud, we decided to design and
Scheme 1. Synthetic route for the preparation of chiral imidazolium ionic
liquids (S)-4, (S)-7, and (S)-8.
With chiral imidazolium ionic liquids (S)-4, (S)-7 and (S)-8 at
hand, we examined their efficiency as organocatalysts in the
asymmetric Michael addition reaction between cyclohexanone
and -nitrostyrene. Bromide imidazolium salt (S)-4 gave the
poorest results, in terms of both yield and selectivity, even in the
presence of p-nitrobenzoic acid (p-NBA) as an additive (Table 1,
entries 1 and 2). On the other hand, chiral ionic liquids (S)-7 and
(S)-8 afforded rather similarly good,results (Table 1, entries 3
[a]
[b]
Departamento de Química, Centro de Investigación y de Estudios
Avanzados, Avenida Instituto Politécnico Nacional 2508, Colonia
Zacatenco, 07360 Ciudad de México, México.
E-mail: juaristi@relaq.mx
El Colegio Nacional, Donceles 104, Centro Histórico, 06020 Ciudad
de México, México.
and 4). In subsequent work, (S)-8 was discarded owing to the

high cost of Tf2N anion relative to PF6 .
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700133
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Table 1. Catalyst evaluation in the asymmetric Michael reaction between
cyclohexanone and -nitrostyrene.
(Table 3, entries 4 and 5). On the other hand, and contrary to
previous observations,[8] chiral Brønsted acid additives (R)- and
(S)-mandelic acid did not improve the reaction’s stereoselectivity
(Table 3, entries 6 and 7). Interestingly enough, strong acids
such as oxalic and trifluoroacetic acid inhibited product formation
(Table 3, entries 8 and 9). Based on these observations,
subsequent studies were carried out with p-NBA as an additive.
O
Ph
O
Cat. 10 mol%
NO2
anti
NO2
+
diastereoisomer
+
Ph
p-NBA 10 mol%
9a
10 equiv.
1 equiv.
Entry
Cat.
p-NBA
additive
No
Yes
Yes
Yield
dr
er
(%)[a]
44
(syn/anti)[b]
70:30
(syn)[c]
87:13
86:14
89:11
88:12
Table 3. Evaluation of acid additives in the outcome of the asymmetric
Michael reaction.
1
2
3
4
(S)-4
(S)-4
(S)-7
(S)-8
86
92
95
70:30
90:10
91:9
O
Ph
O
CIL (S)-7 10 mol%
Yes
NO2
anti
NO2
+
diastereoisomer
+
Ph
Additive 10 mol%
9a
[a] Determined after purification by flash chromatography. [b] Determined by
1H NMR from the crude reaction product. [c] Determined by HPLC with chiral
stationary phase.
6 equiv.
1 equiv.
Entry
Additive
Yield
dr
er
(%)[a]
92
88
91
76
43
8
(syn/anti)[b]
90:10
88:12
90:10
88:12
90:10
90:10
90:10
-
(syn)[c]
90:10
85:15
90:10
1
2
3
4
5
6
7
8
9
p-NBA
Benzoic acid
Salicylic acid
Formic acid
Acetic acid
(S)-Mandelic acid
(R)-Mandelic acid
Oxalic acid
We then screened different reaction conditions in order to
optimize the reaction yield. Firstly, the effect of solvent polarity
was evaluated, finding eventually that higher yields and shorter
reaction times were achieved under neat conditions (Table 2,
compare entries 2-8 with entry 1). Catalyst loading was also
analyzed, concluding that 10 mol% corresponds to the best
catalyst load. Indeed, 5 mol% and 15 mol% concentrations
resulted in lower yields and/or stereoselectivities (compare entry
1 with entries 9-11 in Table 2). Finally, seeking to minimize the
amount of ketone employed in the reaction it was found that 6
equivalents of cyclohexanone were sufficient to maintain a good
reaction performance (compare entries 12-16 in Table 2).
