New chiral ionic liquids based on imidazolinium salts

Article abstract of DOI:10.1016/j.tetasy.2009.09.015

The preparation and application of a new series of chiral ionic liquids are described. The salts are based on imidazolinium cations. Some of the cations also incorporated an axial chirality at the C(2) position next to the central chirality. These cations

Full text of DOI:10.1016/j.tetasy.2009.09.015

Tetrahedron: Asymmetry 20 (2009) 2344–2350
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New chiral ionic liquids based on imidazolinium salts
*
Andreas Winkel, René Wilhelm
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation and application of a new series of chiral ionic liquids are described. The salts are based on
imidazolinium cations. Some of the cations also incorporated an axial chirality at the C(2) position next to
the central chirality. These cations display a very high rotational barrier along the arene–imidazolinium
axis. Furthermore, an analogue with a chiral anion was prepared. The salts have low melting points. Their
potential as solvents and as chiral shift reagents was explored, resulting for the first time in an example of
a chiral ionic liquid as a shift reagent for a neutral compound.
Received 6 August 2009
Accepted 22 September 2009
Available online 14 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
uids,32–36 we were interested in preparing chiral analogues of
imidazolinium salts incorporating ether functions with a different
Over the years, ionic liquids and salts with a melting point be-
low 100 °C have proven to be a promising class of organic materials
due to their potential as novel solvents for reactions and electro-
chemical processes.1 Many of these liquids could be potential
‘green solvents’, due to their negligible vapor pressure or efficient
recovery.2 However, a few studies have been reported that show
that ionic liquids are not inert but do react with some reagents,3,4
which could be a disadvantage in some applications, for example,
in recovery. Imidazolium cations are most frequently applied in
many standard ionic liquids. These cations can be deprotonated
with medium and strong bases.5–9 Therefore, a number of alterna-
tive ionic liquids have recently been reported, which can be used in
the presence of basic Grignard reagents.10–15 The first example, re-
ported by Clyburne et al.,10 was a phosphonium ionic liquid. There-
after, we reported the application of an imidazolinium salt.11
Handy reported that an iPr group at the C-2 position of an imi-
dazolium cation leads to a base-stable imidazolium RTIL for the
Grignard addition to aldehydes.13 In addition, Chan et al.12 re-
ported the application of n-butylpyridinium tetrafluoroborate in
this reaction. It was also possible to prepare the Grignard reagent
in this ionic liquid. In addition, Itho reported the use of salts based
on phosphonium cations with alkyl ether side arms for the Grig-
nard addition to aldehydes.15
chiral environment and an aryl substituent at the C(2) position,
which would also allow the introduction of an axial chirality. The
salts were investigated as solvents in the Grignard addition to alde-
hydes and as chiral shift reagents.
2. Results and discussion
The synthesis of chiral ionic liquids is shown in Scheme 1. First
L
-valinol37 1a was reacted with either benzoyl- or o-toluoyl chlo-
ride in the presence of potassium carbonate in methanol.38 The
corresponding amides could be obtained as white solids in 73%
yield for 2a and 95% yield for 2b, respectively. Furthermore, the
achiral N-benzoylethylamine 2c and N-(2-hydroxyethyl)-2-meth-
ylbenzamide 2d were obtained from ethanolamine 1b and benzoyl
chloride or toluoyl chloride in 93% and 71% yield, respectively.
These amides were then treated with neat thionyl chloride and
subsequently with aqueous methylamine to give the desired
1-methylimidazolines.
(S)-4-Isopropyl-1-methyl-2-phenyl-4,5-
dihydro-1H-imidazole 3a was isolated in 82% yield, whereas (S)-
4-isopropyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-imidazole 3b was
obtained only in 47% yield probably due to increased steric hin-
drance during the reaction with thionyl chloride. 1-Methyl-
phenyl-4,5-dihydro-1H-imidazole 3c was obtained as a colorless
liquid in 77% yield, whereas 1-methyl-2-o-tolyl-4,5-dihydro-1H-
imidazole 3d was obtained in 67% yield.
The prepared 4,5-dihydro-1H-imidazoles 3a–d were afterwards
subjected to nucleophilic substitution reactions with electrophiles
containing ether moieties, namely MOM-chloride, MEM-chloride,
and (ꢀ)-menthyl chloride. (ꢀ)-Menthyl chloride was prepared via
the standard procedure from menthol, paraformaldehyde, and
hydrochloric acid.39 The chlorides obtained were directly dissolved
in water and the addition of LiNTf2 led to the precipitation of the
chiral ionic liquids. Depending on the synthetic route, the final
If ionic liquids are chiral, they have an additional potential as
chiral solvents, shift reagents, and catalysts.16–31 Most of these chi-
ral ionic liquids incorporate a central chirality and only a few are
known based on planar28 and axial chirality.30 Chiral ionic liquids
based on imidazolinium salts can have a stereogenic center at
the C(4) or C(5) position, and it is known that no racemization oc-
curs at these positions.31 Due to our efforts on the chiral ionic liq-
* Corresponding author. Tel.: +49 5323 723886; fax: +49 5323 722834.
E-mail address: rene.wilhelm@tu-clausthal.de (R. Wilhelm).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.015

A. Winkel, R. Wilhelm / Tetrahedron: Asymmetry 20 (2009) 2344–2350
2345
R1
R1
R1
OH
Cl
R2COCl
K2CO3, MeOH
R3Cl
O
Cl
SOCl2
MeNH2
N
N
R3
N
N
R1
N
H
R2
R1
N
R2
H2N
OH
R2
Cl
R2
1a: R1 = iPr
2a: R1 = iPr, R2 = Ph
1b: R1 = H
3a: R1 = iPr, R2 = Ph
3b: R1 = iPr, R2 = o-tolyl
3c: R1 = H, R2 = Ph
2b: R1 = iPr, R2 = o-tolyl
2c: R1 = H, R2 = Ph
LiNTf2
2d: R1 = H, R2 = o-tolyl
R1
3d: R1 = H, R2 = o-tolyl
N
N
R3
NTf2
R2
4a: R1 = iPr, R2 = Ph, R3 = MOM
4b: R1 = iPr, R2 = Ph, R3 = MEM
4c: R1 = iPr, R2 = o-tolyl, R3 = MOM
4d: R1 = iPr, R2 = o-tolyl, R3 = MEM
4e: R1 = H, R2 = Ph, R3 = (−)-menthyl
4f: R1 = H, R2 = o-tolyl, R3 = (−)-menthyl
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
4e
4a
4b
+
+
+
O
O
O
O
N
N
N
N
N
N
NTf2
NTf2
NTf2
4c
4d
4f
Scheme 1. Synthesis of chiral ionic liquids.
cation carried the chiral information directly at the imidazolium
ring or at the imidazoline nitrogen atom.
