Design of a Chiral Ionic Liquid System for the Enantioselective Addition of Diethylzinc to Aldehydes

Article abstract of DOI:10.1002/ejoc.201701426

An important contribution to the field of asymmetric catalysis is described in this work, as it merges the search for new ligands that can provide high performance in asymmetric catalysis with the extremely important and increasing need for sustainability. New chiral ionic liquids have been synthesised from the amino acid l-cysteine by straightforward routes. With these ligands, we have developed a chiral ionic system that includes chiral ionic liquids and their immobilisation in ionic solvents to provide a chiral supramolecular structure. These new catalytic systems were used in the enantioselective addition of alkylzinc to aldehydes and proved to be very efficient, capable of providing chiral secondary alcohols in excellent enantiomeric excesses and yields. This system also enabled the recycling of the ionic media and the ionic ligand, taking into account green chemistry considerations.

Full text of DOI:10.1002/ejoc.201701426

A Journal of
Accepted Article
Title: Design of a New Chiral Ionic Liquids System for the
Enantioselective Addition of Diethylzinc to Aldehydes
Authors: Paulo Henrique Schneider, Mariana Ferrari Bach, Cassiana
Herzer Griebeler, and Caroline Gross Jacoby
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701426
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
Design of a New Chiral Ionic Liquids System for the
Enantioselective Addition of Diethylzinc to Aldehydes
Mariana Ferrari Bach,[a] Cassiana Herzer Griebeler, [a] Caroline Gross Jacoby[a] and Paulo Henrique
Schneider*[a]
Abstract: An important contribution to the field of asymmetric
catalysis is described in this work, as it merges the search for new
ligands that can provide high performance in asymmetric catalysis
with the extremely important and increasing need for sustainability.
New chiral ionic liquids were synthesized from the amino acid L-
cysteine by straightforward routes. With these ligands, we could
develop a chiral ionic system which included chiral ionic liquids and
organic solvents.[5] In addition, they provide the possibility of
recycling both the reaction medium and the ligands/catalysts,
because of their tunable properties through simple structural
changes.[6] More important, in asymmetric catalysis, chiral ionic
liquids (CILs) have being successfully used as recyclable
ligands/catalysts.[7] Despite their potential, there have been only
a few examples reported of the asymmetric diethylzinc addition
to aldehydes using CILs as ligands, however in conventional
organic solvents.[8]
their immobilization in ionic solvents providing
a
chiral
supramolecular structure. These new catalytic systems were used in
the enantioselective addition of alkylzinc to aldehydes and proved to
be very efficient, capable of providing chiral secondary alcohols in
excellent enantiomeric excesses and yields. This system enabled
also the recycling of the ionic media and the ionic ligand, taking into
account green chemistry considerations.
O
OH
L*, Et2Zn, Toluene
H
O
S
S
S
HO
S
HO
S
O
O
N
N
N
NH
NH
Introduction
2
2
2
Carbon–carbon bond formation is one of the most important
transformations in organic chemistry and its asymmetrical
version is a useful tool in the synthesis of several biologically
active molecules.[1] In this context, the enantioselective alkylzinc
70
81%
[>99% ee
57%
[40% ee
67%
[41% ee (R)]
56%
[0%]
(
S
)]
[88% ee (S)]
(
S
)]
Scheme 1. Ligands derived from L-cysteine applied in the asymmetric addition
of diethylzinc to aldehydes.
addition to aldehydes and ketones is
a well-established
methodology for the synthesis of optically active alcohols, which
are important synthetic intermediates towards more complex
molecules.[2]
One example of an enantioselective addition of alkylzinc to
aldehydes in an ionic liquid as solvent and using CILs as ligands
was reported by Lombardo et al. in 2008.[9] Three
diphenylprolinol derivatives containing an ionic moiety were
prepared and their activities were evaluated in the
enantioselective addition of diethylzinc to benzaldehyde. The
CILs were efficient as ligands and furnished the product with
89% ee and 96% yield when the reaction was carried out in 1-
In the literature, a wide range of ligands can be found for the
organozinc addition to aldehydes. Ligands derived from amino
acids are outstanding due to their easy access from natural
sources and to their excellent performance in asymmetric
reactions.[3] In this way, our group has described a series of
ligands from the amino acid L-cysteine, which have proved to be
very efficient in the enantioselective addition of alkylzinc,
alkynylzinc and arylzinc to aldehydes, as well as in the
palladium-catalysed asymmetric allylations and enantioselective
direct aldol reactions.[4] Some examples of the use of these
ligands in the asymmetric addition of diethylzinc to aldehydes
can be seen in Scheme 1.
The search for methodologies that are environmentally benign,
practical and economic has become a target for chemical
communities. In this context, ionic liquids play a pivotal role, as
they can be used as solvents with high thermal stability and
negligible vapor pressure, instead of the commonly used volatile
butyl-1-methylpyrrolidinium
bis(trifluoromethylsulfonyl)amide
([BMPy][N(Tf)2]) as solvent at 0 °C for 3 h using 10 mol% of the
ligand. Additionally, the ligand and the reaction medium were
recycled without decreasing yield and enantioselectivity.
Despite all the advantages and outcome of the use of ILs in the
asymmetric alkylzinc addition reaction, there has clearly been a
lack of study and development of a chiral ionic system to include
the synthesis of chiral ionic liquids and their immobilization in
ionic solvents to provide a chiral supramolecular structure, as
only a few articles have been reported.[9,10]
As part of our broader programme to explore the preparation
and use of chiral catalysts in asymmetric synthesis,[4,11] we
describe in this article the design and synthesis of a new class of
chiral ionic liquids derived from L-cysteine (Scheme 2) in efficient
synthetic routes. In order to prove our new catalytic system
reaction we envisioned their application in an organometallic
reaction, taking into account the importance of replacing the use
of volatile organic solvents with clean ones, such as ionic liquids.
We chose as a probe reaction the well-known enantioselective
[a]
Instituto de Química, Universidade Federal do Rio Grande do Sul,
P.O. Box 15003, 91501-970, Porto Alegre-RS, Brazil.
FAX +55 51 3308 7304; Tel +55 51 3308 9636.
E-mail: paulos@iq.ufrgs.br
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
addition of diethylzinc to aldehydes. Additionally, in an important
feature of this work, we investigated the possibility of recycling
the chiral reaction medium, using a model reaction.
through an esterification with 6-bromohexanoic acid, furnished 7
in excellent yield. To form the ionic pair, compound 7 was
treated with 1,2-dimethylimidazole, in acetonitrile, or with
pyridine at 65 °C to provide the bromides 1a or 2a, respectively,
in quantitative yields. Finally, compound 1b was obtained by the
anion exchange of 1a in water by treatment with LiN(Tf)2. It was
not possible to perform the anion exchange for 2a, as
decomposition was observed.
