[bmim][OTf]: a versatile room temperature glycosylation promoter

Article abstract of DOI:10.1016/j.tetlet.2008.11.042

[bmim][OTf] is a versatile, ionic liquid promoter for the room temperature glycosylation of both thiophenyl and trichloroacetimidate glycoside donors; the conditions are mild, with no requirement for molecular sieves, and are compatible with a wide range

Full text of DOI:10.1016/j.tetlet.2008.11.042

Tetrahedron Letters 50 (2009) 442–445
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Tetrahedron Letters
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[bmim][OTf]: a versatile room temperature glycosylation promoter
*
M. Carmen Galan , Claire Brunet, Monica Fuensanta
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
[bmim][OTf] is a versatile, ionic liquid promoter for the room temperature glycosylation of both thio-
phenyl and trichloroacetimidate glycoside donors; the conditions are mild, with no requirement for
molecular sieves, and are compatible with a wide range of donors and protecting groups.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 9 October 2008
Revised 3 November 2008
Accepted 11 November 2008
Available online 17 November 2008
Glycosidic bond formation is a crucial step in oligosaccharide
synthesis but despite many efforts, there is still a need to identify
a general, mild and convenient glycosylation promoter.
typically considered polar. Furthermore, their physical and chemi-
cal properties can be tuned by altering the cation or the anion.
There are currently many applications of ILs as solvents in chemis-
try, with some able to act as recyclable catalysts as well as reaction
media in organic reactions.12–14
Anomeric trichloroacetimidates and thioglycosides are among
the most effective and commonly used glycosyl donors in the
chemical synthesis of oligosaccharides. Trichloroacetimidates are
activated by strong Lewis acids such as TMSOTf,1 boron trifluoride
etherate2 and lithium triflate3 among others. Thioglycosides, which
are convenient and attractive building blocks due to their
stability, accessibility and compatibility,4 are activated by N-iodo-
succinimide/TMSOTf or trifluoromethanesulfonic acid (TfOH)
combinations,5 dimethyl(thiomethyl)sulfonium trifluoromethane-
sulfonate,6 methylsulfenyl triflate,7 benzeneselenyl triflate,8 iodo-
nium dicollidine perchlorate9 and benzenesulfinyl piperidine/
triflic anhydride.10 Although these promoters are convenient for
the assembly of oligosaccharides, there are several drawbacks—
typically low temperature and molecular sieves are required—
and other problems, mainly due to side reactions with by-products
resulting from the promoters.11
These issues, in conjunction with our interest in developing
new approaches that would allow automated oligosaccharide syn-
thesis, encouraged our search for a new promoter that satisfied
several criteria: mild enough to be used at room temperature
and tolerant of a wide range of saccharide donors and acceptors,
compatible with various protecting groups and recyclable. Herein,
we report the identification and mode of activation of a versatile
ionic liquid, 1-butyl-3-methylimidazolium triflate ([bmim][OTf],
1a) (Fig. 1), as a co-solvent and glycosylation promoter for
activated thioglycoside and trichloroacetimidate donors. This
promoter is used at room temperature without requirement
for molecular sieves and is recyclable.
More recently, examples of base-catalysed reactions involving
ILs have been described in oligosaccharide synthesis.15–18 Interest-
ingly, the use of 1a as a catalyst for Mannich-type reactions had
previously been reported.19 Furthermore, NMR studies by Rencu-
rosi et al.20 on protected glucoside
a- and b-trichloroacetimidates
have suggested that triflate-based ionic liquids participate in gly-
cosylation reactions in combination with a Lewis acid catalyst, by
formation of a transient
a-glycosyl triflate that yields predomi-
nantly b-glycoside products.17 This is in agreement with Toshima’s
observations in terms of selectivity.18
Herein, we report the ability of [bmim][OTf] 1a to act as a room
temperature glycosylation promoter and co-solvent towards a
range of donors and acceptors (Fig. 1).
In our initial studies, peracetylated galactose trichloroacetimi-
date 221 was used as a model donor in combination with a series
of acceptors 9a–e to yield a series of corresponding glycoside prod-
ucts 10a–e (Fig. 2). In general, reactions proceeded smoothly at
room temperature with the expected a/b-selectivities and in good
yields; in some cases, yields exceeded those of reactions performed
with TMSOTf at ꢀ40 °C (Table 1, entries 1–8). Having demon-
strated that 1a catalyses the glycosylation of 2, trichloroacetimi-
date donors 3a,2 4a22 and 4b23 were prepared and reacted with
commercially available 1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose 9c (Table 1, entries 9–14). Trichloroacetimidate 4b gave
disaccharide 13b in 78% yield, which represents a slight increase
when compared to the same reaction in the presence of a Lewis
acid (Table 1, entries 13 and 14). Peracetylated glycoside donors
are considered to be electronically deactivated species (disarmed)
and in general, require a more potent activator. In the case of the
less activated peracetylated donors 3a and 4a, the addition of a cat-
alytic amount of triflic acid for efficient activation was required
(see entries 10 and 12, Table 1, respectively).
Ionic liquids (ILs) are a class of solvents which have attracted
growing interest due to their unique physical and chemical proper-
ties.12,13 ILs consist of poorly coordinating ion pairs and are
* Corresponding author. Tel.: +44 01179287654; fax: +44 01179298611.
E-mail address: M.C.Galan@bristol.ac.uk (M. C. Galan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.042

