An Expedient Method for Kinetically Controlled Acetonide Formation from d-Fructose Induced by Ionic Liquid Catalyst Accompanied with SrCl2·6H2O

Article abstract of DOI:10.1007/s10562-020-03175-2

Abstract: The present work was undertaken to ascertain whether IL-metal salt catalyzed isopropylidenation of d-fructose yield desired acetonides. For the first time, an imidazole based ionic liquid compound accompanied with strontium chloride has been identified as a suitable dual catalyst system for the chemoselective O-isopropylidenation of d-fructose with acetone. In the present protocol, mainly the kinetically controlled less stable cyclic ketal 1,2;4,5-di-O-isopropylidene-β-d-fructopyranose is formed as an initial product with satisfactory yield and without isomerization to the thermodynamically more stable cyclic ketal 2,3;4,5-di-O-isopropylidene-β-d-fructopyranose. Therefore, this protocol is more advantageous compared to other mineral acid catalyzed protocols that require more sensitive reaction conditions. Graphic Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-020-03175-2

Catalysis Letters
https://doi.org/10.1007/s10562-020-03175-2
An Expedient Method for Kinetically Controlled Acetonide Formation
from d‑Fructose Induced by Ionic Liquid Catalyst Accompanied
with SrCl2·6H2O
Ayhan Yıldırım1
Received: 15 January 2020 / Accepted: 8 March 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
The present work was undertaken to ascertain whether IL-metal salt catalyzed isopropylidenation of d-fructose yield desired
acetonides. For the frst time, an imidazole based ionic liquid compound accompanied with strontium chloride has been
identifed as a suitable dual catalyst system for the chemoselective O-isopropylidenation of d-fructose with acetone. In the
present protocol, mainly the kinetically controlled less stable cyclic ketal 1,2;4,5-di-O-isopropylidene-β-d-fructopyranose is
formed as an initial product with satisfactory yield and without isomerization to the thermodynamically more stable cyclic
ketal 2,3;4,5-di-O-isopropylidene-β-d-fructopyranose. Therefore, this protocol is more advantageous compared to other
mineral acid catalyzed protocols that require more sensitive reaction conditions.
Graphic Abstract
Keywords d-fructose · O-isopropylidenation · Ionic liquid · Chemoselective · Acetonation
1 Introduction
compounds with desirable biological activities and therapeu-
tical properties [8–13]. The present work was undertaken to
ascertain whether IL-metal salt catalyzed isopropylidenation
of d-fructose yield kinetically controlled or thermodynami-
cally more stable acetonides.
The condensation reaction of monosaccharides with ace-
tone also serving as the solvent, leading to the formation
of acetonides, which are also known as O-isopropylidenes.
The preparation of isopropylidene group is one of the earli-
est convenient methods for protection of vicinal hydroxyl
groups in carbohydrate chemistry which method is still
extensively used [1]. These sugar derivatives are widely
used in the development of chiral auxiliaries [2–7] and
When a comprehensive literature review is conducted,
there are many studies on the preparation of acetonides
based on monosaccharides [14–27]. In general, cataly-
sis with protic acids (toluenesulfonic acid is also one of
them) or Lewis acids has been shown to give thermody-
namically more stable or kinetically controlled cyclic ket-
als as condensation products respectively [28]. In classical
O-isopropylidenation method, d-fructose in dry acetone
and in the presence of concentrated sulfuric acid forms
two isomeric acetonides 1 (1,2;4,5-di-O-isopropylidene-
β-d-fructopyranose with an exocyclic dioxolane ring and
an isopropylidene group fused to the pyranosyl ring) or 2
(2,3;4,5-di-O-isopropylidene-β-d-fructopyranose with two
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-020-03175-2) contains
supplementary material, which is available to authorized users.
* Ayhan Yıldırım
yildirim@uludag.edu.tr
1
Department of Chemistry, Faculty of Arts and Sciences,
Bursa Uludağ University, Bursa, Turkey
Vol.:(0123456789)
1 3

