A facile and eco-friendly method for the synthesis of 1,2-orthoesters of carbohydrates in ionic liquid

Article abstract of DOI:10.1055/s-2005-864818

A facile method for the synthesis of 1,2-orthoesters of carbohydrates in ionic liquid [bmim]PF₆ is described. The method described herein is simpler, eco-friendly and avoids the addition of quaternary ammonium salts as promoters.

Full text of DOI:10.1055/s-2005-864818

LETTER
997
A Facile and Eco-Friendly Method for the Synthesis of 1,2-Orthoesters of
Carbohydrates in Ionic Liquid
S
ynthesis of 1,2-O
.
rthoesters of
VCarbohydrates in
.Ionic LiquidRadhakrishnan,* V. S. Sajisha, Jessy Maria Chacko
Organic Chemistry Section, Chemical Sciences Division, Regional Research Laboratory (CSIR), Trivandrum 690519, India
Fax +91(471)2491712; E-mail: radhupreethi@rediffmail.com
Received 12 December 2004
kinetically controlled process, whereas soft nucleophiles
such as alcohols and phenols add at C-4/5 in a thermody-
namic process. The latter has been utilized in the glycosi-
dation reaction. A schematic representation of the process
is shown in Scheme 1. 1,2-Orthoesters have also been
used as a protecting group for C-1/2 hydroxyl groups.12
Abstract: A facile method for the synthesis of 1,2-orthoesters of
carbohydrates in ionic liquid [bmim]PF6 is described. The method
described herein is simpler, eco-friendly and avoids the addition of
quaternary ammonium salts as promoters.
Key words: ionic liquid, 1,2-orthoesters, carbohydrates, glycosyl
bromides, quaternary ammonium salts
Technologies based on ionic liquids have become an im-
portant area over the last few years.1 Efforts are going on
to make use of the property of ionic liquids to replace the
conventional organic solvents used in organic chemistry.
Reports indicate that ionic liquids can coordinate with
polar molecules very well2 and in effect this will serve in
solubilizing the organic compounds in ionic liquids.
When it comes to polar organic molecules, pre-eminent
are the carbohydrates.3 There has been a resurgence of
interest in carbohydrate chemistry in recent years, mainly
due to the current developments in glycobiology.4 The
common solvents used in carbohydrate chemistry such as
DMF, pyridine, methanol, etc. cause serious environmen-
tal problems. An efficient and eco-friendly solvent as a
substitute for these solvents is a topic of current interest.
Ionic liquids have been used for the acetylation of sugars5
and glycosyl trichloroacetamidates are known to react
smoothly in presence of trimethylsilyl triflate in ionic
liquid leading to glycosides and disaccharides.6
Scheme 1
1,2-Orthoesters are usually prepared by the reaction of
peracetylated or perbenzoylated glycosyl bromides with
alcohol in the presence of a quaternary ammonium salt13
or silver triflate14 and a base, usually syn-collidine or 2,6-
lutidine or with alcohol and potassium fluoride.15 They
can also be prepared by the reaction of 1-hydroxy sugars
with tetramethyl-a-chloro enamine and alcohol in pres-
ence of triethylamine.16 It is to be noted that in the classi-
cal method of preparation of orthoesters, the anomeric
bromide is refluxed with alcohol in the presence of 2,6-lu-
tidine in dry dichloromethane for five days.9,17 The
modified method which involves the use of tetrabutylam-
monium iodide also involves use of dry dichloromethane
and refluxing for 24 hours. The major disadvantages of
both methods are the use of dry dichloromethane, longer
reaction time and cumbersome work-up to remove the
dissolved salts.
Cyclic orthoesters are valuable intermediates for a variety
of synthetic transformations.7 In synthetic carbohydrate
chemistry, 1,2-orthoesters have been utilized as glycoside
donors3,8 and a number of reports is available on the use
of 1,2-orthoesters of carbohydrates in oligosaccharide
synthesis. Among various 1,2-orthoesters of carbo-
hydrates, n-pentenyl orthoesters (NPOEs)9 of sugars have
received much attention. Fraser-Reid and co-workers
have extensively utilized n-pentenyl orthoesters (NPOEs)
as glycosyl donors in the synthesis of oligosaccharides of
biological importance.10 Upon treatment with a Lewis ac-
id, they are converted into highly stabilized ambident di-
oxolenium ions. The oxonium ions undergo reaction with
nucleophiles at either C-2 or C-4/5 depending on the na-
ture of the nucleophile.11 Hard nucleophiles such as silyl
enol ethers, cuprates and titanium enolates add at C-2 in a
SYNLETT 2005, No. 6, pp 0997–0999
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864818; Art ID: D37204ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
4.
2
0
0
5
Scheme 2 Reagents and conditions: i) alcohol (1.5 equiv),
2,6-lutidine (2 equiv), [bmim]PF6, r.t., 8 h.