Results and Discussion
According to our objectives, as the starting point we designed
four new CILs, 1–4 (Scheme 2), from the amino acid L-cysteine,
which is an inexpensive and widely available source of chirality.
As a general strategy, we used a linear synthesis to obtain chiral
molecules of an ionic nature, containing coordinating atoms (O,
N and S). 1,2-dimethylimidazolium and pyridinium rings were
chosen as cations due to the easy access to these materials and
to the absence of acidic hydrogens present in the structure of 1-
methylimidazolium, a commonly used cation, as it could react
with the Et2Zn.[8c,10a,12] The N(Tf)2 anion was chosen because of
the properties that it confers to ionic liquids, such as good
thermal stability, low melting point, good miscibility with polar
organic solvents, low miscibility with water and lower
viscosity.[10b]
O
1:
2:
O
S
=
=
N
5
N
N
A
N
2
O
O
N
O
N
O
O
N
S
5
9
HS
OH
S
N
N
NH
NH2.HCl
A
A
L
-Cysteine
4
3
a:
b:
Our strategy to synthesize the CILs 1 and 2 (Scheme 3), started
with the disulfide 5, which was obtained in two steps from L-
cysteine, as previously described.[4a] The disulfide 5 was treated
with iodomethane and K2CO3 to provide the disulfide 6, which
A
Br or
N(Tf)2
=
Scheme 2. Chiral ionic liquids synthesised from L-cysteine.
O
O
Br
HO
S
O
S
HO
S
Br
5
CH3I, K2CO3
Acetone
HO
N
N
NH
5
EDCI, DMAP, CH2Cl2
r.t., 24 h
2
2
2
7
6
5
98 %
59 %
2:
1:
N
N
or
N
Acetonitrile
65 °C, 24 h
65 °C, 24 h
O
O
5
N
N
O
S
O
5
S
LiN(Tf)2
N
N
Br
H2O, 12 h
N(Tf)2
2
2
1b: 91 %
2b:
1a: >99 %
2a:
>99 %
x
Scheme 3. Synthesis of chiral ionic liquids 1 and 2.
To synthesize the CIL 3b, we started from the same disulfide 5,
which was easily converted to the thiazolidine alcohol 8
(Scheme 4) in two steps, as previously described.[4d] The alcohol
8 was used in an esterification with 6-bromohexanoic acid to
provide 9 in good yield. The target CIL 3b was obtained by
treatment of 9 with 1,2-dimethylimidazole followed by anion
exchange with LiN(Tf)2, in excellent overall yields.
with Boc2O to provide 10 (Scheme 5), as previously described.[4i]
After esterification of 10 with 9-bromo-1-nonanol, followed by a
deprotection, compound 12 was treated with 1,2-
dimethylimidazole to give the CIL 4a. The anion exchange was
performed with LiN(Tf)2 in water to provide the CIL 4b in
excellent yields for all reaction steps.
The synthesis of CILs 4 started with the cyclisation of L-cysteine
with formaldehyde followed by protection of the amine group
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
O
After screening the initial experimental parameters, we
evaluated the different characteristics of compounds 3b, 4b and
7 in regard to their structural diversity, in order to identify the
ligands with superior performance. The CIL 3b provided the best
result (45% ee, 37% yield, entry 6) using 10 mol% load and 4
equiv diethylzinc. Even increasing the amount of ligand to 20%
O
Br
O
OH
N
Br
5
S
S
5
N
HO
N
N
EDCI, DMAP, CH2Cl2
r.t., 24 h
Acetonitrile
65 °C, 24 h
9
8
and the reaction time to 72
h did not increase the
81 %
enantioselectivity (Table 1, entry 7). When ligand 4b was used,
poor yields and ees were obtained, even when 20 mol % of the
ligand was used, as well as 4 equiv diethylzinc, affording 51%
ee and 16% yield as the best result among the conditions tested
(entry 8-10).
O
O
N
N
N
N
O
O
5
S
S
5
N
LiN(Tf)2
H2O, 12 h
N
Br
N(Tf)2
3b
3a
92 %
99 %
Table 1. Enantioselective addition of diethylzinc to benzaldehyde promoted
by different CILs.[a]
Scheme 4. Synthesis of chiral ionic liquids 3.
O
O
O
OH
HO
Br
S
O
9Br
TFA, CH2Cl2
10 min
O
9Br
S
9
N
S
O
N
NH
EDCI, DMAP, CH2Cl2
rt., 24 h
Boc
O
12
Entry
1[d]
2
Ligand (mol%)
1b (5)
Et2Zn (eq)
ee (%)[b]
72
Yield (%)[c]
11
99 %
63 %
10
2
2
2
2
2
4
4
2
4
4
2
2
2
27
30
35
18
16
37
66
25
5
Acetonitrile
65 °C, 24 h
N
N
1b (5)
86
O
O
O
LiN(Tf)2
N
O
N
9
3
1b (10)
3b (5)
88
9
S
N
S
N
H2O, 12 h
NH
NH
Br
4
28
N(Tf)2
4b
85 %
4a
>99 %
5
3b (10)
3b (10)
3b (20)
4b (10)
4b (10)
4b (20)
7 (5)
37
Scheme 5. Synthesis of chiral ionic liquids 4.
6
45
7[e]
8
39
With the target compounds (CILs 1–4) in our hands, we focused
our attention on exploring their potential as chiral ligands in the
enantioselective addition of diakylzinc to aldehydes. Our studies
started by examining the efficiency of these CILs, using as a
model reaction the asymmetric addition of diethylzinc to
benzaldehyde (Table 1). The CILs chosen for these initial
studies were those containing N(Tf)2 as anion to maintain the
homogeneous nature of the anions in the system. As solvent,
the ionic liquid [BPy][N(Tf)2] was chosen, as it has already been
reported in the literature to be an efficient solvent for this
reaction.[9,12]
11
9
31
10
11
12
13
51
16
23
24
10
0
1a (5)
84
2a (5)
77
[a] The reactions were carried with 0.25 mmol benzaldehyde in 0.25 mL of
ionic solvent; 0.25 mL of toluene was added in addition to the toluene from
Et2Zn solution, and reactions quenched with HCl 1M. [BPy]
In our first attempt, the test reaction was performed in the
presence of 5 mol % of CIL 1b, 2 equiv diethylzinc, ionic solvent,
= 1-
butylpyridinium. [b] Determined by HPLC analysis (chiracel OD-H column).