All the salts prepared are ionic liquids, respectively, with melt-
ing points at 39 °C, 4a; 44 °C, 4c; and 58 °C, 4e or are room-temper-
ature ionic liquids at 20 °C, 4b, 4d, and 4f.
To explore whether the reaction temperature of the quaterniza-
tion step would have an influence on the diastereomeric ratio of
the product, imidazoline 3b was reacted with ethyliodide in aceto-
nitrile at rt and at reflux. In addition, acetonitrile was replaced with
hexane and the reaction was carried out at rt to investigate the
influence of the solvent (Scheme 2). From the obtained NMR data,
in all cases, a diastereomeric ratio of ꢁ1:1 was obtained.
The ionic liquids, which have an o-tolyl group at the C2-position
of the imidazolinium ring, also have next to an element of central
chirality an element of axial chirality. The rotation around the axis
is hindered, which makes it possible to observe in the NMR sepa-
rate signals for each diastereomer. Scheme 1 shows the different
diastereomers of the ionic liquids bearing additional axial chirality.
The diastereomeric ratios for the described ionic liquids were
calculated from the 1H NMR data. The following ratios were ob-
served: 3:2, 4c; 4:3, 4d; and 1:1, 4f. It was not possible to separate
the diastereomers with any of the several standard methods or
with HPLC with normal or reversed phase. The assignment of the
peaks to a specific diastereomer was not possible by NOE. How-
ever, it is reasonable to assume for 4c and 4d that the less sterically
demanding diastereomer is formed in excess.
N
N
N
N
ethyl iodide
CH3CN, rt or
CH3CN, reflux or
hexane, rt
I
dr 1:1
3b
5
Scheme 2. Synthesis of salt 5.
While free rotation in salts 4c, 4d, and 4f is restricted, there is
no rotational barrier in the corresponding imidazolines 3c, 3d,
and 3f. The tolyl group is locked in the quaternization process
and an obviously high rotation barrier prevents free rotation
around the C2–C(tolyl) axis because of steric hindrance between
the newly introduced substituent at the C1-carbon and the methyl
group of the tolyl ring. In order to determine the rotational barrier,
IL 4c was heated in DMSO-d6 during the NMR measurement from
rt to 50, 100, and 150 °C in order to evaluate any changes in the
diastereomeric ratio. However, even at 150 °C, no change in the
NMR was observed meaning that one can assume a high rotational
barrier around the imidazolinium–tolyl C–C axis.
An imidazolinium salt was prepared with a chiral anion based
on (ꢀ)-camphorsulfonic acid as shown in Scheme 3. The precursor
3c was treated with butyl chloride in refluxing acetonitrile to give
the desired product 6 in 65% yield. Subsequent anion metathesis
with commercially available (ꢀ)-ammonium camphorsulfonate
gave the new rt chiral ionic liquid 7 in 86% yield.
The ionic liquids 4a–f were tested in the Grignard addition to
aldehydes (Scheme 4). The THF solvent of the commercial Grignard
solution was evaporated under high vacuum and the ionic liquid
was added to the remaining solid Grignard. After heating to

2346
A. Winkel, R. Wilhelm / Tetrahedron: Asymmetry 20 (2009) 2344–2350
N
N
N
N
BuCl
CH3CN, reflux
Cl
3c
6
O
SO3NH4
CH2Cl2, H2O
N
N
O
SO3
7
Figure 1. (a) ( )-1-Phenyl-2,2,2-trifluoroethanol in toluene-d8, (b) ( )-1-phenyl-
2,2,2-trifluoroethanol (1 equiv) + 7 (2 equiv) in toluene-d8, 1-phenyl-2,2,2-trifluo-
roethanol [50% ee, (S)-enriched, 1 equiv] + 7 (2 equiv) in toluene-d8, (c) 1-phenyl-
2,2,2-trifluoroethanol [33% ee, (S)-enriched, 1 equiv] + 7 (2 equiv) in toluene-d8.
Scheme 3. Synthesis of salt 7.
OH
O
CIL , 3 h
Ph-MgBr
Ph
3. Conclusion
Scheme 4. Grignard addition to aldehydes.
40 °C, the aldehyde was added and the reaction mixture was stir-
red for 3 h.
In conclusion, it was possible to synthesize a series of chiral
ionic liquids containing ether functions of which some incorpo-
rated axial chirality. In the future, analogues with larger groups
in the backbone of the imidazolinium ring and at the ortho posi-
tion of the aryl substituent will be prepared in order to increase
the diastereoselectivity. While the ionic liquids did not induce
any asymmetric excess in the addition of Grignard reagent to
aldehydes, it was possible to show that they are able to form dia-
stereomeric salt pairs with Mosher’s carboxylates. More impor-
tantly, it was possible to show that a salt with a chiral camphor
sulfonate anion can be used as a chiral shift reagent for a neutral
alcohol.
Ionic liquids 4e and 4f gave the desired product in yields com-
parable to an achiral analogue.11 Since ionic liquid 4e gave the
highest yield, the addition of phenylmagnesiumbromide to 1-
naphthaldehyde was also tested herein. The corresponding product
was isolated in 52% yield. In all the reactions, no optical activity
was found. Two reactions were carried out in the presence of a Le-
wis acid and 4a as a solvent. Moreover, 10 mol % of the Lewis acids,
zinc chloride or scandium triflate, was used. However, the yields
decreased to 30% with zinc chloride and to 20% with scandium
triflate.
