Practical preparation of mono- and di-O-isopropylidene derivatives of monosaccharides and methyl 4,6-O-benzylidene glycosides from free sugars in a deep eutectic solvent

Article abstract of DOI:10.1080/07328303.2017.1347262

Free sugars were rapidly converted into the corresponding di-O-isopropylidene derivatives and methyl O-benzylidene glycosides in excellent yields and purity in a deep eutectic solvent made from choline chloride and malonic acid (ChCl:MA). Reaction conditions were mild; work-up was easy, and further purification was not necessary. Given the inexpensive, nontoxic, and recyclable nature of ChCl:MA, this protocol is environmental friendly.

Full text of DOI:10.1080/07328303.2017.1347262

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
Practical preparation of mono- and di-O-
isopropylidene derivatives of monosaccharides
and methyl 4,6-O-benzylidene glycosides from free
sugars in a deep eutectic solvent
Sunil M. Rokade & Prakash M. Bhate
To cite this article: Sunil M. Rokade & Prakash M. Bhate (2017): Practical preparation of
mono- and di-O-isopropylidene derivatives of monosaccharides and methyl 4,6-O-benzylidene
glycosides from free sugars in a deep eutectic solvent, Journal of Carbohydrate Chemistry, DOI:
10.1080/07328303.2017.1347262
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Date: 20 September 2017, At: 20:50

JOURNAL OF CARBOHYDRATE CHEMISTRY
, VOL. , NO. , –
https://doi.org/./..
Practical preparation of mono- and di-O-isopropylidene
derivatives of monosaccharides and methyl
,-O-benzylidene glycosides from free sugars in a deep
eutectic solvent
Sunil M. Rokade and Prakash M. Bhate
Department of Dyestuff Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received  April 
Accepted  June 
Free sugars were rapidly converted into the corresponding di-O-
isopropylidene derivatives and methyl O-benzylidene glycosides
in excellent yields and purity in a deep eutectic solvent made
from choline chloride and malonic acid (ChCl:MA). Reaction con-
ditions were mild; work-up was easy, and further purification was
not necessary. Given the inexpensive, nontoxic, and recyclable
nature of ChCl:MA, this protocol is environmental friendly.
KEYWORDS
Deep eutectic solvents;
methyl O-benzylidene
glycosides; O-Isopropylidene
sugar derivatives
GRAPHICAL ABSTRACT
A mild and efficient preparation of O-isopropylidene derivatives
and methyl 4,6-O-benzylidene glycosides from monosaccharides
in a deep eutectic solvent.
CONTACT Prakash M. Bhate
pm.bhate@ictmumbai.edu.in
Chemical Technology, N. P. Marg, Matunga, Mumbai,   Maharashtra, India.
Department of Dyestuff Technology, Institute of
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lcar.
Supplemental data for this article can be accessed on the publisher’s website.
©  Taylor & Francis Group, LLC

2
S. M. ROKADE AND P. M. BHATE
Introduction
O-Isopropylidenation, glycosidation, and O-benzylidenation of monosaccharides
are some basic reactions widely employed in synthetic carbohydrate chemistry.[1–3]
The conventional method consists of condensing a sugar with acetone, an alcohol,
and benzaldehyde in the presence of a suitable catalyst under anhydrous condi-
tions. Catalysts used include mineral acids,[4] anhydrous zinc chloride along with
phosphoric acid,[5] ion exchange resins,[6] anhydrous copper(II) sulfate,[7] iodine,[8]
anhydrous ferric chloride,[9] γ -Fe2O3,[10] anhydrous aluminum chloride,[11] Zeolite
HY,[12] BDMS,[13] and CAN.[14] However, these methods sometimes suffer from low
yields[11] and long reaction times.[12,13] In some cases, work-up is tedious and col-
umn chromatography becomes necessary for obtaining pure products.[8,10,11,12,13]
Hence, there is a clear need for a practical methodology for the preparation of these
useful sugar derivatives on a large scale.
A deep eutectic solvent (DES) is a mixture of a quaternary ammonium salt, e.g.,
choline chloride, with hydrogen bond donating compounds, such as urea, glyc-
erol, malonic acid, etc. These mixtures form eutectics that exhibit melting points
much lower than that exhibited by the individual components. DESs possess many
beneficial properties, such as non-volatility, non-toxicity, biodegradable nature, and
recyclability,[15,16] and have emerged as alternatives to solvents generally used in
organic synthesis. A partial list of some reactions conducted in DES includes prepa-
ration of nitroaldols,[17] esters,[18] phthalimides,[19] coumarins,[20] xanthenes,[21]
formamides,[22] and bisamides.[23] We recently reported a one-pot synthesis of per-
O-acetylated hemiacetals from free sugars[24] and the Ferrier reaction of glycals in a
DES.[25] Described herein is a simple and convenient large scale method for the syn-
thesis of O-isopropylidene sugar derivatives and methyl O-benzylidene glycosides
from free sugars by using a DES prepared from choline chloride and malonic acid
(ChCl:MA).
Results and discussion
We initially treated D-glucose (1.0 mmol) with dry acetone (2 mL) in the presence
of ChCl:MA (2 g) at room temperature. Thin layer chromatography (TLC) analysis
indicated the formation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside (1a)
that was isolated in a 78% yield after 4 h. The same reaction when carried out at 55°C
was complete within 20 min and afforded 1a in a 90% yield as a free flowing crys-
talline material by extraction with ethyl acetate (3 × 20 mL) followed by evaporation
of the extract. When DESs prepared from choline chloride:urea and choline chlo-
ride:glycerol (entries 2–3, Table 1) were used we obtained lower yields. D-Galactose,
D-mannose, D-xylose, L-arabinose, D-fructose, and D-glucal likewise afforded the
corresponding O-isopropylidene derivatives in 82–93% yields (Table 2).
The reaction could be conveniently carried out on a large scale. Thus, 10 g of
D-glucose was converted into 13 g (a 90% yield) of glucose diacetonide within 1 h.
Acetonation of D-lactose by using our protocol was not as successful. While TLC
did show the formation of a slightly less polar product, a significant amount of

