Efficient organocatalyst supported on a simple ionic liquid as a recoverable system for the asymmetric diels-alder reaction in the presence of water

Article abstract of DOI:10.1002/cctc.201402973

The synthesis, characterization, and evaluation of a new highly efficient organocatalyst, namely, (5S)-2,2,3-trimethyl-5-thiobenzylmethyl-4-imidazolidinone hydrochloride, has been achieved. The catalyst possesses important structural features that should increase the catalytic efficiency and solubility in polar media. The application of the ionic-liquid-supported imidazolidinone catalyst in enantioselective Diels-Alder reactions was investigated. The Diels-Alder reactions of several dienes and dienophiles proceeded efficiently in the presence of the catalyst to provide the desired products in moderate to good yields and from good to excellent enantioselectivities. The conformation study confirms that in the transition state the Re face is shielded completely by the phenyl ring and an approach on the less hindered Si face is preferred. Particularly remarkable is the fact that the entire ionic liquid/HCl 0.01 M/catalyst system can be recovered and reused in up to six runs without an appreciable loss of catalytic activity. Confirming the conformation: The synthesis, characterization, and evaluation of a new highly efficient imidazolidinone organocatalyst is achieved. The catalyst is investigated in enantioselective Diels-Alder reactions, and a conformation study confirms the approach on the less hindered Si face. [mPy][OTf]=Methylpyridinium triflate.

Full text of DOI:10.1002/cctc.201402973

DOI: 10.1002/cctc.201402973
Full Papers
Efficient Organocatalyst Supported on a Simple Ionic
Liquid as a Recoverable System for the Asymmetric
Diels–Alder Reaction in the Presence of Water
[
a]
[a]
[b]
[a]
Antonio De Nino,* Loredana Maiuolo,* Pedro Merino, Monica Nardi,
[c]
[b]
[a]
[a]
Antonio Procopio, David Roca-Lꢀpez, Beatrice Russo, and Vincenzo Algieri
The synthesis, characterization, and evaluation of a new highly
efficient organocatalyst, namely, (5S)-2,2,3-trimethyl-5-thio-
benzylmethyl-4-imidazolidinone hydrochloride, has been
achieved. The catalyst possesses important structural features
that should increase the catalytic efficiency and solubility in
polar media. The application of the ionic-liquid-supported imi-
dazolidinone catalyst in enantioselective Diels–Alder reactions
was investigated. The Diels–Alder reactions of several dienes
and dienophiles proceeded efficiently in the presence of the
catalyst to provide the desired products in moderate to good
yields and from good to excellent enantioselectivities. The con-
formation study confirms that in the transition state the Re
face is shielded completely by the phenyl ring and an ap-
proach on the less hindered Si face is preferred. Particularly re-
markable is the fact that the entire ionic liquid/HCl 0.01m/cata-
lyst system can be recovered and reused in up to six runs with-
out an appreciable loss of catalytic activity.
Introduction
[
3]
Asymmetric organocatalysis is an attractive branch of chemis-
try and, in particular, the development of new chiral catalysts
integrated with nontraditional solvents to form highly recycla-
ble systems is one of the most innovative fields of chemistry
to access a wide variety of chiral compounds under eco-friend-
Initially, MacMillan studied iminium ion organocatalysis in
Diels–Alder reactions through a typical mechanism based on
LUMO-lowering activation. MacMillan’s imidazolidinone catalyst
is highly efficient in terms of yield and selectivity; however, it
still has some drawbacks such as high catalyst loading and no
possibility of recycling. In this context, several attempts have
[
1]
ly conditions. Asymmetric Diels–Alder reactions provide
a simple and direct access to a variety of important chiral
cyclic compounds, and the elaboration of several efficient and
reliable enantioselective catalytic methods is realized using
[4]
been made to recycle the catalyst in recent years. In a previ-
[4a]
ous study we demonstrated that the use of methylpyridini-
um ILs, such as methylpyridinium triflate ([mPy][OTf]), as a sol-
vent in the Diels–Alder reactions of a,b-unsaturated aldehydes
with both cyclic and acyclic dienes lead to the corresponding
endo-cycloadducts with excellent diastereoselectivities and
enantioselectivities. Higher selectivity, better yields, and shorter
reaction times were observed in comparison with reactions
performed in classical organic solvents.