Next, the behavior of the salts as chiral shift reagents was tested
with enantiomerically and diastereomerically pure ionic liquids 4a,
4b, and 4e, and with ionic liquid 7. For the NMR measurements,
racemic Mosher’s acid potassium salt with 18-crown-6 or 1-phe-
nyl-2,2,2-trifluoroethanol was used. In a typical NMR experiment,
the CIL/substrate ratio was 2:1. With 4a and 4b, racemic potassium
Mosher’s carboxylate and 18-crown-6, a splitting of 15.14 Hz and
5.17 Hz in the 19F NMR was observed when CDCl3 was used as a
solvent. In the 1H NMR no splitting was found. With salt 4e no
splitting was observed in either the 1H or 19F NMR.
4. Experimental
4.1. General experimental
Toluene was dried over sodium. L
-Valinol 1a37 was prepared
according to the literature. Flash column chromatography40 was
performed on silica gel. All reactions were monitored by TLC
plates. 1H NMR spectra were acquired with a Bruker AC 200F
(200 MHz) at ambient temperature. Chemical 13C NMR spectra
were recorded at ambient temperature with AC 200F (50 MHz)
instruments and chemical shifts were reported in parts per mil-
lion (ppm) relative to tetramethylsilane as the internal standard.
NMR samples were dissolved if not otherwise stated in CDCl3.
Mass spectra (ESI) were recorded with a Hewlett–Packard MS
LC/MSD Series 1100 MSD instrument, while HRMS were recorded
on a Bruker Daltonik Tesla-Fourier Transform-Ion Cyclotron Reso-
nance Mass spectrometer mit Electrospray-Ionisierung by Dr.
Dräger at the Institute of Organic Chemistry, University of Han-
nover. Infrared spectra were recorded with a Bruker Vektor 22
FTIR spectrometer, as KBr pellets in case of solid compounds
and as thin films between NaCl plates in cases of oils and liquids.
HPLC analysis was carried out using a Daicel CHIRALPACK OD-H
column with a Waters 510 Pump system, an ISCO Model UA-5
UV–vis Detector (254 nm), and a Waters 410 differential refrac-
tometer. Melting points were taken with a Dr. Tottoli apparatus
and are uncorrected.
´
In order to evaluate salt 7, Moshers acid was added to the salt in
toluene-d8. However, no splitting was observed. Next ( )-1-phe-
nyl-2,2,2-trifluoroethanol with 7 in CDCl3 showed no splitting of
the C1-proton of the alcohol, but a downfield shift of 0.2 ppm
was observed. The results changed drastically when toluene-d8
was used as the solvent. The alcohol’s C1-proton signal was shifted
from 4.38 ppm (without ionic liquid) to 5.62 ppm. Also a splitting
of the quadruplet was observed. The chiral recognition by ionic li-
quid 7 caused a splitting of about 2.5 Hz in the 1H NMR. However,
in some cases, a splitting of the quadruplet signal was observed
although no ionic liquid was applied. This was due to the fact that
the decreased humidity of the reagents and solvents used in the
experiments caused a further coupling of the CH-proton of the
alcohol with the hydroxyl proton. To exclude this influence in
determining the splitting, enantiomerically enriched 1-phenyl-
2,2,2-trifluoroethanol [(S)-enriched, 50% ee and 33% ee] was ap-
plied. In the 19F NMR, the splitting of the CF3 doublet was 6.9 Hz
as shown in Figure 1.

A. Winkel, R. Wilhelm / Tetrahedron: Asymmetry 20 (2009) 2344–2350
2347
4.2. Preparation of hydroxy-protected bis-hydroxy amines
4.2.2.1. (S)-4-Isopropyl-1-methyl-2-phenyl-4,5-dihydro-1H-imid-
azole 3a. As a colorless liquid (82%). ½a D25
¼ ꢀ84:0 (c 1.07, CHCl3);
ꢃ
4.2.1. Preparation of benzamides 2a–2d: General procedure
Potassium carbonate (12.5 g) was suspended in methanol
(400 mL). The aminoalcohol 1a or 1b (83.1 mmol) was added and
the mixture was cooled down to 0 °C. Afterwards, the acid chloride
(91.4 mmol) was added and the mixture was stirred for 15 h at rt.
The remaining solid was decanted off and the solvent was distilled
off. Water (100 mL) and chloroform (200 mL) were added and the
mixture was stirred for 15 min. The organic phase was separated,
and the aqueous phase was washed with chloroform
(3 ꢂ 100 mL). The combined organic phases were dried over so-
dium sulfate. After distilling off the solvent, the remaining solid
was washed with a small amount of cold toluene and afterwards
dried in high vacuum.
MS (EI), m/e 202 (M+, 3%), 185 (3), 174 (5), 159 (100), 132 (3), 118
(7), 104 (20), 91 (10), 77 (27); IR (NaCl) 3060, 3022, 2955, 2870,
1957, 1895, 1653, 1614, 1597, 1573, 1448, 1383, 1364, 1310,
1264, 1217, 1064, 1026, 971, 945, 923, 778, 702, 588, 544,
433 cmꢀ1 1H NMR (200 MHz) d 7.52–7.34 (m, 2H), 7.34–7.18 (m,
;
3H), 3.77 (ddd, J = 10.4, 9.2, 6.0 Hz, 1H), 3.40 (dd, J = 10.3, 9.2 Hz,
1H), 2.94 (t, J = 9.2 Hz, 1H), 2.63 (s, 3H), 1.89–1.63 (m, 1H), 0.92
(d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H); 13C NMR (50 MHz) d
166.3, 131.1, 129.2, 127.9 (2C), 70.0, 55.9, 35.8, 32.9, 18.8, 17.8.
