Synthesis and properties of thiazoline based ionic liquids derived from the chiral pool

Article abstract of DOI:10.1039/b308814f

A novel class of chiral ionic liquids derived from amino alcohols is prepared in multi-gram scale. Their potential in chiral recognition is shown in a preliminary example with racemic Mosher's acid salt.

Full text of DOI:10.1039/b308814f

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Synthesis and properties of thiazoline based ionic liquids derived from
the chiral pool
Jocelyne Levillain, Guillaume Dubant, Isabelle Abrunhosa, Mihaela Gulea and Annie-Claude
Gaumont*
Laboratoire de Chimie Moléculaire et Thioorganique UMR-CNRS 6507, ENSI-CAEN, ISMRA, Université de
Caen, 6 Bd du Maréchal Juin, F-14050 Caen, France. E-mail: gaumont@ismra.fr; Fax: 33 2 31 45 28 77;
Tel: 33 2 31 45 28 73
Received (in Cambridge, UK) 29th July 2003, Accepted 14th October 2003
First published as an Advance Article on the web 24th October 2003
A novel class of chiral ionic liquids derived from amino
alcohols is prepared in multi-gram scale. Their potential in
chiral recognition is shown in a preliminary example with
racemic Mosher’s acid salt.
phoric acid (HPF6), tetrafluoroboric acid (HBF4) or lithium
bis(trifluoromethanesulfonyl)imide (LiNTf2) (Scheme 2). They
were purified by washing with aqueous sodium bicarbonate or
water until neutrality was reached, then with sodium thiosulfate
to remove iodine traces, followed by filtration over black
charcoal. Compounds 4b–d can be prepared in multi-gram scale
with correct overall yields (68% in pure form).
The chiral salts 4b–d are soluble in dichloromethane,
chloroform, acetonitrile and strongly polar solvents, slightly
soluble in ether, toluene and other weakly polar solvents and
soluble in water. All the salts show good chemical stability
under aqueous basic and acidic conditions. Hydrolysis to the
amino alcohol was not observed even under acidic conditions,
in contrast to oxazolinium derivatives.8 Thiazolinium salts also
exhibit good thermal stability up to at least 170 °C as shown by
TGA measurements. The effect of the thiazolinium counter ions
on the melting point of salts 4 was examined by DSC. Salts 4a–c
having respectively iodide, hexafluorophosphate or tetra-
fluoroborate as counter ion display high melting points
(respectively of 137, 136 and 111 °C). Only the bis(tri-
fluoromethanesulfonyl)imide derivative 4d is liquid at room
temperature (glass transition temperature = 268 °C). Thus,
except for 4d, the high melting points of salts 4 prohibit their use
as chiral solvents.
Ionic liquids (ILs) are low melting point salts ( < 100 °C) that
have attracted considerable attention recently as greener
alternatives to classical environmentally damaging solvents.1
This is mainly due to their peculiar properties such as the
absence of flammability, the lack of measurable vapour
pressure and their ability to dissolve a wide range of organic,
organometallic and even some inorganic compounds. In
addition, reactions carried out in these new media frequently
have different thermodynamic and kinetic behaviours with
respect to those in traditional solvents. Several excellent reports
concerning their applications in organic synthesis (Diels–Alder,
Friedel–Crafts, Wittig reactions…) and in catalysis (cyclopro-
panation, Heck, Suzuki reactions…) can be found in the recent
literature.2 The most widely used ionic liquids are the quite
expensive N,N-dialkylimidazolium salts. Recently, new fami-
lies of ILs derived from ammonium, pyrrolidinium or phos-
phonium cations have been synthesized and studied.3 Never-
theless, chiral derivatives remain limited so far4 although they
could provide a simple entry into the area of chiral solvents with
potential applications in resolution chemistry, chromatography
and even synthesis. Four types of chiral ionic liquids have been
reported until now: imidazolium with chirality brought either by
the anion5 or the cation,6,7 ammonium derived from chiral
amino alcohol8 and oxazolinium derived from valinol.8 Finally,
a novel imidazolium based ionic liquid with cyclophane type
planar chirality was proposed.9 This compound is obtained in a
racemic form and must be resolved before being used. Among
these various examples, the chiral ammonium based ionic liquid
derived from ephedrine was shown to be successful in chiral
discrimination.8
To lower the melting point, we then changed the alkylating
agent chain length. Using the same methodology but replacing
the butyl chain by a dodecyl one when performing the N-
alkylation led to compound 5a in 31% yield after purification.
