New chiral imidazolinic derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.01.014

Novel C-2 substituted 4,5-dihydroimidazoles and imidazoles bearing an N-linked stereogenic group were rapidly prepared from a chiral primary amine. Quaternization of these derivatives resulted in a range of scalemic room temperature ionic liquids. The abi

Full text of DOI:10.1016/j.tetasy.2005.01.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1017–1023
New chiral imidazolinic derivatives
a,
Yves Genisson, Nancy Lauth-de Viguerie, Chantal Andre,
b
a
*
´
´
Michel Baltasa and Liliane Gorrichona
a
´
SPCMIB, UMR 5068 CNRS, Universite Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex 04, France
b
´
IMRCP, UMR 5623 CNRS, Universite Paul Sabatier, 118 route de Narbonne,
31062 Toulouse cedex 04, France
Received 17 November 2004; accepted 4 January 2005
Abstract—Novel C-2 substituted 4,5-dihydroimidazoles and imidazoles bearing an N-linked stereogenic group were rapidly pre-
pared from a chiral primary amine. Quaternization of these derivatives resulted in a range of scalemic room temperature ionic liq-
uids. The ability of the imidazolium species to act as reaction medium and/or phase transfer catalyst was also assessed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
some enantioselection arises from the association be-
tween the negatively charged nucleophilic reagent and
a chiral imidazolium cation during such RTIL-mediated
transformations. In addition, the electron-rich dihydro-
imidazole and imidazole precursors of these salts could
also be of interest as chiral bases and/or nucleophiles.10
Chiral non-racemic pyridinium salts bearing a stereo-
genic center connected to the nitrogen atom have
already received much attention (Fig. 1).1 They have
proven to be highly valuable synthetic intermediates2
and have lately given rise to a new family of chiral room
temperature ionic liquids (RTILs).3,4
We thus report herein the preparation of new imidazoli-
nic derivatives with an N-linked stereogenic appendage
and, as a first illustration of their usefulness, their trans-
formation into novel chiral RTILs.
R1
R2
R1
R2
N
N
N
-
R4
R3
-
R3
X
X
2. Results and discussions
Figure 1.
Our synthetic route was based on the preparation of the
key imidazolinic moiety by oxidative dehydrogenation
of the partially saturated heterocycle (Scheme 1). Syn-
thesis of the 4,5-dihydroimidazole intermediate was in
turn envisioned via condensation of a chiral 1,2-ethane-
diamine with a carboxylic acid equivalent.
The imidazolinic equivalents of these pyridinium salts
have been far less exploited, only recently being de-
scribed for the first time.5 These imidazolium derivatives
may, however, represent interesting candidates for
RTIL and/or asymmetric phase transfer catalysis devel-
opment. The use of a water/RTIL biphasic system has
been applied to base-catalyzed alkylation of glycine
esters6 or Michael addition to enones.7,8 Furthermore,
it has been proposed that the RTIL plays a dual role
of solvent and phase transfer catalyst over the course
of biphasic hydrogen peroxide epoxidation of a,b-unsat-
urated compounds.9 It might therefore be expected that
4
5
R1
R2
R1
R2
R1
R2
N
N
N
N
NH NH2
2
R3
R3
R3
Scheme 1.
Preparation of the required monosubstituted diamine
precursor was thus studied (Scheme 2). Alkylation of a
chiral primary amine with chloroethylamine appeared
*
Corresponding author. Tel.: +33 05 61 55 62 99; fax: +33 05 61 55 82
45; e-mail: genisson@chimie.ups-tlse.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.014

´
Y. Genisson et al. / Tetrahedron: Asymmetry 16 (2005) 1017–1023
1018
H
H
H
H
ii
iii
i
Me
Me
Me
Me
NH NH2
N
N
N
N
NH2
1
Ph
Ph
Ph
Ph
2
R
R
3a, R = C2H5
3b, R = CH3
3c, R = H
4a, R = C2H5
4b, R = CH3
4c, R = H
Scheme 2. Reagents and conditions: (i) ClCH2CH2NH2 (0.5 equiv), 100 ꢁC, 3 h of addition then 3 h additional, 45% based on the chloride; (ii)
RC(OEt)3 (1.06 equiv), AcOH (1.06 equiv), CH3CN, reflux, 1 h, 93% (3a or ent-3a), 81% (ent-3b), 80% (ent-3c); (iii) BaMnO4 (1000 wt%), 4 A MS
˚
(100 wt%), CH2Cl2, reflux, 20 h, 58% (4a or ent-4a), 59% (ent-4c); or KMnO4 (1.4 equiv), BnEt3NBr (0.05 equiv), benzene/water (1:2), rt, 1 h, 66% (4a
or ent-4a), 61% (ent-4b).
to be the most direct option and the readily available a-
methylbenzylamine was chosen as a suitable starting
material. After careful optimization, it was established
that slow addition of an aqueous solution of the electro-
phile to a 2-fold excess of neat primary amine 1 heated
at 100 ꢁC allowed the formation of the desired mono-
alkylation product 2 (or ent-2 from ent-1) in 45% puri-
fied yield. The 1-fold excess of starting amine could be
easily recovered during purification over Al2O3 and
enantiomeric purity of the recovered material was
checked by determination of its specific rotation. The
only isolated side product was the dimeric triamine
resulting from the alkylation of 2.
and triazole.16 The mild c-MnO2 (500 wt% c-MnO2,
14
˚
100 wt% 4 A MS, benzene, reflux, 4 h, 30% yield) re-
quired forcing conditions and gave a rather complicated
transformation. On the other hand, the moderate reac-
tivity of BaMnO4 allowed a clean reaction,15 delivering
the essentially pure imidazole 4a in 58% yield. More-
over, it was found that the powerful KMnO4 could give
rise to even better results if used under phase transfer
catalysis conditions16 rather than in homogeneous con-
ditions (2 equiv, acetone, 0 ꢁC to rt, 7 h, 43% yield).