M. C. Galan et al. / Tetrahedron Letters 50 (2009) 442–445
443
Ionic Liquids
-OTf
N
N+
1a R=H
1b R=CH3
2
R
Trichloroacetimidate Donors
Thioglycoside Donors
OR
OAc
O
OAc
AcO
OR
RO
OAc
O
OR
O
AcO
AcO
O
RO
SPh
AcO
RO
AcO
OC(NH)CCl3
RO
RO
SPh
2
OC(NH)CCl3
3a
6a R=Ac
6b R=Bn
5a R=Ac
5b R=Bn
RO
RO
RO
RO
BnO
OBn
O
RO
RO
RO
RO
O
OBn
SPh
O
OC(NH)CCl3
R1
4a R=Ac
8
7a R=Ac, R1=SPh
7b R=Bn, R1=SPh
7c R=Bn, R1=OH
4b R=Bn
Acceptors (R2OH)
O
Ph
O
R2=
O
O
Br
O
Ph
O
SPh
9a
9b
O
NHP
9d P=Troc
9e P=Phth
O
9c
Figure 1. Ionic liquids, trichloroacetimidate and thioglycoside donors used in this study.
OR
OR
R2 =
O
b
a
c
Ph
OR2
Br
O
RO
OR
R= OAc
O
Ph
O
O
10a-e
O
O
d P= Troc
e P= Phth
SPh
11a-d R= OBn
O
O
NHP
BnO
OBn
OR
O
OR
O
RO
OBn
RO
RO
O
RO
O
O
RO
OR
12a R=Ac
12b R=Bn
O
O
O
14
O
O
13a R=Ac
13b R=Bn
O
O
O
O
O
O
O
O
O
O
O
Figure 2. Structures of glycoside products 10–14.
Interestingly, donors 3a and 4a are stable in CH2Cl2 solution
with IL 1a as co-solvent and did not hydrolyse to the corresponding
hemiacetals, when exposed to air and/or heat. To assess the stabil-
ity of 4a in CDCl3 and [bmim][OTf] 1a (10% v/v), 1H NMR spectra
were recorded over seven days followed by heating the sample
to 50 °C; no degradation of 4a was observed. This stability may
be due to the reported ability of ILs to act as ‘liquid molecular
sieves’.24 That imidate 2, which is also a deactivated glycoside
requirement for TMSOTf, can be explained by the higher reactivity
profile of 2 as a glycosyl donor in comparison with the correspond-
ing glucose and mannose thioglycosides.25
Encouraged by these results, we decided to extend the method-
ology to thiophenyl glycosides, another commonly used class of
glycosyl donor. Activated phenyl 2,3,4,6-tetra-O-benzyl-1-thio-b-
D
-galactopyranoside 5b26 was used as a model donor with alcohols
9a–c as acceptors (Table 2). Glycosylation reactions were extre-
mely clean, and were complete within a few hours at RT and
donor, could be activated with [bmim][OTf] 1a without
a