HRMS (EI): calcd for C13H18N2 [M+]: 202.1470, found 202.1472.
4.2.2.2. (S)-4-Isopropyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-imid-
azole 3b. As a yellow liquid (47%). ½a D25
¼ þ58:3 (c 1.43, CHCl3);
ꢃ
MS (EI), m/e 216 (M+, 18%), 201 (5), 173 (100), 117 (22), 103 (8),
91 (21), 85 (7), 77 (11); IR (NaCl) 3061, 3022, 2955, 2870, 1619,
1597, 1497, 1458, 1382, 1364, 1309, 1262, 1232, 1061, 1040,
4.2.1.1. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-benzamide 2a.
As a white solid (73%). 1H NMR (200 MHz) d 7.91–7.63 (m, 2H),
7.61–7.30 (m, 3H), 6.60 (d, J = 8.3 Hz, 1H), 4.03–3.80 (m, 1H), 3.82–
3.64 (m, 2H), 3.19 (s, 1H), 2.19–1.78 (m, 1H), 1.00 (d, J = 3.2 Hz, 3H),
0.97 (d, J = 3.3 Hz, 3H); 13C NMR (50 MHz) d 168.5, 134.6, 131.6,
128.7, 127.1, 63.6, 57.5, 29.3, 19.7, 19.1. The spectral data were
consistent with literature values.41
944, 771, 732, 588, 532, 446, 436, 428 cmꢀ1 1H NMR (200 MHz)
;
d 7.34–7.13 (m, 5H), 3.92 (ddd, J = 10.3, 9.2, 6.0 Hz, 1H), 3.47 (dd,
J = 18.3, 9.2 Hz, 1H), 3.08 (t, J = 9.2 Hz, 1H), 2.57 (s, 3H), 2.32 (s,
3H), 1.98–1.74 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz,
3H); 13C NMR (50 MHz) d 166.2, 136.3, 131.5, 130.2, 129.1, 128.7,
125.7, 70.7, 55.3, 34.5, 33.2, 19.5, 19.1, 18.4. HRMS (EI): calcd for
C14H20N2 [M+]: 216.1626, found 216.1625.
4.2.1.2. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-methylbenz-
amid 2b. As a white solid (95%). Mp 89.2 °C; ½a D25
¼ ꢀ27:8 (c 0.42,
ꢃ
CHCl3); MS (EI), m/e 222 (M++H, 3%), 136 (11), 119 (100), 91 (42);
4.2.2.3. 1-Methyl-phenyl-4,5-dihydro-1H-imidazole 3c. As
a
IR (KBr) 3293, 3069, 2964, 2880, 2360, 1638, 1538, 1463, 1338,
colorless liquid (77%). 1H NMR (200 MHz) d 7.60–7.45 (m, 2H),
7.46–7.30 (m, 3H), 3.95–3.76 (m, 2H), 3.52–3.33 (m, 2H), 2.78 (s,
3H); 13C NMR (50 MHz) d 168.1, 131.3, 129.6, 128.2, 128.1, 54.1,
53.2, 36.4. The spectral data were consistent with literature
values.43
1314, 1068, 1017, 901, 878, 845, 778, 742, 724, 698 cmꢀ1 1H
;
NMR (200 MHz) d 7.35–7.02 (m, 4H), 5.99 (d, J = 7.7 Hz, 1H),
3.93–3.75 (m, 1H), 3.74–3.56 (m, 2H), 2.78 (s, 1H), 2.36 (s, 3H),
1.99–1.78 (m, 1H), 0.95 (d, J = 3.3 Hz, 3H), 0.91 (d, J = 3.4 Hz, 3H);
13C NMR (50 MHz) d 171.2, 136.7, 136.0, 131.1, 130.0, 126.7,
125.9, 64.0, 57.4, 29.2, 19.9, 19.7, 19.0. HRMS (EI): calcd for
C13H19NO2 [M+]: 221.1416, found 221.1418.
4.2.2.4. 1-Methyl-2-o-tolyl-4,5-dihydro-1H-imidazole 3d. As a
colorless liquid (67%). MS (EI), m/e 173 (88%, [M+]), 159 (67%), 91
(23%), 84 (100%), 77 (28%); IR (NaCl) 3061, 3022, 2926, 2861,
1922, 1720, 1618, 1595, 1496, 1451, 1381, 1327, 1272, 1227,
4.2.1.3. N-(2-Hydroxyethyl)-benzamide 2c. As
a white solid
(93%). 1H NMR (200 MHz) d 7.85–7.66 (m, 2H), 7.52–7.14 (m,
4H), 4.05 (s, 1H), 3.74 (t, J = 4.9 Hz, 2H), 3.62–3.45 (m, 2H), OH-pro-
ton not observed; 13C NMR (50 MHz) d 168.9, 134.1, 131.7, 128.6,
127.1, 61.8, 42.9. The spectral data were consistent with literature
values.42
1182, 1119, 1085, 1057, 1039, 989, 942, 770, 731, 589, 533 cmꢀ1
;
1H NMR (200 MHz) d 7.36–7.13 (m, 4H), 3.98–3.78 (m, 2H), 3.49–
3.30 (m, 2H), 2.57 (s, 3H), 2.32 (s, 3H); 13C NMR (50 MHz) d
167.4, 136.2, 131.4, 130.0, 128.9, 128.3, 125.5, 53.4, 53.0, 34.6,
19.2. HRMS (EI): calcd for C11H14N2 [M+]: 174.1157, found
174.1158.
4.2.1.4. N-(2-Hydroxyethyl)-2-methylbenzamide 2d. As a white
solid (71%). Mp 65 °C; MS (EI), m/e 179 (M+, 7%), 136 (11), 119
(100), 91 (57), 77 (3); IR (KBr) 3279, 3070, 3025, 2971, 2932,
2884, 1966, 1933, 1816, 1637, 1420, 1315, 1164, 1119, 1095,
4.2.3. Synthesis of ionic liquids 4a–4f: General procedure
The particular 4,5-dihydro-1H-imidazole (5.2 mmol) was dis-
solved in dry acetonitrile (3 mL), and the electrophilic chloride
[MOM-, MEM-, or (ꢀ)-menthyl chloride] was added (10.4 mmol).