86:14
77:23
87:13
86:14
-
89
n/r
n/r
TFA
-
-
[a] Determined after purification by flash chromatography. [b] Determined by
1H NMR from the crude product. [c] Determined by HPLC with chiral stationary
phase.
The reaction was also carried out at 3 °C in order to examine the
effect of low temperature on stereoinduction by the
Table 2. Screening of reaction conditions for the optimization of the
asymmetric Michael reaction.
organocatalyst.
However,
stereoselectivities
remained
O
Ph
O
unchanged. Thus, ambient temperature was deemed as most
convenient.
CIL (S)-7 X mol%
p-NBA 10 mol%
NO2
anti
NO2
+
diastereoisomer
+
Ph
Solvent (1mL)
9a
X equiv.
Entry
1 equiv.
Table 4. Scope of the asymmetric Michael reaction.
Solvent
Cat.
mol%
Ketone
equiv.
Yield
(%)[a]
dr
er
(syn/anti)[b]
(syn)[c]
O
R3
O
CIL (S)-7 10 mol%
p-NBA 10 mol%
24 h
R1
NO2
NO2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Neat
H2O
MeOH
DMF
CH2Cl2
Toluene
BMImPF6
BMImBr
Neat
Neat
Neat
Neat
Neat
10
10
10
10
10
10
10
10
15
5
2.5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
8
92
60
28
70
74
75
60
37
88
75
60
92
92
85
76
72
90:10
85:15
90:10
90:10
90:10
90:10
90:10
89:11
88:12
91:9
90:10
84:16
87:13
88:12
88:12
85:15
90:10
88:11
87:13
89:11
90:10
86:14
90:10
87:13
90:10
90:10
anti
R1
R3
1 equiv.
R1
+
+
diastereoisomer
R2
R2
9b-o
6 equiv.
Entry
R2
R3
Yield
dr
er
(%)[a]
97
99
99
94
92
96
85
95
n/r
n/r
85
99
n/r
n/r
(syn/anti)[b]
(syn)[c]
94:6
92:8
89:11
95:5
84:16
90:10
65:35
91:9
-
1
2
3
4
5
6
7
8
9
10
11[d]
12
13
14
-(CH2)4-
2-Cl-C6H4
2-MeO-C6H4
2-Br-C6H4
4-F-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-BnO-C6H4
4-Me-C6H4
C6H5
93:7
94:6
93:7
85:15
91:9
91:9
88:12
89:11
-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)5-
91:9
88:12
90:10
88:12
89:11
90:10
6
4
2
1
Neat
Neat
Neat
C6H5
C6H5
C6H5
C6H5
-
-
-(CH2)2C[O(CH2)2O]CH2-
88:12[e]
-
90:10
55:45
-
[a] Determined after purification by flash chromatography. [b] Determined by
1H NMR from the crude reaction product. [c] Determined by HPLC with chiral
stationary phase.
Me
Et
Ph
H
Me
H
-
-
C6H5
-
[a] Determined after purification by flash chromatography. [b] Determined by
1H NMR from the crude product. [c] Determined by HPLC with chiral stationary
phase. [d] Reaction performed with 2 equiv. of the ketone and 0.1 mL of
CH2Cl2 to dissolve the solid reagents. [e] Determined by HPLC chiral
stationary phase.
In view of the beneficial effect induced by p-NBA as an acidic
additive, it was deemed of interest to explore the potential effect
of other Brønsted acids in the reaction. Benzoic acid and
salicylic acid gave similar results to those obtained with p-NBA
(Table 3, compare entries 1, 2 and 3). By contrast, formic acid
and acetic acid afforded the Michael product with lower yields
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10.1002/ejoc.201700133
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In order to establish the scope of the reaction, cyclohexanone
was added to several substituted -nitrostyrenes (Table 4). The
Michael products were obtained with excellent yields ranging
from 85% to 99%, while diastereomeric ratios varied from 85:15
to 93:7, and enantioselectivities from 65:35 to 95:5.
Table 5. Optimization of reaction conditions for the Michael-intramolecular
aldol cascade reaction.