[
2]
metal-free organocatalysts. In this regard, we have developed
a new chiral organocatalyst and an efficient, recyclable system
that promotes Diels–Alder reactions without the use of metal
complexes. The immobilization of the organocatalyst in the
polar ionic liquid (IL)/H O system facilitates the separation and
2
reuse of the mixture, which promotes economic and environ-
mental benefits.
Herein, we report the new highly efficient organocatalyst
(
5S)-2,2,3-trimethyl-5-thiobenzylmethyl-4-imidazolidinone (3) in
combination with ILs. The new organocatalyst 3 bears an S
atom that increases the solubility and enhances the interac-
tions with the IL; in addition, intramolecular interactions
caused by the S atom ensure the rigidity of the intermediate
iminium ion and provide a high enantiofacial selectivity. Addi-
tional advantages are the ease of the synthetic procedure,
good recovery of products, and recyclability of the whole IL/or-
ganocatalyst system.
[
a] Prof. A. De Nino, Dr. L. Maiuolo, Dr. M. Nardi, Dr. B. Russo, Dr. V. Algieri
Dipartimento di Chimica
Universitꢀ della Calabria
8
7036 Rende (Italy)
E-mail: denino@unical.it
maiuolo@unical.it
[
b] Prof. P. Merino, Dr. D. Roca-Lꢁpez
Departamento de Sꢂntesis y Estructura de Biomolꢃculas
Universidad de Zaragoza
5
0009 Zaragoza, Aragꢁn (Spain)
[c] Prof. A. Procopio
Dipartimento di Scienze della Salute
Universitꢀ “Magna Græcia” di Catanzaro
Results and Discussion
Compound 3 was prepared in excellent chemical yield from
benzylcysteine methyl ester hydrochloride (1) by adding meth-
ylamine in aqueous solution followed by treatment with ace-
8
8100 Germaneto (Italy)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402973.
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Scheme 1. Synthesis of 3.
tone in methanol and p-toluenesulfonic acid (p-TSA;
Scheme 1).
With this product in hand and with the experience of previ-
ous work, we developed a highly efficient IL/HCl 0.01m/cata-
lyst system to promote Diels–Alder reactions of a broad range
of dienes and dienophiles under mild and recyclable condi-
tions, which afforded the corresponding cycle in a high yield
with good to high enantioselectivity (Scheme 2).
Scheme 3. Catalytic cycle for the cycloaddition process.
Alder reaction that involves a,b-unsaturated aldehydes and
various dienes proceeded efficiently in the system [mPy][OTf]/
HCl 0.01m/catalyst to lead to the cycloadduct in good yields
with good to excellent enantioselectivities (Table 2).
Scheme 2. General procedure for Diels–Alder reactions.
With the success of the reactions described above, we stud-
ied the recyclability of the IL/HCl 0.01m/catalyst polar phase
used in the Diels–Alder reaction. The recovery and recycling of
the entire catalytic system can be exemplified as shown below.
After the reaction, the polar phase was extracted three times
Initially, the catalytic ability of 3 in pyridinium-derived ILs
and HCl 0.01m was examined in a model Diels–Alder reaction
between cyclohexadiene 4 and acrolein 5 (Table 1). The cyclo-
addition is performed conveniently at 08C using 6 mol% cata-
lyst and is completed after 16 h with the formation of 6 with
an excellent endo/exo ratio of 98:2% and an enantiomeric ratio
by adding Et O (5 mL per time) directly into the separatory
2
funnel; the extracted crude was purified by routine silica gel
column chromatography, and catalyst 3 remained dissolved in
the IL/water mixture.
(
er) of 95:5%. The catalytic cycle is illustrated in Scheme 3.
In agreement with MacMillan’s model, it is expected that the
Therefore, IL-supported 3 can be reused directly in further
reactions. As shown in the histogram, only a slight decrease in
catalytic activity was observed if IL-supported 3 was recovered
and reused in further reactions (Figure 1).