[c] Yield of isolated product. [d] No extra toluene added. [e] Reaction time:
72 h.
at
0 °C for 48 h, and whit this conditions, the (S)-1-
phenylpropan-1-ol was obtained with 72% ee; however in low
yield (Table 1, entry 1). Due to the high viscosity of the reaction
medium, we thought that the addition of a co-solvent could help
to increase the yields, so we added a small amount of toluene.
With these conditions we could improve the ee to 86%, while a
similar yield of 30% was obtained (Table 1, entry 2). By
increasing the amount of ligand to 10 mol% no significant
influence on enantioselectivity and yield was observed (Table 1,
entry 3).
In order to investigate the necessity for an ionic ligand for this
catalytic system, we tested the nonionic disulfide 7, in IL as
solvent, and the resulting product was obtained with 23% yield in
its racemic form (entry 11). The low yield and enantiomeric
excess could suggest that the CILs are very important for the
formation of a highly organized supramolecular structure in IL
media.[13]
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10.1002/ejoc.201701426
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Finally, we evaluated the effect of the ionic portion of the ligand
(Table 1, entries 12–13). Using the CIL 1a, containing bromide
anion, the enantiomeric excess of the product did not change,
but the yield was lower than when 1b was used (compare
entries 2 and 12). Using the CIL 2a, containing pyridinium as
containing 1-butyl-1-methylpyrrolidinium (BMPy) or 1-butyl-2,3-
dimethylimidazolium (BDMI) as cation and N-triflate as anion. In
both cases the enantiomeric excess dropped; nevertheless, the
yield was higher when [BDMI][N(Tf)2] was used (Table 2, entry
6). To verify the real influence of the use of an ionic liquid as
solvent, a neutral environment was also used. When CH2Cl2 was
used as solvent, the product was obtained with only 5% ee and
8% yield. Thus, we could suggest again that a biphasic reaction
medium is essential to promote the ethyl transfer reaction using
this system.
The next two parameters examined were the reaction time and
the temperature. By increasing the reaction time from 48 to 72 h
the yield raised to 61% without loss of enantioselectivity
(compare entries 2 and 8). When the reaction was carried out at
room temperature the yield increased to 91%, but a large
decrease in enantioselectivity was observed (entry 9).
Having established the optimum reaction conditions (Table 2,
entry 4), the scope and limitations of the alkylzinc addition to
different aldehydes, catalysed by 1b were also examined (Table
3). Very good enantioselectivities and yields were obtained with
aromatic aldehydes substituted at the para and ortho positions,
except for o-bromobenzaldehyde which provided the product
with 68% ee, and for o-tolualdehyde which provided the product
with 42% yield. Moderate ee and yield were obtained with 1-
naphtaldehyde and very good results were obtained using the
aliphatic aldehyde cyclohexanecarboxaldehyde (Table 3, entry
8).
cation and bromide as anion,
a
slight decrease in
enantioselectivity, together with a large decrease in yield was
observed (Table 1, entry 13).
Having established the optimum reaction conditions, as well as
the most efficient ligand, we turned our attention to study some
reaction parameters that we found to be crucial for increasing
the yields (Table 2). Our first observation was that the quenching
of the reaction had a dramatic influence on the yield. As an
example, when the reaction was quenched with NH4Cl
sat.
instead of HCl 1M, the yield increased from 30% (entry 1) to
41% (entry 2). Adding oxalic acid at the end of the reaction and
using acetone for the precipitation of the inorganic compounds
formed increased the yield to 76%, but the ee decreased to 79%
(Table 2, entry 3). On the other hand, using methanol to quench
the reaction and dichloromethane to precipitate the inorganic
compounds formed, increased the yield to 78% with the same
ee of 87% (Table 2, entry 4).
Table 2. Optimisation of the addition of diethylzinc to benzaldehyde
promoted by CIL 1b.[a]
Table 3. Enantioselective addition of diethylzinc to different aldehydes
promoted by CIL 1b.[a]
Entry
Solvent
t
(h)
ee[b]
(%)
Yield[c]
(%)
Quench
1
2
[BPy][N(Tf)2][d]
[BPy][N(Tf)2]
48
48
72
72
48
48
48
72
72
86
85
79
87
71
79
5
30
41
76
78
17
54
8
HCl 1M
NH4Cl sat.
Oxalic Acid
MeOH
Entry
R
ee (%)
89[b]
87[b]
85[b]
87[c]
87[c]
68[c]
64[b]
85[c]
Yield (%)[d]
1
2
3
4
5
6
7
8
p-Me-C6H4
o-Me-C6H4
p-MeO-C6H4
p-CN-C6H4
p-Br-C6H4
o-Br-C6H4
1-naphthyl
cyclohexyl
78
42
77
88
85
97
65
71
3
[BPy][N(Tf)2]
4
[BPy][N(Tf)2]
5
[BMPy][N(Tf)2][e]
[BDMI][N(Tf)2][f]
NH4Cl sat.
NH4Cl sat.
NH4Cl sat.
NH4Cl sat.
NH4Cl sat.
6
[g]
7
CH2Cl2
8
[BPy][N(Tf)2]
[BPy][N(Tf)2]
87
50
61
91
9[h]
[a] The reactions were carried out with 0.25 mmol benzaldehyde in 0.25
mL of ionic solvent; 2 equiv of Et2Zn; 0.25 mL of toluene was added in
addition to the toluene from Et2Zn solution and reactions quenched with
HCl 1M. [b] Determined by HPLC analysis (chiracel OD-H column). [c]
Yield of isolated product. [d] [BPy] = 1-butylpyridinium. [e] [BMPy] = 1-
butyl-1-methylpyrrolidinium. [f] [BDMI] = 1-butyl-2,3-dimethylimidazolium.
[g] No extra toluene added. [h] The reaction was performed at room
temperature.
[a] The reactions were carried out with 0.25 mmol benzaldehyde in 0.25 mL of
ionic solvent; 0.25 mL of toluene was added in addition to the toluene from
Et2Zn solution and reactions quenched with MeOH. [b] Determined by HPLC
analysis. [c] Determined by GC-FID analysis. [d] Yield of isolated product.
An important feature of these CILs and ionic liquids as solvents
is the possibility of recycling, which makes them an excellent
choice when considering economic and environmental aspects.
Thus, we verified the possibility of reusing the catalytic ionic
medium. To generate an efficient recyclable system, it is
The effect of variation of the ionic environment was also verified
(entries 5–7). Two other ionic liquids were tested as solvents,
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
necessary that the product extraction is efficient, that both the
ionic solvent and the ligand are not soluble in the extractant
solvent and that the inorganic zinc salts formed are efficiently
removed from the ionic phase. To perform the recycling, the
methanol used to quench the reaction was completely
evaporated and the product extraction was carried out with
hexane only. After each treatment and extraction method the
recovered ionic liquid was dried under vacuum, at 60 °C and
stirred for 5 h before the addition of a new portion of
benzaldehyde, diethylzinc and toluene for the new catalytic run.