The solution was refluxed for 15 h. After cooling the solvent the
remaining electrophile was distilled off. The remainder was dis-
solved in water (10 mL), and LiNTf2 (7.8 mmol) in water (5 mL)
was added. An organic phase separated immediately. The mixture
was stirred for an additional 30 min. The water was decanted off
and the ionic liquid was washed three times with water. Dichloro-
methane was added and the organic phase was dried over sodium
sulfate. After distilling off the solvent, the ionic liquids were dried
under high vacuum for at least 15 h at 50 °C.
1047, 883, 868, 779, 755, 729, 702, 659, 521, 461, 416 cmꢀ1 1H
;
NMR (200 MHz) d 7.42–7.06 (m, 4H), 6.48 (s, 1H), 3.83–3.63 (m,
2H), 3.61–3.42 (m, 2H), 3.23 (s, 1H), 2.40 (s, 3H); 13C NMR
(50 MHz) d 171.4, 136.1, 136.0, 131.1, 130.1, 126.9, 125.8, 62.2,
42.7, 19.8. Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.97; H, 7.38; N, 7.82.
4.2.2. Preparation of imidazolines 3a–3d: General procedure
Hydroxybenzamides 2a–2d (197 mmol) were carefully treated
with neat thionyl chloride (0.79 mol). The resulting solution was re-
fluxed for 4 h. The excess of thionyl chloride was distilled off. Dry
diethyl ether (200 mL) was added to the remaining oil. The small
amount of insoluble solid was filtered off and the filtrate was cooled
down to 0 °C. Aqueous methyl amine solution (200 mL, 11.85 M)
was added and the resulting mixture was stirred for 1 h at rt. The
organic phase was separated, and the aqueous phase was washed
with chloroform (3 ꢂ 300 mL). The combined organic phases were
dried over sodium sulfate. After distilling off the solvent, the
remaining oil was purified via bulb-to-bulb distillation.
4.2.3.1. (S)-4-Isopropyl-3-(methoxymethyl)-1-methyl-2-phenyl
-4,5-dihydro-1H-imidazol-3-ium bis(trifluoromethylsulfonyl)
amide 4a. As an orange solid (77%). Mp 39 °C; ½a D25
¼ þ20:1 (c
ꢃ
1.33, CHCl3); MS (EI), m/e 247 ([Mcation]+, 100%), 203 (29), 159
(21), 118 (8), 77 (6); MS (ESI, 0 V) m/e 247.3 ([Mcation]+, 100%); IR
(KBr) 3320, 2968, 1624, 1604, 1549, 1491, 1467, 1449, 1395,
1353, 1288, 1195, 1137, 1098, 1057, 944, 917, 788, 740, 700,
654, 617 cmꢀ1 1H NMR (400 MHz) d 7.81–7.49 (m, 5H), 4.60–
;

2348
A. Winkel, R. Wilhelm / Tetrahedron: Asymmetry 20 (2009) 2344–2350
4.17 (m, 4H), 3.72 (dd, J = 10.8, 7.2 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H),
2.47–2.20 (m, 1H), 1.02 (d, J = 0.9 Hz, 3H), 0.98 (d, J = 1.3 Hz, 3H);
13C NMR (100 MHz) d 167.7, 133.8, 130.0, 128.8, 121.1, 120.1 (q,
JCF = 321 Hz), 78.1, 64.6, 56.4, 51.8, 34.8, 28.9, 17.7, 14.5. Anal.
Calcd for C17H23F6N3O5S2: C, 38.71; H, 4.39; N, 7.97. Found: C,
38.58; H, 4.28; N, 8.04.
Calcd for C20H29F6N3O6S2: C, 41.02; H, 4.99; N, 7.18. Found: C,
40.93; H, 4.85; N, 7.16.
4.2.3.5. 3-(((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy)-me-
thyl)-1-methyl-2-phenyl-4,5-dihydro-1H-imidazol-3-ium bis(tri
fluoromethylsulfonyl)amide 4e. As a white solid (75%). Mp
58.5 °C; ½a 2D5
ꢃ
¼ ꢀ39:7 (c 1.02, CHCl3); MS (EI), m/e 328 ([Mcation]+,
4.2.3.2. (S)-4-Isopropyl-3-((2-methoxyethoxy)methyl)-1-methyl
-2-phenyl-4,5-dihydro-1H-imidazol-3-ium bis(trifluoromethyl-
100%), 190 (27), 174 (11), 163 (33), 119 (20); MS (ESI, 0 V) m/e
250.1 (58%), 330.0 ([Mcation]+, 5), 488.7 (100); IR (KBr) 3328,
3094, 3068, 2965, 2877, 2361, 1932, 1847, 1621, 1569, 1493,
1459, 1412, 1352, 1191, 1139, 1057, 935, 923, 850, 790, 774,
sulfonyl)amide 4b. As a yellow liquid (77%). ½a D25
¼ þ18:0 (c 1.29,
ꢃ
CHCl3); MS (EI), m/e 291 ([Mcation]+, 100%), 247 (11), 203 (13), 159
(23); MS (ESI, 0 V) m/e 290.9 ([Mcation]+, 100%); IR (KBr) 3308, 3067,
2968, 2883, 2360 1929, 1623, 1604, 1549, 1491, 1466, 1449, 1352,
1352, 1192, 1136, 1093, 1058, 787, 740, 700, 654, 616, 571, 513,
740, 708, 657, 619, 601, 570, 507 cmꢀ1 1H NMR (400 MHz) d
;
7.74–7.49 (m, 5H), 4.60 (d, J = 10.4 Hz, 1H), 4.55 (d, J = 10.4 Hz,
1H), 4.16 (s, 4H), 3.01 (s, 3H), 3.01–2.92 (m, 1H), 2.08–1.92 (m,
1H), 1.67–1.49 (m, 3H), 1.26–1.08 (m, 2H), 0.94–0.86 (m, 1H),
0.84 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.5 Hz, 3H), 0.77–0.64 (m, 2H),
0.63 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz) d 166.9, 133.5, 129.8,
128.6, 120.9, 119.9 (q, JCF = 321 Hz), 77.5, 74.8, 50.8, 47.9, 46.9,
39.8, 34.7, 34.1, 31.2, 25.4, 22.9, 22.0, 20.9, 15.8. HRMS (ESI): calcd
for C21H33N2O [Mþcation]: 329.2593, found 329.2597.
