Ionic liquids as phase transfer catalysts: Enhancing the biphasic extractive epoxidation reaction for the selective synthesis of β-O-glycosides

Article abstract of DOI:10.1016/j.tetlet.2017.08.033

Ionic liquids promoted the direct epoxidation of glycals acting as PTC. 1,2-anhydrosugars were prepared by the oxidation of glycals under biphasic conditions with dimethydioxirane generated in situ from oxone/acetone and amphiphilic IL's as catalysts. β-O

Full text of DOI:10.1016/j.tetlet.2017.08.033

Accepted Manuscript
Ionic liquids as phase transfer catalysts: enhancing the biphasic extractive ep-
oxidation reaction for the selective synthesis of β-O-glycosides
Cintia C. Santiago, Leticia Lafuente, Rodolfo Bravo, Gisela Díaz, Agustín
Ponzinibbio
PII:
S0040-4039(17)31031-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.033
TETL 49223
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
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12 July 2017
11 August 2017
13 August 2017
Please cite this article as: Santiago, C.C., Lafuente, L., Bravo, R., Díaz, G., Ponzinibbio, A., Ionic liquids as phase
transfer catalysts: enhancing the biphasic extractive epoxidation reaction for the selective synthesis of β-O-
glycosides, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.033
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Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Ionic liquids as phase transfer catalysts: enhancing the biphasic extractive
epoxidation reaction for the selective synthesis of β-O-glycosides
Cintia C. Santiagoa, Leticia Lafuentea, Rodolfo Bravo, Gisela Díaza and Agustín Ponzinibbioa
a Laboratorio de Estudio de Compuestos Orgánicos (LADECOR), Departamento de Química, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ionic liquids promoted the direct epoxidation of glycals acting as PTC. 1,2-
anhydrosugars were prepared by the oxidation of glycals under biphasic
conditions with dimethydioxirane generated in situ from oxone/acetone and
amphiphilic IL´s as catalysts. β-O-glycosides were synthesized in good yields by
the nucleophilic ring opening of epoxy carbohydrate derivatives. Also, 3, 4, 6-
benzyl protected carbohydrates and -N-glycosides could be prepare by this
method.
Available online
Keywords:
Ionic liquids
Phase transfer catalysis
β-O-glycosides
Oxone
2017 Elsevier Ltd. All rights reserved.
Epoxidation
Epoxides are important organic intermediates due to their high reactivity. The nucleophilic ring opening reaction
takes place with high stereocontrol leading selectively to pure products.1-3 Commonly, the oxidation of alkenes to
afford epoxides was achieved with organic peracids and peroxy acids, but lately dioxiranes have been used as new
oxidizing agents.
Dimethyldioxirane (DMDO) is commercially available in low concentration and unstable solutions, nevertheless
it can be prepared in situ by the oxidation of acetone with oxone.4-6 The complete epoxidation methodology often
requires an efficient interchange of species between the organic phase where main substrates are dissolved and the
aqueous media. Phase transfer catalysts (PTC) become irreplaceable reactants for the occurrence of biphasic
reactions. Ionic liquids can be designed and synthesized on demand incorporating different active moieties.
Molecules with amphiphilic structures are often used in organic synthesis to facilitate reactions between organic
reactants and ionic inorganic salts, recently some IL´s were tested as PTC.7-10
In the last years, there has been sustained interest in the selective synthesis of β-glycosides. The synthesis of 1,2-
anhydrosugars and the subsequent nucleophilic ring opening reaction is a promising methodology to achieve this
desired carbohydrate derivatives. Despite some techniques were developed and many synthetic efforts were made,
there is still a demand for green methods in the selective synthesis of 2-hydroxy-glycosides.11-13
For several years, we have been interested in the synthesis of carbohydrate derivatives. In our laboratory,
different methods were applied to the synthesis of C-, O- and N-glycosides with promising biological activity as
antiproliferative agents or enzymatic inhibitors.14 In view of our ongoing efforts to develop new environmentally
friendly catalytic processes, we decided to investigate the use of ionic liquids as phase transfer catalyst for biphasic
synthesis of 1,2-anhydrosugars and 2-hydroxy-glycosides.
As previously stated, eco-friendly ionic liquids as promoters and catalyst represent an interesting alternative in
organic synthesis developments. To study in detail the use of ILs in epoxidation reactions, we tested a series of ILs