Upon ion exchange with either hexafluorophosphoric acid
(HPF6)
or
lithium
bis(trifluoromethanesulfonyl)imide
(LiNTf2), salts 5b,d were obtained. Whatever the nature of the
Herein, we report the synthesis and properties of a novel class
of chiral ionic liquids based on a thiazolinium cation. Chiral
thiazolinium salts are poorly studied derivatives. We found only
one report dealing with such compounds in the literature,10 due
probably to the low availability of chiral aminothiol precursors.
Some of us recently published a general and convenient
synthesis of chiral thiazolines starting from commercial low
cost enantiopure 2-amino alcohols and easily accessible
dithioesters as sulfur source.11 The new chiral ILs can then be
prepared by alkylation of the corresponding chiral thiazolines
with an alkyl halide followed by an anion exchange.
As a preliminary study, we synthesized chiral salt 4a.†
Thioamide 2 was readily prepared by thioacylation of the
commercially available (R)-2-aminobutanol with the appro-
priate dithioester 1. Upon treatment of thioamide 2 with mesyl
chloride and Et3N in CH2Cl2, 3 was obtained in 90% yield.
Thiazoline 3 was then refluxed for 48 hours with butyl iodide (1
eq) in acetonitrile leading to salt 4a (Scheme 1). After
crystallization (acetonitrile/Et2O), 4a was obtained in 69%
overall yield.
Scheme 1 Synthesis of iodide thiazolinium salts 4a and 5a.
Starting from 4a, thiazolinium salts 4b–d were obtained in
quantitative yields upon ion exchange with hexafluorophos-
Scheme 2 Thiazolinium anion exchange.
2914
CHEM. COMMUN., 2003, 2914–2915
This journal is © The Royal Society of Chemistry 2003

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Online
Hz), 1.08 (3H, t, J = 7.4 Hz), 1.41 (3H, d, J = 6.8 Hz), 1.48 (3H, d, J = 6.7
Hz), 1.46–1.51 (2H, m), 1.7–2.1 (4H, m), 3.3–3.5 (2H, m), 3.8–3.88 (1H,
m), 3.95–4.02 (1H, m), 4.28 (1H, dd, J = 11.8 Hz, J = 9.9 Hz), 5.2–5.31
(1H, m); 13C-NMR (62.89 MHz), CDCl3–TMS: d = 8.6, 13.2, 19.6, 21.6,
20
21.7, 23.6, 30.1, 31.6, 33.0, 50.4, 73.1, 199.3. [a]D 240.7 (c 1, acetone).
Anal. Calc. for C12H24INS: C, 42.23; H, 7.09; Found: C, 42.02; H, 7.16%.