To prove our system in these recycling experiments, the model
reaction, using 5 mol % of ligand 1b, was chosen and as we
expected, the catalytic system was successfully recycled three
times (four catalytic cycles) without significant decrease in
chemical yields or enantiomeric excesses (Figure 1).
Experimental Section
General Information
1H NMR, 13C NMR, 2D-COSY NMR and 2D HSQC NMR spectra were
recorded on a Varian Inova 300, Varian VNMRS 300, Varian Inova 400,
Bruker Avance 400 and Varian VNMRS 500. Chemical shifts (δ) are
expressed in ppm with TMS as an internal reference in spectra made in
CDCl3 and the deuterated solvents were used like internal references in
spectra made in acetone-d6, DMSO-d6 and CD3OD. Coupling constants
are reported in Hertz. Optical rotations were measured with a Jasco P-
2000 polarimeter. High resolution mass spectra (HRMS) were measured
by electrospray (ESI) with Micromass Q-Tof micro spectrometer. Chiral
HPLC analysis were performed on a Shimadzu LC-20AT chromatograph
with an UV detector using different columns as described in the
supporting information. Chiral GC analysis were performed on a Agilent
Technologies GC System 6820 chromatograph (Detector: FID, 280 °C;
injector: 220 °C; carrier gas: nitrogen) with a chiral Hydrodex--3P, 25 m
x 0.25 mm capillary column. All the column chromatography separations
were done by using silica gel Sigma Aldrich 230–400 Mesh.
O
OH
1b (5 mol%), toluene, [BPy][N(Tf)2]
Et2Zn
2 eq
0 °C, 72 h
SYNTHESIS OF THE IONIC LIGANDS
(R,R’)-bis[2-(N-benzyl-N-methyl-amino)propan-1-ol]dissulfide (6)
In 25 mL two necked round-bottomed flask under argon atmosphere,
0.39 g (1.0 mmol) of the disulfide 5, obtained in two steps from L-cysteine
as previously described[4a], 3 mL of anhydrous acetone, 0.28 g (2.0
mmol) of potassium carbonate and 0.12 mL (2.0 mmol) of iodomethane
were added. This solution was stirred at room temperature for 20 hours.
Then, the solvent was evaporated. The obtained material was solubilized
in 15 mL of dichloromethane and washed three times with 10 mL of water.
The organic layer was dried over MgSO4 and evaporated. The residue
was purified with column chromatography using the mixture ethyl
20
acetate:hexane 20:80 as eluent providing a yellow oil. Yield: 59%. []D
= +79 (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 7.36-7.22 (m, 10 H),
3.79-3.73 (m, 2H), 3.76 (d, J =13.0, 2H), 3.60 (d, J = 13.0, 2H), 3.50-3.42
(m, 2H), 3.20-3.10 (m, 2H), 3.02 (dd, J = 4.7 e 13.2, 2 H), 2.51 (dd, J =
8.7 and 13.2, 2H), 2.23 (s, 6 H). 13C NMR (75 MHz, CDCl3) δ: 135.9,
126.2, 125.9, 124.8, 60.5, 57.7, 55.7, 33.4, 32.4. HRMS: calculated for
[C22H32N2O2S2+H]+: 421,1985; obtained: 421,1988.
Figure 1. Recycling of the catalytic system [BPy][N(Tf)2] and ligand 1b.
General procedure for esterification
Conclusions
A dry Schlenk tube under argon atmosphere was charged with carboxylic
acid, dry CH2Cl2, EDCI (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
hydrochloride) and DMAP (4-(dimethylamino)pyridine). This solution was
stirred at room temperature for 30 minutes. The alcohol was added and
this solution was stirred at room temperature for 24 hours. Then,
additional amount of CH2Cl2 was added, the organic layer was washed
three times with saturated NaHCO3(aq) solution, was dried over MgSO4
and the solvent was evaporated. The products were purified with column
chromatography.
The results presented in this work are an important contribution
to the field of asymmetric catalysis, as the study merges the
search for new ligands that can provide high performance of
asymmetric catalysis with the extremely important and
increasing need for sustainability. We have accomplished the
synthesis of new chiral ionic liquids derived from the amino acid
L-cysteine by efficient, high-yielding synthetic routes. To test
these new ligands, we chose as
a probe reaction the
(R,R’)-bis-[2-(N-benzyl-N-methylamino)-3-(6-bromohexanoate)-
propyl]dissulfide (7)
enantioselective addition of diethylzinc to aldehydes in ionic
media, and all CILs used (1, 2b, 3b and 4b) were shown to have
catalytic activity, able to furnishing the products in excellent
yields and enantioselectivities. A study was carried out to find an
efficient recyclable system; the ionic ligand 1b and the ionic
solvent [BPy][N(Tf)2] could be used at least four times, proving
here an important concept of catalytic systems.
Reagents and amounts used: 6-bromohexanoic acid (0.44 g, 2.25 mmol),
dry CH2Cl2 (7 mL), EDCI (0.43 g, 2.25 mmol), DMAP (catalytic) and
alcohol 6 (0.24 g, 0.56 mmol). The residue was purified with column
chromatography using the mixture ethyl acetate:hexane 20:80 as eluent
20
providing a yellow oil. Yield: 98%. []D = -2 (c 0.9, CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ: 7.37-7.19 (m, 10H), 4.33 (dd, J = 6.8 and 11.5, 2H),
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
4.20 (dd, J = 4.8 and 11.5, 2H), 3.71 (d, J = 13.6, 2H), 3.66 (d, J = 13.6,
2H), 3.39 (t, J = 6.5, 4H), 3.29-3.21 (m, 2H), 3.05 (dd, J = 7.2 and 13.1,
2H), 2.74 (dd, J = 7.2 and 13.1, 2H), 2.35 (t, J = 7.4, 4H), 2.25 (s, 6H),
1.92-1.82 (m, 4H), 1.72-1.61 (m, 4H), 1.54-1.43 (m, 4H). 13C NMR (100
MHz, CDCl3) δ: 173.1, 139.2, 128.5, 128.2, 127.0, 62.6, 60.6, 58.5, 38.3,
37.0, 34.0, 33.5, 32.3, 27.6, 24.0. HRMS calculated for
[C34H50Br2N2O4S2]+: 772,1579; obtained: 772,1593.