A. Yıldırım
isopropylidene groups fused to the pyranosyl ring) (Fig. 1),
strongly depending on the amount of acid used [29]. There-
fore, isomer 1 which generally occurs at low sulfuric acid
concentrations, is the predominant acetonide product [30,
31]. However, the acetonide compound 1 which is the kineti-
cally controlled product is readily isomerized to the ther-
modynamically more stable acetonide compound 2 in the
presence of sulfuric acid [30, 32]. The main factors deter-
mining this isomerization are the concentration of acid
catalyst used or a prolonged reaction time [32]. Therefore,
in the presence of a protic acid catalysts such as sulfuric
acid, it is necessary to adjust the reaction conditions very
carefully in order to obtain a kinetically controlled aceto-
nide as a predominant product. In many cases, it is quite
difcult to obtain these two isomers separately in pure form
but in the presence of 2,2-dimethoxypropane as a reagent,
the isomer 1 can be obtained in 51–52% yield [3]. Accord-
ing to Verhart et al., when a suspension of d-fructose in
acetone containing molecular iodine as a catalyst is heated
under refux, acetonide 2 is the main product whereas at
room temperature, isomer 1 is formed predominantly [33].
In addition, Pedatella et al. reported that acetonide 2 is the
main product when O- isopropylidenation was carried out by
using the Lewis acid and dehydrating agent triphenylphos-
phine polymer-bound/I2 complex [34]. On the other hand,
Vanlaldinpuia and Bez in one of their studies reported the
formation of 1,2;4,5-di-O-isopropylidene compound as a
predominant isomer in acetone or 2,2-dimethoxypropane
(DMP) promoted by metal-containing catalyst phosphotung-
stic acid [25]. Therefore, in order to obtain the desired aceto-
nide isomer 1, careful control of the reaction conditions and
especially the choice of catalysts are primarily requirements.
As reported in carbohydrate chemistry literature many of
diferent and efcient catalysts have been investigated [26].
But most of these catalysts require challenging preparation
methods and also need inert atmospheric conditions during
isopropylidenation reactions of carbohydrates [25]. In this
study, IL used as a mild Brønsted acid catalyst in combina-
tion with SrCl2·6H2O salt enabled the kinetically controlled
acetonide to be produced in a reasonable yield which isomer
is not easily accessible with the non-IL-catalyzed protocols.
2 Experimental
2.1 General Information
All reagents and solvents were purchased from Merck
(Merck, Darmstadt, Germany), Sigma-Aldrich (St. Louis,
MO) or Acros Organics (Thermo Fisher Scientifc, Geel,
Belgium) and used without further purifcation. Thin layer
chromatography was performed using silica gel (60 F254
,
Merck, Darmstadt, Germany) plates. A Bruker Tensor II
Fourier transform infrared (FT-IR) spectrometer (Billerica,
MA, USA) was used for acquisition of the FT-IR spectra.
The NMR spectra were measured using A600a Agilent DD2
600 MHz NMR spectrometer (Santa Clara, California, USA)
and chloroform-d (CDCl3) as a solvent using tetramethylsi-
lane (TMS) as an internal standard. Chemical shifts (δ) are
reported in ppm and J values in Hertz. The elemental analy-
ses were performed using an LECO CHNS-932 elemental
analyzer (Saint Joseph, MI, USA).
2.2 Preparation of 1,2;4,5‑Di‑O‑isopropylidene‑β‑d‑
fructopyranose
Finely powdered d-fructose (1 g, 5.55 mmol) is suspended
in 50 mL of acetone containing 20 mg of the IL and 20 mg
of SrCl2·6H2O. The obtained mixture is stirred under refux
conditions for about 6 h. The solvent is removed on a vacuum
evaporator and the yellowish syrup is dissolved in chloro-
form and washed with water (15 mL×3). The organic phase
is dried with Na2SO4, fltered and the fltrate is evaporated.
The residue is crystallized from hexane-diethyl ether. White
crystalline solid, mp: 116–118 ºC (lit [2]. 117.5–118 ºC);
IR (ATR): νmax 3455, 2987, 2901, 1825, 1563, 1459, 1368,
1327, 1247, 1217, 1194, 1114, 1067, 1044, 1016, 972, 934,
884, 849, 834, 803, 727, 585, 511, 464, 436 cm−1; 1H NMR
(600 MHz, CDCl3) δ 4.20 (dd, 1H, J1 =5.64 Hz, J2 =1.8 Hz,
H4), 4.17 (d, 1H, J=8.82 Hz, H3), 4.13 (d, 1H, J=6.66 Hz,
5
5
He ), 4.10 (dd, 1H, J1 = 13.02 Hz, J2 = 2.4, Ha ), 3.99 (d,
1H, J=20.94 Hz, H1), 3.97 (d, 1H, J=16.38 Hz, H1), 3.65
(t, 1H, J=7.5 Hz, H2), 2.10 (d, 1H, J=8.16 Hz, OH), 1.52
(s, 3H, CH3), 1.50 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.36 (s,
3H, CH3); C13 NMR (150 MHz, CDCl3) δ 111.86, 109.41,
104.51, 77.30, 73.32, 72.26, 70.37, 60.68, 27.95, 26.40,
26.25, 25.95; Found, %: C 55.40; H 7.72. C12H20O6. Calcu-
lated, %: C 55.37; H 7.75.
Protection of -OH groups
in carbohydrate chemistry
O
O
OH
O
O
O
O
Drug nanocarrier
Biological activity
O
O
O
O
OH
2.3 Preparation of 2,3;4,5‑Di‑O‑isopropylidene‑β‑d‑
1
2
fructopyranose
Chiral auxiliary
Finely powdered d-fructose (1 g, 5.55 mmol) is suspended in
50 mL of acetone containing 20 mg of the IL. The obtained
Fig. 1 d-Fructose derived acetonides
1 3