COOMe
OH
O
O
HO
O
Ph
O
COOMe
Ph
O
CIL (S)-7 X mol%
Ph
+
+
+
COOMe
Ph
COOMe
p-NBA X mol%
HO
2 days
Aldol
by-product
X equiv
1 equiv
Michael-Aldol
product
Michael-Aldol
stereoisomers
10
With the exception of acetone, other ketones failed to react in
the Michael addition reaction. Nevertheless, although acetone
gave the Michael product with 99% yield, this was practically
racemic (Table 4, entry 12). Cyclopentanone, cycloheptanone,
and acetophenone either gave no reaction or proceeded in very
low yields (Table 4, entries 9, 10, 13 and 14).
Essay
mol% CIL (S)-7
and p-NBA
equiv.
ketone
6
6
10
Yield of 10
er[b]
(%)[a]
50
1
2
3
10
20
20
91:9
89:11
88:12
52
50
[a] Determined after purification by flash chromatography. [b] Determined by
HPLC with chiral stationary phase.
With these observations, catalyst (S)-7 was next employed in
the asymmetric Michael reaction of 1,4-cyclohexanedione
monoethylene acetal and -nitrostyrene, obtaining excellent
results both in terms of yield and stereoselectivity (Table 4, entry
11).
Interestingly, the major bicyclic product is structurally similar to
the tropane alkaloids, that are important compounds used as
drugs (Fig. 1, atropine and scopolamine) or narcotics (Fig.1,
cocaine and ecgonine).
Catalyst (S)-7 was also employed in the asymmetric Michael
reaction of 1,4-cyclohexanedione monoethylene acetal and
nitrostyrene, obtaining satisfactory results both in terms of
yield and stereoselectivity (Table 4, entry 11).
Tropane alkaloids
N
N
N
O
COOH
O
N
OH
Ph
OH
Ph
COOMe
OH
O
Ph
O
O
To the best of our knowledge, presently there is only one
cascade reaction that uses chiral ionic liquids. This cascade
reaction was reported by Zlotin and coworkers and consists in
an aza-Michael addition followed by intramolecular acetalization
reaction during the stereoselective preparation of 5-hydroxy-3-
arylisoxazolidines.[9]
O
O
Ecgonine
Atropine
Cocaine
Scopolamine
Figure 1. Representative tropane alkaloids structurally related to the major
cascade product reported herein.
Anticipating that chiral ionic liquid (S)-7 could be recovered and
reused, this catalyst was precipitated once the reaction was
complete by addition of diethyl ether, and separated by
decantation. Upon exposure to a new load of substrate and p-
NBA additive it was observed the enantioselectivity of the
reaction is maintained (Table 6) although the reaction yield
decreases significantly.
Motivated by the high stereoselectivity attained with our chiral
ionic liquid in the asymmetric Michael addition reaction with
cyclohexanone substrates (see above), we decided to expand
its application in a cascade reaction, in particular in the Michael-
Aldol cascade reaction organocatalyzed by N-(pyrrolidin-2-
ylmethyl)trifluoromethanesulfonamide previously reported by
Tang et al.[10] This cascade reaction gives rise to bicyclic
compounds containing up to four stereocenters via a formal
[3+3] intramolecular annulation.
Table 6. Evaluation of chiral ionic liquid recyclability in the asymmetric
Michael-intramolecular aldol cascade reaction.
O
To this end, we carried out an evaluation of the catalyst and p-
NBA additive loads, as well as the amount of cyclohexanone,
finding that the desired cascade reaction proceeds efficiently
with 10 mol% of CIL (S)-7, 10 mol% p-NBA and 6 equivalents of
cyclohexanone (Table 5, entry 1). A yield of 50% of the main
bicyclic product, whose relative and absolute configurations
proved to be similar to those assigned by Tang and coworkers to
their product. In particular, 1H and 13C NMR spectra are identical
and the optical rotation is of the same sign. Furthermore,
comparison of HPLC chromatograms corroborated the
assignment, and indicated a 91:9 enantiomeric ratio. The major
bicyclic product was accompanied by four minor stereoisomers
(combined yield = 14%) and by the aldol product that is
generated in the first step of the cascade reaction (yield = 16%).