A round-bottomed flask, equipped with reflux condenser, was charged
with the bromide, acetonitrile and 1,2-dimethylimidazole. This solution
was stirred at 60 °C for 24 hours. Then, the solvent was evaporated and
the yellow oil was dried under vacuum.
1-{(R,R’)-bis-[2-(N-benzyl-N-methylamino)-3-hexanoate-
propyl]dissulfide}-2,3-dimethylimidazolium bromide (1a)
(4R)-3-benzyl-thiazolidin-4-yl-methyl 6-bromohexanoate (9)
Reagents and amounts used: Bromide 7 (0.36 g, 0.46 mmol), 1,2-
dimethylimidazole (0.18 g, 1.84 mmol) and acetonitrile (10 mL). The
yellow oil obtained consist of a mixture of the ionic product and the
unreacted 1,2-dimethylimidazole in the proportion of 1:1.1 (ionic product:
Reagents and amounts used: 6-bromohexanoic acid (0.21 g, 1.09 mmol),
dry CH2Cl2 (8 mL), EDCI (0.17 g, 0.91 mmol), DMAP (catalytic) and
alcohol 8 (0.18 g, 0.91 mmol) obtained in two steps from disulfide 5 as
1
20
1,2-dimethylimidazole) calculated by H NMR. Yield: >99%. []D = +13
previously described[4a]
.
The residue was purified with column
(c 1.0, MeOH). *Product: H NMR (400 MHz, CDCl3) δ: 7.70 (d, J = 2.0,
1
chromatography using the mixture ethyl acetate:hexane 10:90 as eluent
2H), 7.64 (d, J = 1.8, 2H), 7.42-7.15 (m, 10H), 4.37-4,14 (m, 8H), 3.98 (s,
6H), 3.67 (quart, J = 13.6, 4H), 3.28-3.17 (m, 2H), 3.03 (dd, J = 6.9 and
13.2, 2H), 2.79 (s, 6H), 2.74 (dd, J = 7.4 and 13.2, 2H), 2.39-2.31 (m, 4H),
2.24 (s, 6H), 1.85 (q, J = 7.4, 4H), 1.65 (q, J = 7.4, 4H), 1.50-1.36 (m, 4H).
13C NMR (100 MHz, CDCl3) δ: 173.1, 143.7, 139.3, 128.6, 128.2, 126.4,
122.9, 121.3, 62.6, 60.5, 58.5, 48.6, 38.3, 37.1, 36.1, 33.8, 29.6, 25.7,
24.1, 10.9. *1,2-dimethylimidazole unreacted: 1H NMR (400 MHz, CDCl3)
δ: 6.88 (s, 1H), 6.81 (d, J = 1.1, 1H), 3.57 (s, 3H), 2.38 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ: 144.9, 127.0, 120.4, 32.8, 12.8. HRMS calculated
20
providing a yellow oil. Yield: 81%. []D = -51 (c 0.9, CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ: 7.37-7.24 (m, 5H), 4.15 (d, J = 10.1, 1H), 4.08 (dd, J
= 7.6 and 11.2, 1H), 4.00 (d, J = 10.1, 1H), 3.88 (dd, J = 6.6 and 11.2,
1H), 3.72-3.64 (m, 1H), 3.67 (d, J = 13.4, 1H), 3.58 (d, J = 13.3, 1H), 3.39
(t, J = 6.7, 2H), 3.08 (dd, J = 6.8 and 10.9, 1H), 2.77 (dd, J = 2.5 and 10.9,
1H), 2.33 (t, J = 7.2, 2H), 1.91-1.83 (m, 2H), 1.69-1.60 (m, 2H), 1.52-1.43
(m, 2H). 13C NMR (100 MHz, CDCl3) δ: 173.0, 138.4, 128.8, 128.4, 127.4,
67.0, 63.9, 58.7, 58.4, 33.9, 33.4, 32.3, 31.9, 27.6, 24.0. HRMS
calculated for [C17H24BrNO2S+H]+: 386,0791; obtained: 386,0749.
for cation [C44H66N6O4S2]2+
: 403,2288; obtained: 403,2292. HRMS
calculated for anion [Br]-: 78,9189; obtained: 78,9154.
4-(9-bromononyl) 3-(tert-butyl) (R)-thiazolidine-3,4-dicarboxylate (11)
1-[(4R)-3-benzyl-thiazolidin-4-yl-methylhexanoate]-2,3-
dimethylimidazolium bromide (3a)
Reagents and amounts used: Protected thiazolidinic acid 10 (2.33 g, 10.0
mmol) obtained in two steps from L-cysteine as previously described[4i,j]
,
dry CH2Cl2 (20 mL), EDCI (1.91 g, 10.0 mmol), DMAP (catalytic) and 9-
bromo-1-nonanol (3.35 g, 15.0 mmol). The residue was purified with
column chromatography using the mixture ethyl acetate:hexane 5:95 as
Reagents and amounts used: Bromide 9 (0.04 g, 0.11 mmol), 1,2-
dimethylimidazole (0.02 g, 0.23 mmol) and acetonitrile (2 mL). The yellow
oil obtained consist of a mixture of the ionic product and the unreacted
1,2-dimethylimidazole in the proportion of 1:1 (ionic product: 1,2-
20
eluent providing a colorless oil. Yield: 63%. []D = -56 (c 0.2, CH2Cl2).
1H NMR (300 MHz, CDCl3, conformers mixture) δ: [4.94-4.84 (m), 4.74-
4.62 (m) and 4.57 (d, J = 8.5), 2H], [4.48 (d, J = 8.8) and 4.41 (d, J = 8.4),
1H], 4.25-4.07 (m, 2H), 3.41 (t, J = 6.8, 2H), 3.38-3.14 (m, 2H), 1.85 (q, J
dimethylimidazole) calculated by H NMR. The mixture of the compound
1
3a with 1,2-dimethylimidazole was solubilized in 2 mL of water and
washed with ethyl ether (6 x 3 mL) to remove the 1,2-dimethylimidazole
unreacted. Then, 3a was extracted with CH2Cl2 and the solvent was
evaporated providing and yellow oil consisting in a mixture of ionic
= 6.9, 2H), 1.72-1.59 (m, 2H), 1.55-1.39 (m, 9H), 1.39-1.21 (m, 10H). 13
C
NMR (75 MHz, CDCl3, conformers mixture) δ: 170.8, 170.4, 153.2, 153.1,
81.08, 65.6, 61.6, 48.9, 48.0, 34.7, 34.0, 33.2, 32.7, 29.2, 29.0, 28.6,
28.5, 28.2, 28.1, 25.7. HRMS calculated for [C18H32BrNO4S+Na]+:
460.1133; obtained: 460.1146.
1
product:1,2-dimethylimidazole 1:0,15 calculated by H NMR. Yield: 99%.
