O-Glycosidation reactions promoted by in situ generated silver N-heterocyclic carbenes in ionic liquids

Article abstract of DOI:10.1016/j.carres.2011.03.007

We herein report O-glycosidation reactions promoted via silver N-heterocyclic carbene complexes formed in situ in ionic liquids. Seven different room temperature ionic liquids were screened for the glycosidation reaction of 4-nitrophenol with tetra-O-acetyl-α-d-galactopyranosyl bromide. Good to excellent yields were obtained using Ag-NHC complexes derived from imidazolium halide salts to promote the glycosidation reaction, whereas yields considered moderate to low were obtained without use of the silver carbene complex. Anion metathesis of the ionic liquids with inexpensive alkylammonium halides also resulted in silver N-heterocyclic carbene formation and subsequent O-glycosidation in the presence of silver carbonate. Effective utility of this methodology has been demonstrated with biologically relevant acceptors (including flavones and steroids) where O-β-glycoside products were obtained selectively in moderate to good yields. We have also demonstrated that the Ag-NHC complex is a superior promoter to traditionally used silver carbonate for the glycosidation of polyphenolic acceptors. The ionic liquids used in the study could be recycled three times without apparent loss in activity.

Full text of DOI:10.1016/j.carres.2011.03.007

Carbohydrate Research 346 (2011) 883–890
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
O-Glycosidation reactions promoted by in situ generated silver N-heterocyclic
carbenes in ionic liquids
⇑
Ian Jamie Talisman , Vineet Kumar , Jacqueline Razzaghy, Sanjay V. Malhotra
Laboratory of Synthetic Chemistry, SAIC-Frederick Inc., National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report O-glycosidation reactions promoted via silver N-heterocyclic carbene complexes
formed in situ in ionic liquids. Seven different room temperature ionic liquids were screened for the gly-
cosidation reaction of 4-nitrophenol with tetra-O-acetyl-a-D-galactopyranosyl bromide. Good to excel-
Received 27 December 2010
Received in revised form 23 February 2011
Accepted 3 March 2011
lent yields were obtained using Ag–NHC complexes derived from imidazolium halide salts to promote
the glycosidation reaction, whereas yields considered moderate to low were obtained without use of
the silver carbene complex. Anion metathesis of the ionic liquids with inexpensive alkylammonium
halides also resulted in silver N-heterocyclic carbene formation and subsequent O-glycosidation in the
presence of silver carbonate. Effective utility of this methodology has been demonstrated with biologi-
cally relevant acceptors (including flavones and steroids) where O-b-glycoside products were obtained
selectively in moderate to good yields. We have also demonstrated that the Ag–NHC complex is a supe-
rior promoter to traditionally used silver carbonate for the glycosidation of polyphenolic acceptors. The
ionic liquids used in the study could be recycled three times without apparent loss in activity.
Ó 2011 Published by Elsevier Ltd.
Available online 8 March 2011
Keywords:
O-Glycosidation
Ionic liquids
Carbohydrates
Ag–NHC complexes
Anion metathesis
1. Introduction
although it required high reaction temperatures that might be
unsuitable for sensitive substrates. As a result of this study, we
The investigations of stereoselective glycosidation reactions,
driven by the need to synthesize therapeutically active carbohy-
drates,1–3 have led to numerous advances in donor, acceptor, pro-
moter, and solvent technology.4–6 There have been a number of
reports in this context describing the use of ionic liquids (ILs) as
both solvents and promoters for glycosidation reactions.7–9 A few
examples of IL-facilitated glycosidation reactions include acid-pro-
moted O- and C-glycosidation of glycosyl fluorides with aliphatic
or aromatic alcohols in imidazolium-based ILs,10,11 IL-mediated
stereoselective addition of aliphatic alcohols to trichloroacetimi-
date donors in the presence of a Lewis acid,12,13 and IL-promoted
reaction of thioglycosides and trichloroacetimidates with aliphatic
alcohols.14,15 The benefits of employing ILs over traditional organic
solvents and promoters often include higher product yields, con-
trol over reaction stereoselectivity, and recyclability of the IL
solvent.
subsequently identified silver N-heterocyclic carbene (Ag–NHC)
complexes of imidazolium salts as promoters for O-glycosidation
reactions of various steroid, coumarin, and flavone acceptors with
glycosyl halide donors (Fig. 1).
This method produced O-glycoside derivatives in yields consid-
ered to be good to excellent in traditional organic solvents, and the
reaction mechanism involved the dual role of Ag–NHC complexes
as heavy metal ion sources and as bases. We herein describe an
in-depth study of room temperature IL (RTIL) mediated O-glycosi-
dation reactions promoted by Ag–NHC complexes generated in situ
from imidazolium halides, which are present either as additives or
generated by anion metathesis.