In contrast with the report of Tang et al., we did not observe any
Diels-Alder by-product. It is worthy of mention that only 6
equivalents of cyclohexanone were required in the present work
instead of the 48 equivalents employed by Tang et al.
Furthermore, our reaction employs 10 mol% of organocatalyst
and additive, to be compared with the 20 mol% used with Tang’s
organocatalyst.
O
O
CIL (S)-7
Ph
10 mol%
+
Ph
COOMe
1 equiv.
COOMe
p-NBA
10 mol%
HO
10
6 equiv.
2 days
Cycle
Yield (%)[a]
er[b]
91:9
91:9
90:10
1
2
3
50
21
10
[a] Determined after purification by flash chromatography. [b] Determined by
HPLC with chiral stationary phase.
The catalyst recyclability was also examined in the model
Michael addition reaction, recording similar observations, that is
the stereoselectivity in the product is maintained although the
reaction yield decreases in subsequent cycles (Table 7).
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Table 7. Evaluation of chiral ionic liquid recyclability in the model asymmetric
Michael reaction.
the stirring was continued for 24 h at room temperature. Finally, the
solvent was removed under vacuum and the product was purified by
flash chromatography using hexane/EtOAc 1:1 as mobile phase. (S)-2
was obtained as a viscous yellow liquid, 5.30 g (14.97 mmol, 76% yield).
1H NMR (399.78 MHz, DMSO-d6, 120 °C): δ 7.37-7.25 (m, 5H, Ar), 5.08
(bs, 2H, N-CH2-Ph), 3.98 (bs, 2H, Br-CH2-CO), 3.97 (bs, 1H, NH), 3.81
(m, 1H, N-CH-CH2), 3.43-3.20 (m, 4H, N-CH2-CH and N-CH2-CH2), 1.91-
1.72 ppm (m, 4H, CH2-CH2). 13C NMR (100.52 MHz, DMSO-d6, 120 °C):
δ 172.6, 155.0, 137.8, 128.8, 128.1, 127.9, 66.5, 62.2, 57.5, 47.0, 41.8,
28.9, 23.4 ppm. IR film (cm-1): 3298, 2952, 2880, 1659, 1536, 1409, 1358.
O
Ph
O
CIL (S)-7
NO2
10 mol%
NO2
+
Ph
p-NBA
10 mol%
9a
6 equiv.
1 equiv.
24 h
25
HR MS-TOF: calcd. for C15H20O3N2Br+: 355.0652, found: 355.0655. []D
Cycle
Yield
(%)[a]
93
63
40
dr
(syn/anti)[b]
91:9
90:10
88:12
er
(syn)[c]
90:10
88:12
86:14
= 46.69, c = 1.037, MeOH.