444
M. C. Galan et al. / Tetrahedron Letters 50 (2009) 442–445
Table 1
Glycosylation yields for deactivated sugar glycosides are typi-
cally lower in comparison to the corresponding electronically
activated (armed) glycosides.31 Although [bmim][OTf] did not effi-
ciently activate donors 5a, 6a and 7a and the reactions proceeded
very slowly, the addition of 0.2 mol % TfOH provided the desired
glycosides in excellent yields (Table 2, entries 2, 10 and 14) with
the added advantages that these reactions take place at room tem-
perature in a matter of hours, do not produce significant amounts
of side products and these glycosylations do not require the use of
molecular sieves.
In order to understand the role of IL 1a in the mechanism of
thioglycoside activation, a model reaction with donor 7a in the
presence of N-iodosuccinimide (NIS), [bmim][OTf] 1a and CD2Cl2
was followed by 1H NMR and 19F NMR spectroscopy at room tem-
perature and spectra were recorded at regular time intervals until
completion of the reaction (Fig. 3). It is important to note that the
CD2Cl2 used contains traces of water, thus when thiophenyl
mannoside derivative 7b is activated, the hydrolysed hemiacetal
product 7c will be produced.
Summary of the glycosylation reactions with trichloroacetimidate donorsa
O
O
ROH (9a-e)
PO
PO
OC(NH)CCl3
OR
Promoter
DCM
Product
Donor
Entry
Donor
Acceptor
Promoter
Product
Yield (%)
a
/b ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
2
2
2
2
2
2
2
3a
3a
4a
4a
4b
4b
9a
9a
9b
9b
9c
9d
9e
9e
9c
9c
9c
9c
9c
9c
TMSOTf
1a
TMSOTf
1a
1a
1a
10a
10a
10b
10b
10c
10d
10e
10e
12a
12a
13a
13a
13b
13b
70
78
77
75
69
78
70
80
75
85
70
77
65
78
Only b
Only b
Only b
Only b
Only b
Only b
Only b
Only b
Only b
Only b
TMSOTf
1a
TMSOTf
1a, TMSOTf
TMSOTf
1a, TMSOTf
TMSOTf
1a
Only
Only
3/2
a
a
5/1
a
All reactions were performed in DCM in the presence of TMSOTf (0.2 equiv) at
This experiment showed that 7b (H-1, doublet at 5.59 ppm,
J = 1.74 Hz) was converted within 3 h to the corresponding hemi-
acetal 7c (H-10, doublet at 5.13 ppm, J = 1.92 Hz, observed
[M+Na]+ = 563.3)32 (Fig. 3). Additionally, the appearance of charac-
teristic resonances corresponding to N-iodosuccinimide (singlet at
2.87 ppm) which yields electrophilic I+ and succinimide (singlet at
2.67 ppm), typically catalysed by acid,33 were also detected over
the course of the reaction (Fig. 2, Supplementary data). The signals
corresponding to [bmim][OTf] 1a remained constant throughout
the reaction in both the 1H NMR spectra (singlet at 8.99 ppm
(1H), multiplet at 1.85 ppm (2H), multiplet at 1.35 ppm (2H) and
a triplet at 0.96 ppm (3H)) and in the 19F NMR spectra (singlet at
77.21 ppm, see Fig. 3, Supplementary data). In order to establish
if H-2 of the imidazolium moiety was involved in the reaction, 1-
butyl-2,3-dimethylimidazolium triflate 1b was prepared and its
ability to promote glycosylation was tested. If the IL is acting as
an acid and the formation of the iodonium ion, substituting H-2
for CH3 should suppress the reaction. Using donor 5b in combina-
tion with acceptor 9c and with 1b as the IL component, the desired
disaccharide 11c was obtained in good yield, suggesting that the
imidazolium ring does not participate directly in the activation of
NIS. Furthermore, no TfOH was detected in the 1H or 19F NMR spec-
tra associated with 1a, however, when K2CO3 (20 mol %) was added
to this control reaction, the formation of 11c was completely
suppressed.
These results imply that the counterion of [bmim][OTf] 1a is
critical for catalysing the formation of the iodonium ion and we
suggest that slowly released TfOH is the catalyst. To identify the
source of H+, Karl Fisher titration experiments34 were used to mea-
sure the water content of 1a, which was found to be 0.58 0.03% in
weight, which is consistent with the water content of other ionic
liquids of similar chemical nature.35
Another aspect we wanted to explore was the recyclability of
the IL. Reactions were carried out using donors 4a and 5b with
acceptor 9c. After extraction of the products and reagents with a
mixture of ether and hexanes, the IL could be reused up to three
times without loss of activity (Table 1, Supplementary data).
In summary, we have shown that [bmim][OTf] 1a in anhydrous
dichloromethane serves as a room temperature selective glycosyl-
ation promoter for activated (armed) thiophenyl and trichloroace-
timidate glycosyl donors, while the less active (disarmed) donors
require the addition of catalytic triflic acid. The glycosylation con-
ditions are mild and compatible with a range of hydroxyl protect-
ing groups, such as acetates, benzyl ethers, acetals, and are also
amenable to NH2 masking strategies, that is, phthalimide (Phth)
and trichloroethylcarbamate (Troc). Mechanistically, we suggest
that 1a works by slow release of triflic acid but 1a also acts as a
ꢀ40 °C or with 1a (10% v/v) at room temperature (rt) or with 1a (10% v/v) and
TMSOTf at rt as promoter.
b
Determined by NMR spectroscopy (1H and HMQC data).
Table 2
Summary of the glycosylation reactionsa with thioglycoside donors
O
O
ROH (9a-c)
PO
PO
SPh
OR
Promoter
NIS (2equiv), DCM
Donor
Product
Entry
Donor
Acceptor
Promoter
Product
Yield (%)
a
/b ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
5a
5a
5b
5b
5b
5b
5b
5b
6a
6a
6b
6b
7a
7a
7b
7b
8
9c
9c
9a
9a
9b
9b
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
TMSOTf
1a, TMSOTf
TMSOTf
1a
TMSOTf
1a
TMSOTf
1a
TMSOTf
1a, TMSOTf
TMSOTf
1a
TMSOTf
1a, TMSOTf
TMSOTf
1a
TMSOTf
1a
10c
10c
11a
11a
11b
11b
11c
11c
12a
12a
12b
12b
13a
13a
13b
13b
14
83
95
96
92
83
86
82
83
70
80
75
85
70
80
75
87
75
70
71
Only b
Only b
>99 b
>99 b
2/8
2.5/7.5
0.2/1
0.7/1
Only b
Only b
0.02/1
0.7/1
Only
Only
1/1.3
1.5/1
1/1
a
a
8
14
12b
0.9/1
0.7/1
6a, 6b
1a
a
All reactions were performed in DCM, in the presence of NIS (2 equiv) and
TMSOTf (0.2 equiv) at ꢀ40 °C or with 1a (10% v/v) at room temperature (rt) or with
1a (10% v/v) and TMSOTf at rt as promoter.
b
Determined by NMR spectroscopy (1H and HMQC data).
proceeded in excellent yields (Table 2, entries 3–8). In order to ex-
plore the scope of this process, a series of thioglycoside donors
5a,27 6a,28 6b,27 7a,29 7b29 and 830 were utilised and glycosylations
with acceptor 9c were performed under the same conditions; see
Table 2 for details.
In general, conversion yields were excellent for activated do-
nors, and comparable or in some cases exceeding those achieved
in reactions where TMSOTf was used at ꢀ40 °C as the activator.
Interestingly, an increase in a-selectivity was observed using [bmi-
m][OTf] 1a (Table 2, see entries 7 and 8, 11 and 12, 15 and 16),
when glycosylation reactions were performed with activated
glycosides where non-participating groups at C-2 were present.

