HClO4-SiO2 catalyzed per-O-acetylation of carbohydrates

Article abstract of DOI:10.1016/j.carres.2004.11.021

An efficient per-O-acetylation of carbohydrates catalyzed by HClO ₄-SiO₂ is reported using a stoichiometric quantity of acetic anhydride avoiding the use of pyridine and excess acetic anhydride under solvent-free conditions.

Full text of DOI:10.1016/j.carres.2004.11.021

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 325–329
Note
HClO4–SiO2 catalyzed per-O-acetylation of carbohydratesq
Anup Kumar Misra,* Pallavi Tiwari and Soni Kamlesh Madhusudan
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001, India
Received 25 August 2004; accepted 21 November 2004
Abstract—An efficient per-O-acetylation of carbohydrates catalyzed by HClO4–SiO2 is reported using a stoichiometric quantity of
acetic anhydride avoiding the use of pyridine and excess acetic anhydride under solvent-free conditions.
Ó 2004 Published by Elsevier Ltd.
Keywords: Acetylation; HClO4–SiO2; Carbohydrates; Stoichiometric; Solvent-free
The application of heterogeneous catalysts such as inor-
ganic solid acids in organic synthesis is an attractive area
of research.1 Several inorganic acids such as montmoril-
lonite clays,2 zeolites,3 and nafion-H,4 have been used as
effective catalysts for various organic transformations.
The advantages of these heterogeneous catalysts over
the homogeneous catalysts include stability,insensitivity
towards air and moisture,ease of handling,lack of cor-
rosion and other environmental hazards,and ease of
recovery and regeneration.
Per-O-acetylation is one of the most commonly used
techniques for the protection of hydroxyl groups in car-
bohydrates. Per-O-acetylated sugars are inexpensive
and useful intermediates for the synthesis of naturally
occurring glycosides,oligosaccharides and other glyco-
conjugates.5 Structural elucidations of many natural
products containing carbohydrates have been confirmed
by transforming them into their per-O-acetates. Acetyl-
ation of sugars is often carried out using a large excess
of acetic anhydride as the reagent and solvent and the
catalysts employed include pyridine,6 sodium acetate,6
sulfuric acid7 and perchloric acid.8 Pyridine is the most
widely used despite of its toxicity and unpleasant odor.9
In some cases,pyridine derivatives,for example,4-( N,N-
dimethylamino)pyridine and 4-(pyrrolidino)pyridine
have been used as a cocatalysts to speed up the reac-
tions.10 A variety of other catalysts,in combination with
excess acetic anhydride and solvents have been em-
ployed in the O-acetylation of carbohydrates and
11
non-carbohydrates,including zinc chloride,
iron(III)
chloride,12 ion exchange resin,13 iodine,14 scandium tri-
flate,15 copper triflate,16 trifluoromethanesulfonate
triflate,17 indium triflate,18 and bismuth triflate.19 In
many cases,these reactions require extended reaction
times and the use of excess acetic anhydride as the sol-
vent sometimes causes troublesome workup during the
neutralization process. Recently,acetylation has been
achieved via indium chloride in conjunction with micro-
wave irradiation;20 however,an excess of acetic anhy-
dride is required. Despite the number of available
methods,there is a need to develop a fast clean reaction
protocol for the per-O-acetylation of sugars using an
economically convenient heterogeneous catalyst and a
stoichiometric quantity of acetic anhydride.
Prompted by a recent report21 on the HClO4–SiO2
catalyzed acetylation of simple alcohols,a series of
monosaccharides,disaccharides and trisaccharides have
been successfully per-O-acetylated in the presence of a
stoichiometric quantity of acetic anhydride and a cata-
lytic amount of HClO4–SiO2 (25 mg/mmol of free sugar)
under solvent free conditions within a few minutes. In
q C.D.R.I. Communication No. 6688.
earlier report,HClO catalyzed the acetylation reaction
4
*
Corresponding author. Fax: +91 522 223938/22340; e-mail:
akmisra69@rediffmail.com
using a large excess of acetic anhydride at extended
0008-6215/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.carres.2004.11.021