1
2
3
(S)-3-(2-((1-(Benzyloxycarbonyl)pyrrolidin-2-yl)methylamino)-2-
oxoethyl)-1-methyl-1H-imidazol-3-ium bromide, (S)-3. In a 50 mL
round bottomed flask provided with magnetic stirrer, bromoamide (S)-2
(5.538 g, 15.59 mmol) was dissolved in 30 mL of EtOAc. 1-
Methylimidazole (1.50 mL, 18.7 mmol) was then added and the reaction
mixture was let to react with vigorous stirring for 18 h at ambient
temperature. The crude product (yellow viscous precipitate) was
decanted and washed with additional EtOAc (3x2 mL) to remove the
excess of 1-methylimidazole. The product was dissolved in MeOH (4 mL)
and then precipitated with Et2O (40 mL). The heterogeneous mixture was
left standing for 90 minutes to assure complete precipitation. The upper
layer was removed and the pure product was dried under vacuum until
constant weight. (S)-3 was isolated as a highly hygroscopic creamy solid,
mp = 63-66 °C, 6.688 g (15.29 mmol, 98% yield). 1H NMR (399.78 MHz,
DMSO-d6, 120 °C): δ 8.98 (bs, 1H, N-CH-N), 8.15 (bs, 1H, NHCO), 7.58
(m, 1H, N-CH-CH-N+), 7.56 (bs, 1H, +N-CH-CH-N), 7.36-7.26 (m, 5H, Ar),
5.07 (bs, 2H, CH2-Ph), 4.93 (bs, 2H, N-CH2-CO), 3.96-3.91 (m, 1H, N-
CH-CH2), 3.88 (bs, 3H, N-CH3), 3.43-3.29 (m, 4H, N-CH2-CH and N-CH2-
CH2), 1.94-1.71 ppm (m, 4H, CH2-CH2). 13C NMR (100.52 MHz, DMSO-
d6, 120 °C): δ 165.6, 155.2, 138.2, 137.7, 128.9, 128.2, 127.9, 124.1,
123.7, 66.6, 57.3, 51.5, 47.0, 42.4, 36.4, 28.8, 23.4 ppm. IR film (cm-1):
[a] Determined after purification by flash chromatography. [b] Determined by
1H NMR from the crude product. [c] Determined by HPLC with chiral stationary
phase.
Seeking an explanation for the fast deactivation of catalyst (S)-7
in recycling experiments, MS-TOF spectra of both the recovered
catalyst (precipitated upon diethyl ether addition to the crude
reaction product) and the ethereal phase were acquired and
analysed (see Supporting Information). It was found that part of
the catalyst dissolves in the ether phase, and thus lost in each
cycle. This observation might be in line with the observations
recorded in Table 2, entries 10 and 11: as the catalyst load is
diminished, the yield of product decreases, although the
observed stereoselectivity of the process remains high.
3206, 3062, 2878, 1681, 1563, 1412, 1358. HR MS-TOF: calcd. for
Conclusions
25
C19H25N4O3: 357.1921, found: 357.1924. Mp = 63 – 66 °C. []D
14.48, c = 1.05, MeOH.
=
Novel chiral imidazolium ionic liquids (S)-4, (S)-7 and (S)-8 were
synthesized and tested in the asymmetric Michael addition
reaction between cyclohexanone and several substituted -
nitrostyrenes, affording moderate to excellent reaction yields and
good to excellent stereoselectivities (see entries 1 to 8 in Table
4). Most importantly, for the first time a chiral ionic liquid was
used as organocatalyst in an asymmetric Michael-intramolecular
aldol cascade reaction achieving good stereoselectivities
although with moderate reaction yields. Reuse of the chiral ionic
liquid catalyst was evaluated observing no loss in
stereoselectivity. Studies in other asymmetric cascade reactions
are being conducted in order to expand the applicability of chiral
ionic liquids as sustainable, enantioselective organocatalysts.[11]
General metathesis method: preparation of compounds (S)-5 and
(S)-6 from (S)-3. In a 50 mL round bottomed flask provided with
magnetic stirrer, imidazolium salt (S)-3 (1.0 g, 2.287 mmol) was placed
and dissolved in 23 mL of water. The appropriate salt (KPF6 or Tf2NLi)
(1.1 equiv.) was added to the resulting solution and the reaction mixture
turned cloudy. The reaction mixture was vigorously stirred for 4 hours.
The upper layer was decanted and the precipitated product was washed
with water (2x10 mL). Finally, the product was dried in vacuum until
constant weight. No further purification process was required.
(S)-3-(2-((1-(Benzyloxycarbonyl)pyrrolidin-2-yl)methylamino)-2-
oxoethyl)-1-methyl-1H-imidazol-3-ium hexafluorophosphate(V), (S)-5.