The 2-methyl analogue ent-4b was prepared in similar
yield by this method. The sensitivity of the phenylethyl
radical to benzylic oxidation likely constituted a limit
to the efficiency of this transformation, as suggested by
the traces of benzophenone present in the crude reaction
mixture. The C-2 unsubstituted substrate ent-3c behaved
in a comparable fashion, the corresponding imidazole
ent-4c, for example, being prepared in 59% yield with
BaMnO4.
1,2-Diamines are known to undergo facile ring closure
to form 4,5-dihydroimidazoles when treated with an
appropriate electrophile, such as an orthoester.11 In-
deed, diamine 2 (or ent-2) was condensed cleanly with
triethylorthopropionate in the presence of an equimolar
amount of acetic acid to give the expected five-mem-
bered ring heterocycle 3a (or ent-3a) in 93% yield
(Scheme 2). Running the cyclization with triethylortho-
acetate readily gave the corresponding 2-methyl-4,5-
dihydroimidazole ent-3b in 81% yield from ent-2. Simi-
larly, the C-2 unsubstituted derivative ent-3c was also
obtained in 80% yield from ent-2 and triethylorthofor-
mate. Introduction of a substituent at the sensitive C-2
position of the imidazolinic moiety was important to en-
sure stability of the corresponding imidazolium cation
toward basic medium. Moreover, such C-2 substituted
chiral imidazole derivatives have never been described.12
We therefore focused the rest of our study on this series.
X-ray diffraction analysis of a single crystal of imidazole
ent-4b chlorhydrate unambiguously confirmed the pro-
posed chemical structure17–19 and (S)-configuration20
(Fig. 2). Interestingly, this solid-state conformation cor-
responds to a minimized A[1,3] strain with a quasi-syn-
periplanar arrangement between the chiral carbon
hydrogen and the C-2 (dihedral angle 30.2ꢁ), as a conse-
quence of the methyl radical in this position. It is worth
noting that, to the best of our knowledge, no existing
method allows access to such C-2 substituted chiral
imidazoles.
We were then in a position to consider the key oxidative
aromatization of the heterocyclic core (Scheme 2). An
extensive study, conducted with the 2-ethyl derivate
3a, revealed that this transformation suffered from the
sensitivity of the benzylic portion of the molecule to-
ward either reductive or oxidative conditions. The use
of palladium as a hydrogen acceptor13 appeared attrac-
tive for its simplicity. However, prolonged reflux in tolu-
ene, xylene, or acetic acid (in the presence of 100 wt% of
10% Pd/C) did not yield any appreciable transforma-
tion, whereas carrying out the reaction at a higher tem-
perature was hampered by the sensitivity of the benzylic
chiral appendage to hydrogenolysis. Clean formation of
2-ethylimidazole in ca. 60% yield was indeed observed in
refluxing p-cymene.
Figure 2. Crystal structure for chiral imidazole ent-4b chlorhydrate.17–20
With these new imidazoles in hands, we next looked at
their quaternization with the prospect of preparing novel
chiral RTILs for possible use under aqueous biphasic
conditions. It was reasoned that a C5 alkyl chain could
provide enough lipophilicity, while maintaining suitably
Manganese-based oxidants have been employed to pro-
duce various heterocycles such as oxazole14 imidazole,15

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Y. Genisson et al. / Tetrahedron: Asymmetry 16 (2005) 1017–1023
1019
H
H
H
Me
ii
i
Me
N
N
Me
N
N
Br
N
N
X
Pent
Pent
-
-
Ph
Ph
Ph
Et
Et
Et
4a, 4,5-didehydro
3a, 4,5-dihydro
5, 4,5-didehydro
6, 4,5-dihydro
7a, 4,5-didehydro, X= BF4
7b, 4,5-didehydro, X= NTf2
8a, 4,5-dihydro, X= BF4
8b, 4,5-dihydro, X= NTf2
Scheme 3. Reagents and conditions: (i) n-PentBr (5 equiv), 1,1,1-trichloroethane, reflux, 5 days, 91% (5 or ent-5), 83% (6); (ii) NaBF4 (1 equiv),
acetone, rt, 4 days, 93% (ent-7a), 91% (8a); or LiNTf2 (1 equiv), water, 70 ꢁC, 30 min, 76% (7b), 81% (8b).
low viscosity and liquid–solid transition temperature.21
The 2-ethyl derivative 4a (or ent-4a) was thus reacted
smoothly with n-pentyl bromide to form the expected
imidazolium bromide salt 5 (or ent-5) isolated as a foam
(Scheme 3).
pathway described above, counter anion metathesis
was applied to the quaternized dihydroimidazolium bro-
mide 6 prepared in 83% yield. Tetrafluoroborate 8a and
bis(trifluoromethanesulfonyl)imide 8b were obtained
(91% and 81% yields, respectively) as water immiscible
liquids. A glass transition was observed in DSC at even
lower temperatures (Tg = ꢀ50 and ꢀ55 ꢁC, respectively)
than for the related imidazolium species. Salts 8a and 8b
were also found to be notably less viscous than their imi-
dazolium congeners, although this empirical observa-
tion has not yet been quantified. This behavior may be
attributed to the disruption of the aromatic imidazolium
nucleus detrimental to H-bonding and p–p stacking-
based ion–ion interactions.