462, 444, 436 cmꢀ1 1H NMR (400 MHz) d 7.78–7.54 (m, 5H),
;
4.70 (d, J = 10.9 Hz, 1H), 4.59 (d, J = 10.9 Hz, 1H), 4.49 (ddd,
J = 12.0, 8.1, 3.6 Hz, 1H), 4.24 (t, J = 12.0 Hz, 1H), 3.80 (dd,
J = 12.0, 8.1 Hz, 1H), 3.56–3.37 (m, 4H), 3.29 (s, 3H), 3.07 (s, 3H),
2.47–2.27 (m, 1H), 1.03 (d, J = 1.8, 3H), 1.01 (d, J = 2.0 Hz, 3H);
13C NMR (100 MHz) d 167.3, 133.6, 129.9, 128.7, 120.9, 120.0 (q,
JCF = 321 Hz,), 76.3, 71.5, 68.3, 63.6, 58.8, 51.5, 34.6, 28.1, 17.6,
14.2. Anal. Calcd for C19H27F6N3O6S2: C, 39.93; H, 4.76; N, 7.35.
Found: C, 40.07; H, 4.76; N, 7.45.
4.2.3.6. 3-(((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy)-me-
thyl)-1-methyl-2-o-tolyl-4,5-dihydro-1H-imidazol-3-ium bis(tri
fluoromethylsulfonyl)amide (mixture of diastereomers, dr
ꢁ 1:1.2) 4f. As a colorless liquid (69%). MS (EI), m/e 343 ([Mcation]+,
100%), 329 (2), 203 (39), 175 (54); MS (ESI, 0 V) m/e 343.0 ([Mcat-
ion]+, 97%); IR (NaCl) 3324, 3066, 2957, 2929, 2873, 2725, 2597,
2378, 2191, 1929, 1846, 1798, 1620, 1604, 1558, 1490, 1457,
1354, 1294, 1183, 1138, 1058, 935, 844, 788, 766, 740, 655, 617,
4.2.3.3. (S)-4-Isopropyl-3-(methoxymethyl)-1-methyl-2-o-tolyl-
4,5-dihydro-1H-imidazol-3-ium bis(trifluoromethylsul-fonyl)a-
mide (mixture of diastereomers, dr ꢁ 2:3) 4c. As a yellow solid
(73%). MS (EI), m/e 261 ([Mcation]+, 100%), 246 (2), 218 (13); MS (ESI,
0 V) m/e 261.8 ([Mcation]+, 100%); IR (KBr) 3306, 2963, 2771, 2683,
2593, 2366, 2194, 2017, 1930, 1847, 1770, 1625, 1550, 1467,
1350, 1284, 1052, 942, 916, 789, 772, 739, 699, 613, 569,
571, 513 cmꢀ1 1H NMR (400 MHz) (diastereomer 1, 45.5%) d
;
7.60–7.44 (m, 1H), 7.46–7.31 (m, 3H), 4.60–4.36 (m, 2H), 4.31–
4.07 (m, 4H), 3.03–2.84 (m, 4H), 2.26 (d, J = 2.3, 3H), 2.04–1.78
(m, 1H), 1.64–1.44 (m, 3H), 1.27–1.03 (m, 2H), 0.94–0.82 (m,
1H), 0.81–0.72 (m, 7H), 0.71–0.62 (m, 1H), 0.53 (d, J = 3.4 Hz,
3H); 13C NMR (100 MHz) (diastereomer 1, 45.5%) d 167.0, 136.7,
133.0, 131.4, 128.4, 127.2, 120.5, 119.9 (q, JCF = 321 Hz), 77.3,
74.5, 50.4, 47.9, 31.3, 25.2, 22.8, 21.9, 20.8, 18.8, 15.6; 1H NMR
(400 MHz) (diastereomer 2, 54.5%) d 7.60–7.44 (m, 1H), 7.46–
7.31 (m, 3H), 4.60–4.36 (m, 2H), 4.31–4.07 (m, 4H), 3.03–2.84
(m, 4H), 2.26 (d, J = 2.3, 3H), 2.04–1.78 (m, 1H), 1.64–1.44 (m,
3H), 1.27–1.03 (m, 2H), 0.94–0.82 (m, 1H), 0.81–0.72 (m, 7H),
0.71–0.62 (m, 1H), 0.59 (d, J = 3.6 Hz, 3H); 13C NMR (100 MHz)
(diastereomer 2, 54.5%) d 166.9, 136.9, 133.0, 131.4, 128.2, 127.1,
120.5, 119.9 (q, JCF = 321 Hz), 77.4, 74.5, 50.5, 47.9, 31.1, 25.3,
22.8, 21.9, 20.8, 18.7, 15.7. Anal. Calcd for C24H35F6N3O5S2: C,
46.22; H, 5.66; N, 6.74. Found: C, 45.89; H, 5.83; N, 6.89.