The General procedure was followed to afford (S)-5 as a white solid, mp
= 51-55 °C, 0.968 g (1.92 mmol, 84% yield). 1H NMR (399.78 MHz,
DMSO-d6, 120 °C): δ 8.97 (bs, 1H, N-CH-N), 8.10 (bs, 1H, NHCO), 7.60
(t, 1H, J = 3.4 Hz, J = 1.8 Hz, +N-CH-CH-N), 7.57 (t, 1H, J = 3.4 Hz, J =
1.8 Hz, N-CH-CH-N+), 7.37-7.25 (m, 5H, Ar), 5.10 (d, 2H, J = 1.58 Hz,
CH2Ph), 4.90 (bs, 2H, N-CH2-CO), 3.98-3.91 (m, 1H, N-CH-CH2), 3.90
(bs, 3H, N-CH3), 3.47-3.30 (m, 3H, N-CH2-CH and N-CHH-CH2), 3.30-
3.19 (m, 1H, N-CHH-CH2), 1.95-1.71 ppm (m, 4H, CH2-CH2). 13C NMR
(100.52 MHz, DMSO-d6, 120 °C): δ 165.5, 155.1, 138.3, 137.8, 128.9,
128.2, 127.9, 124.2, 123.7, 66.6, 57.4, 51.5, 47.0, 42.4, 36.4, 28.8, 23.4
Experimental Section
(S)-Benzyl 2-((2-bromoacetamido)methyl)pyrrolidine-1-carboxylate,
(S)-2. In a 100 mL round bottomed flask provided with magnetic stirrer
and addition funnel, was placed (S)-prolinamine (4.637 g, 19.79 mmol)
and triethylamine (3.00 mL, 21.7 mmol) and dissolved in CH2Cl2 (20 mL).
Then bromoacetyl bromide (1.90 mL, 21.7 mmol) dissolved in 20 mL of
CH2Cl2 was added to the addition funnel. The flask was submerged in an
ice bath and the reagents in the funnel were added dropwise. After that,
ppm. 31P NMR (161.83 MHz, DMSO-d6, 120 °C): δ 142.7, ppm (JP-F
=
710.8 Hz). IR film (cm-1): 1674, 1544, 1415, 1360, 1343, 1178, 1107.
Elemental analysis: calcd. C: 45.42%, H: 5.02%, N: 11.15%, found. C:
+
45.39%, H: 4.76%, N: 10.91%. HR MS-TOF: calcd. for C19H25N4O3
:
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10.1002/ejoc.201700133
European Journal of Organic Chemistry
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357.1921, found: 357.1919. Calcd. for PF6: 144.9647, found: 144.9647.
1H, N-CH-CH2), 3.13 (s, 1H, CH2-NH-CH), 3.10-2.98 (m, 2H, CH-CH2-
CO), 2.85-2.68 (m, 2H, N-CH2-CH2), 1.94-1.53 (m, 3H, CHHCH2), 1.32-
1.21 ppm (m, 1H, CHHCH2). 13C NMR (100.52 MHz, DMSO-d6): δ 165.4,
138.2, 124.3, 123.5, 121.3, 118.7, 57.8, 51.0, 46.3, 44.4, 36.3, 29.4, 25.5
ppm. IR film (cm-1): 3382, 3126, 2964, 1667, 1570, 1423, 1346, 1176,
[]D25 = 13.56, c = 1.01, MeOH.
