Design and synthesis of imidazolinium salts derived from (L)-valine, Investigation of their potential in chiral molecular recognition

Article abstract of DOI:10.1039/b402368d

Several imidazolinium salts are synthesized from (L)-valine. A study of the structure relationships is achieved to obtain high diastereomeric interactions with an anionic substrate. High splitting up to 60 Hz of the (rac)-potassium Mosher's salt are obser

Full text of DOI:10.1039/b402368d

Design and synthesis of imidazolinium salts derived from ( )-valine.
L
Investigation of their potential in chiral molecular recognition†
Hervé Clavier,a Loïse Boulanger,a Nicolas Audic,a Loïc Toupet,b Marc Mauduit*a and Jean-Claude
Guillemin*a
a UMR CNRS 6052, ENSCR, Institut de Chimie de Rennes, 35700 Rennes, France.
E-mail: marc.mauduit@ensc-rennes.fr
b UMR CNRS 6626, Université de Rennes 1, 35700 Rennes, France
Received (in Cambridge, UK) 17th February 2004, Accepted 18th March 2004
First published as an Advance Article on the web 26th April 2004
Several imidazolinium salts are synthesized from (
L
)-valine. A
a bulky counter cation like potassium, leading to increased
diastereomeric interactions. To confirm this, we added the crown
ether 18C6 to trap the potassium cation9 and obtained better
interactions, affording a doubling of the chemical shifts difference
study of the structure relationships is achieved to obtain high
diastereomeric interactions with an anionic substrate. High
splitting up to 60 Hz of the (rac)-potassium Mosher’s salt are
observed by NMR spectroscopy.
1
(Dd = 20–30 Hz) observed in both H and 19F NMR spectros-
copy.
In the context of a sudden awareness of environmental problems,
development of new cleaner processes to minimize chemical
wastes has became a high priority for chemical industries.1 In this
area, room temperature ionic liquids (RTILs), such as imidazolium,
imidazolinium and pyridinium salts, have received considerable
attention for their use as novel clean media in organic chemistry.2
By their interesting properties such as ease to reuse, non-volatility,
absence of flammability, these new solvents are promising
candidates to replace volatile organic solvents traditionally used in
industry.3 In the area of chiral solvents,4 because RTILs show a
high degree of organisation,5 their chiral version should be more
attractive than classical solvents for a potential application in chiral
discrimination, including asymmetric synthesis. However, devel-
opment of chiral RTILs (cRTILs) is currently in preliminary stage
and only few have been reported.6,7
Herein, we report the synthesis of new chiral imidazolinium salts
4 derived from natural amino acid ( )-valine. By diastereomeric
L
interactions with a racemic anionic substrate, we have investigated
the effect of a hydroxyalkyl side chain in the chiral molecular
recognition ability of these new salts.
The synthesis of chiral imidazolinium salts 4 is shown in Scheme
1. Starting from commercially available N-Boc-( )-valine 1, the
L
aryl group was introduced via a classical coupling between
substituted aniline and 1 to generate the corresponding amide.8
After hydrolysis of the carbamate by methanolic hydrochloric acid,
the amide function was reduced with LiAlH4 to afford, after
chromatography, the diamine 2 in excellent yield. Formation of the
diamine chlorhydrate followed by condensation of trimethylortho-
formate in toluene delivered the corresponding enantiopure imida-
zoline 3 (Fig. 1). Finally, the desired chiral imidazolinium salts 4
were obtained by a simple alkylation with various alkyl halides
followed by anion exchange. The choice of the counter anion was
crucial for the properties of these salts. Indeed, NTf2 led to a RTIL
while PF6 gave only solid salts. Accordingly, 5 imidazolinium salts
have been isolated after purification on silica gel with moderate to
good yields. One X-ray structure has been realised with PF6
imidazolinium salt 4a.‡
Scheme 1 Synthesis of imidazolinium salts 4a–e.