At this stage of our study, the stereospecificity of our ap-
proach was checked running H NMR analysis of imi-
1
dazolium bromides rac-5, 5, and ent-5 in the presence
of tris[3-(trifluoromethylhydroxymethylene)-D-camph-
orato]europium(III). No sign of epimerization was noted.
The potential of imidazolium 5 as a phase transfer cata-
lyst was briefly explored. It was shown to catalyze the
condensation of dimethyl malonate and chalcone under
solid–liquid biphasic conditions (1 equiv chalcone,
1.5 equiv dimethyl malonate, 6 equiv K2CO3, 0.1 equiv
salt 5, toluene/CH2Cl2, 9:1; rt, 10 h) affording the ex-
pected Michael adduct, although as a racemic mixture,
in a satisfactory 75% yield.22 The catalyst proved to be
3. Conclusion
We have accessed scalemic C-2 substituted dihydroimi-
dazole and imidazole derivatives, available in two or
three steps, respectively, from a chiral primary amine.
These derivatives, otherwise potentially interesting as
chiral nucleophilic bases, proved useful for the prepara-
tion of a range of novel chiral non-racemic RTILs. The
capacity of the imidazolium species to act as reaction
medium and/or phase transfer catalyst was also
assessed. More extensive analysis of physicochemical
properties as well as further development of these mol-
ten salts in asymmetric synthesis will be reported in
due course.
1
stable under these conditions, as judged by H NMR
analysis and optical rotation measurement.
Counter anion metathesis was finally required to reach
the targeted RTILs. In order to ensure once again a
compromise between viscosity, solidification tempera-
ture, and water immiscibility, the highly fluorinated tet-
rafluoroborate and bis(trifluoromethanesulfonyl)amide
anion were selected. Imidazolium ent-7a and 7b could
be readily prepared from bromide salt ent-5 and 5,
respectively. Gratifyingly, they were both found to be
water immiscible liquids at room temperature. Differen-
tial scanning calorimetry (DSC) analysis was conducted
in order to gain more information about their thermal
behavior. Salts ent-7a and 7b were shown to be liquid
down to ꢀ39 and ꢀ48 ꢁC, respectively, temperatures
at which they exhibited a glass transition. These solidifi-
cation points (Tg) are appreciably low considering the
presence of a C-2 alkyl substituent and phenyl ring, ex-
pected to favor ion–ion pairing through aromatic and
H-bonding interactions. Preliminary experiments were
conducted with derivative 7b in order to assess the abil-
ity of these molten salts to act as reaction medium. Ionic
liquid mediated Michael addition of dimethyl malonate
to chalcone in the presence of solid K2CO3 was shown to
proceed smoothly (1 equiv chalcone at 0.3 M in 7b,
1.5 equiv dimethyl malonate, 6 equiv K2CO3, rt, 10 h)
affording 74% yield of the desired condensation product,
yet as an unexpected epimeric mixture.
4. Experimental
The following solvents were dried prior to use: acetoni-
˚
trile (from calcium hydride, stored over 3 A MS), and
dichloromethane (freshly distilled from calcium hy-
dride). BaMnO4 was prepared according to the described
procedure.23 Thin layer chromatography reaction moni-
toring was carried out with Macherey–Nagel ALU-
GRAMꢂ SIL G/UV254 (0.2 mm) plates visualized with
a Dragendorff reagent as dipping solution. Neutral grade
I Macherey–Nagel alumina was used, from which grade
III was prepared by addition of 6% v/v of water. Bulb to
bulb distillations were realized with a Buchi GKR-51
¨
apparatus. NMR spectroscopic data were obtained with
Bruker AC250 instrument operating 1H spectra at
250 MHz and 13C spectra at 63 MHz. Chemical shifts
are quoted in parts per million (ppm) downfield from
tetramethylsilane and coupling constants given in hertz.
Mass spectrometry (MS) data were obtained on a NER-
MAG R10-10 (DCI) or a Perkin–Elmer SCIEX API365
We were also able to prepare chiral RTILs of a novel
type from 2-ethyl dihydroimidazole 3a. Following the

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Y. Genisson et al. / Tetrahedron: Asymmetry 16 (2005) 1017–1023
1020
spectrometer (ES). High resolution mass spectra
(HRMS) were performed on a ThermoFinnigan MAT
95 XL spectrometer. Optical rotations were measured
on a Perkin–Elmer model 141 polarimeter. Differential
scanning calorimetry (DSC) analysis were conducted
on a Perkin–Elmer DSC 7 apparatus.
dryness. Bulb to bulb distillation of the residue (heating
at 120–130 ꢁC at 0.05 mbar) gave the expected dihydro-
imidazole 3a (2.3 g, 11.4 mmol, 93% yield) as a colorless
liquid. Rf 0.3 (EthOAc–MeOH, 95:5/NH3 atmosphere).
20
D
½aꢁ ¼ ꢀ56 (c 1.3, CHCl3). 1H NMR (CDCl3) d
(ppm): 7.38–7.21 (m, 5H, Ph), 4.81 (q, 1H, J = 7.0 Hz),
3.75–3.58 (m, 2H), 3.40–3.26 (m, 1H), 3.17–3.03 (m, 1H),
2.28 (q, 2H, J = 7.3 Hz), 1.53 (d, 3H, J = 7.0 Hz), 1.22
(t, 3H, J = 7.3 Hz). 13C NMR (CDCl3) d (ppm): 168.0
(Cquat. Imid.) 142.3 (Cquat. Ph), 129.2, 127.7, 127.1
(CH, Ph), 53.3 (Ch2Imid.), 52.7 (CH), 44.9 (CH2Imid.),
21.9 (CH2CH3), 18.5 (CH3), 11.49 (CH2CH3). MS (DCI/
NH3) m/z 203 (M+H+). HRMS (EI) m/z calcd for
C13H18N2: 202.1470, found: 202.1473.