(S)-3-(2-((1-(Benzyloxycarbonyl)pyrrolidin-2-yl)methylamino)-2-
oxoethyl)-1-methyl-1H-imidazol-3-ium bis(trifluoromethylsulfonyl)-
amide, (S)-6. The General procedure was followed to afford (S)-6 as an
amber viscous liquid, 1.297 g (2.03 mmol, 89% yield). 1H NMR (399.78
MHz, DMSO-d6, 120 °C): δ 8.99 (bs, 1H, N-CH-N), 8.11 (bs, 1H, NHCO),
7.61 (t, 1H, J = 3.39 Hz, J = 1.81 Hz, +N-CH-CH-N), 7.59 (t, 1H, J = 3.4
Hz, J = 1.8 Hz, N-CH-CH-N+), 7.36-7.25 (m, 5H, Ar), 5.10 (d, 2H, J = 1.6
Hz, CH2Ph), 4.91 (bs, 2H, N-CH2-CO), 3.95-3.91 (m, 1H, N-CH-CH2),
3.90 (bs, 3H, N-CH3), 3.48-3.31 (m, 3H, N-CH2-CH and N-CHH-CH2),
3.31-3.20 (m, 1H, N-CHH-CH2), 1.95-1.70 ppm (m, 4H, CH2-CH2). 13C
NMR (100.52 MHz, DMSO-d6, 120 °C): δ 165.4, 155.0, 138.4, 137.8,
128.8, 128.2, 127.9, 124.2, 123.7, 66.6, 57.4, 51.5, 47.0, 41.3, 36.4, 28.9,
23.4 ppm. IR film (cm-1): 1681, 1592, 1416, 1346, 1177, 1133. HR MS-
TOF: calcd. for C19H25N4O3+: 357.1921, found: 357.1927. Calcd. for
1133, 1052. HR MS-TOF: calcd. for C11H19N4O+: 223.1553, found:
25
223.1554. Calcd. for C2F6NO4S2: 279.9178, found: 279.9176. []D
=
8.50, c = 0.4, MeOH.
General procedure for the asymmetric Michael addition reaction. In
a small vial, CIL (0.05 mmol), p-NBA (8.3 mg, 0.05 mmol), -nitrostyrene
(0.5 mmol) and ketone (3.0 mmol) were placed. The reaction was stirred
at room temperature for 24 hours or until TLC showed no presence of -
nitrostyrene. Subsequently, the reaction was washed with diethyl ether (3
x 1 mL) and the precipitated CIL was subjected to the next reaction cycle,
by means of the addition of additive and substrates. The crude ethereal
phase was subjected to flash chromatography using silica gel as
stationary phase and Hexane/EtOAc (9:1 to 6:4) as mobile phase to
afford the pure Michael products.
-
C2F6NO4S2 : 279.9178, found: 279.9182. []D25 = 12.7, c = 0.393, MeOH.
General method for the hydrogenolysis reaction: preparation of
compounds (S)-4, (S)-7 and (S)-8). In a 25 mL round bottomed flask
provided with magnetic stirrer, substrate (S)-3, (S)-5 or (S)-6 (1 mmol)
was dissolved in 10 mL of MeOH before the addition of 10 wt% of Pd/C.
The reaction flask was sealed with a septum, purged with H2 and allowed
to react for 24 hours at ambient temperature with vigorous stirring and
under H2 atmosphere. The heterogeneous mixture was filtered through
Celite to remove the Pd/C catalyst, and the solvent was removed under
vacuum until a constant weight of the product was reached.
General procedure for the asymmetric Michael-intramolecular aldol
cascade reaction. In a small vial, CIL (S)-7 (18.4 mg, 0.05 mmol), p-
NBA (8.3mg, 0.05 mmol), benzylidenpyruvate (95 mg, 0.5 mmol) and
cyclohexanone (0.31 mL, 3.0 mmol) were placed. The reaction was
stirred at room temperature for 48 hours. Subsequently, the reaction was
washed with diethyl ether (3 x 1 mL) and the precipitated CIL was
subjected to the next reaction cycle, by the addition of additive and
substrates. The crude ethereal phase was subjected to column
chromatography using silica gel as stationary phase and Hexane/EtOAc
(9:1 to 1:1) as mobile phase to afford the pure cascade product and its
by-products.
