Click Reactions as a Key Step for an Efficient and Selective Synthesis of d-Xylose-Based ILs

d-Xylose-based ionic liquids have been prepared from d-xylose following a five steps reaction sequence, the key step being a click cycloaddition. These ionic liquids (ILs) have been characterized through classical analytical methods (IR, NMR, mass spectroscopy, elemental analysis) and their stability constants, Tg and Tdec, were also determined. Considering their properties and their hydrophilicity, these compounds could be alternative solvents for chemical applications under mild conditions.

Carbohydrates are among the most abundant and low-cost natural sources of chiral materials and represent building blocks of choice for the formation of various compounds with a broad spectrum of applications [35]. The use of ILs as solvents for the transformation of carbohydrates was first reviewed by Linhardt in 2005 [36]. Next, ILs have been shown to exhibit excellent solubilizing properties, facilitating a wide range of chemical transformations, including acetylation, ortho-esterification, benzylidenation and glycosylation reactions of carbohydrates [36][37][38][39][40][41]. Recently, Afonso and Tran discussed respectively the application of ILs in carbohydrate dissolution [42] and the recent developments of ionic liquids in oligosaccharide synthesis [43]. Therefore, sugar-based chiral ionic liquids (CILs) could be used as solvent or catalyst in asymmetric synthesis [44][45][46][47][48] or as chiral phases in gas chromatography [49].

Results and Discussion
For the glycosylation step, treatment of peracetylated D-xylose with propargyl alcohol in the presence of BF 3 ·Et 2 O was used to access the β-propargyl xyloside 1 [77]. This method was preferred because previous trials on D-xylose using the Fisher method [78] with para-toluenesulfonyl acid as catalyst led to a mixture of anomers which are could not be separated, even after acetylation. Cu I -"catalyzed" Huisgen 1,3-dipolar cycloaddition reaction of the modified alkynyl sugar with phenyl or hexyl azide, was carried out in the presence of an excess of Cu I in a homogeneous THF/water mixture (Scheme 1). Several reactions were performed with catalytic and stoichiometric amounts of copper, but led to very poor yields, a part of the copper salt probably being involved in the complexation of the acetate groups. The propargyl xyloside/azide ratio was also optimized after several trials to afford good yields for the cycloaddition adducts.
The excess of Cu salt was removed as [Cu(NH 3 ) 2 (H 2 O) 2 ][SO 4 ] by washing with an ammonia solution. Purification by precipitation with CH 2 Cl 2 /petroleum ether in order to remove the excess of sugar provided compounds 2 and 3 in good yields. The presence of signals at 7.42 ppm and 7.49 ppm for 2 and 3, respectively, in their 1 H-NMR spectrum, unambiguously proved the formation of the triazole ring. The composition of compounds 2 and 3 was further confirmed by 13 C-NMR and elemental analysis. The acetylated benzyl and hexyl compounds 2 and 3 were then deprotected in the presence of sodium methanolate to give the corresponding derivatives 4 and 5 with free hydroxyl groups (Scheme 1). No signals were found for methyl groups or carbonyl carbons in the 1 H-and 13 C-NMR spectra, respectively. This set of derivatives was purified by precipitation.

Scheme 1. Synthesis of ILs 6 and 7.
In line with previous observations, trimethyloxonium tetrafluoroborate (Meerwein's salt) proved to be a very powerful methylating agent (29 equivalents used as described [79]), affording benzyl and hexyl triazolium salts 6 and 7 in good isolated yields in 5 h at room temperature in dry MeCN (Scheme 1). Alternative reaction conditions applied to the hexyl derivative, using methyl iodide (20 equivalents) in dry MeCN under reflux gave improved yields (95%) but required longer reaction times (85 h). The new ILs 6 and 7 were highly soluble in water and in methanol and insoluble in diethyl ether, therefore their purification was done by precipitation of the crude products from MeOH/Et 2 O. The presence of signals around 4.32 ppm in their 1 H-NMR spectrum and at 38.7 ppm in their 13 C-NMR spectrum for the benzyl and hexyl derivatives, respectively, showed the quaternisation of the triazole ring.
In addition of the IR, NMR, elemental analyses and mass spectroscopy, ILs 6 and 7 were characterized by DSC (Table 1) and TGA ( Figure 4). Both compounds are stable until 120 °C and 150 °C, respectively, and showed a slight positive glass transition temperature (Tg). As previously described for tetrabutylammonium galacturonate and glucuronate [58], positive Tg and low decomposition temperature are observed what seems to be in relation with the presence of sugar moities. Considering these temperatures, 6 and 7 could be used only under mild conditions as solvents or chiral agents for chemical transformations or catalysis.  The thermal stability of 6 and 7 was determined by thermogravimetric analysis (TGA) under argon ( Figure 4). The TG curve shows an initial weight loss of 1.33% and 0.76% of water respectively for 6 and 7 between room temperature and 110 °C followed by a second loss of water (3.20% and 3.01%). Such a noticeable mass loss corresponds to the hydroxyl groups. The thermal degradation (Tdec) occurring during the second step gives a loss of F (m/z = 19) fragments by mass spectrometry analysis originating from BF 4 − decomposition.

General Procedures
All reagents were commercially available and used as received. CH 2 Cl 2 was dried over CaH 2 and distilled under argon before use. CH 3 CN was dried using a Pure Solv solvent drying system over aluminum oxide under an argon atmosphere before use. 1

4'
The acetylated compound 2 (170 mg, 0.38 mmol) was dissolved in CH 2 Cl 2 /MeOH 1:1 (v:v) (5 mL) under Ar and NaOMe (61.8 mg, 1.14 mmol) was then added. After stirring for 24 h at room temperature, the mixture was neutralized with Amberlite IR120 and filtered. The organic phase was concentrated to dryness in vacuo. The crude product was dissolved in a minimum of MeOH and precipitated with an excess of diethylether. Compound 4 was obtained as a white solid in 70% yield The corresponding triazole 4 (936 mg, 2.9 mmol) and Me 3 OBF 4 (517 mg, 3.5 mmol) were stirred in dry acetonitrile (40 mL) for 5 h at room temperature. The reaction was quenched with MeOH (10 mL), and the solvent was removed under reduced pressure to give the crude product, which was in a minimum of MeOH and precipitated with excess of diethyl ether. Compound 6 was obtained as a white wax in 23% yield (m = 291 mg 3.2.6. Preparation of 1-((1-Hexyl-3-methyl-1,2,3-triazol-4-yl)methoxy)β-D-xylopyranoside tetrafluoroborate (7) The same procedure as described for compound 6 was followed with the triazole 5 (900 mg, 2.8 mmol) and Me 3 OBF 4 (506 mg, 3.4 mmol) in dry acetonitrile (40 mL

Conclusions
D-Xylose-based ILs have been prepared from D-xylose following an original pathway, the key step being a click cycloaddition. These ILs have been fully characterized and are hydrophilic. After determination of their ecotoxicity and their biodegradability in a near future, these solvents could be used as alternative solvents or chiral agents for synthesis or catalysis in water under mild conditions.