4.1. N-[(1R)-Phenylethyl]ethane-1,2-diamine, 2
Chlorethylamine hydrochloride (5.0 g, 43.1 mmol) was
dissolved in water (8 mL) and the solution (pH 3–4)
was alkalized (pH 8) by the addition of a few drops of
a saturated aqueous K2CO3 solution. The resulting free
amine solution was added dropwise over 3 h to neat (R)-
a-methylbenzylamine (11.0 mL, 85.8 mmol, 2 equiv)
heated at 100 ꢁC with stirring. The heating with stirring
was maintained for three additional hours after the end
of addition. The reaction mixture was then allowed to
cool to rt before being poured into a vigorously stirred
mixture of 25% aqueous KOH (8 mL) and dichloro-
methane (50 mL). The aqueous layer (pH 8) was alkal-
ized (pH 10) by the addition of KOH pellets, and the
organic layer separated by decantation. The aqueous
layer was further extracted with dichloromethane
(3 · 100 mL) and the combined organic layers dried over
anhydrous Na2SO4, filtered, and concentrated to dry-
ness to give a residue that was chromatographed over
neutral grade III Al2O3. Elution with CH2Cl2 allowed
recovery of the unreacted starting chiral amine (5.0 g,
41.0 mmol) while the use of increasing amount of
MeOH in CH2Cl2 (5%, 10%, 15%, and 20%) yielded
the expected 1,2-ethanediamine 2 3.2 g (19.5 mmol,
45% yield) as a colorless liquid. Compound 2 could also
be purified by bulb to bulb distillation (heating at 80–
4.4. 2-Ethyl-1-[(1S)-1-phenylethyl]-4,5-dihydro-1H-imid-
azole, ent-3a
Prepared from diamine ent-2 in the same way as
20
D
for C13H18N2: 202.1470, found: 202.1471.
3a. ½aꢁ ¼ þ55 (c 1.3, CHCl3). HRMS (EI) m/z calcd
4.5. 2-Methyl-1-[(1S)-1-phenylethyl]-4,5-dihydro-1H-
imidazole, ent-3b
Diamine ent-2 (1.0 g, 6.10 mmol) was reacted with ethyl
orthoacetate according to the procedure described for
the preparation of 3a to give dihydroimidazole ent-3b
(0.93 g, 4.95 mmol, 81% yield) as a colorless liquid.
20
D
½aꢁ ¼ þ67 (c 1.7, CHCl3). 1H NMR (CDCl3) d
(ppm): 7.40–7.20 (m, 5H, Ph), 4.78 (q, 1H, J = 7.0 Hz),
3.71–3.58 (m, 2H), 3.39–3.26 (m, 1H), 3.15–3.02 (m,
1H), 2.00 (s, 3H), 1.53 (d, 3H, J = 7.0 Hz). 13C NMR
(CDCl3) d (ppm): 163.7 (Cquat. Imid.), 142.1 (Cquat.
Ph), 129.0, 127.6, 126.9 (CH Ph), 53.3 (CH), 52.2, 44.7
(CH2 Imid.), 18.5, 15.2 (CH3). MS (DCI/NH3) m/z 189
(M+H+). HRMS (EI) m/z calcd for C12H16N2:
188.1313, found: 188.1318.
90 ꢁC under 0.05 mbar) for analysis. Rf 0.3 (EthOAc–
20
MeOH, 95:5/NH3 atmosphere). ½aꢁ ¼ þ51 (c 1.1,
D
1
CHCl3). H NMR (CDCl3) d (ppm): 7.36–7.28 (m, 4H,
Ph), 7.28–7.19 (m, 1H, Ph), 3.76 (q, 1H, J = 6.7 Hz),
2.80–2.71 (m, 2H), 2.63–2.40 (m, 2H) 1.43 (br s, 3H),
1.36 (d, 3H, J = 6.7 Hz). 13C NMR (CDCl3) d (ppm):
146.5 (Cquat., Ph), 128.9, 127.4, 127.1 (CH, Ph), 58.8
(CH), 51.0, 42.6 (CH2), 25.1 (CH3). MS (DCI/NH3)
m/z 165 (M+H+). HRMS (CI) m/z calcd for C10H17N2:
165.1392, found: 165.1391.
4.6. 1-[(1S)-1-Phenylethyl]-4,5-dihydro-1H-imidazole,
ent-3c
Diamine ent-2 (1.0 g, 6.10 mmol) was reacted with tri-
ethyl orthoformate according to the procedure described
for the preparation of 3a to give dihydroimidazole
ent-3c (0.85 g, 4.90 mmol, 80% yield) as a colorless
4.2. N-[(1S)-Phenylethyl]ethane-1,2-diamine, ent-2
20
D
1
liquid. ½aꢁ ¼ ꢀ27 (c 1.6, CHCl3). H NMR (CDCl3) d
Prepared from (S)-a-methylbenzylamine in the same
(ppm): 7.40–7.22 (m, 5H, Ph), 7.00 (s, 1H), 4.33 (q,
1H, J = 7.0 Hz), 3.77 (dt, 2H, J = 9.8 Hz and 1.5 Hz),
3.10 (t, 2H, J = 9.8 Hz), 1.57 (d, 3H, J = 7.00 Hz). 13C
NMR (CDCl3) d (ppm): 155.9 (CH Imid.), 142.6
(Cquat. Ph), 129.2, 128.0, 127.1 (CH, Ph), 57.00 (CH),
55.0, 47.1 (CH2 Imid.), 21.4 (CH3). MS (DCI/NH3) m/z
175 (M+H+). HRMS (EI) m/z calcd for C11H14N2:
174.1157, found: 174.1157.