[]D20 = -37 (c 0.7, CH2Cl2). *Product: 1H NMR (400 MHz, CDCl3) δ: 7.70
(d, J = 2.0, 1H), 7.56 (d, J = 2.0, 1H), 7.38-7.24 (m, 5H), 4.24 (t, J = 7.4,
2H), 4.13 (d, J = 10.1, 1H), 4.07 (dd, J = 7.5 and 11.2, 1H), 4.00 (s, 3H),
3.99 (d, J = 10.0, 1H), 3.87 (dd, J = 6.7 and 11.2, 1H), 3.73-3.65 (m, 1H),
3.67 (d, J = 13.3, 1H), 3.58 (d, J = 13.0 1H), 3.09 (dd, J = 6.8 and 10.9,
1H), 2.80 (s, 3H), 2.77 (dd, J = 2.4 and 10.9, 1H), 2.34 (t, J = 7.3, 2H),
1.92-1.80 (m, 2H), 1.70-1.59 (m, 2H), 1.46-1.35 (m, 2H). 13C NMR (100
MHz, CDCl3) δ: 172.1, 143.9, 138.5, 128.9, 128.6, 127.6, 123.2, 121.4,
67.2, 64.2, 58.8, 58.6, 48.8, 36.3, 33.8, 32.1, 29.7, 25.9, 24.2, 11.1. *1,2-
dimethylimidazole unreacted: 1H NMR (400 MHz, CDCl3) δ: 6.89-6.86 (m,
1H), 6.81-6.78 (m, 1H), 3.56 (s, 3H), 2.37 (s, 3H). HRMS calculated for
cation [C22H32N3O2S]+: 402,2210; obtained: 402,2239.
9-bromononyl (R)-thiazolidine-4-carboxylate (12)
A round-bottomed flask was charged with the protected compound
11 (2.7 g, 6.27 mmol) and TFA:CH2Cl2 1:1 solution (20 mL). The reaction
was monitored by thin layer chromatography and was completed in 10
minutes. The solvent was evaporated. To the residue was added water
and the pH was adjusted to 8 by the addition of NaHCO3. The product
was extracted with 3 x 5 mL of CH2Cl2, the organic layer was dried over
MgSO4 and the solvent was evaporated providing an yellow oil without
further purification. Yield: 99%. []D20 = -52 (c 0.5, CH2Cl2). 1H NMR (400
MHz, CDCl3) δ: 4.39 (d, J = 9.6, 1H), 4.18 (t, J = 6.7, 2H), 4.12 (d, J = 9.6,
1H), 3.83 (t, J = 7.6, 2H), 3.41 (t, J = 6.8, 2H), 3.26 (dd, J = 7.2 and 10.4,
1H), 2.87 (dd, J = 7.9 and 10.4, 1H), 2.33 (s, 1H), 1.85 (q, J = 7.1, 2H),
1.66 (q, J = 7.0, 2H), 1.49-1.38 (m, 2H), 1.38-1.27 (m, 8H). 13C NMR
(100 MHz, CDCl3) δ: 171.3, 65.6, 65.3, 54.4, 37.0, 33.9, 32.7, 29.2, 29.0,
28.6, 28.4, 28.1, 25.7. HRMS calculated for [C13H24BrNO2S+H]+:
338,0791; obtained: 338,0816.
1-(nonyl
(R)-thiazolidine-4-carboxylate)-2,3-dimethylimidazolium
bromide (4a)
Reagents and amounts used: Bromide 12 (2.09 g, 6,17 mmol), 1,2-
dimethylimidazole (1.19 g, 12.3 mmol) and acetonitrile (50 mL). The
yellow oil obtained consist of a mixture of the ionic product and the
unreacted 1,2-dimethylimidazole in the proportion of 1:1 (ionic product:
20
1,2-dimethylimidazole) calculated by 1H NMR. Yield: >99%. []D = -36
(c 0.4, CH2Cl2). *Product: 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J = 2.0,
1H), 7.58 (d, J = 2.1, 1H), 4.36 (d, J = 9.5, 1H), 4.24 (t, J = 7.5, 2H), 4.16
(t, J = 6.7, 2H), 4.12 (d, J = 9.5, 1H), 4.03 (s, 3H), 3.90 (t, J = 7.3, 1H),
General procedure to generate the ionic species containing
imidazolium cation
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
3.24 (dd, J = 7.2 and 10.3, 1H), 2.89 (dd, J = 7.4 and 10.3, 1H), 2.82 (s,
3H), 1.88-1.78 (m, 2H), 1.71-1.60 (m, 2H), 1.42-1.23 (m, 10H). 13C NMR
(100 MHz, CDCl3) δ: 171.4, 143.6, 123.0, 121.1, 65.5, 65.3, 54.4, 48.9,
36.9, 36.1, 29.8, 29.1, 28.9, 28.9, 28.4, 26.2, 25.6, 10.9. *1,2-
dimethylimidazole unreacted: 1H NMR (400 MHz, CDCl3) δ: 6.96 (d, J =
1.3, 1H), 6.90 (d, J = 1.1, 1H), 3.65 (s, 3H), 2.32 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 144.8, 126.8, 120.3, 32.7, 12.8. HRMS calculated for
cation [C18H32N3O2S]+: 354,2210; obtained: 354,2258.
mL). The organic layer was dried with MgSO4 and the solvent was
evaporated. After this reaction no unreacted 1,2-dimethylimidazole was
20
observed in 1H NMR analysis. Yield: 92%. []D = -8.0 (c 0.3, CH2Cl2).
1H NMR (400 MHz, CDCL3) δ: 7.36-7.23 (m, 5H), 7.17 (d, J = 2.2, 1H),
7.16 (d, J = 2.2, 1H), 4.11 (d, J = 10.1, 1H), 4.09-3.94 (m, 4H), 3.85 (dd,
J = 6.7 and 11.2, 1H), 3.76 (s, 3H), 3.71-3.64 (m, 1H), 3.65 (d, J = 13.4,
1H), 3.56 (d, J = 13.4, 1H), 3.07 (dd, J = 6.8 and 10.9, 1H), 2.75 (dd, J =
2.5 and 10.9, 1H), 2.56 (s, 3H), 2.32 (t, J = 7.4, 2H), 1.84-1.74 (m, 2H),
1.68-1.58 (m, 2H), 1.41-1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ:
173.0, 143.7, 138.4, 128.8, 128.4, 127.4, 122.5, 120.8, 119.7 (quart, J =
321.4, CF3), 67.0, 64.0, 58.6, 58.4, 48.4, 35.2, 33.4, 31.8, 29.1, 25.6,
23.9, 9.5. HRMS calculated for cation [C22H32N3O2S]+:402,2210;
obtained: 402,2238. HRMS calculated for anion [C2F6NO4S2]-: 279,9178;
obtained: 279,9143.