326
A. K. Misra et al. / Carbohydrate Research 340 (2005) 325–329
Ac2O; HClO4-SiO2
neat; 0oC-rt
(HO)n
O
(AcO)n
O
OH
OAc
Scheme 1.
reactions times.8 To avoid the presence of water in the
reaction medium,which certainly has a deleterious effect
on the formation of product,HClO has been impreg-
1.3. Typical experimental protocol, 1,2,3,4,6-penta-O-
acetyl-a,b-D-galactopyranose
4
nated on silica gel,which also increases the effective
surface area of the catalyst. HClO4–SiO2 acted as an
inexpensive insoluble catalyst,which could be removed
from the reaction mixture by simple filtration. The
catalyst is a non-corrosive free flowing powder,which
can be stored at room temperature for several months
without losing its catalytic activity. Although HClO4
acetic anhydride mixtures are known to explode,we
had no problems handing this reagent.
In most cases clean formation of the products was ob-
served. However,for the preparation of analytical sam-
ples of the product,the crude reaction mixture was
passed through a short pad of silica gel using hexane–
ethyl acetate as the eluant. With the hydrated sugars,a
slight decrease in the yield was observed,which may
be due to the partial consumption of acetic anhydride
by the water present in the starting materials. Products
of all known compounds gave acceptable 1H NMR
and 13C NMR spectra that matched the data reported
in the cited references. In the case of reducing sugars,
per-O-acetylation gave a mixture of a- and b-acetates,
the ratio of which was determined by NMR spectro-
scopy (Scheme 1).
A suspension of D-galactose (1.8 g,10.0 mmol) in Ac O
2
(4.82 mL,51.0 mmol) was placed in an ice bath with
continuous stirring. To the cold suspension of the reac-
tion mixture was added HClO4–SiO2 (250 mg). An exo-
thermic reaction started immediately and the reaction
mixture was allowed to stir for an appropriate time as
mentioned in the Table 1. After completion of the reac-
tion (monitored by TLC),the reaction mixture was fil-
tered through Celite and evaporated to dryness. The
crude reaction mixture was co-evaporated with toluene
twice to remove traces of acetic acid and the crude prod-
uct was purified by column chromatography on silica gel
using 3:1 hexane–EtOAc to furnish 1,2,3,4,6-penta-O-
acetyl-a,b-D-galactopyranose (3.7 g; 95%; a:b = 3:1).
1.4. 1-Propanonyl 2,3,4,6-tetra-O-acetyl-b-D-C-gluco-
pyranoside (entry 9)
1H NMR: d 5.20 (t, J = 9.4 Hz,1H),5.03 (t, J = 9.4 Hz,
1H),4.88 (t, J = 9.4 Hz,1H),4.28–4.19 (dd, J = 12.4,
5.0 Hz,1H),4.06 (d,
1H),3.72–3.56 (m,1H,H-5),2.80–2.68 (dd,
J = 2.0 Hz,1H),4.02–3.90 (m,
J = 25.4,
8.8 Hz,1H),2.52–2.42 (dd, J = 16.6,3.2 Hz,1H),2.18
(s,3H,CH 2COCH3),2.06,2.04,2.02,2.00 (4 s,12H,4
COCH3). FABMS: m/z 389 [M+1]; Anal. Calcd for
C17H24O10: C,52.57; H,6.23. Found: C,52.48; H,6.30.
In conclusion,a fast,simple and convenient method-
ology has been developed for the preparation of per-
O-acetylated carbohydrate derivatives using stoichiome-
tric quantity of acetic anhydride avoiding pyridine under
solvent-free conditions. A large number of functional
groups used for protecting group manipulation of car-
bohydrates remained unaffected under the reaction
condition.
1.5. 2,3,4,6-Tetra-O-acetyl-(2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl)-a-D-glucopyranoside (entry 15)
1H NMR: d 5.49 (t, J = 9.8 Hz,2H,H-2,H-2 0),5.28 (d,
J = 3.6 Hz,2H,H-1,H-1 0),5.09 (t, J = 8.7 Hz,2H,H-3,
H-30),5.02 (t, J = 8.7 Hz,2H,H-4,H-4 0),4.22–3.92 (m,
6H,H-5,H-5 0,H-6,H-6 0),2.09,2.08,2.04,2.03 (4s,
24H,8 COC H3). FABMS: m/z 679 [M+1]. Anal. Calcd
for C28H38O19: C,49.56; H,5.64. Found: C,49.47; H,
5.72.
1. Experimental
1.1. General methods22
1.2. Preparation of HClO4–SiO2 catalyst21
1.6. 2,3,4,6-Tetra-O-acetyl-a-D-galactopyranosyl-(1!6)-
2,3,4-tri-O-acetyl-a-D-glucopyranosyl-(1!2)-1,3,4,6-
tetra-O-acetyl-b-D-fructofuranose (entry17)
HClO4 (1.8 g,12.5 mmol,as a 70% aq solution) was
added to a suspension of SiO2 (230–400 mesh,23.7 g)
in Et2O (70.0 mL). The mixture was concentrated and
the residue was heated at 100 °C for 72 h under vacuum
to furnish HClO4SiO2 (0.5 mmol/g) as a free flowing
powder (50 mg = 0.025 mmol of HClO4).
1H NMR: d 5.67 (d, J = 3.5 Hz,1H),5.48–5.44 (m,3H),
5.38–5.30 (m,2H),5.13 (br s,1H),5.11–5.00 (m,2H),
4.77 (dd, J = 9.0,3.0 Hz,1H),4.42–4.23 (m,5H),

