Synthesis of novel enantiopure ionic liquids from ( S )-malic acid

A straightforward and practical synthesis of six novel pyrrolidinium salts based on ( S )-malic acid is reported. Two of them were liquid at room temperature, and can be employed as novel chiral ionic liquids for enantioselective applications

We recently reported the synthesis of a novel class of pyrrolidinium cations for the obtainment of chiral ionic compounds based on L-tartaric acid (compounds 1-12). 22Two out of the twelve ionic compounds 1-12 synthesized (namely 8 and 12) were liquid at room temperature, and 4 showed a low melting point (50-53 °C).Therefore, the bis(triflyl)amide anion proved to be the best for lowering the melting point of the resulting salts.Moreover, also disrupting the C 2 -symmetry of the molecule (compound 12 vs 8) resulted an effective way for obtaining lower melting point salts.Thus we speculated that (S)-malic acid, that does not have the C 2 symmetry, could be a promising starting material for the synthesis of novel pyrrolidinium cations.

N
We present in this work the synthesis of six novel ionic salts from natural (S)-malic acid, two of which turned out to be liquid at room temperature.While malic and tartaric acids have already been reported as anions of some chiral ionic liquids, [23][24][25] the use of (S)-malic acid for the synthesis of chiral ionic liquids based on a chiral cation is unprecedented, to the best of our knowledge.

Results and Discussion
Our strategy started from low cost (S)-malic acid (13, Scheme 1).Since direct condensation with benzylamine at reflux followed by reduction with LiAlH 4 had been reported to occur with partial epimerization at C3, 26 we followed a much milder procedure that implied prior activation with acetyl chloride, reaction with benzylamine at 20-25 °C and then further treatment with acetyl chloride. 27This afforded compound 14 in 90% yield.The subsequent reduction with lithium aluminum hydride gave (3S)-1-benzyl-3-pyrrolidinol (15) in 87% yield following a slight modification of the published procedure during the quench of the reaction (Scheme 1).Scheme 1. Preparation of the 3(S)-1-benzyl-3-pyrrolidinol (15) from (S)-malic acid (13).
Quaternization of pyrrolidinol 15 was achieved using a slight excess of benzyl bromide in acetonitrile at 90 °C (Scheme 2).The reaction was performed either with traditional and microwave (MW) heating, obtaining comparable yields (68% and 71% yields, respectively) but lower reaction times with the MW heating (10 min vs 1 h) on a gram scale of 15.Scheme 2. Synthesis of the pyrrolidinium salt 16.
The bromide salt 16 was purified by crystallization from ethyl acetate and diethyl ether obtaining a solid compound with mp 149-150 °C.Compound 16 was soluble in acetonitrile, MeOH and water 28 while it did not dissolve in acetone, diethyl ether and ethyl acetate at room temperature.Anion exchange was attempted by dissolving in water or suspending in acetone, respectively, the solid material 16 in the presence of 1 equivalent of the appropriate salt at room temperature overnight (Table 1).The reaction in acetone did not occur, probably due to the low solubility of 16 in this solvent (entries 1 and 4, Table 1).Heating the mixture at reflux for 1 h gave no better results.Instead, the anion exchange reaction was successful using water as solvent.After overnight stirring, extraction with ethyl acetate afforded salts 17 and 18 in good to excellent yields (Table 1, entries 2 and 3).In the case of the bis(triflyl)amide salt 19, formation of some drops of an oil that separated from the aqueous phase was observed.Upon extraction with ethyl acetate, the pure ionic liquid 19 was isolated in 91% yield (Table 1, entry 5) after removal of the solvent.Similarly to what observed for the pyrrolidinium compounds derived from L-tartaric acid, 22 the bis(triflyl)amide anion was able to lower the melting point of the ionic material much more efficiently than the tetrafluoroborate or the hexafluorophosphate anions.Ionic liquid 19 was soluble in methanol, ethyl acetate and chloroform, 28 and had an excellent thermal stability, showing no sign of decomposition upon heating at 120 °C for 15 hours.Ionic compound 17, that is solid at r.t. with a mp 146-147 °C, was soluble in water, ethyl acetate and acetone, 28 while 18, that is solid at r.t. with a mp 151-152 °C, showed solubility in ethyl acetate and chloroform. 28n X-ray structure of compound 17 was collected after crystallization from a solution in acetone by slow addition of diisopropyl ether.Crystals of 17 (Figure 1) showed a N-B distance of 4.523 Å within each molecule and no -stacking between the aromatic rings were observed, nor CH- interactions.We then turned to investigate the possibility of introducing a different substituent on the nitrogen atom.(3S)-1-benzyl-3-pyrrolidinol (15) was then subjected to catalytic hydrogenolysis providing pyrrolidinol 20 in quantitative yield (Scheme 3). 27Subsequent alkylation with 1.2 equivalents of n-butyl bromide in CH 3 CN at room temperature in the presence of K 2 CO 3 gave (3S)-1-butyl-3-pyrrolidinol (21) in 69% yield.Quaternization of 21 using 1.5 equivalents of BuBr in acetonitrile at reflux for 4 h afforded the salt 22 in 73% yield, while the reaction under MW heating gave a complex mixture of products.Compound 22 was obtained as a highly hygroscopic white solid, that dissolved immediately in the presence of traces of water.Anion exchange was achieved by reaction of 1 equivalent of LiNTf 2 in water, since this solvent had allowed the best results for the anion exchange of bromide salt 16.Compound 23 was isolated in quantitative yield after extraction with AcOEt and was liquid at room temperature.Ionic liquid 23 was soluble in water, ethyl acetate and chloroform, 28 and had a good thermal stability, showing no appreciable decomposition upon heating at 120 °C for 15 hours.

