Ionic Liquid Catalyzed Per- O -Acetylation and Benzylidene Ring-Opening Reaction

: Tunable aryl imidazolium ionic liquids acting as Brønsted acid ionic liquids were found to be e ﬃ cient catalysts for per- O -acetylation and reductive ring opening of benzylidene acetals. This method requires a truly catalytic amount of the least expensive available ionic liquids that are water-stable and reusable and also stable at room temperature. The reactions were obtained in one hour with good to excellent yields. These reactions can form C − O and C − H bonds with a high atom economy. Furthermore, the ionic liquid is an anomeric selective catalyst in per- O -acetylation and reductive ring opening of benzylidene acetals of sugar moieties. were obtained from good-value sources and were nor puriﬁed unless otherwise mentioned. Flash column chromatography was enforced to Silica Gel 60. Thin-layer chromatography (TLC) was performed on precoated glass plates of Silica Gel 60 F254 disclosure was accomplished by spraying with a solution of Ce(NH 4 ) 2 (NO 3 ) 6 (0.5 g), (NH 4 ) 6 Mo 7 O 24 (24.0 g) and H 2 SO 4 (28.0 mL) in water (500.0 mL) and heating on a hot plate. Optical rotations were measured at 589 nm (Na), 1 H and 13 C NMR were recorded with 400 MHz instruments. Chemical shifts are in ppm from Me 4 Si generated from the CDCl 3 lock signal at δ 7.26. Infrared spectra were taken with a Fourier transform infrared (FT-IR) spectrometer using NaCl plates. Mass spectra were analyzed on an instrument with an ESI source.


Introduction
Regioselectively functionalized carbohydrates have recently become an important development in glycochemistry and glycobiology. Sugar molecules consist of several hydroxyl groups that are difficult to employ selectively as they have similar reactivity profiles. Therefore, methodologies that accomplish potent protection and selective alteration of monosaccharides are fundamental synthetic appliances in organic chemistry [1]. The use of distinctive hydroxyl groups in selective protection of carbohydrate molecules is a key step in the chemical synthesis of complex carbohydrates. Per-O-acetylation of sugars is an essential intermediate in carbohydrate transformation and synthesis [2]. In this respect, the ring-opening of cyclic benzylidene acetals comparable to O-benzyl ethers, in a regioselective aspect, is a favorable path owing to the ease of formation of the acetal, as well as the well-established quality of the benzyl ether protection [3]. One major and important transformation in carbohydrate chemistry is the acetylation of monosaccharides. In particular, per-acetylated carbohydrates are imperative and convenient intermediates in the chemical synthesis of complex carbohydrates, particularly for chemical glycosylation. Per-O-acetylated sugars can be employed directly as glycosylation donors [4,5]. Per-O-acetylation is one of the most commonly utilized reactions in carbohydrates, mainly for primary protection of sugars. The acetylation reaction is commonly performed using acetic anhydride as the reagent and an array of catalysts. However, the surplus of acetic anhydride as a solvent causes tedious work in the neutralization process. A ring conformation that can fix benzylidene acetals Selective per-O-acetylation of D-glucose (1a) was explored as a model compound. Treatment of compound 1a with acetic anhydride (10 equiv.) in the presence of ionic liquid Ia (0.1 equiv.) at room temperature proceeded to completion of the reaction in one hour (Table1, entry 1). Under these conditions, the product 1,2,3,4,6-penta-O-acetyl-D-glucopyranoside (2a) was obtained in 99% yield respectively. Subsequently, ionic liquids Ib, Id, Ie, and If (Scheme 1) were investigated in this transformation. Under the same conditions as described above, these catalysts provided per-Oacetylation 2a in good to excellent yields (Table 1, entry 2, 4, 5, and 6). However, Ic did not proceed with the reaction smoothly, and achieved a 29% yield of 2a (Table 1, entry 3), because of the weak acidity of the Ic.

Results and Discussion
Selective per-O-acetylation of d-glucose (1a) was explored as a model compound. Treatment of compound 1a with acetic anhydride (10 equiv.) in the presence of ionic liquid Ia (0.1 equiv.) at room temperature proceeded to completion of the reaction in one hour (Table 1, entry 1). Under these conditions, the product 1,2,3,4,6-penta-O-acetyl-d-glucopyranoside (2a) was obtained in 99% yield respectively. Subsequently, ionic liquids Ib, Id, Ie, and If (Scheme 1) were investigated in this transformation. Under the same conditions as described above, these catalysts provided per-O-acetylation 2a in good to excellent yields (Table 1, entry 2, 4, 5, and 6). However, Ic did not proceed with the reaction smoothly, and achieved a 29% yield of 2a (Table 1, entry 3), because of the weak acidity of the Ic.

