Per-O-acetylation of sugar is a frequently used transform-ation in carbohydrate chemistry as it provides an efficient and cheap means for protecting the hydroxy groups of sugars [ 1 ].Peracetylated sugars are widely used as important and inexpensive building blocks to synthesize biologically important oligosaccharides and oligosaccharides and many bioactive natural products [ 2,3,4,5 ]. Therefore the synthesis of peracetylated sugars is an important topic in the preparation of functional glycoc-onjugates and oligosaccharides [ 6,7 ]. Considerable efforts have been made in the development of efficient and mild strategies for the per-O-acetylation of sugars [ 8,9,10 ].
In general,a large excess of acetic anhydride is routinely used as acylating agent and solvent in the presence of an acidic or basic catalyst,such as pyridine [ 11 ],sodium acetate [ 12 ],H2SO4 [ 13 ],and HClO4 [ 14 ]. Although the above catalysts have been widely applied to prepare peracetylated sugars,many of these are associated with several obvious shortcomings,such as environmental toxicity,unpleasant odour,equipment corr-osion,formation of unwanted side products,and incomp-atibility with carbohydrate derivatives containing acid-labile functional groups.
A variety of Lewis acid catalysts such as InCl3 [ 15 ],In(OTf)3 [ 16 ],ZnCl2 [ 17 ],Fe2(SO4)3 [ 18 ],FeCl3 [ 19 ],Bi(OTf)3 [ 20 ],Sc(OTf)3 [ 21 ],(CH3)3SiOTf [ 22 ],Cu(OTf)3 [ 23 ],Ce(OTf)3 [ 24 ],and BF3∙Et2O [ 25 ] have been introduced for the acid catalyzed per-O-acetylation of sugars. However,these catalysts also suffer from significant drawbacks,such as expensive reagent,long reaction time,harsh reaction conditions,and difficulty in the recovery and reusability of the catalyst. Solid acid catalysts can mitigate these problems as they are inexpensive and allow the straightforward removal of the catalysts from the reaction system [ 31 ].
Recently,molecular I2 has drawn considerable attention as an efficient,mild,and readily available Lewis acid catalyst for various organic reactions [ 32 ]. In 1997,I2 was used successfully for the synthesis of per-O-acetylated sugars in excellent yield with a short reaction time [ 1 ]. However,it is difficult to use I2 because it has good solubility in most organic solvents and easily sublimate at high temperature. In addition,the used I2 in the reaction mixture was not recovered. It was difficult to use I2 in large scale synthesis due to environmental and economic concerns. Therefore,there is a need to find a simple and efficient support for reusable I2 in the per-O-acetylation of sugars.
As a non-conventional energy source,microwave (MW) irradiation leads to a large reduction in reaction time and obvious enhancement in conversion,and has emerged as a useful technology in organic chemistry [ 2 ]. As a part of our continuing interest in improving the practicability and efficiency of MW irradiation technology [ 3 ],we report here a simple,rapid,and scalable strategy for the synthesis of per-O- acetylated sugars catalyzed by I2 in PEG400-based ionic liquid (I2/IL400) under MW irradiation (Scheme 1). IL400 is an appealing polar solvent. It is ambience friendly because it has a high boiling point and has low toxicity and is biodegradable. Interestingly,the IL400 and toluene system gives heterogeneous phases at room temperature,such that the product can be easily recovered from the reaction mixture by simple extraction with toluene while the catalyst I2 remains in IL400 and can be reused in the next cycle. I2 /IL400 can be reused at least six times without significant loss of its catalytic activity. No previous example of a rapid and efficient synthesis of fully acetylated sugars catalyzed by recyclable I2/IL400 has been reported.
All reagents and solvents were obtained from commercial sources and used without further purification. All the per-O- acetylation reactions were carried out in a commercial MW reactor equipped with a stirring bar and were monitored by TLC. The MW bench top reactor (MAS-II) was manufactured by Sineo Microwave Chemistry Technology (Shanghai) Co. IR spectra were obtained using a Fourier transform infrared (FT-IR,4000-400 cm-1) spectrometer (Nicolet Nexus FTIR spectrometer,USA) using 4 cm-1 resolution and 32 scans. Samples were prepared using the KBr disc method. NMR spectra were acquired in CDCl3 on a Bruker DMX-400 spectrometer at 400 MHz for 1H NMR. The chemical shifts were given in δ values from TMS as an internal standard.
The revised route for the preparation of IL400 is outlined in Scheme 2. To a solution of PEG400 (60 mmol) and Et3N (120 mmol) in toluene (200 mL) was added methylsulfonyl chloride (120 mmol) dropwise in 30 min under N2 atmosphere. Then the mixture was stirred at room temperature. After 3 h,the mixture was filtered. The filtrate was added to N-methyli-midazol (120 mmol),and the mixture was stirred at 80 °C for 30 min under MW irradiation (200 W). After the reaction,the ionic liquid layer was separated and washed with petroleum ether (PE,3×10 mL). Evaporation of residual PE under reduced pressure gave the desired pure product IL400 in 90% yield.