Conclusions
A facile and straightforward synthesis of six novel ionic compounds having a chiral pyrrolidinium cation derived from (S)-malic acid and several different anions is reported.Two of them were liquid at room temperature, and therefore can be applied as novel reaction media for asymmetric organic reactions or other enantioselective applications.

Experimental Section
General.Commercial reagents were used as received.Rf values refer to thin-layer chromatography (TLC) on 0.25-mm silica gel plates (Merck F254).Melting points were determined on a RCH Kofler apparatus or on a Buchi 510 apparatus and are uncorrected. 1H and 13 C-NMR spectra were recorded on Varian Gemini ( 1 H, 200 MHz) and Varian MERCURY plus ( 1 H, 400 MHz) instruments; the chemical shifts for 1 H and 13 C-NMR spectra are given in ppm relative to TMS at 25 °C, and coupling constants are given in Hz.IR spectra were recorded with a BX FT-IR Perkin-Elmer System spectrophotometer.Mass spectra were recorded with a QMD 1000 Carlo Erba instrument (EI, 70 eV) after direct inlet (relative percentages are given in brackets).Elemental analyses were performed with a Perkin-Elmer 240 C instrument.Small scale microwave-assisted synthesis was carried out in a Microwave apparatus for synthesis CEM Discover with an open reaction vessel and external surface sensor.X-ray data for structure resolution were collected with a Goniometer Oxford Diffraction KM4 Xcalibur2, using Cu/K radiation (40mA/-40KV) at room temperature .
Copies of the data can be obtained, free of charge, from CCDC, 12 Union Road, Cambridge, CB2 1EZ UK (internet://www.ccdc.cam.ac.uk).(3S)-1,1-Dibenzyl-3-hydroxypyrrolidinium hexafluorophosphate (18).To a solution of 16 (0.198g, 0.57 mmol) in 4 mL of water KPF 6 (0.105 g, 0.57 mmol) was added.The mixture was left stirring at room temperature overnight, then it was extracted with AcOEt (3X5mL).After addition of dry Na 2 SO 4 and decantation the organic phase was concentrated under reduced pressure to give 18 (  ) and butyl bromide (1.2 mL, 11.17 mmol, 1.2 equiv.)were added.The mixture was left stirring at room temperature overnight.A TLC control showed the disappearance of the starting material.The mixture was evaporated to dryness and the reside was dissolved in 25 mL of water.After extraction with AcOEt (3X10 mL), the combined organic

Table 1 .
Anion exchange reaction.Synthesis of compounds 17-19 a Mp were given for those salts that are solid at room temperature.