To evaluate the chiral recognition ability of these imidazolinium
salts, we have attempted to detect diastereomeric interactions
between the enantiopure cations 4 and the racemic anion of
Mosher’s salt. We modified the NMR experiment developed by
Wasserscheid et al.7a to improve these interactions.§ Indeed, we
used the potassium salt 5 instead of the sodium salt and recorded
NMR spectra in acetone-d6, where both salts are completely
soluble. This protocol gives a better difference in the chemical shift
(Dd = 10–20 Hz) for both methoxy and CF3 groups of the two
enantiomers of Mosher’s carboxylate 5. This result can be
explained by the tightness of the anion pair, which is decreased by
Fig. 1 1H (a) and 19F (b) NMR spectra (400 and 376 MHz, respectively,
CD2Cl2) of (rac)-Mosher salt 5 in imidazolinium 4c in presence of crown
ether 18C6. (c) 1H NMR spectrum of an enantioenriched sample of Mosher
salt 5 (60% ee).
† Electronic supplementary information (ESI) available: preparative details
and NMR data for 4a–e. See http://www.rsc.org/suppdata/cc/b4/b402368d/
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C h e m . C o m m u n . , 2 0 0 4 , 1 2 2 4 – 1 2 2 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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We then investigated the role of the side chain on the chemical
shift difference. If the length of alkyl chain presents a minimal
effect (imidazoliniums 4a, b: Dd = 20–30 Hz), the introduction of
a polar group, such as a hydroxyethyl chain (imidazolinium 4c),
increases considerably the chemical shift difference. Up to 54.7 and
In summary, we have designed and synthesized new imidazolin-
ium salts using a simple route starting from ( )-valine. They are
L
water tolerant and stable under acidic conditions. By structure–
interaction relationships, we showed the crucial role of the
hydroxyalkyl lateral side chain and the bulky aromatic substituents
to obtain higher diasteromeric interactions with a racemic anionic
substrate. These interactions have been shown by 1H and 19F NMR
spectroscopy with high splitting up to 60 Hz of the (rac)-potassium
Mosher’s salt. This study leads us to develop new cRTILs with high
molecular recognition ability, based on hydroxyalkyl ammonium,
imidazolium or pyridinium salts. The large scale synthesis of these
new chiral solvents is under way in our laboratory and their use in
asymmetric synthesis will be reported in due course.
40.4 Hz between the two enantiomers were obtained in 1H and 19
F
NMR spectroscopy respectively [Fig. 1(a) and (b)]. Consequently,
it is thus easy to confirm the enantiomeric excess of an
enantioenriched sample of Mosher’s salt by a simple integration of
NMR signals [81:19, 60% ee, Fig. 1(c)].
Increasing the chain length with a hydroxypropyl chain (imida-
zolinium 4d), improved again these splitting up to 60 Hz in proton
and 63 Hz in fluorine NMR spectroscopy. However, in the case of
longer hydroxyl chain such as a hydroxyoctyl chain (imidazolium
4e), very small difference was obtained (Dd = 12 Hz). To explain
this, we postulated that diastereomeric interactions were favoured
by hydrogen bonding between the hydroxyl group and the anionic
substrate, leading to a folding up of the hydroxyl chain toward the
cation. The bad splitting observed with the hydroxyoctyl chain
showed that this folding up conformation was favoured only for C2
or C3 hydroxyalkyl chain. To prove this folding up conformation,
we have added a few drops of water in the NMR solvent, destroying
the hydrogen bonds and leading to a diminution of the chemical
shift difference.
On the other hand, it is important to note that the presence of a
bulky substituent on the ortho position of the aromatic ring is also
responsible of the chiral discrimination (Fig. 2). Indeed, replace-
ment of the initial bulky 2-tert-butyl group by a 2-methyl group
decreased considerably the splitting of the NMR signals. In the
structure-interaction relationships, a polar group on the lateral side
chain and a bulky ortho substituent on the aromatic ring were
complementary and necessary to obtain high diastereomeric
interactions between the chiral cation and the anionic substrate.