514 cmꢀ1 1H NMR (400 MHz) (diastereomer 1, 40%) d 7.66–7.25
;
(m, 4H), 4.65–4.18 (m, 4H), 3.86 (ddd, J = 14.9, 12.1, 8.9 Hz, 1H),
3.18 (s, 3H), 2.98 (s, 3H), 2.43–2.34 (m, 1H), 2.33 (s, 3H), 1.09–
0.97 (m, 6H); 13C NMR (100 MHz) (diastereomer 1, 40%) d 167.8,
137.0, 133.4, 131.7, 128.2, 127.3, 120.5, 119.9 (q, JCF = 321 Hz),
76.9, 64.1, 56.7, 51.3, 34.08, 28.3, 18.8, 17.6, 14.3; 1H NMR
(400 MHz) (diastereomer 2, 60%) d 7.66–7.25 (m, 4H), 4.65–4.18
(m, 4H), 3.86 (ddd, J = 14.9, 12.1, 8.9 Hz, 1H), 3.17 (s, 3H), 2.97 (s,
3H), 2.43–2.34 (m, 1H), 2.29 (s, 3H), 1.09–0.97 (m, 6H); 13C NMR
(100 MHz) (diastereomer 2, 60%) d 167.4, 136.3, 133.1, 131.5,
128.3, 127.4, 121.0, 119.9 (q, JCF = 321 Hz), 77.2, 63.8, 56.6, 51.1,
34.13, 27.7, 19.1, 17.8, 14.7. Anal. Calcd for C18H25F6N3O5S2: C,
39.92; H, 4.65; N, 7.76. Found: C, 40.17; H, 4.76; N, 7.73.
4.2.3.4. (S)-4-Isopropyl-3-((2-methoxyethoxy)methyl)-1-methyl
-2-o-tolyl-4,5-dihydro-1H-imidazol-3-ium bis(trifluoromethyl-
sulfonyl)amide (mixture of diastereomers, dr ꢁ 1:1.1) 4d. As a
yellow liquid (62%). MS (EI), m/e 261 305 ([Mcation]+, 100%), 261
(9), 217 (11), 173 (11), 132 (2); MS (ESI, 0 V) m/e 305.1 ([Mcation]+,
100%); IR (NaCl) 3312, 3067, 2968, 2937, 2883, 2591, 2366, 1931,
1847, 1799, 1623, 1604, 1550, 1465, 1352, 1287, 1190, 1135,
1057, 985, 942, 890, 850, 788, 769, 7,39, 655, 617, 571,
4.2.3.7. (S)-3-Ethyl-4-isopropyl-1-methyl-2-o-tolyl-4,5-dihydro
-1H-imidazol-3-ium iodide (mixture of diastereomers, dr ꢁ 1:1)
5. As a yellow solid (46%). MS (EI), m/e 245 ([Mcation]+, 46%), 216
(8), 173 (52), 132 (5), 119 (67), 91 (26), 84 (100), 51 (51); MS
(ESI, 0 V) m/e 245.2 ([Mcation]+, 100%), 617.2 (2[Mcation]+ + [Manion]ꢀ,
40%); IR (KBr) 3427, 2959, 2872, 1601, 1561, 1487, 1457, 1416,
1397, 1380, 1345, 1274, 1209, 1163, 1112, 1096, 1075, 1042,
513 cmꢀ1 1H NMR (400 MHz) (diastereomer 1, 48%) d 7.65–7.22
;
(m, 4H), 4.75–4.38 (m, 3H), 4.36–4.14 (m, 1H), 3.83 (dd, J = 20.6,
10.6 Hz, 1H), 3.57–3.28 (m, 4H), 3.24 (s, 3H), 2.97 (s, 3H), 2.45–
2.34 (m, 1H), 2.33 (s, 3H), 1.11–0.92 (m, 6H); 13C NMR
(100 MHz) (diastereomer 1, 48%) d 167.9, 137.3, 133.4, 131.85,
128.2, 127.4, 120.7, 119.9 (q, JCF = 321 Hz), 76.1, 71.8, 68.7, 63.8,
58.9, 51.4, 34.2, 28.2, 18.9, 17.7, 14.4; 1H NMR (400 MHz) (diaste-
reomer 2, 52%) d 7.65–7.22 (m, 4H), 4.75–4.38 (m, 3H), 4.36–4.14
(m, 1H), 3.83 (dd, J = 20.6, 10.6 Hz, 1H), 3.57–3.28 (m, 4H), 3.25
(s, 3H), 2.96 (s, 3H), 2.45–2.34 (m, 1H), 2.26 (s, 3H), 1.11–0.92
(m, 6H); 13C NMR (100 MHz) (diastereomer 2, 52%) d 167.4,
136.2, 133.2, 131.5, 128.5, 127.6, 121.0, 119.9 (q, JCF = 321 Hz),
75.8, 71.6, 68.6, 63.6, 59.0, 51.2, 34.2, 27.6, 19.3, 17.9, 14.8. Anal.
947, 811, 788, 732, 595 cmꢀ1 1H NMR (400 MHz) (diastereomer
;
1) d 8.19 (dd, J = 7.6, 1.0, 1H), 7.62–7.37 (m, 3H), 4.94–4.77 (m,
1H), 4.67 (dd, J = 12.8, 11.3, 1H), 3.75 (dd, J = 11.1, 8.7, 1H), 3.36–
3.22 (m, 2H), 3.04 (s, 3H), 2.48 (s, 3H), 2.43–2.31 (m, 1H), 1.27 (t,
J = 7.3, 3H), 1.10–1.02 (m, 6H); 13C NMR (100 MHz) (diastereomer
1) d 166.1, 135.0, 133.0, 131.9, 129.8, 127.4, 121.5, 63.2, 51.0, 40.7,
34.7, 26.9, 20.5, 18.2, 15.2, 13.0; 1H NMR (400 MHz) (diastereomer
2) d 7.62–7.37 (m, 3H), 7.23 (d, J = 7.7, 1H), 4.94–4.77 (m, 2H), 3.89
(dd, J = 10.0, 5.9, 1H), 3.36–3.22 (m, 1H), 3.16 (dq, J = 14.6, 7.4, 1H),
2.97 (s, 3H), 2.43–2.31 (m, 1H), 2.29 (s, 3H), 1.23 (t, J = 7.3, 3H),
1.10–1.02 (m, 6H); 13C NMR (100 MHz) (diastereomer 2) d 165.9,
137.0, 132.5, 130.9, 127.7, 127.6, 122.0, 63.5, 51.4, 40.1, 34.6,

A. Winkel, R. Wilhelm / Tetrahedron: Asymmetry 20 (2009) 2344–2350
2349
27.6, 19.3, 17.9, 14.8, 13.5. HRMS (ESI): calcd for C16H25N2 [Mþcation]:
245.2018, found 245.2023.
added afterwards and the mixture was stirred for 3 h. Work-up
was as described above.