{(R,R’)-bis-[2-(N-benzyl-N-methylamino)-3-hexanoate-
propyl]dissulfide} pyridinium bromide (2a)
In a round-bottomed flask, equipped with reflux condenser, was added
the bromide 7 (0.15 g, 0.20 mmol) and 2 mL of pyridine (used as reagent
and solvent). This solution was stirred at 65 °C for 24 hours. Then, was
added 10 mL of toluene to precipitate the product as brown oil. The
supernatant solvent was pipetted. The oil was solubilized in methanol
1-(nonyl(R)-thiazolidine-4-carboxylate)-2,3-dimethylimidazolium
bis(trifluoromethylsulfonyl)amide (4b)
and the purification procedure by addition of toluene was repeated two
20
more times. The brown oil was dried under vacuum. Yield: >99%. []D
=
The mixture of the compound 4a with 1,2-dimethylimidazole was
solubilized in 5 mL of water and washed with ethyl ether (6 x 10 mL) to
remove the 1,2-dimethylimidazole unreacted. Considering that the entire
starting amount of the compound 4a was maintained in the aqueous
layer (0.29 g; 0.65 mmol), LiN(Tf)2 (0.13 g; 1.31 mmol) was added and
this solution was stirred at room temperature for 12 hours. The
precipitation of the product as a yellow oil was observed. The product
was extracted with CH2Cl2 (3 x 10 mL). The organic layer was dried with
MgSO4 and the solvent was evaporated. After this reaction, the ratio of
ionic product:1,2-dimethylimidazole varied from 1:0.4 to 1:0,25. Yield: 78-
1
+12 (c 0.9, MeOH). H NMR (500 MHz, methanol-d4) δ: 9.04 (d, J = 6.1,
4H), 8.63 (d, J = 7.8, 2H), 8.14 (t, J = 7.0, 4H), 7.37 (d, J = 7.3, 4H), 7.31
(t, J = 7.5, 4H), 7.24 (t, J = 6.6, 2H), 4.68 (t, J = 7.5, 4H), 4.37 (dd, J =
11.6 and 7.2, 2H), 4.26 (dd, J = 11.6 and 4.5, 2H), 3.72 (s, 4H), 3.23-3.30
(m, 2H), 3.10 (dd, J = 13.4 and 6.4, 2H), 2.77 (dd, J = 13.4 and 7.8, 2H),
2.44 (t, J = 7.3, 4H), 2.28 (s, 6H), 2.12-2.03 (m, 4H), 1.78-1.69 (m, 4H),
1.51-1.42 (m, 4H). 13C NMR (125 MHz, CDCl3) δ: 173.3, 145.5, 144.5,
139.3, 128.5, 128.1, 127.9, 126.7, 62.3, 61.4, 60.4, 58.1, 37.0, 36.1, 33.2,
30.7, 25.1, 23.8. HRMS calculated for cation [C44H60N4O4S2]2+: 386,2022;
obtained: 386,2062. HRMS calculated for anion [Br]-: 78,9189; obtained:
78,9146.
20
85%. []D = -20 (c 0.1, DCM). *Product: 1H NMR (400 MHz, CDCl3) δ:
7.22 (d, J = 2.2, 1H), 7.18 (d, J = 2.1, 1H), 4.37 (d, J = 9.6, 1H), 4.17 (td,
J = 6.7 and 1.0, 2H), 4.12 (d, J = 9.6, 1H), 4.04 (t, J = 7.6, 2H), 3.86 (t, J
= 7.4, 1H), 3.8 (s, 3H), 3.25 (dd, J = 7.2 and 10.4, 1H), 2.88 (dd, J = 7.7
and 10.4, 1H), 2.6 (s, 3H), 1.84-1.74 (m, 2H), 1.70-1.60 (m, 2H), 1.39-
1.24 (m, 10H). 13C NMR (100 MHz, CDCl3) δ: 171.5, 143.7, 122.5, 120.8,
119.4 (quart, J = 321.3, CF3), 65.6, 65.3, 54.4, 48.8, 37.0, 35.3, 29.5,
29.1, 28.9, 28.8, 28.4, 26.2, 25.7, 9.5. *1,2-dimethylimidazole unreacted:
1H NMR (400 MHz, CDCl3) δ: 7.02 (d, J = 1.7, 1H), 7.01 (d, J = 1.7, 1H),
3.7 (s, 3H), 2.5 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 144.8, 124.9,
120.9, 33.1, 12.3. HRMS calculated for cation [C18H32N3O2S]+: 354,2210;
obtained: 354,2247.
1-{(R,R’)-bis-[2-(N-benzyl-N-methylamino)-3-hexanoate-
propyl]dissulfide}-2,3-dimethylimidazolium
bis(trifluoromethylsulfonyl)amide (1b)
The mixture of the compound 1a with 1,2-dimethylimidazole was
solubilized in 2 mL of water and washed with CH2Cl2 (5 x 2 mL) to
remove the 1,2-dimethylimidazole unreacted. Considering that the entire
starting amount of the compound 1a was maintained in the aqueous
layer (0.46 mmol), LiN(Tf)2 (0.26 g, 0.92 mmol) was added and this
solution was stirred at room temperature for 12 hours. The precipitation
of the product as a yellow oil was observed. The product was extracted
with CH2Cl2 (3 x 3 mL). The organic layer was dried with MgSO4 and the
General procedure for asymmetric addition of diethylzinc to
aldehydes
solvent was evaporated. Yield: 91%. []D = +3.9 (c 0.4, CH2Cl2). 1H
20
NMR (400 MHz, acetone-d6) δ: 7.61 (d, J = 2.1, 2H), 7.58 (d, J = 2.1, 2H),
7.40-7.19 (m, 10H), 4.37 (dd, J = 7.2 and 11.6, 2H), 4.28 (t, J = 7.5, 4H),
4.22 (dd, J = 4.6 e 11.6, 2H), 3.93 (s, 6H), 3.76 (d, J = 13.6, 4H), 3.71 (d,
J = 13.6, 4H), 3.33-3.25 (m, 2H), 3.18 (dd, J = 7.1 and 13.1, 2H), 2.85
(dd, J = 7.2 and 13.1, 2H), 2.76 (s, 6H), 2.39 (t, J = 7.4, 4H), 2.25 (s, 6H),
1.95 (q, J = 7.6, 4H), 1.68 (q, J = 7.5, 4H), 1.45 (q, J = 7.7, 4H). 13C NMR
(100 MHz, acetone-d6) δ: 172.5, 144.7, 139.8, 128.5, 128.1, 126.8, 122.5,
120.9, 120.11 (quart, J = 321, CF3), 62.2, 60.9, 58.1, 48.0, 37.6, 36.4,
34.6, 33.5, 29.2, 25.5, 24.1, 8.8. HRMS calculated for cation
[C44H66N6O4S2]2+ = 403,2288; obtained = 403,2286. HRMS calculated for
anion [C2F6NO4S2]- = 279,9178; obtained: 279,9181.