E isomer will be formed preferentially, which prevents interac-
tions between the olefin and the methyl substituent in the
geminal position. Under these circumstances, the benzyl group
on the catalyst framework acts as a shield on the Re face of
the dienophile and promotes the approach of the diene by
the less hindered Si face.
Theoretical calculations
To explore the scope of the reaction, we applied the opti-
mized reaction conditions to various substrates. The Diels–
The asymmetric induction observed in all cases that involve
catalyst 3 is consistent with the conformation of the iminium
ion 7.
The conformational preferences of the iminium intermediate
were studied in detail. We considered the three dihedral
Table 1. Screening of reaction time and catalyst loading.
[5]
angles a, b, and g illustrated in Figure 2. For each dihedral
angle, three staggered conformations were studied, and both
the E and Z configurations of the iminium moiety were in-
volved. Thus, a total of 54 conformers were considered of
which 10 were eliminated because they led to a collision of
atoms. The resulting 44 conformers were optimized fully at the
[
a]
[b]
[b]
Entry
t
Catalyst
[mol%]
Yield
[%]
endo/exo
endo er
[
h]
1
2
3
4
10
10
10
16
3
6
10
6
70
75
80
98
98:2
98:2
98:2
98:2
92:8
95:5
95:5
95:5
[6]
CPCM=H O/M06-2X/6-31G(d) level. A total of 42 energy
2
[
a] Isolated yield. [b] Determined by GC analysis.
minima that have different dihedral angles were obtained. In
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spect to the global minimum
that accounts for 91.6% of all
the conformations are listed in
Table 2. [mPy][OTf]-mediated Diels–Alder reaction of various dienes and dienophiles catalyzed by 3.
Entry
Diene
R
Product
6a–g)
Yield
[%]
endo/exo
endo er
(
[7]
Table 3. As a result of the large
number of conformations stud-
ied, calculations that involve
higher levels of theory were not
performed for all of them. Full
optimizations at the CPCM=
1
2
H
H
98
93
98:2
94:6
95:5
97:3
H O/M06-2X/6-311+G (d,p) level
2
3
4
5
H
H
H
97
90
95
–
96:4
99:1
94:6
of theory were performed for
the above-mentioned seven
energy minima. The relative
energy values are also listed in
Table 3.
95:5
86:14
No substantial changes were
observed between calculations
at the 2x and 3x levels, and the
observed dihedral angles are
almost identical in all cases. Cal-
culations at the highest level
provided four conformations
within a difference of 1.0 kcal
6
7
Me
Ph
85
90
75:25
82:18
95:5
83:17
À1
mol (Figure 3). Of these confor-
mations, three ((E)-c06, (E)-c07,
and (E)-c02), which include the global minimum (E)-c06, pres-
ent a stabilizing CÀH···S interaction between one of the methyl
groups at position C2 of the imidazolidinone ring and the
methylthio group at position C5. The SÀH distance was in the
range of 2.91–2.95 ꢂ. The differences between these conform-
ers correspond to the rotation of dihedral angles b and g,
which corresponds to different orientations of the SÀbenzyl
group. CÀH···S interactions have been reported experimental-
[8]
[9]
ly and studied theoretically.
In particular, theoretical calculations at the MP2/6-
[10]
3
3
11+G(d,p) level found an optimum SÀHC(sp ) distance of
.095 ꢂ. Notably, the global minimum of iminium ion 7 ((E)-
3
c06) places the phenyl ring directly above the double bond to
shield the Re face of the dienophile and promote approach of
the diene by the less hindered Si face.
Therefore, the S atom plays a major role in the high enantio-
selectivity observed experimentally by fixing a partial confor-
mation (through the above-mentioned CÀH···S interaction)
Figure 1. Histogram of recovery and reuse of the IL/HCl 0.01m/catalyst
system.
