Simple and straightforward synthesis of novel enantiopure ionic liquids via efficient enzymatic resolution of (±)-2-(1H-imidazol-1-yl)cyclohexanol

Article abstract of DOI:10.1016/j.tetlet.2007.05.138

Both enantiomers of enantiopure imidazolium ionic liquids were synthesized by a simple and straightforward procedure from (R,R)- and (S,S)-2-(1H-imidazol-1-yl)cyclohexanol derivatives obtained via lipase-catalyzed resolution. Structural properties and the

Full text of DOI:10.1016/j.tetlet.2007.05.138

Tetrahedron Letters 48 (2007) 5251–5254
Simple and straightforward synthesis of novel enantiopure
ionic liquids via efficient enzymatic resolution of
(
± ±)-)(ꢀH)imidazol)ꢀ)yl±cyclohexanol
a
a
a
Eduardo Busto, Vicente Gotor-Fern a´ ndez, Nicol a´ s R ´ı os-Lombard ´ı a,
Eduardo Garc ´ı a-Verdugo, Ignacio Alfonso, Santiago Garc ´ı a-Granda,
Amador Men e´ ndez-Vel a´ zquez, M. Isabel Burguete, Santiago V. Luis
b
b
c
d
b
b,
*
a,
*
and Vicente Gotor
a
Departamento de Qu ı´ mica Org a´ nica e Inorg a´ nica, Instituto Universitario de Biotecnolog ı´ a de Asturias,
Universidad de Oviedo, E-33071 Oviedo, Spain
b
Departamento de Qu ı´ mica Inorg a´ nica y Org a´ nica, Universidad Jaume I, E-12071 Castell o´ n, Spain
c
Departamento de Qu ı´ mica F ı´ sica y Anal ı´ tica, Universidad de Oviedo, E-33071 Oviedo, Spain
Instituto de Ciencia de Materiales de Madrid, CSIC, Cantoblanco Ctra. de Colmenar Km 15, E-28049 Madrid, Spain
d
Received 29 March 2007; revised 16 May 2007; accepted 23 May 2007
Available online 26 May 2007
Abstract—Both enantiomers of enantiopure imidazolium ionic liquids were synthesized by a simple and straightforward procedure
from (R,R)- and (S,S)-2-(1H-imidazol-1-yl)cyclohexanol derivatives obtained via lipase-catalyzed resolution. Structural properties
and thermal stability of these compounds have been studied to elucidate their potential applications in asymmetric catalysis.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Ionic liquids (ILs) are attracting considerable attention
imidazolium salts as potential ionic liquids prepared
from chiral (1R,2R)-2-(1H-imidazol-1-yl)cyclohexyl
acetate and (1S,2S)-2-(1H-imidazol-1-yl)cyclohexanol
obtained through lipase-catalyzed resolution.
1
2
as reaction solvents, extraction liquids, and electrolyte
3
materials as a result of their remarkable properties. ILs
are now expected to be designed liquids with controlla-
ble physical and chemical properties or even specific
4
functions (task-specific ILs). Structural diversity often
The chemical synthesis of (± )-2-(1H-imidazol-1-yl)cyclo-
hexanol (± )-3 was developed as described by Yus and
plays an important role in ionic liquid physicochemical
5
8
properties. The introduction of chirality is by far one
co-workers, and the enzymatic resolution of the race-
of the goals mostly pursued by organic chemists. There-
fore, the design and synthesis of novel enantiopure ionic
liquids with the possibility of easy structural tuneability
is highly attractive. In this sense, a great effort is being
mic alcohol 3 was performed by biocatalyzed enantio-
selective acylation (Scheme 1). Firstly, the reaction was
carried out using Candida antarctica lipase B (CAL-B)
and a 3-fold excess of vinyl acetate as acyl donor in
9
devoted to design and synthesize chiral ionic liquids
THF at 30 ꢁC (Table 1, entry 1).
6
(
CILs). However, most of the known CILs are derived
from chiral pools and provide a very limited scope for
structural modifications. Herein, we describe a flexible
and simple synthetic approach for the synthesis of chiral
The O-acylation of the (R,R)-3 enantiomer took place
smoothly and a 49% conversion was reached after
39 h. Both the substrate and the product were isolated
with very high enantiomeric excesses and an excellent
enantioselectivity (E >200). The resolution was faster
when Pseudomonas cepacia lipase (PSL-C) was used
instead of CAL-B finding a 50% of conversion just
after 14 h (entry 2). The reaction in tert-butyl methyl
ether (TBME) using PSL-C at 30 ꢁC led to (R,R)-4 in
7
Keywords: Imidazol derivatives; Ionic liquids; Pseudomonas cepacia
lipase; Thermogravimetric analysis; X-ray.
*
Corresponding authors. Tel./fax: +34 985103448 (V.G.); e-mail
addresses: luiss@qio.uji.es; vgs@fq.uniovi.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.138