2. Results and discussion
Glycosidation reactions of tetra-O-acetyl-a-D-galactopyranosyl
In our ongoing effort to produce therapeutically relevant carbo-
hydrates for the treatment of cancer, we recently reported on
halide molten salts as novel glycosidation media for Koenigs–Knorr
type reactions.16 This method produced O-glycosides in high yields
under ambient atmosphere without using molecular sieves,
bromide (1a) and 4-nitrophenol were performed with silver car-
bonate in various imidazolium RTILs both in the absence or pres-
ence of the corresponding imidazolium chloride. In general,
glycosidation yields without imidazolium chloride were low
regardless of the nature of the RTIL anion or cation (Table 1, entries
1–10). Previously, we demonstrated that treatment of imidazolium
halide salts with silver carbonate generated Ag–NHC complexes
that subsequently promoted O-glycosidation reactions.16 There-
fore, to see the effect of the added salt, we next doped the RTILs
with the corresponding imidazolium halide. As expected,
⇑
Corresponding author. Tel.: +1 301 846 5141; fax: +1 301 846 5206.
E-mail address: malhotrasa@mail.nih.gov (S.V. Malhotra).
Both authors have contributed equally to this work.
0008-6215/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.carres.2011.03.007

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I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
AgCl2
N
N
N
R
R
Ag
N
a
b
a: R = C6C5CH2 -
b: R = CH3OCH2CH2-
Y
OR
X
OR
CH3CN, rt
O
O
X
ArOH
Y
RO
a or b, 51-94%
RO
OAr
OR
Br
OR
ArOH = Phenols, steroids,
coumarins, flavones, etc.
X,Y = H or OR
R = Ac or Bn
Figure 1. Glycosidation reactions promoted by isolated Ag–NHC complexes a and b in acetonitrile.
Table 1
Effect of chloride salts on glycosidation of tetra-O-acetyl-
a
-D-galactopyranosyl bromide and p-nitrophenol in RTILsa
OAc
OAc
OAc
OAc
NO2
NO2
Ag2CO3
O
O
AcO
AcO
IL, rt, 2 h
O
OAc
Br
HO
OAc
1a
2
Entry
ILb
Isolated yield (%)
a:b ratio
Entry
ILb/Clꢁ additivec
Isolated yield (%)
a:b ratio
1
2
3
4
5
6
7
8
9
BMImꢀOTf
16
33
18
41
21
46
24
33
14
37
ndd
11
12
13
14
15
16
17
18
19
20
BMImꢀOTf/BMImꢀCl
BMImꢀTf2N/BMImꢀCl
BMImꢀPF6/BMImꢀCl
EMImꢀBF4/EMImꢀCl
BMImꢀBF4/BMImꢀCl
83
80
80
69
82
81
82
59
67
79
b only
b only
b only
b only
b only
b only
b only
b only
ndd
BMImꢀTf2N
BMImꢀPF6
ndd
ndd
EMImꢀBF4
b only
b only
b only
b only
ndd
BMImꢀBF4
HxMImꢀBF4
OcMImꢀBF4
BMImꢀN(CN)2
MoeMImꢀMs
MoeMImꢀTf2N
HxMImꢀBF4/HxMImꢀCl
OcMImꢀBF4/OcMImꢀCl
BMImꢀN(CN)2/BMImꢀCl
MoeMImꢀMs/MoeMImꢀCl
MoeMImꢀTf2N/MoeMImꢀCl
b only
10
ndd
b only
a
Reactions were pre-stirred in the RTILs (1.5 g) with Ag2CO3 (2 equiv) and p-nitrophenol (3 equiv) at room temperature (rt) for 5–15 min; tetra-O-acetyl-a-D-galacto-
pyranosyl bromide (1 equiv) was then added and the mixture was stirred at rt for 2 h.
b
Structures of IL cations:
N
N
N
N
N
O
EMIm =
MoeMIm=
BMIm =
HxMIm =
OcMIm =
N
N
N
N
N
5
7
c
The mixture of Clꢁ additive (2 equiv) and the IL (1.5 g) was pre-stirred with phenol and base for 1 h and the reaction was performed as in (a).
nd = not determined.