with alkyl substituents on the quaternary cation. The ILs were prepared with excellent yields using a one-pot
solventless methodology. 15
At first, we studied the cyclohexene oxidation in different ways to optimize the reaction conditions. The method
includes a ketone -acetone-, and a peracid -potassium peroxymonosulphate (KHSO5)- commercially available as
Oxone (2KHSO5.KHSO4.K2SO4). The well known mechanism indicates that KHSO5 is the oxidizing agent and
acetone acts as catalyst.4 Despite many applications have been reported, major problems are, low conversions and
yields of the corresponding dioxirane and their subsequent alkene oxidation. To compile accurate information, we
divided the preliminary experiments in three different systems: 1) epoxidation with KHSO5 and acetone in aqueous
media, 2) epoxidation with KHSO5, acetone and biphasic media (water/dichloromethane), 3) epoxidation with
KHSO5, acetone, biphasic media and a IL as a phase transfer catalyst (1-butyl-3-methylimidazolium
tetrafluoroborate, BMImBF4).
Table 1. Epoxidation of cyclohexene in three different media.
System % Conversion
1
2
3
50
69
91
By comparing the results obtained, it could be concluded that the use of PTC is essential to enhance the reaction
performance. In system 1, KHSO5 was used as an aqueous solution, dimethyldioxirane (DMDO) produced from
acetone and the peracid in the basic aqueous phase reacts with cyclohexene in the organic media and at the interface
of cyclohexene/KHSO5. When a solvent is added to the system (case 2), acetone can be dissolved in both aqueous
and dichloromethane phases, for this reason DMDO can be formed in the aqueous solution and in the interface. The
presence of CH2Cl2 facilitates the migration of DMDO to the organic phase where cyclohexene was oxidized, so the
yields are higher. It´s a typical extractive reaction process. Finally, system 3 is also an extractive process but with
better efficiency. The DMDO could be formed and transfer to the organic phase easily and faster. The peracid
forms a salt with the organic cation of PTC. This salt moves to the dichloromethane phase and oxidized the acetone
to produce the desired DMDO. (Figure 1)
Figure 1. Oxidation of cyclohexene by DMDO in biphasic media.
Then we screened imidazolium ILs with different alkyl substitutes and anions. As expected ILs with BF4- anion
-
acts more efficiently in the interchange of peracid (-HSO5) between the phases. It´s well known that ILs with PF6
anions are barely soluble in water, therefore their capacity to transfer ions from the aqueous to the organic phase is
lower. Increasing the length of the N-alkyl substituent in the imidazolium cation represents an improvement in the
amphiphilic character of the molecule. Therefore, 1-dodecyl-3-methylimidazolium tetrafluoroborate (DodMImBF4)
represents the best choice to enhance the formation and reactivity of DMDO in the dichloromethane phase.

Considering the promising results obtained we tried to extrapolate this methodology to the biphasic epoxidation
of endo-glycals since the nucleophilic ring opening of the 1,2-anhydrosugars leads to biologically relevant -
glycosides.
Thus, we performed and analyzed the model tandem reaction of biphasic oxidation of 3,4,6-tri-O-benzyl-D-
glucal with DMDO, generated in situ, using several ILs as PTC, and the subsequent MeOH addition to generate
more stable 2-hydroxy-OMe- glycosides. The experiments to test the efficiency of ILs as PTC are shown in Table
2.
Table 2. Epoxidation of TOBnGlu using different IL as PTC.
Entry
PTC
Time of epoxidation step (h)
Yield (%)
5%
1
2
3
4
5
6
BMImBF4
BMImPF6
HMImBF4
HMImPF6
DodMImBF4
DodMImPF6
12
12
12
12
3
5%
40%
10%
70%
15%
12
Room temperature, slightly basic aqueous solution, dichloromethane, intense magnetic stirring (700 rpm) and IL
as PTC to accelerate the exchange of reactive species between phases conforms the method proposed as described
in detail in the experimental section. Very good yields and high  selective products were obtained, after column
chromatography purification, as confirmed by NMR analysis.16
With the method optimized a variety of nucleophilic alcohols were tested for the scope and specificity of the
system (Table 3). With less hindered alcohols the yields were better than ones bearing a secondary or tertiary -OH
group. Comparing the substrate influence, glycals derived from D-glucose and D-galactose were tested, the yields
obtained were similar, regardless of the C4 configuration.