20
D
calcd for C10H17N2: 165.1392, found: 165.1396.
way as 2. ½aꢁ ¼ ꢀ51 (c 1.3, CHCl3). HRMS (CI) m/z
4.3. 2-Ethyl-1-[(1R)-1-phenylethyl]-4,5-dihydro-1H-imid-
azole, 3a
A mixture of diamine 2 (2.0 g, 12.2 mmol), ethyl ortho-
propionate (2.6 mL, 12.9 mmol, 1.06 equiv) and acetic
acid (0.74 mL, 12.9 mmol, 1.06 equiv) in CH3CN
(12 mL) was refluxed for 1 h under inert atmosphere.
The resulting mixture was then allowed to cool to rt be-
fore being concentrated to dryness, taken up in 40%
aqueous KOH (6 mL) and extracted with dichlorometh-
ane (3 · 40 mL). The combined organic layers were then
dried with KOH pellets, filtrated, and concentrated to
4.7. 2-Ethyl-1-[(1R)-1-phenylethyl]-1H-imidazole, 4a
A mixture of dihydroimidazole 3a (200 mg, 0.99 mmol),
˚
4 A molecular sieves (200 mg) and BaMnO4 (2.0 g,
7.80 mmol, 1000 wt%) was refluxed for 20 h under an in-
ert atmosphere. The reaction mixture was then filtered
over Celite and the cake rinsed with dichloromethane.

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Y. Genisson et al. / Tetrahedron: Asymmetry 16 (2005) 1017–1023
1021
The filtrate was concentrated to dryness to give imidaz-
ole 4a (115 mg, 0.58 mmol, 58% yield) as a colorless
liquid that solidified upon standing. Compound 4a
could also be purified by chromatography over neutral
grade III Al2O3 eluted with dichloromethane for analy-
Ph), 7.08 (s, 1H, Imid.), 6.93 (s, 1H, Imid.), 5.35 (q,
1H, J = 7.0 Hz), 1.86 (d, 3H, J = 7.0 Hz). 13C NMR
(CDCl3) d (ppm): 142.2 (Cquat. Ph), 136.7, 130.0 (CH,
Imid.), 129.5, 128.7, 126.6 (CH, Ph), 118.6 (CH, Imid.),
57.2 (CH), 22.7 (CH3). MS (DCI/NH3) m/z 173
(M+H+). HRLSIMS (FAB +) m/z calcd for C11H12N2:
172.1000, found: 172.1003.
sis. Rf 0.4 (CH2Cl2–EthOAc, 80:20/NH3 atmosphere).
20
D
½aꢁ ¼ þ18 (c 1.1, CHCl3). 1H NMR (CDCl3) d
(ppm): 7.35–7.20 (m, 3H, Ph), 7.08–6.95 (4H, Ph and
Imid.), 5.31 (q, 1H, J = 7.0 Hz), 2.70–2.41 (m, 2H),
1.78 (d, 3H, J = 7.0 Hz), 1.23 (t, 3H, J = 7.5 Hz). 13C
NMR (CDCl3) d (ppm): 149.9 (Cquat. Imid.), 142.6
(Cquat. Ph), 129.4, 128.2 (CH, Ph), 127.8 (CH Imid.),
126.2 (CH, Ph), 116.9 (CH, Imid.), 55.0 (CH), 23.1
(CH3), 21.0 (CH2CH3), 12.5 (CH2CH3). MS (DCI/
NH3) m/z 201 (M+H+). HRMS (EI) m/z calcd for
C13H16N2: 200.1313, found: 200.1314.
4.11. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-1H-imid-
azolium bromide, 5
A solution of imidazole 4a (225 mg, 1.10 mmol) and
bromopentane (0.90 mL, 7.30 mmol, 6.6 equiv) in
1,1,1-trichloroethane (3.5 mL) was refluxed for 3 days.
The insoluble oily material was separated by decanta-
tion and washed several times with 1,1,1-trichloroethane
to give 5 (360 mg, 1.00 mmol, 91% yield) as light
20
D
4.8. 2-Ethyl-1-[(1S)-1-phenylethyl]-1H-imidazole, ent-4a
brown foam. ½aꢁ ¼ þ17 (c 1.0, CHCl3). 1H NMR
(CDCl3) d (ppm): 7.8 (d, 1H, J = 2.1 Hz, Imid.), 7.56
(d, 1H, J = 2.1 Hz, Imid.), 7.41–7.22 (m, 5H, Ph), 6.00
(q, 1H, J = 7.0 Hz), 4.31–4.11 (m, 2H), 3.45–3.26 (m,
1H), 3.15–2.98 (m, 1H), 1.94 (d, 3H, J = 7.0 Hz), 1.91–
1.79 (m, 2H), 1.42–1.28 (m, 4H), 0.97 (t, 3H,
J = 7.6 Hz), 0.92–0.83 (m, 3H). 13C NMR (CD3OD) d
(ppm): 149.0 (Cquat. Imid.), 140.9 (Cquat. Ph), 130.4,
129.9, 127.3 (CH, Ph), 122.8, 120.4 (CH, Imid.), 59.0
(CH), 49.0, 30.8, 29.5, 23.2 (CH2), 22.0 (CH3), 17.9
(CH2), 14.2, 11.8 (CH3). MS (DCI/NH3) m/z 271
(M+). HRLSIMS (FAB +) m/z calcd for C18H27N2:
271.2174, found: 271.2172.