d
formation of Ag–NHC complexes (vide infra) by pre-stirring silver
carbonate and imidazolium chloride in the RTIL for one hour had
a dramatic effect on the reaction. Yields improved by 50–60% uti-
lizing in situ Ag–NHC complexes instead of silver carbonate (Table
1, entries 11–20). The yield in 1-butyl-3-methylimidazolium dicy-
anamide [BMImꢀN(CN)2] was slightly lower than the yields result-
ing from the use of other anions (Table 1, compare 11–13, 15, and
18). 1-Ethyl-4-methylimidazolium tetrafluoroborate (EMImꢀBF4)
did not perform as efficiently as RTILs with longer alkyl cations
having the same anion (Table 1, compare 14–17). Further optimi-
zation studies revealed that increasing the reaction temperature
had no effect on the overall yield, while bases, such as NaH, Cs2CO3,
K2CO3, and LiOH were ineffective for the transformation. Interest-
ingly, the ability of NHC carbenes to act as strong bases has been
previously reported. For example, Alder et al. demonstrated that
the conjugate acid of 1,3-diisopropyl-4,5-dimethylimidazol-2-yli-
dene, an imidazolium carbene structurally similar to our N-hetero-
cylic carbene, had a pKa of 24 in DMSO, which made it significantly
more basic than 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-
diazabicycloundec-7-ene (DBU).17 Given our previous report
describing the merits of Ag–NHCs in similar reactions, the higher
yields that were obtained with in situ complexes suggested that
they act as sources of carbene bases and heavy metal ions that
were more effective in promoting the glycosidation reaction than
silver carbonate. We speculate that this may be due, in part, to
more efficient deprotonation of the phenol by the carbene.

I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
885
Table 2
Effect of different halide salts as metathesis promoters on glycosidation of tetra-O-acetyl-
a
a
-D-galactopyranosyl bromide and p-nitrophenol in BMIMꢀBF4
Entry
Halide salts
Isolated yield (%)
a:b ratio
1
2
3
4
5
Tetrabutylammonium chloride (TBACl)
Tetrabutylammonium bromide (TBABr)
Tetrabutylammonium iodide (TBAI)
Benzyltriethyltetraammonium chloride (BTEACl)
Benzyltriethyltetraammonium bromide (BTEABr)
84
82
79
87
79
b only
b only
b only
b only
b only
a
BmIMꢀBF4 (1.5 g), halide source (2 equiv), Ag2CO3 (2 equiv) and 4-nitrophenol (3 equiv) were premixed at rt for 1 h followed by addition of tetra-O-acetyl-
a-D-galac-
topyranosyl bromide (1 equiv), and the mixture was stirred at rt for 2 h.
Although the ionic liquid was easily recycled (vide infra) using
current protocol, the expensive imidazolium halides were con-
sumed during the course of the reaction. Toward developing a
method amenable to process applications, we decided to test inex-
pensive and readily available ammonium halide salts in metathesis
reactions with imidazolium RTILs. The ability of imidazolium salts
to undergo halide exchange reactions is well known in the litera-
ture. For example, the exchange of iodide with chloride was re-
ported by Lin and co-workers when imidazolium iodide salts
were reacted with silver in dichloromethane.18 We examined a ser-
ies of ammonium salts as halide sources for the model reaction of
compared with its bromide analog. Although the difference in
yields may be within the range of experimental error, this
trend correlated with the order of stability of halogeno Ag–NHC
complexes, which increases from chloride to iodide.19
In situ formation of Ag–NHC complexes via metathesis with
alkylammonium halides was supported by 1H and 13C NMR
spectroscopy. The mixture of silver carbonate (1 equiv), BTEACl
(1 equiv), and BMImꢀBF4 (1 equiv) was stirred for 3 h at room tem-
perature and analyzed by 1H NMR spectroscopy using CDCl3 as sol-
vent. For comparison, the 1H NMR of BMImꢀBF4 and BMImꢀCl were
taken under identical conditions. As the mechanism of Ag–NHC
carbene formation involves abstraction of the H2 imidazolium
proton, H2 signals of imidazolium halides disappear when they
are converted to Ag–NHC complexes. The 1H NMR spectra of
BMImꢀBF4, BMImꢀCl, and the above mixture illustrated the loss of
the H2 imidazolium proton which suggested in situ carbene
formation under our reaction protocol (Fig. 2). While NMR solvents,
such as D2O and DMSO-d6, have been known to undergo deuterium
exchange with the labile H2 proton of imidazolium salts, we did
not observe this phenomenon with CDCl3 under our experimental
conditions for BMImꢀCl and BMImꢀBF4. A 13C NMR spectrum in
tetra-O-acetyl-a-D-galactopyranosyl bromide with 4-nitrophenol
in the presence of silver carbonate and BMImꢀBF4. The results are
summarized in Table 2. In all cases, the yields were significantly
improved via the addition of ammonium salts (compare Table 2,
entries 1–5 with Table 1, entry 1). In some cases, the yields were
higher with alkylammonium chlorides than with imidazolium
chlorides (compare Table 2, entries 1 and 4 with Table 1, entries
11–20). Tetrabutylammonium chloride (TBACl) performed slightly
better than its bromide and iodide analogs (Table 2, compare
entries 1–3) as did benzyltriethylammonium chloride (BTEACl)
193
191
189
187
185
183
6.0
181
179
177
175
173
171
169
167
165
(c)
9.0
8.5
8.0
7.5
7.0
6.5
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
H2 of BMIm.BF4
(b)
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(a)
H2 of BMIm.BF4
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Figure 2. (a) 1H NMR spectra of BMImꢀBF4; (b) 1H NMR spectra of BMImꢀBF4 (1 equiv) + Ag2CO3 (1 equiv) after stirring for 3 h; (c) 1H NMR spectra of BMImꢀBF4
(1 equiv) + BTEACl (1 equiv) + Ag2CO3 (1 equiv) after stirring for 3 h; (d) 13C NMR spectra of a mixture of BMImꢀBF4 (1.5 g), BTEACl (1.5 mmol), and Ag2CO3 (1.5 mmol)
showing the appearance of the carbene resonance.