(S)-1-Methyl-3-(2-oxo-2-(pyrrolidin-2-ylmethylamino)ethyl)-1H-
imidazol-3-ium bromide, (S)-4. The General procedure for
hydrogenolysis was followed to afford (S)-4 as a highly hygroscopic
yellow syrup, 0.299 g (0.99 mmol, 99% yield). 1H NMR (500.16 MHz,
DMSO-d6): δ 9.09 (bs, 1H, N-CH-N), 8.57 (bs, 1H, NHCO), 7.67 (bs, 2H,
N-CH-CH-N), 4.97 (bs, 2H, N-CH2-CO), 3.85 (s, 3H, N-CH3), 3.45 (bs, 1H,
NH), 3.11 (m, 1H, N-CH-CH2), 3.11-3.05 (m, 2H, CH-CH2-CO), 2.85-2.70
(m, 2H, N-CH2-CH2), 1.81-1.54 (m, 3H, CHHCH2), 1.36-1.23 ppm (m, 1H,
CHHCH2). 13C NMR (125.76 MHz, DMSO-d6): δ 165.5, 138.2, 124.2,
123.5, 57.9, 51.1, 46.1, 43.9, 36.3, 29.2, 25.2 ppm. IR film (cm-1): 3404,
3222, 3149, 3062, 2949, 2870, 1681, 1563, 1410, 1172. HR MS-TOF:
Acknowledgements
We are indebted to CONACYT for financial support via grant
220945. A. Obregón-Zúñiga thanks CONACYT for scholarship
283367. We also thank Teresa Cortez-Picasso for her
assistance in the acquisition of NMR spectra.
25
calcd. for C11H19N4O+: 233.1553, found: 233.1550. []D = 6.34, c =
1.467, MeOH.
Keywords: Chiral ionic liquids • Imidazolium ionic liquids •
Michael reaction • Cascade reaction • Asymmetric reaction
(S)-1-Methyl-3-(2-oxo-2-(pyrrolidin-2-ylmethylamino)ethyl)-1H-
imidazol-3-ium hexafluorophosphate(V), (S)-7. The General procedure
for hydrogenolysis was followed to afford (S)-7 as a slightly yellow serous
solid, mp = 58-61 °C, 0.342 g (0.93 mmol, 93% yield). 1H NMR (399.78
MHz, DMSO-d6): δ 9.05 (bs, 1H, N-CH-N), 8.55 (bs, 1H, NHCO), 7.65 (bs,
2H, N-CH-CH-N), 4.96 (bs, 2H, N-CH2-CO), 3.87 (s, 3H, N-CH3), 3.45 (bs,
1H, NH), 3.18-3.00 (m, 3H, N-CH-CH2 and CH-CH2-CO), 2.90-2.70 (m,
2H, N-CH2-CH2), 1.86-1.56 (m, 3H, CHHCH2), 1.40-1.24 ppm (m, 1H,
CHHCH2). 13C NMR (100.52 MHz, DMSO-d6): δ 165.48, 138.24, 124.29,
123.52, 57.91, 51.06, 46.19, 44.09, 36.31, 29.30, 25.34 ppm. 31P NMR
(161.83 MHz, DMSO-d6): δ 143.00 ppm (JP-F = 710.8 Hz). IR film (cm-1):
3419, 3169, 2965, 2875, 1678, 1567, 1429, 1364, 1260, 1178. HR MS-
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TOF: calcd. for C11H19ON4+: 223.1553, found: 223.1554. Calcd. for PF6 :
-
[2]
[3]
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DMSO-d6): δ 9.02 (bs, 1H, N-CH-N), 8.39 (bs, 1H, NHCO), 7.64 (bs, 2H,
N-CH-CH-N+), 4.92 (bs, 2H, N-CH2-CO), 3.84 (bs, 3H, N-CH3), 3.23 (m,
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Ionic liquids
Arturo Obregón-Zúñiga, Marco
Guerrero-Robles and Eusebio Juaristi*
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Chiral Imidazolium Ionic Liquids
derived from (S)-Prolinamine as
Organocatalysts in the Asymmetric
Michael Reaction and Michael-Aldol
Cascade Reaction under Solvent-Free
Conditions
A solvent-free enantioselective synthesis of Michael adducts employing chiral
imidazolium ionic liquids is described. The same strategy can be used in Michael-
intramolecular aldol cascade reactions affording enantioenriched products that are
analogues of tropane alkaloids, containing four stereocenters.
*one or two words that highlight the emphasis of the paper or the field of the study
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