Per-O-Acetylation
The study of the ionic liquid suggested that Ia was the best catalyst for the per-O-acetylation reaction, providing 2a in excellent yield. The reaction was routinely monitored using TLC and produced 2a after applying purification compounds. Based on these preliminary results, the acetic anhydride loading was explored. To determine the minimum amount of acetyl reagent required, we used 7.5 equivalents and 6.0 equivalents of acetic anhydride with ionic liquid for 24 h (Table 1, entry 10). Increasing the temperature to 80 • C resulted in the formation of selective 2a in an isolated yield of 92% in very short reaction time (Table 1, entry 11). acetylation 2a in good to excellent yields (Table 1, entry 2, 4, 5, and 6). However, Ic did not proceed with the reaction smoothly, and achieved a 29% yield of 2a (Table 1, entry 3), because of the weak acidity of the Ic. The scope, limitations, and generality of the method were explored. Table 1 shows the per-O-acetylation of other important d-hexoses 1b-1d, d-pentose 1e, and disaccharide 1f under this set of optimized conditions. d-galactose 1b readily provided the corresponding penta-acetate 2b quantitatively ( Table 2, entry 1), whereas d-mannose 1c afforded product 2c in excellent yield 93% ( Table 2, entry 2). Reducing the equivalent of acetic anhydride to 4.8 equivalents led to a similar result in the case of methyl glucopyranoside 1d, and the expected compound 2d was isolated in 99% yield ( Table 2, entry 3). Equally, d-xylose 1e led to exclusive formation of the corresponding product 2e in 97% yield (Table 2, entry 4) and increasing the equivalent of acetic anhydride, the substrate 2f produced compound 1f in 96% yield ( Table 2, entry 5), respectively.

Reusability of TAIIL for Per-O-Acetylation of D-Glucose
The anticipation of ionic liquid as a solvent replacement, especially on broad proportion application, counts on the usage of potent recycling to help blunt costs and curtail their environmental impact. In the reaction of 1a with acetic anhydride in the presence of Ia to form 2a.
After the filtration of the reaction mixture and the extraction of the product with ethyl acetate for ionic liquid, the ILs were concentrated, dried under a high vacuum, and reused. Figure 1 shows five

Reusability of TAIIL for Per-O-Acetylation of d-Glucose
The anticipation of ionic liquid as a solvent replacement, especially on broad proportion application, counts on the usage of potent recycling to help blunt costs and curtail their environmental impact. In the reaction of 1a with acetic anhydride in the presence of Ia to form 2a. After the filtration of the reaction mixture and the extraction of the product with ethyl acetate for ionic liquid, the ILs were concentrated, dried under a high vacuum, and reused. Figure 1 shows five cycles of the acetylation in ILs that are recovered and reused for further per-O-acetylation reactions. No significant loss of activity of these products was observed (91-99%). After reuse of ionic liquid Ia, 19 F NMR confirmed that ionic liquid remains in the aqueous phase.

Reusability of TAIIL for Per-O-Acetylation of D-Glucose
The anticipation of ionic liquid as a solvent replacement, especially on broad proportion application, counts on the usage of potent recycling to help blunt costs and curtail their environmental impact. In the reaction of 1a with acetic anhydride in the presence of Ia to form 2a.
After the filtration of the reaction mixture and the extraction of the product with ethyl acetate for ionic liquid, the ILs were concentrated, dried under a high vacuum, and reused. Figure 1 shows five cycles of the acetylation in ILs that are recovered and reused for further per-O-acetylation reactions. No significant loss of activity of these products was observed (91-99%). After reuse of ionic liquid Ia, 19 F NMR confirmed that ionic liquid remains in the aqueous phase. The plausible mechanism (Scheme 2) of the reaction appears to be through the acylium intermediate formed by the reaction of Ionic liquid and Ac2O. The acylium intermediate would be

Reductive Ring Opening of Benzylidene Acetals
This investigation reports a systematic screen of selected ionic liquids (Ia−If, Scheme 1) as catalysts for a regioselective ring opening of benzylidene acetals at the O-4 position of hexopyranosides. Those ionic liquid catalysts have, to our knowledge, not previously been utilized in this transformation. The reaction conditions using the best ionic liquid catalysts were optimized to provide a robust and reliable procedure. The O-4 selective ring-opening reaction was selected for optimization. Initially, sugar 3a was accepted as an excellent substrate. Firstly, 3a with ionic liquid, Ia (1.0 equiv.), and triethylsilane (10.0 equiv.) were used in dichloromethane (DCM) at room temperature. The expected product 4a was assembled, then the reaction mixture was treated with tetra-n-butyl ammonium fluoride (TBAF, 11.0 equiv.) and acetic acid (AcOH, 11.0 equiv.) at room temperature for one hour, providing 4a in 78% yield (Table 3, entry 1). Screening results of ionic Scheme 2. A plausible mechanism of the per-O-acetylation reaction.