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I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
CD2Cl2 was also obtained of a mixture of BMImꢀBF4 (1.5 g), BTEACl
(1.5 mmol), and Ag2CO3 (1.5 mmol). A weak, broad resonance was
observed at 179.8 ppm which was characteristic of an Ag–NHC
complex (Fig. 2d). The low intensity of the signal was most likely
due to the high dilution of the species in BMImꢀBF4 and the large
number of species present in the sample mixture (e.g., BMImꢀBF4,
spectroscopy of the pure fractions. No disaccharide was isolated
from the reaction mixture. This suggested that an acidic hydroxyl
group was necessary for glycosidation reactions using in situ Ag–
NHC complexes.
To examine the recyclability of RTILs with this methodology, we
repeated multiple coupling cycles of 4-nitrophenol with 1a in
BMImꢀBF4. In this case, an aqueous workup was used to separate
the water-soluble BMImꢀBF4 from the product, which was ex-
tracted into dichloromethane. Drying and concentrating the organ-
ics in vacuo afforded a syrup, which was purified by flash
chromatography to give the product; the IL was recovered from
the aqueous layer. In this manner, BMImꢀBF4 was used for three cy-
cles with no loss of product yield (Table 5). Trace metal analysis of
the recovered IL showed only 246 ppm of silver, and CHNCl analy-
sis showed 0.28% of chlorine. The results suggested that the major-
ity of Ag2CO3 and BTEACl are consumed during the course of the
reaction and workup.
BTEABF4, and Ag–NHC).
A mixture of silver carbonate and
BMImꢀBF4 that lacked a halide ion source did not produce the
13
Ag–NHC complex as observed by 1H and
C NMR spectroscopy.
Thus, halide exchange with the RTIL anion appears to be a prere-
quisite for carbene formation.
We next examined the glycosidation of various simple and
complex phenol acceptors with the goal of developing efficient
methodology to synthesize therapeutically relevant aromatic O-
glycosides. The biological activity of these types of compounds
is well known in the literature. For example, chimeric hybrids
of novobiocin and derrubone were recently reported by Blagg
and co-workers to have antiproliferative activity against SkBr3
and MCF-7 breast cancer cell lines.20 Steroid glycosides such as
estradiol-b-3-glucoside have been evaluated in hormone replace-
ment therapies,21 and glycosylated coumarin derivatives have
been evaluated as prodrugs for antifungal therapy;22 in the latter
case, glycosidation was employed as a means to increase couma-
rin solubility. To screen the arylation of 1a using these types of
substrates, we chose BTEACl as our halide additive. The results
are summarized in Tables 3 and 4. Simple phenols with elec-
tron-withdrawing groups gave higher yields compared to those
with neutral or electron-donating substituents (Table 3, compare
entries 1–11) with the exception of trifluoromethyl substituted
acceptors. Galactosyl bromide 1a produced higher yields than
the corresponding glucosyl bromide 1b due to the increased ten-
dency of 1b to undergo b-elimination (Table 3: compare entries
2, 4, and 10 with Table 4, entries 1–3). For example, when 4-
nitrophenol was coupled with 1b, 47% of glycoside 3a and 36%
of the elimination product were isolated after column chroma-
tography. All reactions with flavones (Table 3, entries 13, 14,
and 18), isoflavone (Table 3, entry 15), chromanone (Table 3, en-
try 16), and coumarin (Table 3, entry 17) afforded corresponding
glycoside derivatives in good to excellent yields. This is in con-
trast to reactions performed with silver carbonate in organic sol-
vents. For example, reaction of 7-hydroxyflavone with 1a in
acetonitrile using silver carbonate gave only 32% of the glycoside
product after 24 h, whereas silver carbene-promoted glycosida-
tion afforded 59% of the product in 3 h (Table 3, entry 13). Thus,
Ag–NHC complexes may be superior promoters to silver carbon-
ate for O-glycosidation of polyphenolic acceptors. In the case of
3,7-dihydroxyflavone (Table 3, entry 14), a 1:7 separable mixture
of monoglycoside 2n and diglycoside 2o was produced. Interest-
ingly, monoglycosidation was observed only in the vinylic hydro-
xyl group suggesting that it may be more reactive toward
O-glycosidation under our reaction conditions. A similar observa-
tion was made for the reaction of 3,30-dihydroxyflavone, where
glycosidation occurred exclusively in the vinylic hydroxyl group
(Table 3, entry 18). All of the products were isolated exclusively