Prepared from dihydroimidazole ent-3a in the same way
as 4a. ½aꢁ ¼ ꢀ19 (c 1.0, CHCl3). HRMS (EI) m/z calcd
20
D
for C13H16N2: 200.1313, found: 200.1316.
4.9. 2-Methyl-1-[(1S)-1-phenylethyl]-1H-imidazole,
ent-4b
A biphasic mixture of dihydroimidazole ent-3b (214 mg,
1.14 mmol) in benzene (6 mL) and KMnO4 (270 mg,
1.71 mmol, 1.5 equiv) in water (12 mL) containing ben-
zyltriethylammonium bromide (13 mg, 0.06 mmol,
0.05 equiv) was vigorously stirred at rt for 1 h. A satu-
rated aqueous solution of Na2S2O3 (3 mL) was then
added and the reaction mixture diluted with dichloro-
methane before being filtered over Celite. The cake
was rinsed with dichloromethane and water. The organ-
ic layer was separated, washed with water and brine,
dried over Na2SO4, filtered, and concentrated to dryness
to afford imidazole ent-4b (130 mg, 0.70 mmol, 61%
yield) as a colorless liquid that solidified upon standing.
Compound ent-4b could also be purified by chromato-
graphy over neutral grade III Al2O3 eluted with dichlo-
4.12. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-1H-imid-
azolium bromide, ent-5
Prepared from imidazole, ent-4a in the same way as
20
D
5. ½aꢁ ¼ ꢀ17 (c 1.1, CHCl3).
4.13. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-4,5-
dihydro-1H-imidazolium bromide, 6
4,5-Dihydroimidazole 3a (306 mg, 1.51 mmol) was re-
acted with bromopentane according to the procedure
described for the preparation of 5 to give salt 6
romethane for analysis. Rf 0.6 (CH2Cl2–EthOAc, 80:20/
20
D
NH3 atmosphere). ½aꢁ ¼ ꢀ14 (c 1.4, CHCl3). 1H NMR
(CDCl3) d (ppm): 7.40–7.22 (m, 3H, Ph), 7.11–6.95 (m,
4H, Ph and Imid.), 5.30 (q, 1H, J = 7.0 Hz), 2.27 (s,
3H), 1.80 (d, 3H, J = 7.0 Hz). 13C NMR (CDCl3) d
(ppm): 145.3 (Cquat. Imid.), 142.4 (Cquat. Ph), 129.5,
128.3 (CH Ph), 127.7 (CH Imid.), 126.3 (CH Ph),
117.1 (CH Imid.), 55.5 (CH), 22.9, 14.1 (CH3). MS
(DCI/NH3) m/z 187 (M+H+). HRMS (EI) m/z calcd
for C12H14N2: 186.1157, found: 186.1156. Anal. Calcd
for C12H14N2ÆHCl + 1/4 H2O: C, 63.43; H, 6.87; N,
12.33. Found: C, 63.51; H, 6.73; N, 12.55.
(440 mg, 1.25 mmol, 83% yield) as a light brown foam.
20
D
½aꢁ ¼ ꢀ16 (c 1.4, CHCl3). 1H NMR (CDCl3) d
(ppm): 7.37–7.19 (m, 5H, Ph), 5.15 (q, 1H, J = 7.0 Hz),
4.12–4.03 (m, 2H), 3.93–3.79 (m, 1H), 3.58–3.49 (m,
1H), 3.48–3.39 (m, 2H), 2.89–2.61 (m, 2H), 1.76 (d,
3H, J = 7.0 Hz), 1.63–1.49 (m, 2H), 1.30–1.18 (m, 4H),
1.16–1.10 (m, 3H), 0.79 (t, 3H, J = 6.7 Hz). 13C NMR
(CDCl3) d (ppm): 168.9 (Cquat. Imid.), 137.9 (Cquat.
Ph), 129.5, 128.9, 127.1 (CH, Ph), 55.4 (CH), 47.9,
47.7 (CH2, Imid.), 44.2, 28.9, 27.32, 22.5, 18.9 (CH2),
18.8, 14.2, 11.2 (CH3). MS (ES +) m/z 273 (M+). HRL-
SIMS (FAB +) m/z calcd for C18H29N2: 273.2331,
found: 273.2332.
4.10. 1-[(1S)-1-Phenylethyl]-1H-imidazole, ent-4c
Dihydroimidazole ent-3c (213 mg, 1.24 mmol), was re-
acted with BaMnO4 according to the procedure used
for the preparation of 4a to afford ent-4c (126 mg,
4.14. 2-Ethyl-3-pentyl-1-[(1S)-1-phenylethyl]-1H-
imidazolium tetrafluoroborate, ent-7a
0.73 mmol, 59% yield) as a yellow liquid. Rf 0.6
20
D
(CH2Cl2–EthOAc, 80:20/NH3 atmosphere). ½aꢁ ¼ ꢀ5
A solution of imidazolium bromide ent-5 (210 mg,
0.60 mmol) in acetone (0.5 mL) containing ammonium
tetrafluoroborate (63 mg, 0.60 mmol, 1 equiv) was
(c 1.9, CHCl3). 1H NMR (CDCl3) d (ppm): 7.60 (s,
1H, Imid.), 7.39–7.25 (m, 3H, Ph), 7.17–7.11 (m, 2H,

´
Y. Genisson et al. / Tetrahedron: Asymmetry 16 (2005) 1017–1023
1022
allowed to stir at rt for 4 days. The reaction mixture was
then filtered over Celite and concentrated to dryness. The
residue was solubilized in dichloromethane and filtered
again over Celite. The filtrate was concentrated to dry-
ness to give ent-7a (200 mg, 0.56 mmol, 93% yield) as
(CH3), 18.3 (CH2), 14.5, 10.9 (CH3). MS (ES +) m/z
273 (M+). MS (ES ꢀ) m/z 87 (BFꢀ4 ). HRLSIMS (FAB
+) m/z calcd for C18H29N2: 273.2331, found: 273.2331.