À1
Table 3. Dihedral angles [8] and relative energies [kcalmol ] of the more stable con-
formers of iminium intermediate 7.
general,
Z isomers are
less stable than the cor-
responding E conformers
in agreement with previ-
ous results reported by
[
a]
[b]
DG (2x level)
DG (3x level)
Conformer
a
b
g
DDG
a
b
g
DDG
E-c06
E-c07
E-c21
E-c02
E-c24
E-c26
E-c04
À55.8 À97.1
À53.5 1.6
164.0 1.3
À56.3 0.4
60.7 0.0
À32.9 1.5
47.3 1.6
À54.7 À97.6
À55.4 0.0
163.9 0.2
À56.6 0.5
63.1 0.6
À33.4 1.4
47.7 1.7
À66.8
71.5
À58.3
79.0
119.5
93.8
À67.0
71.6
À67.3
78.0
115.9
89.4
[
6]
Houk et al. that demon-
strated a high steric hin-
drance between the two
Figure 2. Dihedral angles of 7.
64.4 À84.2
65.5 À85.0
64.8
49.5
65.8
50.1
methyl groups at C2 of the imidazolidinone ring and
the substituent attached to N1. The seven energy
À59.5 À93.8 À169.6 1.7 À59.5 À93.6 À168.9 1.6
2
O/M06-2X/6-31G(d). [b] CPCM=H O/M06-2X/6-311+G(d,p).
À1
[a] CPCM=H
2
minima below a difference of 2.0 kcalmol with re-
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Figure 3. Most stable conformers for 7. (Structures optimized at the
CPCM=H
mol ).
2
O/M06-2X/6-311+G(d,p) level; relative energies given in kcal
À1
Figure 5. NCI analysis showing NCI isosurfaces for conformers (E)-c06,
(
2
E)-c07, (E)-c21, and (E)-c24. Color-coded according to (l )1, the eigenvalue
of the density Hessian, to indicate attraction (green–blue) or repulsion (red).
The cutoff (1=0.2 a.u.) was chosen to isolate purely noncovalent interac-
tions.
that facilitates the orientation of the phenyl ring to hinder one
of the diasterofaces of the iminium intermediate 7 completely.
Conformer (E)-c21 presents a CÀH···p interaction between
the phenyl ring and a vinylic proton (Figure 3). This sort of sta-
bilizing interaction has been reported in the case of MacMil-
lan’s catalyst, for which the global minimum exhibits a stabiliz-
ing CÀH···p interaction between the methyl group at C2 and
To evidence the stabilizing interactions, the M06-2X/6-
311+G(d,p) wave functions were used for further NCI analysis,
a semiquantitative visualization index based on the electron
density and its derivatives that enables the identification of
[
1,6a]
the phenyl ring of the benzyl group at C5.
The same inter-
[11]
action has also been found for one of the more stable con-
formers of iminium ion 7 ((E)-c24). These interactions are illus-
trated in Figure 4 for both the iminium ion of MacMillan’s cata-
lyst (2.42 ꢂ) and conformer (E)-c24 of the iminium ion of 3
noncovalent interactions. Visualization of favorable and un-
[12]
favorable interactions was performed with NCI Plot Program
[13]
and VMD software.
Both (E)-c06 and (E)-c07 conformers show a reduced density
gradient (RDG) green surface that confirms the CÀH···S nonco-
valent stabilizing interactions. In addition, the global minimum
(E)-c06 shows a green surface that corresponds to a stabilizing
interaction between the phenyl ring and the double bond.
This interaction, difficult to identify by a mere visual inspection
of the model, can be identified as a p–p interaction and it sta-
bilizes the (E)-c06 conformer.
(2.84 ꢂ). The NCI (non-covalent interaction) analyses performed
for conformers (E)-c06, (E)-c07, (E)-c21, and (E)-c24, which show
three different types of interactions, are illustrated in Figure 5.
Conformers (E)-c21 and (E)-c24 show a typical RDG surface
that corresponds to a CÀH···p interaction in which a green
conical form with a vertex that points to the center of the aro-
matic ring can be appreciated. As stated above, the CÀH···p in-
teraction takes place between the aromatic ring and the vinylic
hydrogen atom for conformer (E)-c21 and the methyl group at
C2 for conformer (E)-c24.
We used the most stable conformation of the catalyst (E)-
c06 to locate the preferred transition structures for endo and
exo approaches of cyclopentadiene by both Re and Si faces.