To a 10.0 mL round bottom flask,D-glucose (2.0 mmol) and acetic anhydride (12.0 mmol,1.2 equiv. per OH) in the IL400 (2.0 mL) was added I2 (0.05 mmol) at room temperature. Then the mixture was heated to 50 °C under MW irradiation (200 W) until the TLC analysis showed that the reaction was complete. Then the reaction mixture was cooled to room temperature,and toluene (2.0 mL × 3) was added. The mixture was vigor-ously stirred for several minutes and then kept stationary. The upper toluene layer containing the product was collected. Tolu-ene was removed by a rotary evaporator,and the crude prod-uct was purified by recrystallization in ethyl alcohol. The desi-red peracetylated sugars were obtained in 90%-99% yields. The bottom phase was the ionic liquid containing the I2 catalyst and produced acetic acid. The I2/IL400 system was reused after the removal of the acetic acid under reduced pressure.
To a 100 mL round bottom flask,the D-glucose (50 mmol) and acetic anhydride (0.25 mol) in the IL400 (20 mL) were added I2 (0.25 mmol) at room temperature. Then the mixture was heated to 50 °C under MW irradiation (200 W) until the TLC analysis showed that the reaction was complete. The work-up of the reaction mixture was carried out by the same procedure as the model reaction.
In general,IL400 is prepared by nucleophilic substitution between CH3SO2-OPEG400O-SO2CH3 and substituted imidazoles under conventional heating conditions. However,this synthesis method has an obvious disadvantage in that it needed a long reaction time (several hours to 2 d) and harsh reaction condition (> 80 °C).
In this work,a modified method was developed to synth-esize PEG400 imidazolium salt ionic liquid,as depicted in Scheme 2. First,CH3SO2-OPEG400O-SO2CH3 was synthesized by a reaction of HO-PEG400-OH with methanesulfonyl chloride using Et3N as a base in toluene at 0 °C under N2 atmosphere. After completion of the reaction,the white solid byproduct was removed by filtration. Without any purification,the filtrate was added to 1-methylimidazol,the mixture was then heated to 80 °C under MW irradiation (200 W) for 30 min,and the desired IL400 was obtained. Compared to the traditional heating method,the use of MW irradiation dramatically reduced the reaction time. In the synthesis of IL400,the key step was the nucleophilic substitution between CH3SO2-OPEG400O-SO2CH3 and 1- methylimidazol under MW irradiation.
The IL400 was characterized using FT-IR and 1H NMR. Figure 1 shows the FT-IR spectra of PEG400 and IL400. The peaks at 1043 and 1109 cm-1 of IL400 were the characteristic absorption bands of S=O. In the case of IL400,the broad band at 2900 cm-1 can be attributed to the C-H stretching of the -CH2- group,and the peak at 1196 cm-1 was from the C-O stretch in PEG400. The peak at 3107 cm-1 was assigned to C-H stretching of the imidazole ring. The IL400 also exhibited other characteristic absorption bands at 1350 cm-1,which was assigned to the symmetric stretching of -CH3. The peaks at 1537 and 1653 cm-1 which appeared,were related to the band of C=C and C=N,respectively.
The 1H NMR spectrum (not shown) showed the peaks at 9.48,7.67,and 7.52 ppm assigned to Himid. The single peak at 3.99 ppm was assigned to the protons of NCH3. The peaks between 3.88 and 3.55 ppm were due to PEG-H. The single peak at 2.71 ppm was assigned to the protons of -SO2CH3. The results confirmed the successful preparation of IL400.
First,the per-O-acetylation reaction of glucose with acetic anhydride was chosen as a model reaction to screen the catalysts. The reaction was performed under MW irradiation. The per-O-acetylation reaction was simply performed by stirring the mixture of glucose with a slight excess of acetic anhydride (1.2 equiv. per OH),and by using different catalysts in IL400 at 50 °C. The results are summarized in Table 1.
The optimization study revealed that per-O-acetylated glucose was only obtained in 60% yield using acetic anhydride in the absence of a metal salt catalyst at 50 °C after 3 min under MW irradiation. It was also observed that when the per-O- acetylation of glucose was carried out using metal salts catalysts such as Co(OAc)2,FeCl3,Cu(OAc)2,and ZnCl2 under the same condition,per-O-acetylated glucose was prepared in moderate yields (67%-77%). To our delight,after the screening experiment with the target catalyst,that is I2,the reaction occurred the most efficiently and yielded the product in 99% isolated yield. Thus I2 was reasonably chosen as the best catalyst for sugar per-O-acetylation under MW irradiation due to its high efficiency,low toxicity,and easy recyclability.