Table 3. Reactions of 1,2-anhydro-3,4,6-tri-O-benzyl-β-D-glucopyranoside with several nucleophiles.a
Yield
Entry
Glycal
Alcohol
Product
(%)b
1
MeOH
70
2
3
EtOH
75
64
iPrOH
4
BnOH
MeOH
60
77
5
6
7
EtOH
73
65
iPrOH
8
BnOH
60
a Reagents and conditions: i) Oxone (2 equiv.), acetone, DodMImBF4 (0.1 equiv.), NaHCO3, H2O, CH2Cl2 ii) Alcohol, rt
b Yields calculated after purification by column chromatography.
In all cases, excellent to very good yields were obtained. The anomeric selectivity was studied by the analysis of
1H NMR spectra. As expected, due to the anti nucleophilic opening of the α-epoxide generated by oxidation of
TOBnGlu by DMDO, all β- configuration products were obtained, deducted by the chemical shifts and coupling
constants of the anomeric proton.
During preliminary studies, it was detected in some cases that 1,2 diols were obtained, presumably due to the
nucleophilic attack of H2O after the oxidation reaction. Especially for non-imidazolium IL´s such as BPyBF4 and
trihexyl(tetradecyl)phosphonium dicyanamide (Cyphos 105). An endeavor to expand the scope was done to
synthesize sugar derived 1,2 diols. Carbohydrate derivatives with selective protection of their multiple -OH groups
are useful intermediates in glycoside synthetic chemistry.17 As seen in Table 4, BuPyBF4 and Cyphos 105 are
effective catalyst for the transformation of protected glycals into their corresponded 1,2 diols in moderate yields.
NMR analysis indicates that the stereochemistry at C2 is equatorial in every case, nevertheless anomeric mixtures
of the diols were obtained (anomeric ratio α/β 1.5:1 in all cases).18

Table 4. Synthesis of 1,2 diols from glycals via DMDO oxidation.a
Yield
(%)b
Entry
Glycal
IL
Product
1
BuPyBF4
70
75
77
2
3
Cyphos 105
BuPyBF4
4
Cyphos 105
45
a Reagents and conditions: i) Oxone (2 equiv.), acetone, IL (0.1 equiv.), NaHCO3, H2O, CH2Cl2 0° C to rt
b Yields calculated after purification by column chromatography.
Finally, we studied the selectivity towards different nucleophilic moieties in the reagents. An interesting result
was achieved when ethanolamine was used as nucleophile. A -N-glycoside was obtained after 6 hours through a
regio- and stereoselective ring opening reaction in good yields and enantiopure form (Figure 2).
Figure 2. Nucleophilic attack of 1,2-anhydroglycal with ethanolamine.
The complete analysis by 1H, 13C NMR and gHSQC, gCOSY and NOESY experiments confirm the selectivity
of the product formed.19
In summary, the use of amphiphilic IL´s as PTC in the oxidation of benzyl protected glycals conforms a simple,
rapid and efficient method to the synthesis of β-O-2-hydroxyglycosides, current building blocks of biologically
active molecules. Moreover, under certain reaction conditions 1,2 unprotected carbohydrates could be prepared.
Further work expanding on the scope of the substrates and on the suitability of the protocol to prepare -N-
glycosides are under way in our laboratory.
Acknowledgments