An Expedient Method for Kinetically Controlled Acetonide Formation from d‑Fructose Induced…
mixture is stirred under refux conditions for about 6 h. The
solvent is removed on a vacuum evaporator and the yel-
lowish syrup is dissolved in chloroform and washed with
water (15 mL×3). The organic phase is dried with Na2SO4,
fltered and the fltrate is evaporated. The residue is crys-
tallized from hexane-diethyl ether. Colorless needles, mp:
94–95 ºC (lit [33]. 94–95 ºC); IR (ATR): νmax 3279, 2984,
1455, 1372, 1242, 1212, 1158, 1104, 1063, 1010, 979, 897,
879, 863, 836, 708, 664, 626, 572, 542, 522, 506, 451 cm−1;
1H NMR (600 MHz, CDCl3) δ 4.60 (d, 1H, J=7.86 Hz, H4),
4.33 (t, 1H, J=2.76 Hz, H3), 4.24 (d, 1H, J=7.92 Hz, H2),
3.90 (d, 1H, J=13.02 Hz, H1), 3.76 (d, 1H, J=13.02 Hz,
H1), 3.67 (dd, 2H, J1 =23.04 Hz, J2 =16.38 Hz, H5), 2.16
(s, 1H, OH), 1.53 (s, 3H, CH3), 1.47 (s, 3H, CH3), 1.38 (s,
3H, CH3), 1.34 (s, 3H, CH3); C13 NMR (150 MHz, CDCl3)
δ 109.04, 108.51, 103.04, 70.93, 70.75, 70.00, 65.47, 61.23,
26.44, 25.74, 25.32, 23.93; Found, %: C 55.33; H 7.70.
C12H20O6. Calculated, %: C 55.37; H 7.75.
to wash the organic phase with water during the extraction
of the product. On the other hand, this method does not
require solvent (also reagent) and catalyst to be anhydrous.
However, acetonide hydrolysis may be occur with the min-
eral acids used in the conventional methods and this can
decrease the product yield. It has been found that the activity
of IL catalyst is further enhanced with selected metal salts.
The acetonation of substrate d-fructose is carried out sim-
ply by stirring a suspension of the fnely powdered sugar in
acetone, in the presence of various of catalysts as indicated
in Table 1. When the IL compound was used only as the
catalyst, the acetonide 2 instead of acetonide 1 was obtained
in 16% yield after a period of 6 h. However, by increas-
ing the reaction time and the amount of the IL catalyst, the
acetonide 1 isomer was obtained predominantly. In order to
increase the yield of acetonide 1 some selected hydrated and
anhydrous metal salts were also used in conjunction with
IL and it is evident from the Table 1 that the most satisfac-
tory results were obtained when SrCl2·6H2O was used as a
cocatalyst. In the present study, some of the tested hydrated
salts did not form the desired product when used alone as the
catalyst. (Table 1, entry 6). In order to obtain acetonides, the
catalytic reaction process of D-fructose is extremely com-
plicated. The yields are generally moderate, because this
reaction is usually reversible and diferent by-products (such
as mono ketals) can also occur. In the present work, detailed
spectroscopic and chromatographic analysis of the reaction
mixture was not performed and the yields given in Table 1
belong to the pure acetonide 1 isomer after crystallization
from suitable solvent mixture. However, when the reaction
mixture is analyzed by TLC (Thin Layer Chromatography)
and after the visualization with iodine, a dense spot of the
product and a few other spots belonging to more polar by-
products were observed on the silica gel plate.
3 Results and Discussion
To the best of my knowledge there are no studies using
ionic liquids (ILs) as catalysts in the preparation of aceton-
ide derivatives of carbohydrate molecules. In this context,
it was decided to investigate the catalytic efectiveness of
an easily accessible 1-hexadecyl-3-sulfoimidazolium chlo-
ride [35] as an ionic liquid (IL) based mild Brønsted acid
molecule in the conversion of d-fructose to acetonides 1, 2
and especially to isomer 1 (Scheme 1). This isomer is more
important because methyl α-d-fructofuranoside is obtained
from this isomer, which is transformed regioselectively into
the corresponding 6-S-thioacetate in one step via the thio-
Mitsunobu reaction [36]. In their study, Polchow and Voss
used the classical method [29] to prepare acetonide 1, but
this method requires additional basic washing during the
isolation of this isomer, which may be a disadvantage for
large-scale synthesis. However, in this study, it is sufcient
When d-fructose and sulfuric acid are stirred at room tem-
perature in excess acetone for about 10 h, as a major product
only the 2 isomer is formed. However, in this study with
the selected IL-SrCl2·6H2O binary catalyst system, only the
Scheme 1 Synthesis of aceto-
O
O
nides
IL
O
O
/SrCl2 6H2O
6 h, rx
O
O
OH
O
OH
, %44
O
OH
1
+
OH
HO
HO
excess
O
OH
IL
O
D-Fructose
6 h, rx
O
O
= [C16ImSO3H]Cl
2
, %16
IL
1 3