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
Table . Screening of deep eutectic solvents and optimization of reaction temperature.
Entry

Deep eutectic solvent
ChCl:Malonic acid
Time
Temperature (°C)
Yield (%)
. h
. h
. h
 min
. h
. h
rt



rt



rt











ChCl:Ethylene glycol
ChCl:Urea
. h
 min
. h
. h
. h
 min






ChCl = Choline chloride
D-lactose remained unreacted even after boiling the DES–acetone–sugar mixture
under reflux for 24 h. Furthermore, we were unable to extract the product formed
owing to its poor solubility in solvents such as ethyl acetate and dichloromethane.
Inability to convert disaccharides to their O-isopropylidene derivatives is a limita-
tion of our protocol.
We next attempted the preparation of methyl glycosides in ChCl:MA. We were
delighted to observe the formation of methyl α-D-glucopyranoside by stirring
a mixture of methanol (8.0 mL), D-glucose (2.5 g, 13.8 mmol), and ChCl:MA
(15 g) at 60°C for 30 min. However, we were not able to extract it from its
solution in ChCl:MA on account of its poor solubility in solvents such as ethyl
acetate and dichloromethane. We then added benzaldehyde (1.4 mL) in order to
find out whether it could be converted into a 4,6-O-benzylidene derivative and
thereby facilitate extraction. TLC indeed indicated the formation of methyl 4,6-O-
benzylidene-α-D-glucopyranoside (2a), which could now be readily extracted with
ethyl acetate. We obtained a yield of 78%. We have thus developed a quick and con-
venient one-pot preparation of this very useful intermediate that does not require
(a) large amounts of methanol and benzaldehyde and (b) isolation of methyl α-D-
glucopyranoside. D-Mannose and D-galactose likewise afforded the corresponding
methyl 4,6-O-benzylidene glycosides (see Table 2). The preparation could be readily
scaled up and we have prepared 6.2 g of 2a from 5.0 g of D-glucose in a few hours.
The results showed that ChCl:MA promoted O-isopropylidenation, glycosida-
tion, and O-benzylidenation of free sugars were comparable to or better than con-
ventional methods with respect to yields obtained. These were considerably faster
and more convenient as well. The rapid rate of reaction may be explained by the
presence of multi-molar quantities of malonic acid resulting in a large Bronsted acid
concentration together with the high hydrogen bonding capacity of the eutectic.[35]
Free flowing powdery material is obtained in case of derivatives that exist as solids.
Although optical rotation, melting point (wherever applicable) and 1H NMR spec-
tra of isolated materials do not indicate absolute analytical purity, we believe that
the described derivatives are sufficiently purely based on comparison of 1H NMR
spectra recorded by us with those reported (see supporting information), which
can be used for further synthetic transformations without additional purification.

4

5

6

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
Table . Recyclability of DES (ChCl:MA).
Preparation of 1a
Preparation of 2a
Sr. No
Number of runs
Yield %
Amount of DES obtained (g)
Yield %
Amount of DES obtained (g)

Fresh
First
Second
Third
Fourth





.
.
.
.
.





.
.
.
.
.