Authors wish to thank Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA),
UNLP and CONICET for their financial support to the present work.
References and notes
1. Cerny, M. In Advances in Carbohydrate Chemistry and Biochemistry, Baker, D. C.; Horton, D., Eds, Academic Press, London, 2003,
Vol. 58, pp. 121-198.
2. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc, 1989, 111, 6661-6666.
3. Liu, K. K. C.; Danishefsky, S.J. J. Org. Chem., 1994, 59, 1895-1897.
4. O´Connell, A.; Smyth, T.; Benjamin, K. Catal. Today, 1996, 32, 273-278
5. Kachasakul, P.; Assabumrungrat, S.; Praserthdam P.; Pancharoen U. Chem. Eng. J. 2003, 92, 131-139.
6. Alavi Nikje, M. M.; Mozaffari, Z. Des. Mon. Polym. 2007, 10, 67-77.
7. Muthusamy, S.; Gnanaprakasam, B., Tetrahedron Lett., 2005, 46, 635-638
8. Okamoto, S.; Takano, K.; Ishikawa, T.; Ishigami, S.; Tsuhako, A. Tetrahedron Lett., 2006, 47, 8055-8058.
9. Cokoja, M.; Reich, R. M.; Wilhelm, M. E.; Kaposi, M.; Schaffer, J.; Morris, D. S.; Mìnchmeyer, C. J.; Anthofer, M. H.; Markovits,
I. I. E.; Kìhn, F. E.; Herrmann, W. A.; Jess, A. E.; Love, J. B. ChemSusChem, 2016, 9, 1773-1776.
10. Kumar, V.; Talisman, I. J.; Bukhari, O.; Razzaghy, J.; Malhorta. S. V. RSC Adv., 2011, 1, 1721-1727.
11. Sanhueza, C. A.; Mayato, C.; Machin, R. P.; Padron, J. M.; Dorta, R. L.; Vazquez, J. T. Bioorg. Med. Chem. Lett., 2007, 17, 3676-
3681.
12. Shaffer, K. J.; Taylor, C. M. Org. Lett., 2006, 8, 18, 3959-3962.
13. Kim, J-Y.; Di Bussolo, V.; Gin, D. Y., Org. Lett., 2001, 3, 2, 303-306.
14. Lafuente, L.; Díaz, G.; Bravo, R.; Ponzinibbio, A. Lett. Org. Chem., 2016, 13, 3, 195-200; b. Díaz, G.; Ponzinibbio, A.; Bravo, R.D.;
Carbohydr. Res., 2014, 393, 23-25; c. Díaz, G.; Ponzinibbio, A.; Bravo, R.D. Top. Catal., 2012, 55, 644-648; d. Tasca, J.E.,
Ponzinibbio, A., Diaz, G. Bravo, R.D., Lavat, A. González, M.G., Top. Catal., 2010, 53, 1087-1090; e. Ponzinibbio, A. Colinas,
P.A., Lieberknecht, A., Bravo, R.D., Lett. Org. Chem., 2006, 3, 6, 459-462; f. Colinas, P.A., Ponzinibbio, A., Lieberknecht, A.,
Bravo, R.D, Tetrahedron Lett., 2003, 44, 43, 7985-7988.
15. 1-dodecyl-3-methylimidazolium tetrafluoroborate. Anhydrous sodium tetrafluoroborate (15.30 g, 0.14 mol), 1-methylimidazole (11.5
ml, 0.14 mol) and 1-bromododecane (33.55 ml, 0.14 mol) were placed in a round bottom flask equipped with a reflux condenser. The
mixture was stirred at 80°C for 4 hs, under inert atmosphere. The resultant suspension was diluted with 25.0 ml of acetonitrile and
then filtered. After the solvent was removed under reduce pressure, the ionic liquid was dried at 80°C in vacuo (0,02 torr) for 6 hs to
1
obtained a light yellow semi-solid product (yield=97%). H NMR (500 MHz, CDCl3): δ 8.97 (s, 1 H, H-2), 7.42 (s, 1 H, H-4), 7.34
(s, 1 H, H-3), 4.14 (t, J = 7.78 Hz, 2 H, H-5), 3.91 (s, 3 H, H-1), 1.81 (broad t, 2 H, H-6), 1.25-1.18 (m, 18 H, H7-15), 0.81 (t, J= 7.28
Hz, 3 H, H-16). 13C NMR (125 MHz, CDCl3): δ 136.20 (C2), 123.79 (C3), 122.13 (C4), 49.96 (C5), 36.22 (C1), 31.83 (C6), 30.07,
29.55, 29.53, 29.47, 29.34, 29.26, 28.93, 26.16, 22.60 (C7-C15), 14.04 (C16).
16. Ionic liquid (10% mmol) and 3,4,6-tri-O-benzyl-D-glucal (200 mg, 0.48 mmol) were placed in a round-bottomed flask and dissolved
in 2.0 ml of dichloromethane, then were added acetone (0.8 ml) and saturated NaHCO3 aqueous solution (1.5 ml). To this vigorously