as the b anomer with the exception of compound 2c, which was
3. Conclusion
In conclusion, we have shown the application of in situ gener-
ated Ag–NHC complexes in RTILs for efficient and selective O-gly-
cosidation reactions. The results suggest that Ag–NHC complexes
are superior promoters to traditional heavy-metal bases for glycos-
idation reactions of glycosyl halides with polyphenolic acceptors,
which are therapeutically valuable substrates. The method is par-
ticularly amenable to process development because inexpensive
alkylammonium halides can be used to promote Ag–NHC forma-
tion via anion metathesis with imidazolium RTILs. Formation of
the Ag–NHC complex in situ has the advantage of circumventing
its preparation and storage, and the RTIL reaction medium can be
easily recovered and reused in subsequent glycosidations. High
yields were obtained using commercially available donors with a
variety of simple and biologically relevant phenolic acceptors un-
der ambient conditions.
4. Experimental
4.1. General methods
TLCs were run on pre-coated E. Merck Silica Gel 60 F254 plates
and observed by charring with 3.5% H2SO4–1% AcOH–2.5% p-anis-
aldehyde–EtOH and with UV light. The products were isolated and
purified using a Teledyne ISCO Rf flash chromatography system
with hexanes and EtOAc as eluents. For verification of the product
and purity analysis, the LC–MS was taken on an Agilent 1200 series
system with an Agilent 6210 Time-Of-Flight (TOF) mass detector.
The 1H (400 MHz), 13C (101 MHz), gCOSY and gHSQC NMR spectra
were taken on a Varian 400MR spectrometer. Chemical shifts (d)
are expressed in ppm, coupling constants (J) are expressed in hertz
(Hz), and splitting patterns are described as follows: s = singlet;
d = doublet; t = triplet; q = quartet; qAB = AB quartet; quintet; sex-
tet; septet; br = broad; m = multiplet; dd = doublet of doublets;
dt = doublet of triplets; td = triplet of doublets; ddd = doublet of
doublet of doublets. Trace metal (ICP–OES) and elemental analyses
were performed by Robertson Microlit Laboratories, Ledgewood,
NJ, USA. All the imidazolium ionic liquids used in this study were
purchased from E. Merck KgaA (EMD Chemicals), Darmstadt, Ger-
many. 1-Butyl-3-methyl imidazolium chloride (BMImꢀCl) and all
other chemicals were purchased from Sigma–Aldrich Chemical
Co. and used without any further purification. The spectral charac-
teristics of previously reported compounds 2a–g, 2i, 2j, 2m, 2p–r,
and 3a–c were analyzed and determined to be consistent with
literature values.
isolated as a 10:90
a:b mixture. The reactions were complete
within 3 h upon addition of glycosyl bromide, and little decom-
position to anomeric hydroxide was observed in the absence of
molecular sieves or inert conditions. In contrast, reaction with
carbohydrate acceptors such as tetra-O-acetyl-
D
-glucopyranose,
-glucopyr-
tetra-O-acetyl- -galactopyranose, and tetra-O-benzyl-
D
D
anose resulted primarily in decomposition of the halide donor
to the anomeric hydroxide. For the reaction of tetra-O-acetyl-
D-galactopyranose with 1a, the acceptor was recovered by
column chromatography in addition to a small quantity of per-
acetylated galactose as determined by LC–MS and 1H NMR

I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
887
Table 3
Glycosidation of 1a and different acceptors in RTILs using TBEAC and silver carbonatea
OAc
OAc
OAc
OAc
Ag2CO3
O
O
+
ArOH
IL, BTEACl, rt
AcO
AcO
OAr
OAc
OAc
1a
2a-r
Br
Entry
Acceptor (ArOH)
Product
Isolated yield (%)
BMImꢀBF4/
94/b only
a
:b ratio
BMImꢀPF6/
90/b only
a:b ratio
NO2
OH
1
2
3
4
5
2a
2b
2c
2d
2e
OH
88/b only
91/10:90
72/b only
60/b only
82/ndb
O2N
CN
OH
92/9:91
76/b only
61/b only
OH
NC
CF3
OH
OH
OH
6
7
2f
2g
2h
2i
59/b only
70/b only
82/b only
63/b only
63/b only
61/b only
F3C
57/b only
OH
8
—
—
—
Br
OH
9
OH
10
2j
H3CO
OH
11
12
2k
2l
62/b only
51/b only
—
—
H3C
HO
N
HO
O
O
13
2m
59/b only
—
(continued on next page)

888
I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
Table 3 (continued)
Entry
Acceptor (ArOH)
Product
Isolated yield (%)
BMImꢀBF4/
a:b ratio
BMImꢀPF6/a:b ratio
HO
HO
O
14
2n/2o
74(11c)/both b only
—
OH
O
O
15
16
17
2p
2q
2r
76/b only
79/b only
82/b only
—
—
—
O
O
O
O
O
HO
HO
O
O
OH
O
O
18
2s
69d/b only
—
OH
a
BmIMꢀBF4 (1.5 g), BTEACl (2 equiv) and Ag2CO3 (2 equiv) were premixed at rt for 1 h followed by addition of ArOH (1.5 equiv) and tetra-O-acetyl-
a-D-galactopyranosyl
bromide (1 equiv); the mixture was stirred at rt for 3 h.