Reductive Ring Opening of Benzylidene Acetals
This investigation reports a systematic screen of selected ionic liquids (Ia-If, Scheme 1) as catalysts for a regioselective ring opening of benzylidene acetals at the O-4 position of hexopyranosides. Those ionic liquid catalysts have, to our knowledge, not previously been utilized in this transformation. The reaction conditions using the best ionic liquid catalysts were optimized to provide a robust and reliable procedure. The O-4 selective ring-opening reaction was selected for optimization. Initially, sugar 3a was accepted as an excellent substrate. Firstly, 3a with ionic liquid, Ia (1.0 equiv.), and triethylsilane (10.0 equiv.) were used in dichloromethane (DCM) at room temperature. The expected product 4a was assembled, then the reaction mixture was treated with tetra-n-butyl ammonium fluoride (TBAF, 11.0 equiv.) and acetic acid (AcOH, 11.0 equiv.) at room temperature for one hour, providing 4a in 78% yield (Table 3, entry 1). Screening results of ionic liquids (Table 3, entry 2−6) indicated that Ia was superior to Ib-If, probably due to weak acidity of ionic liquid Ib-If. hexopyranosides. Those ionic liquid catalysts have, to our knowledge, not previously been utilized in this transformation. The reaction conditions using the best ionic liquid catalysts were optimized to provide a robust and reliable procedure. The O-4 selective ring-opening reaction was selected for optimization. Initially, sugar 3a was accepted as an excellent substrate. Firstly, 3a with ionic liquid, Ia (1.0 equiv.), and triethylsilane (10.0 equiv.) were used in dichloromethane (DCM) at room temperature. The expected product 4a was assembled, then the reaction mixture was treated with tetra-n-butyl ammonium fluoride (TBAF, 11.0 equiv.) and acetic acid (AcOH, 11.0 equiv.) at room temperature for one hour, providing 4a in 78% yield (Table 3, entry 1). Screening results of ionic liquids (Table 3, entry 2−6) indicated that Ia was superior to Ib-If, probably due to weak acidity of ionic liquid Ib−If.

Entry
Solvent IL (eq) t (h) P (Yield) a 1 DCM The yields are isolated yields.
Performing the reaction with ACN as the solvent yielded 88% of the product 4a (Table 3, entry 7). Decreasing the ionic liquid catalyst to 0.5 and 0.25 equivalents yielded product 4a in 90% and 77% yield respectively (Table 3, entry 8-9).
The optimized conditions were examined. Thus, compounds commonly used in carbohydrate chemistry with different protection groups were tested in this transformation. As indicated in (Table 4, entry 1), the corresponding product 4b was obtained in excellent yield after increasing reaction time. Under the same optimized condition, 3c was transformed into 4c as the only product (Table 4, entry 2). In the subsequent reaction, with a longer reaction time of 8h, 3d was converted into 4d with a 72% yield (Table 4, entry 3). However, the reaction of 3e afforded 4e as the final compound in good yield (Table 4, entry 4). . Decreasing the ionic liquid catalyst to 0.5 and 0.25 equivalents yielded product 4a in 90% and 77% yield respectively (Table 3, entry 8-9).
The optimized conditions were examined. Thus, compounds commonly used in carbohydrate chemistry with different protection groups were tested in this transformation. As indicated in (Table  4, entry 1), the corresponding product 4b was obtained in excellent yield after increasing reaction time. Under the same optimized condition, 3c was transformed into 4c as the only product (Table 4, entry 2). In the subsequent reaction, with a longer reaction time of 8h, 3d was converted into 4d with a 72% yield (Table 4, entry 3). However, the reaction of 3e afforded 4e as the final compound in good yield (Table 4, entry 4). The plausible mechanism (Scheme 3) shows that acetals oxygen (O-4) 3 abstract a proton from ionic liquid Ia to form the intermediate 3', which should then have converted to intermediate a. Then, the addition of Et 3 SiH to form the 3a. Finally, the treatment of tetra-n-butylammonium fluoride (TBAF) and acetic acid with a' to obtain the desired product 4, with the removal of triethylsilyl fluoride (TESF).
The plausible mechanism (Scheme 3) shows that acetals oxygen (O-4) 1 abstract a proton from ionic liquid Ia to form the intermediate 2, which should then have converted to intermediate 3. Then, the addition of Et3SiH to form the 3a. Finally, the treatment of tetra-n-butylammonium fluoride (TBAF) and acetic acid with 3a to obtain the desired product 4, with the removal of triethylsilyl fluoride (TESF).

Scheme 3.
A plausible mechanism of the benzylidene ring-opening reaction.