Figure 4. CÀH···p interactions for optimized structures (CPCM=H
-311+G(d,p)) of the most stable conformer of the iminium ion of MacMil-
lan’s catalyst and conformer (E)-c24 of the iminium ion of catalyst 3.
2
O/M06-2X/
À1
The geometrical features and relative energies [kcalmol ] of
6
the four transition structures are illustrated in Figure 6.
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vent is necessary except during the final purification step.
These remarkable advantages make this approach effective
and practical in the synthesis of fine chemicals.
Experimental Section
General methods
Commercial starting materials were used without further purifica-
1
13
tion. Solvents were distilled before use. H and C NMR spectra
were recorded at 300 and 75 MHz respectively in CDCl using tetra-
3
methylsilane (TMS) as internal standard (Bruker ACP 300 MHz).
Chemical shifts are given in ppm and coupling constants in Hz.
The diastereoisomeric ratio has been determined by a GC–MS in-
strument (Shimadzu QP2010) equipped with a Quadrex 007–5 MS
column, 30 m, coated with a 0.25 mm film, helium as a carrier gas,
injector temperature of 2708C, and oven temperature program:
À1
5
08C hold 3 min, ramp 148Cmin to 2808C and held for 1 min.
The enantiomeric ratio has been evaluated by using a Focus GC–
FID Thermo Scientific instrument (FID=flame ionization detector)
equipped with a chiral column Megadex DET Beta, 30 m, coated
Figure 6. Transition structures for the reaction between (E)-c06 and cyclo-
pentadiene. (Structures optimized at the CPCM=H2O/M06-2X/6-311+G(d,p)
level; relative energies given in kcalmol ).
with a 0.25 mm film, helium as a carrier gas, injector temperature
À1
2
508C, and oven temperature program: 508C, ramp 28Cmin to
008C and hold for 1 min. ESI-HRMS spectra were recorded by
À1
2
using a Thermo Scientific Q Exactive (Thermo Fisher, Milan, Italy)
mass spectrometer using ESI with positive polarities at 70000 re-
solving power (defined as full width at half maximum (FWHM) m/z
200), IT (injection time)=30 ms, and AGC (automatic gain control)
target=1000000, for selected-ion monitoring (SIM) by infusion at
The energy difference between TS-Si-endo and TS-Si-exo is
À1
0
.84 kcalmol , which justifies the formation of endo/exo mix-
tures in the case of the reaction with cyclopentadiene. A differ-
À1
flow of 10 mLmin . Source conditions were: spray voltage 3.5 kV,
À1
ence of more than 3 kcalmol between the Re and Si ap-
sheath gas: 15 arbitrary units, auxiliary gas: 0 arbitrary units, sweep
gas: 0 arbitrary units. Heater temperature: 308C, cap temperature:
3208C. S-Lens RF level: 50. The instrument was calibrated using
the recommended Thermo Scientific Calibration solution at the be-
ginning of the analysis. Detection of the target compound was
based on the theoretical exact mass. Data were evaluated by using
Xcalibur 2.2.SP1 (Thermo Fisher Scientific, Bremen, Germany): the
mass accuracy, calculated directly from Xcalibur, is defined with the
formula D [ppm]=[(theoretical massÀmeasured mass)/theoretical
À1
proaches in the case of endo adducts (more than 5.0 kcalmol
for exo adducts) justifies the excellent enantioselectivity ob-
served. The bond-formation lengths are in agreement with
a highly asynchronous reaction as expected for a reaction per-
formed in a highly polar medium.