A Schlenk tube was charged with the ionic ligand (5-20 mol%) and the
ionic solvent (0.25 mL). The ionic compounds were dried under vacuum,
heating at 60 °C and stirring for 5 hours. Then, under argon atmosphere,
at 0 °C, 0.25 mL of dried toluene (when toluene extra was used), 0.5-1
mmol of diethylzinc (1,5 mol.L-1 in toluene, added dropwise) and the
aldehyde (0.25 mmol) were added. The mixture was stirred at desired
temperature for 24-72 hours. At the end of the reaction time, HCl(aq)
1
mol.L-1, NH4Cl sat, oxalic acid in acetone or methanol were added. In the
case of aqueous solutions (HCl(aq) and NH4Cl sat) the organic compounds,
including the ionic liquids, were separated from the aqueous layer with
CH2Cl2, dried with MgSO4 and the solvent was evaporated. In the case of
oxalic acid in acetone (1:1 oxalic acid:Et2Zn) and methanol, CH2Cl2 was
added to aid the precipitation of inorganic zinc compounds, the solutions
were filtered and the solvents were evaporated. In all cases, the product
was extracted from the ionic layer with a mixture of 0,5 mL of CH2Cl2 and
4 mL of hexane. For this, 0,5 mL of CH2Cl2 was added to dilute the ionic
liquid. Then, hexane was added under stirring and the stirring was
continued for 15 minutes. The system was rested in the refrigerator for
10 minutes and the supernatant (containing the product and the other
nonionic compounds) was pipetted. This procedure was carried out until
1-[(4R)-3-benzyl-thiazolidin-4-yl-methylhexanoate]-2,3-
dimethylimidazolium bis(trifluoromethylsulfonyl)amide (3b)
A round-bottomed flask was charged with 3a (0.10 g, 0.21 mmol),
LiN(Tf)2 (0.12 g, 0.42 mmol) and 5 mL of water. This solution was stirred
at room temperature for 12 hours. The precipitation of the product as a
yellow oil was observed. The product was extracted with CH2Cl2 (3 x 5
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
FULL PAPER
there was no more product to be extracted (verified by thin-layer
chromatography). The organic solvent was evaporated and the products
were purified with column chromatography. In the case of reaction
carried out in conventional solvent (CH2Cl2) the drying step of the ionic
compounds for 5 hours under stirring, heating and vacuum was not
[3] (a) A. Mori, H. Abe, S. Inoue, Appl. Organomet. Chem. 1995, 9, 189. (b) J.
Paradowska, M. Stodulski, J. Mlynarski, Angew. Chem. Int. Ed. 2009, 48,
4288. (c) S. K. Panday, Tetrahedron: Asymmetry, 2011, 22, 1817. (d) W.
Li, J. Zhang, Chem. Soc. Rev. 2016, 45, 1657. (e) T. Wang, X. Han, F.
Zhong, W. Yao, Y. Lu, Acc. Chem. Res. 2016, 49, 1369. (f) A. Mondal, S.
Bhowmick, A. Ghosh, T. Chanda, K. C. Bhowmick, Tetrahedron:
Asymmetry 2017, 28, 849.
carried out. The quench of this reaction was carried out with NH4Cl
sat
and CH2Cl2 was used to the extraction of the product.
The racemic standards were prepared with typical Grignard protocol.
[4] (a) A. L. Braga, H. R. Appelt, P. H. Schneider, C. C. Silveira, L. A.
Wessjohann, Tetrahedron: Asymmetry 1999, 10, 1733. (b) A. L. Braga, H.
R. Appelt, P. H. Schneider, O. E. D. Rodrigues, C. C. Silveira, L. A.
Wessjohann, Tetrahedron 2001, 57, 3291. (c) A. L. Braga, H. R. Appelt, C.
C. Silveira, L. A. Wessjohann, P. H. Schneider, Tetrahedron 2002, 58,
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Recycling procedure
It was used the general procedure for asymmetric addition of diethylzinc
to aldehydes in ionic liquids described above, modifying only the
extraction method to enable recycling. Reactive conditions used:
benzaldehyde:Et2Zn:1b:BPy.N(Tf2):toluene (0.25 mmol:0.5 mmol:0.0125
mmol:0.25 mL:0.25 mL), 0 °C, 72 hours. At the end of the reaction time,
at 0 ° C, 2 mL of methanol were added and this mixture was stirred and
bubbled with compressed air for 1 hour to oxidize the ionic ligand to their
disulfide form. The formed solid was removed by filtration and CH2Cl2
was used to wash the solid and the filter. The conventional solvents
(methanol and CH2Cl2) were completely evaporated. From the remaining
material (containing the ionic and nonionic organic compounds) the
nonionic compounds were extracted with hexane. For this, 2 mL of
hexane were added under stirring and the stirring was continued for 15
minutes. The system was rested in the refrigerator for 10 minutes and the
supernatant (containing the product and the other nonionic compounds)
was pipetted. This procedure was carried out until there was no more
product to be extracted (verified by thin-layer chromatography), 10 times
on average. The organic solvent (hexane) was evaporated and the
product was purified with column chromatography. To recycling the ionic
solvent and the ionic ligand, after each catalytic cycle these compounds
were dried under vacuum, heating at 60 °C and stirring for 5 hours and a
new charge of benzaldehyde, diethylzinc and dried toluene were added
and a new catalytic cycle was performed.
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Acknowledgements
The authors are grateful to CNPq, INCT-CMN, FAPERGS
(PRONEX) and CAPES for financial support and the fellowship
awards.
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Keywords: ionic liquids • asymmetric catalysis • amino acids •
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10.1002/ejoc.201701426
European Journal of Organic Chemistry
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An important contribution to the field
of asymmetric catalysis is described
in this work, as it merges the search
for new catalytic systems that can
provide high performance in
Mariana Ferrari Bach, Cassiana Herzer
Griebeler, Caroline Gross Jacoby and
Paulo Henrique Schneider*
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asymmetric catalysis with the
extremely important and increasing
need for sustainability
Design of a New Chiral Ionic Liquids
System for the Enantioselective
Addition of Diethylzinc to Aldehydes
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