To optimize the reaction conditions,we first determined the optimum dosage of catalyst. The acetylation of D-glucose was chosen as a model reaction to react with a slight excess of acetic anhydride in the presence of 1.0,3.0,5.0,and 7.0 mol% of I2 in IL400 at 50 °C under MW irradiation. The results are summarized in Table 2. To our delight,thin layer chroma-tography (TLC) showed that the reaction was completed within 3 min in quantitative conversion rate. A 99% isolated yield was obtained when the catalyst amount was 5.0 mol%; it took a longer time (10 min,62%) when the catalyst was used in the amount of 1.0 mol%. Thus,the per-O-acetylation of sugar was performed in the presence of 5 mol% of I2. However,the reaction gave only 60% and 70% yields under I2-free conditions and a conventional heating condition,respectively (entries 8 and 9). The results showed that combining the I2/IL400 catalytic system with the use of microwave irradiation dramatically improved the yield of the reaction.
It is worth mentioning that the reaction mixture was extracted three times with toluene (2.0 mL × 3) and then the obtained toluene solution was titrated with a standard Na2S2O3 solution. It was found that only about 1.5 mg I2existed in the toluene,which was obviously lower than in the I2/IL400 catalytic system (25.4 mg). Thus,this makes the process stable,of low toxicity,and cost effective.
From a practical perspective,the I2/IL400 catalytic system should be used in a wide variety of sugars and sugar alcohols. Thus,with the optimum per-O-acetylation conditions,the substrate scope of the per-O-acetylation reactions between acetic anhydride and various carbohydrate substrates was explored with the I2/IL400 catalytic system (Table 2). The results are summarized in Table 3. The monosaccharides (1a-4a),disaccharides (6a-10a),and sugar alcohols (11a-13a) were peracetylated in excellent yields (90%-99%). Interestingly,saccharide with an acid sensitive protecting group (such as a Schiff base) (5a) can also be peracetylated with high yields (96%). In addition,in the case of reducing sugars,the per-O- acetylation reactions gave a mixture of α- and β-acetate anomers. In all cases,pure products were obtained by a simple extraction with toluene and recrystallization. The configura-tions and ratios of these in Table 3 were determined by 1H NMR spectral analysis (400 MHz). The production of all known compounds gave 1H NMR spectra that matched data reported in the cited references.
The recovery and reusability of the catalyst is a very significant factor for a catalytic process. In order to make the I2/IL400 catalytic system highly efficient and economical,we focused on the reusability of I2/IL400 using the per-O-acetylation of D-glucose and acetic anhydride. Thus,a set of experiments were performed for the per-O-acetylation of D-glucose using a recycled I2/IL400 system. We found that the I2/IL400 system can be easily recovered by extracting the prod-uct with toluene and removing the byproduct acetic acid. After completion of the model reaction in the first run,the product was extracted using toluene,and the I2/IL400 system was easily recovered by removing the acetic acid under reduced pressure without any further purification. Then the I2/IL400 system was subjected to the next reaction cycle with new reactants. As shown in Figure 2,the catalyst can be recycled and reused at least six times without significant loss in product yield (90%-99%).
Peracetylated sugars are important building blocks in carbohydrate chemistry,so it is significant for the per-O-acet-ylation to be performed on the many-gram scale. From the excellent results of the I2/IL400 catalytic system,we set out to further investigate the practicality of the system. To extend this strategy to the many-gram scale synthesis,the scale up synthesis of glucopyranose pentaacetate as a model reaction was investigated. As demonstrated in Table 4,we have shown that glucose was peracetylated on 1,2,and 20 g scales to afford excellent yields. Most importantly,when the scale of the per-O-acetylation of glucose was increased to 50.0 mmol,the per-O-acetylation was found to proceed successfully and glucopyranose pentaacetate was still obtained in 90% yield even after 6 recycles.
In the acetylation,I2 served as an extremely powerful catalyst for the per-O-acetylation of sugars. The initial step was the activation of acetic anhydride by I2 to afford a more active intermediate,which reacted faster with the hydroxyl groups on the sugars. In addition,I2 is also known to absorb microwave energy. Thus,the per-O-acetylation reaction can be completed quickly under I2/IL400 and microwave irradiation conditions.
We have developed a simple,highly efficient,and eco-fri-endly method for the per-O-acetylation of sugars and sugar alcohols using an I2/IL400 catalytic system under MW irradia-tion. The I2/IL400 catalytic system was an environmentally benign and reusable catalyst for the per-O-acetylation of sug-ars. This method gave excellent yields,and the I2/IL400 catalytic system can be reused and recovered at least six times with no loss of catalytic performance. When the scale of the per-O-acet-ylation was increased to 50.0 mmol,the perace-tylated sugar was still obtained in 90% yield after six recycles. This is remarkable and makes the method economically valuable.
2015, Vol. 36 Issue (2): 237-243
PDF (606 KB)
2015, Vol. 36 Issue (2): 237-243
PDF (606 KB)