b
nd = not determined.
OAc
RO
OH
and diglycoside 2o
O
O
O
O
OAc
OAc
OAc
c
Isolated monoglycoside 2n
O
O
R =
OR
AcO
AcO
O
OAc
OAc
OH
d
O
O
OAc
Isolated monoglycoside 2s only
AcO
.
OAc
O
O
OAc
4.2. General procedure for glycosidation of 1a and
4-nitrophenol in RTILs
4.3. General procedure for glycosidation of 1a and
4-nitrophenol in RTILs with halide additive
The ionic liquid (1.5 g), Ag2CO3 (2 equiv) and 4-nitrophenol
(3 equiv) were mixed together in a 14-mL borosilicate glass vial.
The mixture was stirred at 25 °C for 15 min followed by addition
of 1a (0.7 mmol). To check the progress of the reaction, a small
aliquot of the reaction mixture was taken out and diluted with
dichloromethane, and this solution was used for TLC spotting.
The TLC was performed using an 40:60 EtOAc–hexanes solvent
system as the mobile phase. After completion of the reaction in
approximately 3 h, the reaction mixture was diluted with 1–
2 mL of dichloromethane and loaded onto a silica gel cartridge
for product isolation by flash chromatography using a gradient
of EtOAc–hexanes (0–40% EtOAc). The desired product was
obtained as white foam; the yields with corresponding RTILs are
given in Table 1.
Ag2CO3 (2 equiv) and the halide salt (2 equiv) were stirred in
the RTIL (1.5 g) at room temperature for 1 h followed by addition
of 4-nitrophenol (3 equiv). After 20 min at 25 °C, 1a (0.7 mmol)
was added to the reaction mixture. To check the progress of the
reaction, a small aliquot of the reaction mixture was taken out
and diluted with dichloromethane, and this solution was used for
TLC spotting. The TLC was performed using an 40:60 EtOAc–hex-
anes solvent system as the mobile phase. After completion of the
reaction in approximately 3 h, the reaction mixture was diluted
with 1–2 mL of CH2Cl2 and loaded onto a silica gel cartridge for
product isolation by flash chromatography using a gradient of
EtOAc–hexanes (0–40% EtOAc). The desired product was obtained
as white foam, and the yields with corresponding RTILs are given
in Tables 1 and 2.

I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
889
Table 4
Glycosidation of 1a using in situ generated Ag–NHC complexesa
OAc
OAc
Ag2CO3
O
O
+
AcO
ArOH
AcO
AcO
IL, BTEACl, rt
AcO
OAr
OAc
Br
OAc
1b
3a-c
Entry
Acceptor
Product
Isolated yield (%)
a:b ratio
1
2
3
4-Nitrophenol
4-Cyanophenol
4-Methoxyphenol
3a
3b
3c
47/36b
35
37
ndc
b only
b only
a
BmIMꢀBF4 (1.0 g), BTEACl (2 equiv), and Ag2CO3 (2 equiv) were premixed at rt for 1 h followed by addition of ArOH (3 equiv) and 1a (0.24 mmol); the mixture was stirred
at rt for 3 h.
b
Isolated elimination product.
OAc
O
AcO
AcO
OAc
c
Not determined.
Table 5
1.1 Hz, 1H), 5.10 (dd, J = 10.5, 3.4 Hz, 1H), 4.99 (d, J = 8.0 Hz, 1H),
4.20 (ddd, J = 27.9, 11.3, 6.7 Hz, 2H), 4.04 (td, J = 6.9, 1.1 Hz, 1H),
2.30 (s, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H).