A. K. Misra et al. / Carbohydrate Research 340 (2005) 325–329
327
Table 1. HClO4–SiO2 catalyzed per-O-acetylation of carbohydrates using a stoichiometric quantity of acetic anhydridea
Entry
Sugars
Products
Time (min) Ac2O (equiv) Yield (%)
Refs.
OH
O
OAc
O
HO
HO
AcO
AcO
1
5
5
5.1
5.1
92 a/b: 3.3:1 16
OH
OAc
OH
OAc
HO
HO
AcO
AcO
OH
O
OAc
O
2
3
4
5
95 a/b: 3:1
90 a/b: 2:1
16
16
OH
OAc
OH
AcO
HO
HO
AcO
OH
O
OAc
O
AcO
3
5
5
5.1
5.0
4.1
HO
AcO
OH
OH
OAc
OAc
H3C
AcO
O
H3C
HO
O
85 a/b: 2.5:1 16
85 a/b: 3.3:1 16
H2O
AcO
HO
OH
OAc
OAc
OH
OH
H3C
O
OH
H3C
O
OAc
OAc
HO
AcO
OAc
OH
O
HO
HO
O
AcO
AcO
6
15
4.1
90 a/b: 1:2
23
OAc
NPhth
OH
NPhth
OH
O
OAc
HO
HO
O
AcO
AcO
7
20
5
4.1
4.1
4.1
4.1
4.1
3.1
92 a/b: 1:0
24
25
26
27
28
29
OH
OAc
NHAc
NHAc
OH
O
OAc
HO
HO
AcO
AcO
O
8
95
92
92
95
90
OCH3
OCH3
OAc
OH
OH
OAc
O
O
HO
HO
AcO
AcO
O
O
9
5
OH
OAc
CH3
CH3
OH
O
OAc
O
HO
HO
AcO
AcO
10
11
12
5
SC2H5
SC2H5
OH
OAc
HO
HO
AcO
AcO
OH
OAc
O
O
5
SPh
SPh
HO
OH
AcO
OAc
O
O
HO
HO
5
OAllyl
AcO
AcO
OAllyl
NPhth
NPhth
OH
HO
AcO
OAc
HO
CH(SEt)2
OH
AcO
CH(SEt)2
13
14
5
5
5.1
8.1
96
90
30
31
OAc
OH
AcO
OAc
AcO
AcO
OH
OH
OH
O
OAc
O
O
O
HO
O
O
HO
OAllyl
OH
OAllyl
AcO
AcO
OH
OAc
OAc
O
OH
O
AcO
AcO
HO
OAc
OAc
HO
OH
OH
AcO
HO
15
10
8.1
90
—
O
O
O
O
OH
OAc
OH
OAc
(continued on next page)

328
A. K. Misra et al. / Carbohydrate Research 340 (2005) 325–329
Table 1 (continued)
Entry
Sugars
Products
Time (min)
Ac2O (equiv)
Yield (%)
Refs.
HO
HO
HO
AcO
AcO
AcO
O
O
HO
AcO
O
O
16
10
8.1
92
32
HO
O
AcO
O
HO
AcO
OH
OAc
OH
AcO
HO
HO
OH
AcO OAc
O
O
AcO
5H2O
HO
AcO
O
O
O
O
HO
HO
AcO
AcO
17
10
16
87
—
AcO
HO
O
O
AcO
O
HO
O
AcO
HO
OAc
OH
AcO
HO
OH
OAc
O
O
HO
HO
AcO
AcO
AcO
HO
HO
HO
HO
AcO
O
O
H2O
AcO
AcO
18
10
12
85
—
O
O
HO
AcO
O
O
O
O
OH
OAc
HO
AcO
OH
AcO
a Products of all known compounds gave 1H NMR and 13C NMR spectra that matched data reported in the cited references. New compounds were
characterized as outlined in the experimental section.
4.17–4.12 (m,2H),4.10–4.00 (m,2H),3.82–3.70 (m,
1H),3.62–3.50 (m,1H),2.18,2.15,2.13,2.12,2.11,
New Delhi for providing fellowships. This project was
partly funded by the Department of Science and Tech-
nology (DST),New Delhi (SR/FTP/CSA-10/2002),In-
dia. The authors are thankful to referees for their
valuable comments.
2.10,2.06,2.02,1.96 (9s,33H,11 COCH
m/z 967 [M+1]. Anal. Calcd for C40H54O27: C,49.69;
H,5.63. Found: C,49.77; H,5.75.
3). FABMS:
1.7. 2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl-(1!3)-
[(2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl)-(1!2)]-
1,4,6-tri-O-acetyl-b-D-fructofuranose (entry18)
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