stirred biphasic mixture was added dropwise a solution of oxone (600 mg, 0.9760 mmol in 2.5 ml of water) at 0°C for 15 minutes,
maintaining the temperature 20 minutes more. After completion of the reaction, the mixture was extracted with dichloromethane (5 x
2.0 ml) and the combined organic phases were dried over sodium sulphate (Na2SO4). After filtration, the solvent was evaporated and
the residue was immediately dissolved in anhydrous methanol (5.0 ml) and stirred for 12 hs at room temperature. This solution was
concentrated under reduced pressure and the residue was purified by column chromatography to obtain pure methyl 3,4,6-tri-O-
benzyl--D-glucopyranoside. 1H NMR (300 MHz, CCl3D): δ 7.38-7.15 (m, 15 H, 3 C6H5), 4.94-4.81 y 4.64-4.52 (m, 6 H, CH2Ph),
4.19 y 4.16 (d, 1 H, J=7.26 Hz, H-1), 3.74 (m, 2 H, H-6), 3.60-3.58 (m, 3 H, H-3, H-4, H-5), 3.55 (s, 3 H, OCH3), 3.53 (broad s , 1 H,
H-2), 2.46 (broad s, 1 H, OH). 13C NMR (75 MHz, CCl3D): δ 138.65, 138.16, 138.11, 128.56-128.27, 127.99-127.61 (3 C6H5),
103.74 (C1), 84.54 (C3), 77.68 (C4), 75.22 (C10), 75.17 (C9), 75.03 (C8), 74.66 (C2), 73.56 (C5), 68.90 (C6); 57.17 (C22).
17. Rani, S.; Vankar, Y. D.; Tetrahedron Lett., 2003, 44, 907.
18. Ionic liquid (10% mmol) and 3,4,6-tri-O-benzyl-D-glucal (200 mg, 0.48 mmol) were placed in a round-bottomed flask and dissolved
in 2.0 ml of dichloromethane, then were added acetone (0.8 ml) and saturated NaHCO3 aqueous solution (1.5 ml). To this vigorously
stirred biphasic mixture was added dropwise a solution of oxone (600 mg, 0.9760 mmol in 2.5 ml of water) at 0°C for 15 minutes,
maintaining this temperature 20 minutes more. The reaction was controlled by TLC, until no further progress was observed. The
mixture was extracted with dichloromethane (5 x 2.0 ml) and the combined organic phases were dried over sodium sulphate
1
(Na2SO4). This solution was concentrated under reduced pressure and the residue was purified by column chromatography. H NMR
(500 MHz, CCl3D): δ 7.43-7.27 (m, 15 H, 3 C6H5), 5.43 (d, 1 H, J=3.16 Hz, H-1), 4.92-4.73 (m, 1 H, H-2), 4.66-4.43 (m, 6 H,
CH2Ph), 4.30 (d, 1H, J=7.55 Hz, H-C5), 4.01 (d, 1H, H-4), 3.59-3.47 (m, 2 H, H-C6), 1.86 and 1.38 (m, 2H, OH C2 and C3). 13C
NMR (125 MHz, CCl3D): δ 138.15-136.01, 128.50-127.94 (C6H5), 93.38 (C1), 82.73 (C4), 78.39 (C3), 75.22 (C2), 74.87-73.58
(CH2Ph), 73.23 (C5), 69.21 (C6). Minor β anomer: δ 4.82 and 97.39 (H-1 and C1).
19. 1H NMR (600 MHz, CCl3D): δ 7.42-7.18 (m, 15 H, 3 C6H5), 5.00 ( d, 1 H, 11.37 Hz, H-5), 4.88-4.53 (m, 6 H, CH2Ph), 3.90 (d, 1 H,
J=8.83 Hz, H-1), 3.73-3.71 (dd, 1 H, H-6), 3.66-3.53 (m, 5 H, H-3, H-4, H-6 and CH2OH), 3.38-3.35 (t, 1 H, 8.91 Hz, H-2), 3.03-
3.00 (m, 2 H, CH2N). 13C NMR (150 MHz, CCl3D): δ 138.71, 138.08, 137.86, 128.61-127.72 (C6H5), 90.91 (C1), 85.54 (C3), 77.67
(C4), 75.87 (C5), 75.09 (C2), 75.02, 74.58, 73.52 (CH2Ph), 68.98 (C6), 62.99 (CH2OH), 49.48 (NCH2).

Highlights
+ DMDO generated in situ oxidize endo-glycals under biphasic conditions.
+ DodMImBF4 ionic liquid promoted the direct epoxidation of glycals acting as PTC.
+ β-O-glycosides were synthesized in good yields and high stereoselectivity.

Graphical abstract
Ionic liquids as phase transfer catalysts: enhancing the biphasic extractive epoxidation
reaction for the selective synthesis of β-O-glycosides
Cintia C. Santiago, Leticia Lafuente, Rodolfo Bravo, Gisela Díaz and Agustín Ponzinibbio