4.2.3.8. 3-Butyl-1-methyl-2-phenyl-4,5-dihydro-1H-imidazol-3-
ium chloride 6. As an orange, highly hygroscopic solid (65%). MS
(EI), m/e 217 ([Mcation]+, 100%), 77 (54), 57 (24); MS (ESI, 0 V) m/e
217.3 ([Mcation]+, 100%); IR (KBr) 3412, 2960, 2933, 2873, 2427,
1607, 1574, 1491, 1462, 1446, 1375, 1299, 1077, 1029, 932, 774,
4.3.3.1. 1-Phenylhexan-1-ol. As a slightly yellow oil. 1H NMR
(200 MHz) d 7.34–7.10 (m, 5H), 4.53 (dd, J = 7.2, 6.1 Hz, 1H), 2.27
(br s, 1H), 1.81–1.46 (m, 2H), 1.32–1.10 (m, 6H), 0.78 (t,
J = 6.4 Hz, 3H); 13C NMR (50 MHz) d 145.0, 128.4, 127.4, 125.9,
74.6, 39.1, 31.8, 25.5, 22.6, 14.1. The spectral data were consistent
with literature values.44
707, 657, 637, 535 cmꢀ1 1H NMR (200 MHz) d 7.88–7.74 (m,
;
2H), 7.73–7.54 (m, 3H), 4.51–4.18 (m, 4H), 3.30 (t, J = 7.4 Hz, 2H),
3.05 (s, 3H), 1.73–1.50 (m, 2H), 1.25 (dq, J = 14.2, 7.2 Hz, 2H),
0.81 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz) d 165.6, 132.1, 129.1,
128.2, 121.4, 50.3, 47.7, 47.2, 34.5, 28.5, 19.0, 12.8. HRMS (ESI):
calcd for C14H21N2 [Mþcation]: 217.1705, found 217.1700.
4.3.3.2. Naphthalen-1-yl(phenyl)methanol. As a white solid. 1
H
NMR (200 MHz) d 8.10–7.91 (m, 1H), 7.92–7.69 (m, 2H), 7.60 (d,
J = 6.7, 1H), 7.53–7.14 (m, 8H), 6.48 (s, 1H), 2.43 (s, 1H); 13C NMR
(50 MHz) d 143.3, 138.9, 134.1, 130.8, 128.9, 128.7, 128.6, 127.8,
127.2, 126.3, 125.7, 125.5, 124.8, 124.1, 73.8. The spectral data
were consistent with literature values.45
4.2.3.9. 3-Butyl-1-methyl-2-phenyl-4,5-dihydro-1H-imidazol-3-
ium ((1S,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)meth
anesulfonate 7. Salt 6 (29.4 mmol) was dissolved in dichloro-
methane (50 mL). This solution was added to (ꢀ)-camphor-10-sul-
fonic acid ammonium salt (29.4 mmol) in water (15 mL). The
mixture was stirred for 1 h at rt. The aqueous phase was discarded.
The organic phase was washed three times with a minimum
amount of water. The organic phase was dried over sodium sulfate.
After evaporating the solvent, ionic liquid 7 was obtained as a yel-
Acknowledgments
Financial support by Fonds der Chemischen Industrie is grate-
fully acknowledged. In addition, the author would like to thank
Dr. Dräger for HRMS measurements.
low liquid (86%). ½a D25
¼ ꢀ19:2 (c 1.43, CHCl3); MS (EI), m/e 217
ꢃ
References
([Mcation]+, 100%), 77 (94); MS (ESI, 0 V) m/e 217.3 ([Mcation]+,
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2959, 2876, 2478, 1741, 1607, 1575, 1468, 1417, 1300, 1174,
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;
1H NMR
(400 MHz) d 7.71–7.54 (m, 5H), 4.40–4.29 (m, 2H), 4.29–4.17 (m,
2H), 3.34 (d, J = 14.7 Hz), 3.27 (t, J = 7.6 Hz, 2H), 3.01 (s, 3H),
2.88–2.76 (m, 1H), 2.81 (d, J = 14.7 Hz, 1H), 2.31 (dt, J = 18.1,
3.9 Hz, 1H), 2.08–1.92 (m, 2H), 1.86 (d, J = 18.1 Hz, 1H), 1.79–1.66
(m, 1H), 1.54 (quintuplett, J = 7.6 Hz, 2H, CH2)), 1.42–1.29 (m,
1H), 1.26–1.16 (sextett, J = 7.6 Hz, 2H), 1.14 (s, 3H), 0.84 (s, 3H),
0.81 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz) d 217.0, 166.3, 132.4,
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C14H21N2 [Mþcation]: 217.1705, found 217.1705.
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4.2.4. Grignard addition to aldehydes: General procedure
Phenylmagnesiumbromide solution (2.5 mL, 1 M in THF) was
placed in a Schlenk tube. The solvent was distilled off, and the
remaining solid was dried under high vacuum for at least 1 h. Io-
nic liquid was added and the mixture was heated to 40 °C. The
aldehyde was added afterwards and the mixture was stirred for
3 h. Saturated ammonium chloride solution (2.5 mL) was added
and the mixture was stirred for 15 min. The mixture was ex-
tracted several times with n-hexane. The combined organic
phases were dried over sodium sulfate. After distilling off the sol-
vent, the raw alcohols were purified by flash column chromatog-
raphy (eluent PE/EE = 20:1). The ionic liquids were recycled as
follows: After extraction of the raw product with n-hexane,
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phases were separated and the organic phase was washed five
times with water. The organic phase was afterwards dried over
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