(R)-3-Dodecyl-4-ethyl-2-isopropyl-2-thiazolinium iodide 5a (1.96 g, 31%
1
yield, mp = 38 °C). H-NMR (250 MHz), CD3CN–TMS: d = 0.58–0.64
(3H, m), 0.7–0.8 (3H, m), 1–1.1 (23H, m), 1.25–1.75 (5H, m), 3.2–3.5 (3H,
m), 3.6–3.8 (2H, m), 4.6–4.7 (1H, m); 13C-NMR (62.89 MHz), CD3CN–
TMS: d = 9.4, 14.6, 22.2, 22.3, 23.4, 24.3, 27.2, 29.8, 30.1, 30.2, 30.3, 30.4,
32.5, 32.6, 34.2, 51.0, 73.8, 200.3. Anal. Calc. for C20H40INS: C, 52.97; H,
20
8.89; Found: C, 53.04; H, 9.29%. [a]D 238.8 (c 1, acetone). (R)-3-Butyl-
4-ethyl-2-isopropyl-2-thiazoliniumbis(trifluoromethylsulfonyl)imide 4d
was prepared from 4a and LiNTf2 following the anion exchange method for
[Bmpy][NTf2].13 (Tg = 268 °C). 1H-NMR (250 MHz), CD3CN–TMS: d =
0.8–0.91 (6H, m), 1.32 (3H, d, J = 6.9 Hz), 1.37 (3H, d, J = 7.0 Hz),
1.3–1.5 (2H, m), 1.6–1.9 (4H, m), 3.1–3.8 (5H, m), 4.5–4.7 (1H, m); 13C-
NMR (62.89 MHz), CD3CN–TMS: d = 8.9, 13.8, 20.4, 21.7, 21.8, 24.1,
30.7, 32.4, 32.9, 50.4, 74.0, 120.9 (q, J = 321 Hz), 201.0; 19F-NMR (376.50
20
MHz), CDCl3–TMS: d = 280.48. [a]D 229.5 (c 1, acetone). HRMS
calcd, 214.1630; found 214.1619. (R)-3-Dodecyl-4-ethyl-2-isopropyl-
2-thiazolinium hexafluorophosphate 5b was prepared in 84% from 5a and
HPF6 following the anion exchange method described by Carlin et al. for
[Emim][PF6].14 (mp = 42 °C). 1H-NMR (400.13 MHz), CD3CN–TMS: d
= 0.91 (3H, t, J = 7 Hz), 0.99 (3H, t, J = 7.4 Hz), 1.3–1.4 (24H, m),
1.6–1.65 (1H, m), 1.7–2.0 (3H,m), 3.31 (1H, sept, J = 6.75 Hz), 3.42 (1H,
dd, J = 12.1 Hz, J = 4.3 Hz,), 3.5–3.65 (1H, m), 3.76 (1H, dd, J = 12.1
Hz, J = 9.6 Hz), 3.8–3.9 (1H, m), 4.7–4.75 (1H, m); 13C-NMR (62.89
MHz), CD3CN–TMS: d = 8.9, 14.4, 21.6, 21.8, 23.4, 24.0, 27.0, 28.7, 29.7,
30.0, 30.2, 30.3, 32.4, 32.6, 32.9, 50.5, 73.9, 200.9; 31P-NMR (101.25
Fig. 1 19F NMR spectrum of water saturated racemic Mosher’s acid
thiazolinium salt in C6D6.
anion, compounds 5 have a melting point below 50 °C (42 °C
for 5b and < 0 °C for 5d) indicating that the length of the N-
alkyl chain can regulate the melting point of the salt.
As a first study on the chiral recognition ability of the
thiazolinium salts, we attempted to detect diastereomeric
interactions between 4a and racemic Mosher’s acid silver salt.
20
MHz), CD3CN–TMS: d = 2143.3 (sept., J = 699 Hz); [a]D 236.7 (c 1,
acetone). HRMS calcd, 326.2882; found, 326.2879. NMR experiment: to an
acetonitrile solution (1 mL) of thiazolinium salt 4a (0.05 mmol, 18 mg), was
added Mosher’s acid silver(I) salt (0.05 mmol, 18 mg). The mixture was
The formation of diastereomeric complexes was probed by 19
F
NMR (Fig. 1). Interaction between thiazolinium cation and
Mosher’s acid anion induces a downfield shift of the fluorine
atom signal in the 19F NMR spectrum (1 ppm). Moreover the
interaction causes a splitting of the Mosher’s acid salt fluorine
signals, clearly illustrating the formation of diastereomeric
complexes. The chemical shift distance between the two CF3
groups depends on the concentration of the ionic liquid in the
solvent (1 eq: spectrum a) and amounts to 11 Hz with 5 eq of wet
thiazolinium salts12 (spectrum b). As already reported for
ammonium salts,8 water added to the chiral thiazolinium salt
has a major influence on the extent of signal splitting.
In summary, we have designed a new family of chiral ionic
liquids based on amino alcohols derived from the chiral pool.
These enantiopure ILs were easily prepared in multi-gram scale.