5252
E. Busto et al. / Tetrahedron Letters 48 (2007) 5251–5254
Table -. Synthesis and structural properties of ILs
OH
N
OAc
N
O
i)
ii)
c
m
Entry
IL
R
Anion
Yield (%)
T
[a]
D
+
HN
N
a
N
N
1
2
3
4
5
6
7
8
9
0
1
2
3
5a
5b
5c
5d
6a
6b
7a
7b
7c
7d
7e
7f
Bn
Bn
Cl
Br
Cl
Cl
Br
Cl
NTf
BF
NTf
BF
NTf
BF
NTf
88
96
94
94
89
91
95
91
91
91
95
91
219
188
7
2
182
21
+7.0
+6.3
+8.1
+8.9
À2.7
+4.9
+9.3
+8.1
+7.9
+8.3
+7.5
+8.6
+9.8
a
1
2
(±)-4
a
(
±)-3
iii)
n-Bu
n-Oct
Bn
n-Bu
Bn
a
a
a
OAc
N
OH
N
b
2
2
2
2
À29
b
Bn
4
6
+
N
N
b
n-Bu
n-Bu
n-Oct
n-Oct
n-Bu
À50
À26
À51
À35
À42
b
1
1
1
1
4
(R
,
R
)-(-)-4
(
S
,
S
)-(+)-3
b
b
iv)
iv)
4
b
8a
93
OAc
OH
N
a
b
c
Yield corresponding to quaternization reaction.
Yields corresponding to metathesis reaction.
Melting point calculated at onset.
X
X
N
N
R
N R
(
(
R
,
R
)-6 X= Br or Cl
(
(
S
,
S
)-5 X= Br or Cl
)-7 X= BF or NTf2
v)
v)
All organic salts were characterized by spectroscopic
R,
R
)-8 X= NTf2
S,
S
4
1
13
analysis of H NMR, C NMR, IR, and MS (see
Supplementary data). We also obtained suitable crys-
tals for X-ray diffraction analysis of compounds 5a
R= Bn or
n-Bu
R= Bn, n-Bu or n-Oct
Scheme ꢀ. Synthesis of enantiopure ILs. Reagents and conditions: (i)
0 ꢁC; (ii) Ac O (2 equiv), DMAP (0.33 equiv), NEt (3 equiv),
CH Cl
50 rpm; (iv) RX, D; (v) NaBF
MeOH–H O, rt.
6
2
3
(R = Bn, X = Cl) and 5b (R = Bn, X = Br). X-ray anal-
2
2
, rt; (iii) vinyl acetate (3 equiv), enzyme, solvent, 30 or 45 ꢁC,
ysis unambiguously confirmed the proposed chemical
structure and (S,S)-configuration of the chiral imidazole
salts. The structure consists of layers of cations and
anions, which are interconnected by a network of hydro-
gen bonds and p–p interactions between the aromatic
rings.
2
4
(2 equiv) or LiNTf
2
(1.1 equiv),
2
Table ꢀ. Lipase-catalysed resolution of (± )-3
a
a
b
c
Entry Enzyme Solvent
T
t
ee
S
ee
P
c
E
(
ꢁC) (h) (%) (%) (%)
Slight differences in the hydrogen-bond networks
between chiral cation and either chloride or bromide lead
to a different ionic packing for these two compounds
1
2
3
4
CAL-B THF
30
30
39
14
13
93
97
98 49
98 50
>200
>200
>200
>200
PSL-C
PSL-C
PSL-C
THF
TBME 30
TBME 45
33 >99 25
(
Figs. 1 and 3). However, in both the cases, the anion
15 >99 >99 50
showed close contacts with different hydrogen atoms
of the chiral cation. Both the hydroxyl and imidazolium
moieties are implicated in H-bonding with the anion,
being the hydrogen bond established through imidazo-
a
Calculated by chiral HPLC analysis, ee
S
refers to the enantiomeric
P
excess of the substrate and ee for the enantiomeric excess of the
product.
b
c
c = ee
S S P
/(ee + ee ).
E = ln [(1 À c) · (1 À ee
S
)]/ln[(1 À c) · (1 + ee
P
)].
enantiopure form. However, the conversion and enan-
tiomeric excess for the substrate were very low, due to
the low solubility of this substrate in TBME (entry 3).
This problem was overcome by using a higher tempera-
ture. Under these conditions (R,R)-4 and (S,S)-3 were
both obtained in their enantiopure forms (>99% ee)
and in good isolated yields: 91% and 88%, respectively
(
entry 4). The assignment of the absolute configuration
of (+)-3 was done on the basis of its X-ray crystal struc-
ture (see Supplementary data).
The imidazole salts (5a–d and 6a,b) derived from both
hydroxy (S,S)-3 and acetylated (R,R)-4 imidazole com-
pounds were obtained in high to excellent isolated yields
(
88–96%) by heating the chiral imidazole derivatives
with the corresponding halogenated reagent (Table 2,
entries 1–6). The exchange of imidazolium salts with dif-
À
À
ferent anions (BF4 ; NTf2 ) led to the corresponding
compounds 7a–f and 8a also in high yields (entries 7–
1
3). Some representative properties of enantiopure IL
Figure ꢀ. Molecular structures obtained from X-ray analysis. Crystal
packing view of 5a along the a-axis.
are summarized in Table 2.