998
K. V. Radhakrishnan et al.
LETTER
Herein we report a facile method for the synthesis of 1,2- Table 2 Synthesis of 1,2-Orthoesters of Galactose in Ionic Liquida
orthoesters of carbohydrates from the corresponding ano-
meric bromides in ionic liquid [bmim]PF6 without any
promoter.
Our studies were initiated with the reaction of perbenzoyl-
ated glucopyranosyl bromide with 4-penten-1-ol in pres-
ence of 2,6-lutidine in ionic liquid [bmim]PF6. The
No
1
Alcohol (R-OH)
Yield (%)
reaction proceeded smoothly at room temperature (8 h)
affording the glucose pentenyl orthoester in 80% yield
(Scheme 2). The product was separated from the reaction
mixture by extraction with diethyl ether, followed by pu-
rification by silica gel column chromatography (if need-
ed). The water and diethyl ether insoluble ionic liquid was
washed with water followed by diethyl ether, dried in
vacuo and reused. Similar results were obtained with
various other alcohols and the results obtained with glu-
copyranosyl bromide are summarized in Table 1.
75
68
69
82
2
3
Isopropanol
Isooctanol
4
a Alcohol (1.5 equiv), 2,6-lutidine (2 equiv), [bmim]PF6, r.t., 8 h.
Table 3 Synthesis of 1,2-Orthoesters of Mannose in Ionic Liquida
Table 1 Synthesis of 1,2-Orthoesters of Glucose in Ionic Liquid
No
1
Alcohol (R-OH)
Isopropanol
Yield (%)
No
1
Alcohol (R-OH)
Yield (%)
80a
70
90
59
2
2
64a
3
3
58a
a Alcohol (1.5 equiv), 2,6-lutidine (2 equiv), [bmim]PF6, r.t., 8 h.
4
1-Butanol
60a
5
Isopropanol
Isooctanol
52b
Experimental
6
77b
59a
A Typical Experimental Procedure for 3,4,6-Tribenzoyl
Glucose Pentenyl Orthoester18
7
Benzyl alcohol
a Alcohol (1.5 equiv), 2,6-lutidine (2 equiv), [bmim]PF6, r.t., 8 h.
b Alcohol (1.5 equiv), 2,6-lutidine (2 equiv), [bmim]PF6, 45 °C, 3 h.
2,3,4,6-Tetra-O-benzoyl-a-D-glucopyranosylbromide (0.20 g, 0.30
mmol) was dissolved in ionic liquid [bmim]PF6 (2 mL). 2,6-Luti-
dine (0.07 mL, 0.60 mmol) was added to it followed by 4-penten-1-
ol (0.05 mL, 0.46 mmol). The reaction mixture was stirred at r.t. for
8 h. The reaction mixture was extracted with Et2O, dried over
Na2SO4 and the solvent was evaporated off completely. The crude
sample on purification by silica gel column chromatography afford-
ed the pure substance as a viscous liquid (0.16 g, 80%).
To establish the feasibility of this reaction as a general
method for the synthesis of 1,2-orthoesters, we have car-
ried out the preparation of galactose and mannose ortho-
esters and the results are summarized in Table 2 and
Table 3.
Acknowledgment
The results show that the present method can be used for
the synthesis of 1,2-orthoesters of carbohydrates with a
wide range of alcohols. Since quaternary ammonium salts
are not used in the reaction, the work-up of the reaction is
VSS thanks Council of Scientific and Industrial Research, New
Delhi for Junior Research fellowship. We thank Council of Scienti-
fic and Industrial Research, New Delhi (Task Force Project on