A. Yıldırım
Table 1 Investigation of the catalyst system for acetonides 1 or 2 syn-
amounts above 20 mg and longer reaction time are favor
the formation of 1 as the predominant acetonide. Because
it is not practical to isolate the IL catalyst and SrCl2·6H2O
from the aqueous medium, the catalyst reuse studies have
not been performed yet, but a suitable isolation procedure
can be developed in future studies.
thesis from d-fructose
Entry Catalyst
Time (h) Product
Yielda
1
2
3
4
5
IL (20 mg)
IL (100 mg)
IL (20 mg)
IL (40 mg)
6
6
17
17
17
2
1
1
1
16
30
34
23
–
The structure of acetonides 1 and 2 was proved by NMR
and FTIR spectra and the spectral data of these compounds
are consistent with those in reported literature (Fig. 2a and
b) [2–4, 27].
IL (20 mg)+MS-4 Å
Decom-
position
products
The acetonide 1 conformation is elucidated from coupling
6
7
CuSO4·5H2O (20 mg)
7
17
No product
1
–
42
4
5
constant of neighboring He and Ha protons with equatorial-
axial relationship coupling constant (J1) which is indicated
in Fig. 3. Thus as expected, dihedral angle between these
IL (20 mg)+CuSO4·5H2O
(10 mg)
8
IL (20 mg)+CuSO4·5H2O
(20 mg)
7
7
1
1
1
1
1
1
35
14
24
44
44
40
4
5
equatorial-axial hydrogens (He and Ha respectively) is~60º
which leads to the small coupling constant. Additionally, as
seen in the 1H NMR spectrum of acetonide 1, the proton on
the C2 atom splits the signal of the OH proton into a doublet
at 2.10 ppm.
9
IL (40 mg)+CuSO4·5H2O
(20 mg)
10
11
12
13
IL (20 mg)+CdCl2·2H2O
(10 mg)
7
IL (20 mg)+SrCl2·6H2O
7
(10 mg)
IL (20 mg)+SrCl2·6H2O
(20 mg)
6
4 Conclusion
IL (20 mg)+SrCl2·6H2O
17
(10 mg)
In conclusion, in the present work it is developed the frst
practical example for ionic liquid–metal salt catalyzed
synthesis of the kinetically controlled less stable cyclic
ketal 1,2;4,5-di-O-isopropylidene-β-d-fructopyranose and
no isomerization is occurred to the thermodynamically
more stable cyclic ketal 2,3;4,5-di-O-isopropylidene-β-d-
fructopyranose. Another important advantage of this method
is that the moisture-free acetone and dehydrated Lewis acid
catalysts are not required in order to obtain the acetonides
with moderate yields achieved with existing non-ionic liquid
catalyzed methods.
14
15
16
IL (20 mg)+ZnCl2 (10 mg) 17
1
1
1
26
20
18
IL (20 mg)+H3BO3 (20 mg)
7
7
IL (20 mg)+SnCl2·2H2O
(10 mg)
17
18
IL (20 mg)+AlCl3 (10 mg) 17
1
1
24
26
IL (20 mg)+ZrOCl2·8H2O
17
(10 mg)
aYields obtained after crystallization from hexane/ether
isomer 1 is formed even under prolonged refux conditions
(6–17 h) and no isomerization was observed. Ionic liquid
1 3

An Expedient Method for Kinetically Controlled Acetonide Formation from d‑Fructose Induced…
Fig. 2 a 1H NMR spectrum of
a
acetonide 1; b 1H NMR spec-
trum of acetonide 2
O
O
5
4
O
1
3
O
2
O
OH
4.2 4.1 4.0 3.9 3.8 3.7 3.6
f1 (ppm)
14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
-1 -2
f1 (ppm)
b
1
O
OH
5
3
4
O
O
2
O
O
4.6 4.4 4.2 4.0 3.8 3.6
f1 (ppm)
14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
-1 -2
f1 (ppm)
1 3

A. Yıldırım
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