13C NMR (101 MHz, CDCl3): d 170.48, 170.39, 170.26, 169.52,
155.07, 132.97, 130.12 (2C’s), 117.09 (2C’s), 100.24, 71.07, 71.01,
68.85, 67.04, 61.48, 20.87, 20.80, 20.79, 20.73. LC–MS (ESI-TOF):
[M+Na]+ calcd for C21H26O10+Na, m/z 461.1418; found, m/z
461.1405.
Recycling of BMImꢀBF4 from glycosidation of 1a with p-nitrophenola
No. of cycle
Isolated yield (%)
a:b ratio
0
1
2
82
80
78
b only
b only
b only
a
BmIMꢀBF4 (1.0 g), BTEACl (2 equiv), and Ag2CO3 (2 equiv) were premixed at rt
for 1 h followed by addition of 4-nitrophenol (3 equiv) and 1a (0.24 mmol); the
mixture was stirred at rt for 3 h.
4.4.3. Pyridin-2-yl 2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside
4.4. General procedure for glycosidation of 1a with various
phenols in BMImꢀBF4 or BMIMꢀPF6
(2l)
1H NMR (400 MHz, CDCl3): d 8.17 (d, J = 3.8 Hz, 1H), 7.68–7.59
(m, 1H), 6.99 (dd, J = 6.6, 5.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.20
(d, J = 8.3 Hz, 1H), 5.51 (dd, J = 10.2, 8.5 Hz, 1H), 5.48 (d,
J = 3.1 Hz, 1H), 5.18 (dd, J = 10.4, 3.4 Hz, 1H), 4.20–4.12 (m, 3H),
2.18 (s, 3H), 2.02–2.01 (m, 6H), 1.98 (s, 3H). 13C NMR (101 MHz,
CDCl3): d 170.46, 170.40, 170.22, 169.65, 161.46, 146.87, 139.48,
118.97, 111.90, 94.00, 71.27, 71.23, 68.56, 67.13, 61.14, 20.83,
20.81, 20.78, 20.73. LC–MS (ESI-TOF): [M+Na]+ calcd for
Ag2CO3 (2 equiv) and BTEACl (2 equiv) were stirred in the RTIL
(1.5 g) at room temperature for 1 h followed by addition of phenol
(1.5 equiv). After 20 min at 25 °C, 1a (0.7 mmol) was added to the
reaction mixture. To check the progress of the reaction, a small ali-
quot of reaction mixture was taken out and diluted with CH2Cl2,
and this solution was used for TLC spotting. The TLC was per-
formed using an 40:60 EtOAc–hexanes solvent system as the mo-
bile phase. After completion of the reaction in approximately 3 h,
the reaction mixture was diluted with 1–2 mL of CH2Cl2 and loaded
onto a silica gel cartridge for product isolation by flash chromatog-
raphy using a gradient of EtOAc–hexanes (0–40% EtOAc). The de-
sired product was obtained as white foam, and the yields with
corresponding RTILs are given in Table 3.
C19H23NO10+Na, m/z 448.1214; found, m/z 448.1254.
4.4.4. 7-Hydroxy-4-oxo-2-phenyl-4H-chromen-3-yl 2,3,4,6-
tetra-O-acetyl-b- -galactopyranoside (2n)
D
1H NMR (400 MHz, CDCl3): d 8.10–8.04 (m, 3H), 7.98 (s, 1H),
7.46 (dd, J = 5.3, 1.9 Hz, 3H), 6.99–6.93 (m, 2H), 5.60 (d, J = 7.9 Hz,
1H), 5.39 (dd, J = 10.4, 7.9 Hz, 1H), 5.35 (d, J = 3.4 Hz, 1H), 5.07
(dd, J = 10.4, 3.4 Hz, 1H), 4.11 (ddd, J = 16.0, 13.9, 6.9 Hz, 1H),
3.84 (s, 3H), 2.12 (s, 6H), 1.99 (s, 3H), 1.90 (s, 3H). 13C NMR
4.4.1. p-Bromophenyl 2,3,4,6-tetra-O-acetyl-b-D-
galactopyranoside (2h)
(101 MHz, CDCl3): d 174.06, 170.56, 170.44, 170.32, 170.23,
1H NMR (400 MHz, CDCl3): d 7.40 (d, J = 8.8 Hz, 2H), 6.89 (d,
J = 8.8 Hz, 2H), 5.47 (dd, J = 8.6, 6.1 Hz, 1H), 5.45 (d, J = 3.5 Hz,
1H), 5.11 (dd, J = 10.4, 3.4 Hz, 1H), 5.00 (d, J = 7.9 Hz, 1H), 4.19
(ddd, J = 17.5, 11.3, 6.6 Hz, 2H), 4.05 (t, J = 6.7 Hz, 1H), 2.18 (s,
3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H). 13C NMR (101 MHz,
CDCl3): d 170.43, 170.31, 170.20, 169.44, 156.05, 132.60 (2C’s),
118.90 (2C’s), 115.97, 99.76, 71.24, 70.86, 68.67, 66.93, 61.46,
20.84, 20.77, 20.69. LC–MS (ESI-TOF): [M+Na]+ calcd for
162.01, 157.43, 157.28, 136.10, 130.87, 130.82, 129.20 (2C’s),
128.18 (2C’s), 127.44, 117.60, 115.33, 102.97, 99.71, 71.01, 70.76,
69.42, 66.99, 60.91, 21.12, 20.74, 20.72, 20.68. LC–MS (ESI-TOF):
m/z [M+H]+ calcd for C29H28O13+H: 585.1603; found 585.1517.