4.17. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-4,5-
dihydro-1H-imidazolium bis(trifluoromethanesulfonyl)-
imide, 8b
20
1
a reddish liquid. ½aꢁ ¼ ꢀ25 (c 1.0, CHCl3). H NMR
D
(CDCl3) d (ppm): 7.45–7.33 (m, 5H, Ph), 7.22 (d, 1H,
J = 1.5 Hz, Imid.), 7.20 (br s, 1H, Imid.), 5.68 (q, 1H,
J = 7.0 Hz), 4.08 (t, 2H, J = 7.6 Hz), 3.19–2.89 (m,
2H), 1.92 (d, 3H, J = 7.0 Hz), 1.89–1.79 (m, 2H), 1.42–
1.28 (m, 4H), 0.99 (t, 3H, J = 7.6 Hz), 0.94–0.86 (m,
3H). 13C NMR (CDCl3) d (ppm): 148.0 (Cquat. Imid.),
139.6 (Cquat. Ph), 130.1, 129.5, 126.7 (CH, Ph), 122.3,
119.7 (CH, Imid.), 58.6 (CH), 48.9, 30.3, 28.9, 22.7
(CH2), 22.4 (CH3), 17.7 (CH2), 14.4, 12.1 (CH3). MS
(ES +) m/z 271 (M+). MS (ES ꢀ) m/z 87 (BFꢀ4 ). HRL-
SIMS (FAB +) m/z calcd for C18H27N2: 271.2174,
found: 271.2175.
4,5-Dihydroimidazolium
bromide
6
(149 mg,
0.42 mmol) was reacted with lithium bis(tri-
fluoromethanesulfonyl)imide according to the procedure
described for the preparation of imidazolium bis(tri-
fluoromethanesulfonyl)imide 7b to give 8b (190 mg,
0.34 mmol, 81% yield) as
½aꢁ ¼ ꢀ7 (c 1.1, CHCl3). H NMR (CDCl3) d (ppm):
a pale yellow liquid.
20
D
1
7.47–7.35 (m, 3H, Ph), 7.30–7.22 (m, 2H, Ph), 5.10 (q,
1H, J = 7.0 Hz), 4.06–3.87 (m, 2H), 3.85–3.73 (m, 1H),
3.62–3.51 (m, 1H), 3.42 (t, 2H, J = 7.6 Hz), 2.75–2.61
(m, 2H), 1.72 (d, 3H, J = 7.0 Hz), 1.69–1.59 (m, 2H),
1.42–1.26 (m, 4H), 1.23–1.17 (m, 3H), 0.94–0.88 (m,
3H). 13C NMR (CDCl3) d (ppm): 169.0 (Cquat. Imid.),
138.0 (Cquat. Ph), 130.0, 129.4, 127.2 (CH, Ph), 120.5
(q, J = 5.1 Hz, 2 · CF3), 55.9 (CH), 47.7, 47.6 (CH2,
Imid.), 43.9, 29.2, 27.5, 22.7, 18.5 (CH2), 18.5, 14.4,
10.8 (CH3). MS (ES +) m/z 273 (M+). MS (ES ꢀ) m/z
280 (Tf2Nꢀ). HRLSIMS (FAB +) m/z calcd for
C18H29N2: 273.2331, found: 273.2334.
4.15. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-1H-
imidazolium bis(trifluoromethanesulfonyl)imide, 7b
A solution of dihydroimidazolium bromide 5 (240 mg,
0.68 mmol) in water (2 mL) containing lithium bis(tri-
fluoromethanesulfonyl)imide
(195 mg,
0.68 mmol,
1 equiv) was heated with stirring at 70 ꢁC for 1 h and
allowed to stand at rt overnight. The insoluble oily mate-
rial was separated by decantation. It was then dissolved
in dichloromethane, washed with water and brine, dried
over Na2SO4, filtered, and concentrated to dryness. Salt
Acknowledgements
7b (288 mg, 0.52 mmol, 76% yield) was obtained as a
20
D
pale yellow liquid. ½aꢁ ¼ þ17 (c 1.1, CHCl3). 1H
´
Financial support from CNRS and ꢀUniversite Paul
Sabatierꢁ are acknowledged. We are grateful to Heinz
Gornitzka for recording crystallographic data and to
Jany Dandurand for DSC analysis.
NMR (CDCl3) d (ppm): 7.45–7.33 (m, 5H, Ph), 7.22
(d, 1H, J = 2.1 Hz, Imid.), 7.17 (br s, 1H, Imid.), 5.65
(q, 1H, J = 7.0 Hz), 4.12–4.02 (m, 2H), 3.15–2.87 (m,
2H), 1.93 (d, 3H, J = 7.0 Hz), 1.91–1.80 (m, 2H), 1.42–
1.31 (m, 4H), 0.98 (t, 3H, J = 7.6 Hz), 0.94–0.89 (m,
3H). 13C NMR (CDCl3) d (ppm): 147.9 (Cquat. Imid.),
139.4 (Cquat. Ph), 130.2, 129.7, 126.6 (CH, Ph), 122.1
(CH, Imid.), 120.5 (q, J = 5.1 Hz, 2 · CF3), 119.7 (CH,
Imid.), 58.8 (CH), 48.9, 30.2, 28.9, 22.6 (CH2), 22.3
(CH3), 17.8 (CH2), 14.3, 11.9 (CH3). MS (ES +) m/z
271 (M+). MS (ES ꢀ) m/z 280 (Tf2Nꢀ). HRLSIMS
(FAB +) m/z calcd for C18H27N2: 271.2174, found:
271.2179.