E. Busto et al. / Tetrahedron Letters 48 (2007) 5251–5254
5253
Additionally, other C–HÁ Á ÁX interactions involving the
methylene hydrogens of the side chain (R = PhCH –,
2
CH –(CH ) –CH –, and CH –(CH ) –CH –) can be ob-
3
2 2
2
3
2 6
2
served. Thus, the anisochrony of the diastereotopic pro-
tons at the benzylic position (ꢀ5.5 ppm) is much higher
for Cl than for the BF suggesting a more rigid structure
4
for the halogen derivative (Fig. 2). Preliminary DFT cal-
culations on the isolated ion pair of 5a led to minima
showing a C(2)–HÁ Á ÁClÁ Á ÁH–O hydrogen-bond pattern
in an anion-chelated geometry (see Supplementary
data). All these data suggest that the anion must play
a fundamental role in the asymmetric environment
induced by these new chiral ionic liquids and therefore
having an important impact on their physicochemical
properties.
1
0.0
9.0
8.0
7.0
6.0
5.0
δ (ppm)
1
Figure -. Partial H NMR (5 mM, CDCl
3
, 500 MHz) spectra of 5a
(
lower trace) and 7b (upper trace).
However, the characteristics of IL are not only modu-
lated by the hydrogen-bond interactions but also by
the cation–cation interactions and hydrophobic effects.
In this context, the X-ray showed interactions between
the aryl groups of different chiral cations. These interac-
tions will contribute to increase the lattice energy
explaining the high melting points for 5a and 5b. When
aryl groups were substituted by aliphatic chains, which
suppress the above-mentioned interactions, significant
decreases on the melting temperatures were observed
(5c 7 ꢁC and 5d 2 ꢁC).
lium C(2)–H atom specially noteworthy. The OH and
C(2)–H groups from a given cation are bound to differ-
ent anions within the crystal lattice (see packing in Figs.
1
and 3).
Cation–anion H-bond interactions for chloride are
˚
stronger than for bromide C(2)–HÁ Á ÁCl 2.545 A versus
˚
˚
C(2)–HÁ Á ÁBr 2.720 A O–HÁ Á ÁCl 2.244 A versus O–
˚
HÁ Á ÁBr 2.720 A. Such differences are big enough to pro-
duce a change on the T observed for either Cl or Br (5a
m
The thermal stability of the ionic liquids was assessed
using thermogravimetric analysis. The TGA showed
for temperatures below 200 ꢁC a weight loss lower than
2
19 ꢁC and 5b 188 ꢁC). Related H-bond networks have
10
been reported for other imidazole salts. Indeed, hydro-
gen-bond interactions are by far the most important
contribution to the lattice energy in IL compounds. At
that point, we wondered if these interactions are re-
5
% for the NTf derivatives. When 7a was heated at
2
1
50 ꢁC for a period of 3 h, the compound after cooling
1
1
did not show any signals of decomposition by H NMR.
tained for the isolated ion pair. Regarding that, the H
NMR spectra of diluted solutions in deuterochloroform
showed very different chemical shifts for C(2)–H hydro-
gen depending on the anion (see Fig. 2). For instance,
In summary, we have designed and synthesized enantio-
pure room temperature imidazolium ionic liquids. These
novel RTILs can be readily prepared by simple and
straightforward procedures from non-expensive enan-
tiopure synthons obtained via lipase-catalyzed resolu-
tions. The strategy reported here can be used to obtain
a family of chiral RTILs, in which structural diversity
can be introduced by varying either the epoxide or the
imidazole moieties. We are currently investigating how
these modifications can affect the ILs physicochemical
properties and further development of these molten salts
this proton resonates at 8.92 ppm for the BF , while it
4
is shifted to lower field up to 10.23 ppm for Cl, support-
ing that the hydrogen bonds observed in the crystals are
retained in the isolated ion pair for the more basic an-
1
1
ion. Therefore, imidazole salts with lower melting
points (7a T = À29 ꢁC and 7b T = 6 ꢁC) were ob-
m
m
tained by the introduction of less basic anions such as
À
À
NTf2 or BF4 , which have less hydrogen-bond capac-
ity reducing the lattice energy and leading to RTILs.
Figure 3. Molecular structures obtained from X-ray diffraction analysis. Crystal packing view of 5b along the a-axis.