LC–MS (ESI-TOF): [M+Na]+ calcd for C29H28O13+Na, m/z 607.1422;
found, m/z 607.1424.
4.4.5. 3-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyloxy)-4-oxo-
C20H23BrO10+Na, m/z 525.0367; found, m/z 525.0315.
2-phenyl-4H-chromen-7-yl 2,3,4,6-tetra-O-acetyl-b-D-
galactopyranoside (2o)
4.4.2. p-Tolyl 2,3,4,6-tetra-O-acetyl-b-
D
-galactopyranoside (2k)
1H NMR (400 MHz, CDCl3): d 8.17 (d, J = 8.9 Hz, 1H), 8.09–8.03
(m, 2H), 7.54–7.45 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.06 (dd,
J = 8.9, 2.3 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 5.55 (dd, J = 10.5,
1H NMR (400 MHz, CDCl3): d 7.09 (dd, J = 8.7, 0.6 Hz, 2H), 6.90
(d, J = 8.6 Hz, 2H), 5.47 (dd, J = 9.8, 7.3 Hz, 1H), 5.45 (dd, J = 3.3,

890
I. J. Talisman et al. / Carbohydrate Research 346 (2011) 883–890
7.9 Hz, 1H), 5.50 (d, J = 3.0 Hz, 1H), 5.41–5.34 (m, 2H), 5.19 (d,
J = 7.9 Hz, 1H), 5.15 (dd, J = 10.4, 3.4 Hz, 1H), 5.08 (dd, J = 10.4,
3.4 Hz, 1H), 4.25–4.06 (m, 3H), 3.89–3.80 (m, 3H), 2.20 (s, 3H),
2.13 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.05 (d, J = 3.2 Hz, 3H), 2.03
(s, 3H), 1.90 (s, 3H). 13C NMR (101 MHz, CDCl3): d 173.50, 170.44,
170.31, 170.26, 170.21, 170.17, 170.13, 169.41, 160.92, 157.39,
156.61, 136.38, 130.91, 130.73, 129.18, 128.19, 127.52, 119.87,
115.54, 104.26, 99.51, 99.12, 71.70, 70.97, 70.83, 70.76, 69.31,
68.46, 66.95, 66.92, 61.68, 60.81, 21.09, 20.85, 20.77, 20.74,
20.70, 20.67. LC–MS (ESI-TOF): [M+Na]+ calcd for C43H46O22+Na,
m/z 937.2373; found, m/z 937.2374.
Institutes of Health, under Contract No. HSN261200800001E. The
authors would also like to thank Jeffrey R. Deschamps and Mark
Frisch, Naval Research Laboratory, Washington, DC for X-ray crys-
tal structure studies. The contents of this publication do not neces-
sarily reflect the views or policies of the Department of Health and
Human Services, nor does the mention of trade names, commercial
products, or organizations imply endorsement by the U.S.
Government.
Supplementary data
Supplementary data (1H, 13C NMR, GCOSY, and GHSQC relating
to compounds 2h, k, l, n and o and the full 13C NMR in Figure 2d)
associated with this article can be found, in the online version, at
doi:10.1016/j.carres.2011.03.007.
4.5. Recycling ionic liquids from the reaction mixture
The ability to recycle ionic liquids was demonstrated via the
reaction of 1a and 4-nitrophenol in BMImꢀBF4. Once the reaction
was complete, water (5 mL) and CH2Cl2 (5 mL) were added to the
reaction mixture. The organic and aqueous layers were separated,
and the residual product in the aqueous layer was extracted with
CH2Cl2 (3 ꢂ 5 mL). The organic layers were combined, dried over
Na2SO4, and concentrated in vacuo. The residue was loaded onto
a silica gel cartridge to isolate the product. The aqueous layer
was concentrated in vacuo to recover the ionic liquid, which was
dried under vacuum at 80 °C overnight and used for the next cycle
without further purification. The results are given in Table 5.
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