Conclusions
À1
mass] ꢃ1000000. Stock solution at a concentration of 1 mgmL
We have described and characterized a new chiral organocata-
lyst as an efficient, economical, and practical method for enan-
tioselective Diels–Alder reactions by using a reaction medium
composed of an ionic liquid (IL), HCl 0.01m, and organocata-
lyst, which leads to the desired products in good yields with
good to excellent enantioselectivities. Theoretical calculations
confirmed the presence of CÀH···p interactions similar to those
found for MacMillan’s catalyst. However, important CÀH···S sta-
bilizing interactions are also evidenced by both DFT calcula-
tions and NCI analysis, which justifies the high stability of con-
former (E)-c06. In this conformer the phenyl ring is placed over
the unsaturated system to render the Si face as the less hin-
dered one for the attack of the dienophile. The calculated rela-
tive energies between transition structures are in good agree-
ment with both the formation of mixtures of endo/exo adducts
in some cases and the excellent enantioselectivity observed ex-
perimentally. Notably, the complete polar system can be recov-
ered readily and recycled for further transformations at least
six times with the retention of its catalysis and enantioselectivi-
ty. In addition, only 6 mol% of catalyst and a slight excess of
donor aldehyde (1.5 equiv.) are required, and no organic sol-
were prepared in UHPLC–MS-grade methanol. Before analysis, the
solution was diluted 1:1000 v/v in a vial to obtain a concentration
of 1 mgmL
À1
Synthesis of methylpyridinium triflate ([mPy][OTf])
The IL [mPy][OTf] was prepared by halide-free direct synthesis by
placing dry pyridine (0.29 mol) in a two-necked flask to which
methyltrifluoromethanesulfonate (0.30 mol) was added dropwise.
The mixture was reacted at 808C for 12 h. The crude product was
washed with dichloromethane and dried under vacuum to yield
6
8.04 g (96%) of pure IL. The synthesis of [mPy][OTf] was con-
[14]
firmed by comparison of the spectra with literature reports.
Synthesis of catalyst 3
To an aqueous solution of MeNH2 (2m, 60 mL) was added (S)-
benzyl-l-cysteine methyl ester hydrochloride (10 g, 40 mmol), and
the solution was stirred at RT for 10 h. The crude solution was
treated with a saturated aqueous solution of NaHCO (50 mL), and
3
the free amine was extracted with CHCl3 (40 mLꢃ3), dried
(Na SO ), filtered, and concentrated. To this residue was added
2
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MeOH (100 mL), acetone (16.6 mL, 220 mmol), and p-TSA (93.2 mg,
.48 mmol). The solution was heated to reflux for 12 h, cooled to
H. Jiang, D. Cruz Cruz, Y. Li, V. H. Lauridsen, K. A. Jørgensen, J. Am.
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0
RT, and then concentrated in vacuo. The residue was washed with
hexane (30 mLꢃ3), and yielded 8.36 g (80% overall) of (5S)-2,2,3-
trimethyl-5-thiobenzylmethyl-4-imidazolidinone (3) as a yellow oil.
1
H NMR (300 MHz, [D]CHCl , 258C, TMS): d=1.3 (s, 3H; CH ), 1.4 (s,
3
3
3
H; CH ), 2.2 (bs, 1H; NÀH), 2.8 (s, 3H; NÀCH ), 2.8 (dd, 1H;
3
3
[3] K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000,
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3
2
3
J(H,H)=4.2, J(H,H)=14.1 Hz; HCH S), 2.9 (dd, 1H, J(H,H)=5.9,
J(H,H)=14.1 Hz; HCH S), 3.6 (dd, 1H, J(H,H)=4.2, J(H,H)=5.9 Hz;
2
2
3
3
2
2
2
5
-H), 3.7 (d, 1H, J(H,H)=13.4 Hz; HCH Bn), 3.8 (d, 1H, J(H,H)=
2
13
1
2
–5; c) H. Hagiwara, T. Kuroda, T. Hoshi, T. Suzuki, Adv. Synth. Catal.
010, 352, 909–916; d) T. E. Kristensen, K. Vestli, M. G. Jakobsen, F. K.
1
3.4 Hz, HCH Bn), 7.2–7.4 ppm (m, 5H, Ar); C NMR (75 MHz,
2
[
D]CHCl , 258C, TMS): d =25.2, 25.3, 27.0, 33.1, 36.8, 57.8, 75.6,
3
Hansen, T. Hansen, J. Org. Chem. 2010, 75, 1620–1629; e) N. Haraguchi,
Y. Takemura, S. Itsuno, Tetrahedron Lett. 2010, 51, 1205; f) S. Guizzetti,
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1
27.0, 128.5, 128.9, 138.2, 172.4 ppm; HRMS (ESI): m/z: calcd for
+
[
C H ON S+H] : 265.1369; found 265.1368.