5254
E. Busto et al. / Tetrahedron Letters 48 (2007) 5251–5254
as effective solvents, as well as chiral catalysts for a vari-
ety of asymmetric reactions.
3. (a) Bonh oˆ te, P.; Dias, A.-P.; Papageorgiou, N.; Kalyana-
sundaram, K.; Gr a¨ tzel, M. Inorg. Chem. ꢀ996, 35, 1168–
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178; (b) Yoshizawa, M.; Narita, A.; Ohno, H. Aust. J.
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4
5
. Lee, S. Chem. Commun. -006, 1049–1063.
Acknowledgments
. (a) Zhou, Z.-B.; Matsumoto, H.; Tatsumi, K. Chem. Eur.
J. -004, 10, 6581–6591; (b) Tokuda, H.; Hayamizu, K.;
Ishii, K.; Susan, K. M.; Watanabe, M. J. Phys. Chem. B
-005, 109, 6103–6110; (c) Tokuda, H.; Ishii, K.; Susan,
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Financial support by MEC (CTQ2005-08016-003,
MEC-04-CTQ-04185, MAT2006-01997, and Factor ´ı a
de Cristalizaci o´ n Consolider Ingenio 2010) and Fun-
daci o´ Caixa Castell o´ —UJI (P1B2004-13) is acknowl-
edged. I.A. and E.G.-V. (Ram o´ n y Cajal), V.G.-F.
6
. For general revisions see: (a) Baudequin, C.; Baudoux, J.;
Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent,
J.-C. Tetrahedron: Asymmetry -003, 14, 3081–3093; (b)
Ding, J.; Armstrong, D. W. Chirality -005, 17, 281–292;
(
Juan de la Cierva Program), and E.B. (FPU) thank
MEC for personal funding.
(
c) Baudequin, C.; Brjgeon, D.; Levillain, J.; Guillen, J.;
Plaquevent, F.-C.; Gaumont, A.-C. Tetrahedron: Asym-
metry -005, 16, 3921–3945.
Supplementary data
7
. (a) Ni, B.; Headley, A. D. Tetrahedron Lett. -006, 47,
7331–7334; (b) Malhotra, S. V.; Wang, Y. Tetrahedron:
Asymmetry -006, 17, 1032–1035; (c) Luıs, C.; Branco, L.
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Guillen, F.; Bregeond, D.; Plaquevent, J.-C. Tetrahedron
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Supplementary data (experimental procedures, charac-
terization data for new compounds, and X-ray) associ-
ated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.05.138.
8
9
. Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron -007,
63, 469–473.
. For enzymatic studies on related structures: Gonz a´ lez-
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