Notes and references
‡ Crystal data for 4a: C34H54F12N4P2, M = 814.78, monoclinic, a =
9.1683(2), b = 20.2115(7), c = 10.8752(3) Å, b = 101.599(2)°, V =
1974.1(1) Å3, T = 120 K, space group P21, Z = 2, m = 1.97 cm21, 35 228
reflections measured, 5857 unique (Rint = 0.078) which were used in all
calculations. The final wR(F2) = 0.204 (all data). CCDC 227054. See http:
//www.rsc.org/suppdata/cc/b4/b402368d/ for crystallographic data in CIF
or other electronic format.
§
Representative procedure for NMR experiment: 12.5 mg of (rac)-
potassium-2-methoxy-2-(trifluoromethyl)phenylacetate 5 and imidazolin-
ium salt 4c (3.3 equiv.) were dissolved in 0.4 mL of acetone-d6 and the
spectrum was recorded. Recovery of imidazolium salt can be realised after
dilution in dichloromethane following by repeating washing with water.
The organic layer was then dried over MgSO4 and concentrated in vacuo to
afford the pure imidazolium salt without any trace of Mosher salt. With
18C6: the Mosher salt was previously dissolved in 0.4 mL of CD2Cl2 in
presence of 12.1 mg (1 equiv.) of crown ether 18C6, then imidazolinium salt
was introduced and the spectrum was recorded.
1 Green Chemistry: Frontiers in Benign Chemical Syntheses and Proc-
esses, ed. P. T. Anastas and T. C. Williamson, Oxford University Press,
New York, 1999.
2 Ionic Liquids in Synthesis, ed. P. Wasserscheid and T. Welton, Wiley-
VCH, Weinheim, 2003.
3 For recent reviews on ionic liquids, see: (a) J. Dupont, R. F. de Souza and
P. A. Z. Suarez, Chem. Rev., 2002, 102, 3667; (b) P. Wasserscheid and W.
Keim, Angew. Chem., Int. Ed., 2000, 39, 3772; (c) T. Welton, Chem. Rev.,
1999, 102, 3667.
4 (a) J. March and M. B. Smith, Advanced Organic Chemistry, Wiley-
Interscience, New York, 2001, p. 150 and 156; (b) D. Seebach and H. A.
Oei, Angew. Chem., Int. Ed., 1975, 14, 634; (c) A. Gilbert, T. W. Heritage
and N. S. Isaacs, Tetrahedron: Asymmetry, 1991, 2, 969.
5 J. Dupont, P. A. Z. Suarez, R. F. de Souza, R. A. Burrow and J. P.
Kintzinger, Chem. Eur. J., 2000, 6, 2377.
6 For a review on chiral ionic liquids, see: C. Baudequin, J. Baudoux, J.
Levillain, D. Cahard, A. C. Gaumont and J. C. Plaquevent, Tetrahedron:
Asymmetry, 2003, 14, 3081.
7 (a) P. Wasserscheid, A. Bösmann and C. Bolm, Chem. Commun., 2001,
200; (b) Y. Ishida, H. Miyauchi and K. Saigo, Chem. Commun., 2002,
2240; (c) W. Bao, Z. Wang and Y. Li, J. Org. Chem., 2003, 68, 591; (d)
J. Levillain, G. Dubant, I. Abrunhosa, M. Gulea and A. C. Gaumont,
Chem. Commun., 2003, 2914.
8 (a) T. Mukaiyama, Tetrahedron, 1981, 23, 4111; (b) A. R. Katrizky, K.
Suzuki and H. Y. He, J. Org. Chem., 2002, 67, 3109.
9 NMR spectra were thus recorded in CD2Cl2 due to the presence of crown
ether, which solubilises the potassium salt in polar aprotic solvent.
Fig. 2 Influence of the aryl substituent on the chiral discrimination: 1H
spectra (400 MHz, CD2Cl2) of (rac)-Mosher salt 5 in imidazolinium 4c (a)
and 4f (b) in presence of crown ether 18C6.
C h e m . C o m m u n . , 2 0 0 4 , 1 2 2 4 – 1 2 2 5
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