Synthesis of Ionic Liquid
The preparation of ionic liquids Ia-If (Scheme 4) is described below. Ionic liquids Ia-If were synthesized in two steps. The first step is the Ullmann-type coupling reaction: a combination of imidazole A and 1-iodo-4-nitrobenzene B in the presence of 10 mol % copper(II) acetate and cesium carbonate gave aryl imidazole C1, C2, C3, C4 in 74%, 80%, 76%, and 88% yields respectively. In the second step, the aryl imidazole C1, C2, C3, C4 was dissolved in ethanol and treated with triflic acid, methane sulfonic acid, or trifluoroacetic acid in an ice bath to yield acidic ionic liquids Ia−If. For the characterization of ionic liquids, we check the Hammett acidity function using crystal violet dye as a reacting dye to check the acidity of ionic liquid Ia−If (See Supplementary Materials).

Scheme 3.
A plausible mechanism of the benzylidene ring-opening reaction.

Synthesis of Ionic Liquid
The preparation of ionic liquids Ia-If (Scheme 4) is described below. Ionic liquids Ia-If were synthesized in two steps. The first step is the Ullmann-type coupling reaction: a combination of imidazole A and 1-iodo-4-nitrobenzene B in the presence of 10 mol % copper(II) acetate and cesium carbonate gave aryl imidazole C 1 , C 2 , C 3 , C 4 in 74%, 80%, 76%, and 88% yields respectively. In the second step, the aryl imidazole C 1 , C 2 , C 3 , C 4 was dissolved in ethanol and treated with triflic acid, methane sulfonic acid, or trifluoroacetic acid in an ice bath to yield acidic ionic liquids Ia-If.

General Procedure
To a solution of C1, C2, C3, C4 (1 equiv.) and triflic acid, trifluoro methanesulfonic acid, and trifluoroacetic acid (2 equiv.) in ethanol (0.5 ml/mmol). The reaction mixture was stirred for two hours in an ice bath. The solvent was dried and the reaction mixture was washed with ether several times. The solvent was dried to give Ia-Ic as a yellow solid and Id−If as a white solid.

General Procedure
To a solution of C 1 , C 2 , C 3 , C 4 (1 equiv.) and triflic acid, trifluoro methanesulfonic acid, and trifluoroacetic acid (2 equiv.) in ethanol (0.5 mL/mmol). The reaction mixture was stirred for two hours in an ice bath. The solvent was dried and the reaction mixture was washed with ether several times. The solvent was dried to give Ia-Ic as a yellow solid and Id-If as a white solid.

General Information
The reactions were conducted in flame-dried glassware, beneath the N 2 atmosphere. Acetonitrile and dichloromethane were refined and dried from a secure purification system containing activated Al 2 O 3 . All reagents were obtained from good-value sources and were nor purified unless otherwise mentioned. Flash column chromatography was enforced to Silica Gel 60. Thin-layer chromatography (TLC) was performed on precoated glass plates of Silica Gel 60 F254 disclosure was accomplished by spraying with a solution of Ce(NH 4 ) 2 (NO 3 ) 6 (0.5 g), (NH 4 ) 6 Mo 7 O 24 (24.0 g) and H 2 SO 4 (28.0 mL) in water (500.0 mL) and heating on a hot plate. Optical rotations were measured at 589 nm (Na), 1 H and 13 C NMR were recorded with 400 MHz instruments. Chemical shifts are in ppm from Me 4 Si generated from the CDCl 3 lock signal at δ 7.26. Infrared spectra were taken with a Fourier transform infrared (FT-IR) spectrometer using NaCl plates. Mass spectra were analyzed on an instrument with an ESI source. . To a solution of compound 3c (100 mg, 0.27 mmol) and acetonitrile (1 mL), were added triethylsilane (431 µL, 2.7 mmol) and ionic liquid Ia (47 mg, 0.14 mmol) in the sealed tube. After stirring for one hour at 25 • C, the reaction mixture was added 1 M tetra-n-butylammonium fluoride (TBAF, 3 mL, 3 mmol) and acetic acid (171 µL, 3 mmol) for one hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous MgSO 4 , filtered, and concentrated. The residue was purified by chromatography to afford desired product 4c (88 mg, 88%) as yellow liquid.

Conclusions
In summary, the Brønsted-Lowry acidic ionic liquid is a particularly economical catalyst for per-O-acetylation and ring-opening reactions of sugars. This approached lacks the completely catalytic amount of the least costly accessible ionic liquid that is water-stable. However, the per-O-acetylation reactions were conducted under solvent-free conditions, employing a ratio load of acetic anhydride that grants an efficient per-O-acetylation reaction of hexoses, and also allows reductive ring opening of benzylidene acetals reactions to take place very evenly. We are still working on the reusability of the reductive ring opening of benzylidene acetals. The reaction conditions are mild, convenient, and nonhazardous for the above reactions.