We chose the preparation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside
(1a) and methyl 4,6-O-benzylidene-α-D-glucopyranoside (2a) for studying the
recyclability of ChCl:MA. Thus, the residual ChCl:MA obtained after extraction
of 1a with ethyl acetate was dehydrated under vacuum on a rotary evaporator for
15 min and directly used for repeating the reaction. In the case of 2a, the residual
ChCl:MA after extraction of the reaction mass with ethyl acetate was treated with
(5.0 mL) water and the resulting mass was dehydrated under vacuum on a rotary
evaporator at 70°C for 1 h. Table 3 presents data obtained after five such recycles.
The results indicate that ChCl:MA can be recycled four times without significant loss
in activity in the case of 1a and three times in the case of 2a. The slight increases in
weight of the recycled ChCl:MA may be on account of non-volatile and highly polar
sugar residues.
Conclusion
In conclusion, we have developed a clean, efficient, and high yielding one-pot proto-
col for the preparation of O-isopropylidene derivatives and methyl O-benzylidene
glycosides from free sugars by using a DES made from choline chloride:malonic
acid. These derivatives so prepared can be used for further synthetic transforma-
tion without an additional purification step.
Experimental section
General methods
Starting materials and reagents were purchased from commercial suppliers. TLC
was performed on aluminum plates pre-coated with Merck silica gel, spots were
observed by spraying the plates with a solution of 10% (v/v) aqueous H2SO4 with
subsequent heating. Melting points were determined on a Büchi melting point appa-
ratus and are uncorrected. Optical rotations were measured with a Perkin-Elmer 243
polarimeter at 25 ˚C. 1H NMR spectra were recorded on a Varian (500, 400 MHz)
spectrometer.
Preparation of deep eutectic solvent[36,37]
Choline chloride (50 g) and malonic acid (75 g) were mixed and heated to 70–80°C
for 4 h to obtain a clear transparent solution. In a similar way DESs were prepared

8
S. M. ROKADE AND P. M. BHATE
by using choline chloride (50 g) and TsOH (111 g), and choline chloride (50 g) and
oxalic acid (70 g).
General procedure for the preparation of O-isopropylidene derivatives
A mixture of the free sugar (2.5 g, 13.8 mmol), dry acetone (15 mL) and a DES
(15 g) prepared from choline chloride (6.0 g) and malonic acid (9.0 g) was boiled
under reflux for the required time (Table 2). After completion of the reaction as indi-
cated by TLC analysis the resulting mixture was cooled to rt and extracted with ethyl
acetate (3 × 20 mL). The combined ethyl acetate layer was evaporated under vac-
uum to afford the corresponding O-isopropylidene derivative. The DES was treated
with (5.0 mL) water and dehydrated under vacuum on a rotary evaporator at 70°C
for 1 h.
Preparation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (1a)
A mixture of D-glucose (10 g, 55.6 mmol), dry acetone (40 mL), and a DES (30 g)
prepared from choline chloride (13 g) and malonic acid (17 g) was boiled under
reflux for 30 min. After completion of the reaction as indicated by TLC analysis, the
resulting mixture was cooled to rt and extracted with ethyl acetate (3 × 100 mL).
The combined ethyl acetate layer was evaporated under vacuum to afford 1,2:5,6-
di-O-isopropylidene-α-D-glucofuranose (1a, 13.0 g, 90% yield). The raffinate was
treated with (5.0 mL) water and dehydrated under vacuum on a rotary evaporator
at 70°C for 1 h to afford DES that could be reused.
General procedure for the preparation of methyl 4,6-O-benzylidene glycosides
A mixture of the free sugar (2.5 g, 13.8 mmol) in dry methanol (8.0 mL) and DES
(15.0 g) prepared from choline chloride and malonic acid was boiled under reflux
for 30 min and cooled to rt. Benzaldehyde (2.0 mL) was added and the resulting
mixture was heated to 60°C and stirred for 20 min. After completion of the reaction
as indicated by TLC analysis, it was cooled to rt and extracted with ethyl acetate (3
× 20 mL). The combined ethyl acetate layer was evaporated under vacuum to afford
the corresponding methyl 4,6-O-benzylidene glycoside. The residual ChCl:MA was
treated with water (5.0 mL) and the resulting mass was dehydrated under vacuum
on a rotary evaporator at 70°C for 1 h.
Preparation of methyl 4,6-O-benzylidene-α-D-glucopyranoside (2a)
A mixture of D-glucose (5 g, 27.8 mmol) in dry methanol (16 mL) and DES
(20.0 g) prepared from choline chloride (8.0 g) and malonic acid (12.0 g) was
boiled under reflux for 45 min and cooled to rt. Benzaldehyde (3.53 g, 3.40 mL,
33.3 mmol) was added and the resulting mixture was heated to 60°C and stirred
for 30 min. After completion of the reaction as indicated by TLC analysis it was

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
cooled to rt and extracted with ethyl acetate (30 × 20 mL). The combined ethyl
acetate layer was evaporated under vacuum to afford methyl 4,6-O-benzylidene-
α-D-glucopyranoside (2a, 6.2 g, 79.1% yield). The raffinate was treated with water
(5.0 mL) and the resulting mass was dehydrated under vacuum on a rotary evapo-
rator at 70°C for 1 h to afford DES that could be reused.
Acknowledgments
The authors thank Mr. Ganesh More and Prof. B. M. Bhanage, Department of Chemistry,
Institute of Chemical Technology (ICT), Mumbai, India for facilitating the recording of optical
rotations. SMR thanks the Council of Scientific and Industrial Research (CSIR), New Delhi,
India for providing a research fellowship. The authors acknowledge work done at ICT in the area
of deep eutectic solvents by Dr. G. S. Shankarling, Department of Dyestuff Technology.
ORCID
Prakash M. Bhate http://orcid.org/0000-0002-1115-0050
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