14 20 2
General procedure for Diels–Alder reactions (6a–g)
2
012, 14, 2626–2630.
[
5] A similar but simpler conformational analysis for MacMillan’s catalyst
has been performed by Houk and co-workers, see: R. Gordillo, J. Carter,
K. N. Houk, Adv. Synth. Catal. 2004, 346, 1175–1185. In that case the
analysis involved six different conformations as only one dihedral angle
needed to be considered in addition to the E and Z configurations of
the iminium moiety.
In a representative procedure catalyst 3 (0.036 mmol, 6 mol%) was
dissolved in a mixture of [mPy][OTf]/HCl 0.01m 3:1 v/v. The dieno-
phile (0.6 mmol) and the diene (0.4 mmol) were added sequential-
ly. After the appropriate time, the reaction mixture was extracted
with ether (2 mLꢃ3). The ether layer was dried by Na SO , filtered,
2
4
evaporated under reduced pressure, and purified by flash chroma-
[6] a) This level of theory and solvent model was also used by Gordillo and
Houk in a previous study of the organocatalytic Diels–Alder reaction
promoted by MacMillan’s catalyst. See: R. Gordillo, K. N. Houk, J. Am.
Chem. Soc. 2006, 128, 3543–3553; b) As the reaction is performed in
a polar medium composed of a mixture of an aqueous acid solution
and IL, we chose water as a solvent to model a high dielectric constant
by using the conductor-like polarizable continuum model (CPCM),
which has shown its validity for such a solvent (see Ref. [1]). The model-
ing of an IL as a solvent is not well implemented yet and it would re-
quire high computational costs to consider a supermolecule with sever-
al units of IL. For a recent study on approaching solvation models for
ILs see: V. S. Bernales, A. V. Marenich, R. Contreras, C. J. Cramer, D. G.
Truhlar, J. Phys. Chem. B 2012, 116, 9122–9129.
1
13
tography. H and C NMR data were consistent with values report-
[3,15]
ed previously.
Acknowledgements
This work was supported by the Ministerio de Ciencia e Innova-
ciꢁn (MICINN) and FEDER Program (Madrid, Spain, project
CTQ2013-44367-C2-1-P) and the Gobierno de Aragꢁn (Zaragoza,
Spain. Bioorganic Chemistry Group. E-10). We acknowledge the
Institute of Biocomputation and Physics of Complex Systems
[
7] For the complete list of conformers, their relative energies, and abun-
dance according to Boltzmann distribution see the Supporting Informa-
tion.
(BIFI) at the University of Zaragoza (Spain) for computer time at
clusters Terminus and Memento. D.R.-L. thanks the Spanish Minis-
try of Education (MEC) for a pre-doctoral grant (FPU program).
Molecular graphics were generated by using CYLview 1.0 soft-
ware (C. Y. Legault, University of Sherbrooke, Canada). We thank
the Italian Ministry of University and Scientific Research (MIUR)
for a doctoral grant and the University of Calabria for financial
support.
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Keywords: conformation analysis · enantioselectivity · ionic
liquids · organocatalysis · supported catalysts
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Published online on && &&, 0000
&
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
6
ꢁ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPERS
A. De Nino,* L. Maiuolo,* P. Merino,
M. Nardi, A. Procopio, D. Roca-Lꢁpez,
B. Russo, V. Algieri
&& – &&
Efficient Organocatalyst Supported on
a Simple Ionic Liquid as a Recoverable
System for the Asymmetric Diels–
Alder Reaction in the Presence of
Water
Confirming the conformation: The syn-
thesis, characterization, and evaluation
of a new highly efficient imidazolidi-
none organocatalyst is achieved. The
catalyst is investigated in enantioselec-
tive Diels–Alder reactions, and a confor-
mation study confirms the approach on
the less hindered Si face.
[mPy][OTf]=Methylpyridinium triflate.
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
7
ꢁ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