very simple and the ionic liquid can be reused by washing Globally Competitive Chemicals, Processes and Products COR-
0003) and Department of Science and Technology, New Delhi (NO:
SR/S1/OC-38/2003) for financial assistance.
with water and diethyl ether followed by drying in vacuo.
In conclusion, we have developed a facile and eco-friend-
ly method for the synthesis of 1,2-orthoesters of carbo-
hydrates in ionic liquid [bmim]PF6. The method is much
simpler and the solvent can be reused any number of
times.
Synlett 2005, No. 6, 997–999 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,2-Orthoesters of Carbohydrates in Ionic Liquid
999
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Orthoester:
Rf = 0.2926 (25% EtOAc–hexane). IR (neat): nmax = 3070,
2449, 1740, 1644, 1612, 1460, 1275, 1109, 976, 925, 708
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.24–8.60 (m, 20 H),
6.01 (d, 1 H, J = 5.2 Hz), 5.84–5.67 (m, 1 H), 5.47 (d, 1 H,
J = 8.7 Hz), 4.97 (d, 1 H, J = 1.5 Hz), 4.92 (d, 1 H, J = 1.3
Hz), 4.74 (dd, 1 H, J = 3.4, 7.2 Hz), 4.51 (dd, 1 H, J = 4.8,
12.0 Hz), 3.29–3.37 (m, 2 H), 2.01–2.09 (m, 2 H), 1.57–1.62
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 165.68, 164.95,
164.39, 137.68, 135.51, 133.49, 133.32, 132.80, 129.98,
129.85, 129.68, 129.69, 129.46, 129.14, 129.03, 128.46,
128.33, 128.19, 128.10, 126.28, 121.19, 120.02, 114.97,
97.42, 72.08, 69.23, 68.48, 67.42, 63.89, 63.29, 30.10,
28.60.
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(b) 3,4,6-Tri-O-benzoyl Galactopyranosyl Allyl
Orthoester:
Rf = 0.2954 (25% EtOAc–hexane). IR (neat): nmax = 2917,
2366, 1721, 1452, 1263, 1086, 708 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.35–7.97 (m, 20 H), 6.21 (d, 1 H,
J = 5.03 Hz), 5.92–5.80 (m, 1 H), 5.56 (dd, 1 H, J = 4.26,
5.06 Hz), 5.12 (d, 2 H, J = 10.45 Hz), 4.79 (dd, 1 H, J = 7.14,
12.35 Hz), 4.64–4.50 (m, 1 H), 4.38 (dd, 1 H, J = 4.93, 10.60
Hz), 3.93 (d, 2 H, J = 4.87 Hz). 13C NMR (75 MHz, CDCl3):
d = 165.18, 164.91, 164.28, 136.29, 133.78, 133.51, 133.35,
133.13, 129.81, 129.78, 129.73, 129.63, 129.42, 129.11,
128.92, 128.49, 128.35, 128.31, 126.09, 125.98, 120.31,
116.70, 98.55, 98.21, 73.41, 70.09, 68.88, 66.47, 64.96,
62.35, 29.68.
(c) 3,4,6-Tri-O-benzoyl Mannopyranosyl Isopropyl
Orthoester:
Rf = 0.2973 (25% EtOAc–hexane). IR (neat): nmax = 2917,
2849, 2356, 1716, 1458, 1269, 1086 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.23–8.01 (m, 20 H), 5.74 (d, 1 H,
J = 2.98 Hz), 5.62 (dd, 1 H, J = 3.64, 9.97 Hz), 5.04 (t, 1 H,
J = 3.4 Hz), 4.47 (dd, 1 H, J = 3.40, 11.99 Hz), 4.31 (dd, 1
H, J = 4.84, 11.97 Hz), 3.73 (m, 1 H), 1.07 (d, 3 H, J = 6.12
Hz), 1.03 (d, 3 H, J = 6.12 Hz). 13C NMR (75 MHz, CDCl3):
d = 165.78, 165.70, 165.03, 145.37, 137.35, 133.36, 133.26,
132.79, 130.11, 129.91, 129.82, 129.23, 129.18, 128.44,
128.41, 128.23, 128.07, 126.61, 124.29, 123.57, 123.03,
119.16, 97.90, 75.73, 72.41, 71.18, 67.35, 66.77, 63.28,
23.51, 23.43.
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Synlett 2005, No. 6, 997–999 © Thieme Stuttgart · New York