References
´
1. Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco,
D.; Das, B. C. Synlett 1992, 5, 431–434.
2. Guilloteau-Bertin, B.; Compere, D.; Gil, L.; Marazano,
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4.16. 2-Ethyl-3-pentyl-1-[(1R)-1-phenylethyl]-4,5-
dihydro-1H-imidazolium tetrafluoroborate, 8a
4,5-Dihydroimidazolium bromide 6 (154 mg, 0.44 mmol)
was reacted with ammonium tetrafluoroborate accord-
ing to the procedure described for the preparation of
imidazolium tetrafluoroborate ent-7a to give salt 8a
4. Pastrascu, C.; Sugisaki, C.; Mingotaud, C.; Marty, J.-D.;
´
Genisson, Y.; Lauth-de Viguerie, N. Heterocycles 2004,
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(146 mg, 0.40 mmol, 91% yield) as a pale yellow liquid.
20
D
½aꢁ ¼ ꢀ10 (c 1.0, CHCl3). 1H NMR (CDCl3) d
5. (a) Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591–
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(ppm): 7.48–7.24 (m, 5H, Ph), 5.14 (q, 1H, J = 7.0 Hz),
4.11–3.93 (m, 2H), 3.92–3.73 (m, 1H), 3.62–3.50 (m,
1H), 3.45 (t, 2H, J = 7.6 Hz), 2.79–2.64 (m, 2H), 1.73
(d, 3H, J = 7.0 Hz), 1.71–1.56 (m, 2H), 1.42–1.26 (m,
4H), 1.24–1.17 (m, 3H), 0.93–0.88 (m, 3H). 13C NMR
(CDCl3) d (ppm): 169.1 (Cquat. Imid.), 138.4 (Cquat.
Ph), 129.9, 129.2, 127.3 (CH, Ph), 55.6 (CH), 47.6
(2 · CH2, Imid.), 43.9, 29.2, 27.4, 22.8 (CH2), 18.4
6. Lourenc¸o, N. M. T.; Afonso, C. A. M. Tetrahedron 2003,
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7. Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M.
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oil-coated shock-cooled crystal on a Bruker-AXS CCD
1000 diffractometer. The structure was solved by direct
method (SHELXS-97)18 and 188 parameters were refined
using the least-squares method on F2.19 Largest electron
density residue 0.291eꢀ3, R1 (for I > 2r(I)) = 0.0387 and
wR2 (all data) = 0.1026 with R1 = RjFoj–jFcj/RjFojand
wR2 ¼ wðRwðF 2o ꢀ F 2cÞ =RwðF 2oÞ Þ0:5. The absolute struc-
ture parameter was refined to X = ꢀ0.04(7).20 Crystallo-
graphic data (excluding structure factors) for the structure
reported herein have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion no. 240725 for ent-4b. Copies of the data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB1 1EZ, UK [Fax: (internat.)
+44-1223/336-033; e-mail: deposit@ccdc.cam.ac.uk.
18. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
19. Sheldrick, G. M. SHELXL-97: Program for Crystal
Structure Refinement; University of Gottingen, 1997.
20. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
21. For general trends concerning relationships between the
structure of RTIL and their physicochemical properties
see: Anthony, J. L.; Brennecke, J. F.; Holbrey, J. D.;
Maginn, E. J.; Mantz, R. A.; Rogers, R. D.; Trulove,
P. C.; Visser, A. E.; Welton, T.. In Ionic Liquids in
Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH,
2002, pp 41–126; See also: Dupont, J. J. Braz. Chem. Soc.
2004, 15, 341–350.
2
2
11. Gruseck, U.; Heuschmann, M. Chem. Ber. 1987, 120,
2053–2064.
12. For a related examples of non C-2 substituted chiral
imidazole see: (a) Liu, J.; Chen, J.; Zhao, J.; Zhao, Y.; Li,
L.; Zhang, H. Synthesis 2003, 17, 2661–2666; (b) Frantz,
D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski,
E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843–846.
13. Prisinzano, T.; Law, H.; Dukat, M.; Slassi, A.; MaClean,
N.; Demchyshyn, L.; Glennon, R. A. Bioorg. Med. Chem.
2001, 9, 613–619.
14. Barco, A.; Benetti, S.; Pollini, G. P. Synthesis 1977, 837.
15. Hughey, J. L., IV; Knapp, S.; Schugar, H. Synthesis 1980,
489–490.
16. Kadaba, P. K. Synthesis 1978, 694–695.
17. Crystal data for ent-4b: C12H15ClN2, M = 222.71, monocli-
˚
˚
˚
nic, P21, a = 6.097(6) A, b = 8.417(8) A, c = 11.844(13) A,
3
˚
b = 95.76 (5)ꢁ, V = 604.7(10) A , Z = 2, qcalcd
=
22. In the absence of the imidazolium 5 and under otherwise
identical conditions, the Michael adduct was isolated in
only 10% yield.
23. Firouzabadi, H.; Ghaderi, E. Tetrahedron Lett. 1978, 9,
839–840.
1.223 Mg mꢀ3
,
F(000) = 236, k = 0.71073 A, T =
, crystal dimensions
˚
193(2) K, l(MoKa) = 0.286 mmꢀ1
0.1 · 0.5 · 0.6 mm3, 3021 reflections (2072 independent,
Rint = 0.0157) were collected at low temperatures using an