Synthesis of benzylidenated hexopyranosides in ionic liquids

Article abstract of DOI:10.1016/j.carres.2005.10.007

The synthesis of 4,6-O-benzylidenated monosaccharides and disaccharides has been studied using ionic liquids as a unique solvent alternative. An examination of several imidazolium ionic liquids indicates that the benzylidenation of hexopyranosides in 3-bu

Full text of DOI:10.1016/j.carres.2005.10.007

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2812–2815
Note
Synthesis of benzylidenated hexopyranosides in ionic liquids
Jianguo Zhang and Arthur J. Ragauskas*
Department of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
Received 26 August 2005; received in revised form 6 October 2005; accepted 6 October 2005
Available online 14 November 2005
Abstract—The synthesis of 4,6-O-benzylidenated monosaccharides and disaccharides has been studied using ionic liquids as a
unique solvent alternative. An examination of several imidazolium ionic liquids indicates that the benzylidenation of hexopyrano-
sides in 3-butyl-1-methylimidazolium tetrafluoroborate, [bmim]BF4, gives the highest yields for most of the substrates, and that this
solvent system could be readily recycled.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Benzylidenation; Ionic liquid; [bmim]BF4; [emim]BF4; [bmim]PF6; Glycosides
Carbohydrates play an important role in a vast array of
biological recognition processes and in many other
important areas of nutrition and biomaterials.1,2 The
investigation of these properties is often dependent upon
the synthesis of complex carbohydrates, and these syn-
thons frequently rely on selective functionalization of
hydroxyl groups.3 A commonly employed methodology
is the formation and derivatization of 4,6-O-benzylide-
nated monosaccharides.4 In addition, the benzylidena-
tion of monosaccharides has been reported to yield a
novel organogelator that exhibited unique gelling prop-
erties with various solvents.5–8
Studies by Harjani et al.20 have highlighted the unique
reactivity of benzaldehyde and substituted derivatives in
ionic liquids suggesting an alternative methodology for
benzylidenating carbohydrates. Ionic liquids are organic
salts with melting points typically under 100 ꢁC, often
even lower than room temperature.21 However, due to
their ionic nature, these liquids exhibit no measurable
vapor pressure, are nonflammable, possess unique
chemical and thermal stability, and are water and air
stable. These properties and their intrinsic recyclability
have resulted in increasing application of ionic liquids
in the Green Chemistry focus area.22
In light of the versatility and application of benzylid-
enated carbohydrates, their synthesis remains a contin-
uing point of interest. Methyl 4,6-O-benzylidene-D-
hexopyranosides are commonly obtained by reacting
the underivatized glycoside with benzaldehyde and an
acid catalyst.9 Alternatively, benzylidenation can be
accomplished in high yield employing a benzylidene ace-
tal, in the presence of a Lewis acid such as ZnCl2, or via
a Brønsted acid catalyst.10–15 Recent studies have exam-
ined alternative methodologies, including the use of
ultrasonics,16 lanthanide cation-exchange resins,17
tin(II) triflates,18 and microwave19 assisted benzylidena-
tion of carbohydrates.
Ionic liquids have been shown to exhibit excellent sol-
ubilizing properties, facilitating a wide range of chemical
reactions, including alkylations,23 hydrogenations,24
cycloadditions,25 esterifications,26 arylations,27 cyclodi-
merizations28 and Beckmann rearrangements.29 Fur-
thermore, since ionic liquids do not mix with a
number of organic solvents, they provide a unique way
to create valuable two-phase systems for separation
and isolation of compounds.30–32
Since many traditional solvents and catalyst systems
are incompatible with sugars, ionic liquids have been
examined asanalternativereactionmediaforcarryingout
chemical reactions with carbohydrates.33 These reports
have highlighted the potential of ionic liquids to be used
for mild acetylation of sugars34 and glycosylation reac-
tions. Sasaki et al. reported that the glycosidations by
*
Corresponding author. Tel.: +1 404 894 9701; fax: +1 404 894
4778; e-mail: arthur.ragauskas@ipst.gatech.edu
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.10.007

J. Zhang, A. J. Ragauskas / Carbohydrate Research 340 (2005) 2812–2815
2813
glucopyranosyl fluoride with assorted alcohols, using an
ionic liquid and a protic acid catalyst, proceeded under
mild conditions to afford the corresponding glycosides
in good yields.35 The reactivity of glycosyl trichloroace-
timidates and diethyl phosphates with alcohols in the
presence and absence of Lewis acids have been also
recently reported with several ionic liquids.36,37
Selective enzymatic acylations of carbohydrates have
been explored in both organic solvents and ionic liquids,
and it was observed that the reactions in ionic liquids
took place more rapidly and more selectively than those
in conventional organic solvents.38 A facile synthesis of
1,2-orthoesters of carbohydrates in [bmim]PF6 has been
described by Radhakrishnan et al. as a simpler and eco-
friendly method.39 The use of 1-butyl-3-methylimidazo-
lium tetrafluoroborate as the reaction medium and
iron(III) chloride hexahydrate as a catalyst has been
employed for the efficient preparation of a,a0-bis(substi-
tuted benzylidene) cycloalkanones.40 The intrinsic prop-
erties of the ionic liquids described above facilitate
reaction work-up and recycling of the solvent.
The purpose of this investigation was to examine the
potential of employing ionic liquids for the 4,6-O-ben-
zylidenation of hexopyranosides. Herein, we report the
results of benzylidenation of methyl glycosides 1a–4a
by employing several imidazolium ionic liquids (namely,
[bmim]BF4, [emim]BF4, [bmim]PO4, and [bmim]MeSO4)
as reaction media (Scheme 1). The yields of the corre-
sponding benzylidenation products 1b–4b results are
summarized in Table 1.
OH
TsoH
O
Ph
O
O
Benzaldehyde dimethyl acetal
O
HO
HO
HO
Ionic liquids
OH
OMe
OH
1b
OMe
1a
OH
O
Ph
TsoH
O
O
O
Benzaldehyde dimethyl acetal
OMe
HO
HO
HO
OMe
Ionic liquids
OH
OH
2b
Ph
2a
OH
OH
O
O
TsoH
O
O
Benzaldehyde dimethyl acetal
HO
HO
Ionic liquids
OH
OMe
OH
OMe
3b
3a
OH
OH
O
OH
O
TsoH
Ph
O
O
HO
HO
Benzaldehyde dimethyl acetal
HO
Ionic liquids
OMe
OMe
4a
4b
HO
HO
O
O
Ph
HO
TsoH
O
O
Benzaldehyde dimethyl acetal
HO
OH
OH
Ionic liquids
O
O
O
O
HO
HO
HO
HO
OH
OH
OH
OH
5a
5b
OH
O
Ph
TsoH
O
O
O
Benzaldehyde dimethyl acetal
HO
HO
HO
Ionic liquids
OH
OH
OH
OH
6b
6a
Scheme 1. Benzylidenation of 1a–6a in various ionic liquids.