M. C. Galan et al. / Tetrahedron Letters 50 (2009) 442–445
445
Rx followed by NMR.esp
0.3
0.2
7a (H-1)
0.1
t = 1 min
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
7b (H-1’)
t = 40 min
t = 80 min
t = 180 min
t = 300 min
5.65 5.60 5.55 5.50 5.45 5.40 5.35 5.30 5.25 5.20 5.15 5.10 5.05 5.00 4.95 4.90 4.85
Chemical Shift (ppm)
Figure 3. Partial 1H NMR spectra of the IL catalysed glycosylation reaction collected over 300 min.
8. Ito, Y.; Ogawa, T. Tetrahedron Lett. 1988, 29, 1061–1064.
stabilizing agent with respect to hydrolysis, and reactions proceed
cleanly and in good yields at room temperature and without the
need of molecular sieves. When non-participating groups at C-2
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were present, an increase in
a selectivity was observed when com-
pared with reactions carried out using TMSOTf at lower
temperatures.
Moreover, the ability to recycle the IL is also very attractive in
terms of green chemistry, since the amount of organic waste will
be reduced. In addition, the use of an IL to promote glycosylation
reactions at room temperature is amenable to automated synthesis
protocols where low temperatures are not required.
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We gratefully acknowledge financial support from the EPSRC
and thank Professor Timothy Gallagher for discussions and
support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.042.
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