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

Abstract

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.

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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 (cyclopropanation, 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 families of ILs derived from ammonium, pyrrolidinium or phosphonium cations have been synthesized and studied.³ Nevertheless, 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

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 appropriate 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 hexafluorophosphoric 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).

Scheme 2 Thiazolinium anion exchange.

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 tetrafluoroborate as counter ion display high melting points (respectively of 137, 136 and 111 °C). Only the bis(trifluoromethanesulfonyl)imide derivative 4d is liquid at room temperature (glass transition temperature = −68 °C). Thus, except for 4d, the high melting points of salts 4 prohibit their use as chiral solvents.

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 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. The formation of diastereomeric complexes was probed by ¹⁹F 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.

Fig. 1 ¹⁹F NMR spectrum of water saturated racemic Mosher's acid thiazolinium salt in C₆D₆.

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. Diastereomeric 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.

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.

Notes and references

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.
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 for the methoxy group (Δδ 1.3) in ¹H NMR and the CF₃ group in ¹⁹F NMR (Δδ 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.

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Footnote

† The thiazolines 3 were prepared from (R)-(−)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: δ = 1.01 (3H, t, J = 7.3 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: δ = 8.6, 13.2, 19.6, 21.6, 21.7, 23.6, 30.1, 31.6, 33.0, 50.4, 73.1, 199.3. [α]_D²⁰ −40.7 (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% yield, mp = 38 °C). ¹H-NMR (250 MHz), CD₃CN–TMS: δ = 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: δ = 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, 8.89; Found: C, 53.04; H, 9.29%. [α]_D²⁰ −38.8 (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 (T_g = −68 °C). ¹H-NMR (250 MHz), CD₃CN–TMS: δ = 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: δ = 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 MHz), CDCl₃–TMS: δ = −80.48. [α]_D²⁰ −29.5 (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: δ = 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: δ = 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 MHz), CD₃CN–TMS: δ = −143.3 (sept., J = 699 Hz); [α]_D²⁰ −36.7 (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 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).

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