2814
J. Zhang, A. J. Ragauskas / Carbohydrate Research 340 (2005) 2812–2815
Table 1. Isolated yields for benzylidenation of 1a–5a in various ionic
liquids
In summary, we have developed a novel benzylidena-
tion methodology employing ionic liquids. Moreover,
the results indicate that benzylidenation in an ionic
liquid provides a good yield employing a recyclable,
environmentally benign solvent.
Entry
1b (%)
2b (%)
3b (%)
4b (%)
5b (%)
[bmin]BF4
[emin]BF4
[bmin]PF6
[bmin]MeSO4
99
38
<5
75
74
25
64
<5
92
48
<5
<5
88
55
17
<5
61
<5
<5
<5
Bu
Me
1. Experimental
Et
N
Me
N
N
[bmim]:
[emim]:
N
1.1. General methods
Optimization studies indicated that optimal results
required a twofold molar equivalent amount of benzal-
dehyde dimethyl acetal for the benzylidenations of the
substrates studied. For the reaction solvent, we examined
a series of imidazolium ionic liquids, which are liquids at
room temperature, having low viscosity. Among the
ionic liquids studied, [bmim]BF4 exhibited optimal solu-
bility for substrates 1a–5a at 85 ꢁC and gave the highest
yields. The benzylidenation of 1a–4a with benzaldehyde
dimethyl acetal in [bmim]BF4 gave 1b–4b in high yields
ranging from 74% to 99%, and gave 1b–4b in reduced
yields ranging from 25% to 55% when [emim]BF4 was
employed. There were no significant benzylidenated
products in both [bmim]PF6 and [bmim]SO4, except that
the benzylidenation of 2a in [bmim]PF6 gave 2b in 64%
yield, and benzylidenation of 1a in [bmim]MeSO4 gave
2b in 75% yield, as shown in Table 1.
All starting materials and reagents were obtained from
Aldrich or Fluka Chemical Company. TLC was per-
formed on silica gel HF-254 and chromatography on sil-
ica gel 60-PF254 (EM SCIENCE). NMR spectra were
recorded with a Bruker 400 DMX spectrometer in
CDCl3.
1.2. Benzylidenation procedure
The substrate (0.50 mmol) and benzaldehyde dimethyl
acetal (1.00 mmol) were dissolved in ionic liquid (0.70–
2.00 mL) together with PTSAÆH2O (1% molar ratio),
subsequently, the mixture was heated up to 80 ꢁC for
2 h. After cooling to room temperature, an excess
amount of Na2CO3 was added and this mixture was ex-
tracted with EtOAc (3 · 5 mL), washed with brine,
water and dried. Purification of the residue by column
chromatography gave the benzylidenated carbohy-
drate.ꢀ
The solubilizing abilities of ionic liquids for polysac-
charides have been reported by several authors.41 As a
preliminary study for benzylidinating oligo- and poly-
saccharides, we examined the benzylidenation of malt-
ose. Treatment of 5a gave a 61% yield of 5b in
[bmim]BF4. There was no significant reaction with other
imidazolium ionic liquids for the benzylidenation of
maltose. Clearly, the structure of the ionic liquid affected
Acknowledgements
We are grateful to NSF (EEC-0332554) for support of
our research studies.
ꢀ
the reactivity of the substrates, and BF4 is a better
counter anion to facilitate the benzylidenation of the
substrates than other anions. The benzylidenation of
D-glucose (6a) in [bmim]BF4 produced 6b in 86% yield
(a:b = 1:1), higher than that obtained in routine sol-
vents.42 Indeed, in most cases, the optimal ionic liquid
provided the desired 4,6-O-benzylidene in comparable
or enhanced yields than have been reported for conven-
tional organic solvents.10–15,43
In addition, we tested the recycling properties of ionic
liquids employed in this study. In brief, upon comple-
tion of benzylidenation and extraction of the products,
the ionic liquids were quantitatively recycled by washing
with toluene, water, and then filtered through a pad of
Celite. All volatiles were removed by evaporation and
the residue was dried at 70 ꢁC under reduced pressure.
Following this procedure, with 1a–5a the recovered
ionic liquids were reused for the benzylidenation reac-
tion at least five times without any loss in efficiency, pro-
viding the same yields as described above.
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