They are water tolerant and stable under acidic or basic
conditions. By a judicious choice of the anion and the cation,
salts with low melting points are obtained. This property makes
them potential candidates for new chiral solvents. Diaster-
eomeric interactions between thiazolinium 4a and a racemic
substrate were probed by NMR, clearly demonstrating that the
racemic substrate is dissolved in a chiral environment. Use of
these chiral salts in the resolution of racemates or in asymmetric
catalysis is currently under investigation.
shaken at room temp. for 1 h. After removal of AgI by filtration, CH3CN
was evaporated. The new salt (Mosher’s acid thiazolinium salt) was
transferred in an NMR tube containing a solution of C6D6 and a drop of
water. The sample was shaken and the spectrum recorded (a). Then, 4 equiv.
of thiazolinium salts were added to the sample and a new spectrum was
recorded (b).
1 J. H. Davis Jr and P. A. Fox, Chem. Commun., 2003, 1209.
2 For recent reviews, see: P. Wasserscheid and W. Keim, Angew. Chem.,
Int. Ed., 2000, 39, 3772; T. Welton, Chem. Rev., 1999, 99, 2071; R.
Sheldon, Chem. Commun., 2001, 2399; J. Dupont, R. F. de Souza and P.
A. Z. Suarez, Chem. Rev., 2002, 102, 3667; H. Olivier Bourbigou and L.
Magna, J. Mol. Catal. A: Chem., 2002, 3484, 1.
3 For a review, see: S. T. Handy, Chem. Eur. J., 2003, 9, 2938.
4 For a review, see: C. Baudequin, J. Baudoux, J. Levillain, D. Cahard, A.
C. Gaumont and J. C. Plaquevent, Tetrahedron Asymmetry, 2003, 14,
3081–3093.
5 M. J. Earle, P. McCormac and K. R. Seddon, Green Chem., 1999, 1,
23.
6 J. Howarth, K. Hanlon, D. Fayne and P. McCormac, Tetrahedron Lett.,
1997, 38, 3097.
7 W. Bao, Z. Wang and Y. Li, J. Org. Chem., 2003, 68, 591.
8 P. Wasserscheid, A. Bösmann and C. Bolm, Chem. Commun., 2002,
200.
9 Y. Ishida, H. Miyauchi and K. Saigo, Chem. Commun., 2002, 2240.
10 H. Chikashita, S. Komazawa and K. Itoh, Technology Reports of Kansai
University, 1989, 31, 81.
We acknowledge Dr M. Fois, Dr C. Mailhac (URCOM,
Université du Havre) and Dr O. Talon (LCMT, ENSICAEN) for
TGA and DSC measurements. CNRS and le conseil régional de
Basse Normandie are acknowledged for financial support.
11 I. Abrunhosa, M. Gulea, J. Levillain and S. Masson, Tetrahedron
Asymmetry, 2001, 12, 2851.
12 Under similar conditions but in the absence of a co-solvent (water),
diastereomer discrimation between 5b and the Mosher’s acid sodium
salt cannot be observed by NMR indicating that the differences in the
binding energies for the 2 diastereomeric complexes must be too small
under the used conditions. Nevertheless, the chemical shift difference
Notes and references
†
The thiazolines 3 were prepared from (R)-(2)2-aminobutanol in 90%
yield according to prior work.11 Synthesis of 4a and 5a: Thiazoline 3 (2.33
g, 12 mmol) was mixed with alkyl iodide (23.6 mmol) in acetonitrile and
refluxed for 2 days. The remaining alkyl iodide was removed under vacuum
or by washing with heptanes. The crude products were purified by
crystallization in acetonitrile/Et2O for 4a and ethyl acetate for 5a. (R)-
3-Butyl-4-ethyl-2-isopropyl-2-thiazolinium iodide 4a (2.82 g, 69% yield,
mp = 137 °C). 1H-NMR (250 MHz), CDCl3–TMS: d = 1.01 (3H, t, J = 7.3
for the methoxy group (Dd 1.3) in H NMR and the CF3 group in 19F
1
NMR (Dd 0.1) as well as the important broadening of the signals
account for diastereomeric interactions.
13 N. L. Lancaster, P. A. Salter, T. Welton and G. B. Young, J. Org. Chem.,
2002, 67, 8855.
14 J. Fuller, R. T. Carlin, H. C. De Long and D. Haworth, J. Chem. Soc.,
Chem. Commun., 1994, 299.
CHEM. COMMUN., 2003, 2914–2915
2915