Sulfuric acid immobilized on silica: an efficient promoter for one-pot acetalation-acetylation of sugar derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.04.118

Sulfuric acid immobilized on silica gel has been used as an efficient and safe alternative promoter for acetalation and subsequent acetylation of sugar glycosides using stoichiometric reagents without work-up. The synthesis of different types of per-O-ace

Full text of DOI:10.1016/j.tetlet.2006.04.118

Tetrahedron Letters 47 (2006) 4337–4341
Sulfuric acid immobilized on silica: an efficient promoter for
one-pot acetalation–acetylation of sugar derivativesI
Balaram Mukhopadhyay*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, UP, India
Received 26 January 2006; revised 18 April 2006; accepted 26 April 2006
Dedicated to my mentor Professor Nirmolendu Roy
Abstract—Sulfuric acid immobilized on silica gel has been used as an efficient and safe alternative promoter for acetalation and sub-
sequent acetylation of sugar glycosides using stoichiometric reagents without work-up. The synthesis of different types of per-O-
acetylated acetals/ketals has been achieved from various types of O- and S-glycosides in excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The use of stoichiometric reagents and catalytic promot-
ers to minimize waste has become a demanding chal-
lenge for synthetic chemists when atom economy and
green chemistry are considered.1 Various attempts have
been made to achieve this goal by using efficient promot-
ers and so minimizing work-ups.2 Selective protection of
1,2-cis-diols through the formation of acetal or ketal
derivatives is a routine reaction in carbohydrate chemis-
try.3 Usually these reactions are carried out with an
aldehyde or ketone in the presence of a Lewis acid pro-
moter.4 For more efficient reactions, the use of dimethyl
acetals,5 ketals6 or enol–ethers7 are also well known in
the literature. Commonly used catalysts for these reac-
tions include formic acid,8 CuSO4,9 ZnCl2,10 p-toluene-
sulfonic acid,11 camphorsulfonic acid12 and iodine.13
Acetalation under basic conditions using dibromotolu-
ene in the presence of pyridine14 has also been used.
However, most of these systems require a large excess
of the reagents and therefore, extensive work-up, and
chromatographic purification becomes inevitable. So
there is a clear need for a practical synthetic strategy
that will provide access to these important sugar build-
ing blocks using stoichiometric reagents. It is worth not-
ing that recently the use of perchloric acid immobilized
on silica has been reported to provide access to per-O-
acetylated sugar acetals or ketals in excellent yields un-
der stoichiometric conditions.15 However, perchloric
acid is known to be potentially explosive; therefore,
safety concerns limit the use of this reagent for large-
scale preparations. Recent reports on the utilization of
H2SO4–silica in various organic reactions,16 including
the acetylation of aliphatic and aromatic alcohols,17
prompted us to investigate its use as an alternative pro-
moter to synthesize these important sugar building
blocks. This letter describes a one-pot reaction using
H2SO4 immobilized on silica18 that provides access to
per-O-acetylated sugar acetals or ketals from unpro-
tected sugar glycosides.
Treatment of methyl-b-D-glucopyranoside (1) with stoi-
chiometric acetic anhydride and H2SO4–silica led to the
per-O-acetylated derivative 2 in an excellent yield
(Scheme 1). Free reducing sugars also underwent per-
O-acetylation in good to excellent yields. When
methyl-b-D-glucopyranoside (1) was treated with 1 mol
equiv of benzaldehyde dimethylacetal, in the presence
OAc
O
Ac2O
AcO
AcO
OMe
OH
H2SO4 on silica
OAc
O
2
HO
HO
OMe
O
PhCH(OMe)2
Ph
O
OH
O
OMe
RO
H2SO4 on silica
1
OR
3 R = H
q CDRI Communication No. 6923.
Ac2O
4 R = Ac
*
Tel.: +91 522 2612411 18; fax: +91 522 2623938; e-mail:
sugarnet73@hotmail.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.118

4338
B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 4337–4341
of H2SO4–silica in dry acetonitrile,19 the corresponding
4,6-O-benzylidene acetal (3) was formed within 25 min
(TLC). The compound collected after filtration proved
to be pure by NMR and mass spectrometry. After com-
plete conversion to the benzylidene derivative, as judged
by TLC, 4 mol equiv of acetic anhydride were added
and the mixture stirred for 30 min at room temperature.
Filtration and evaporation of the solvents resulted in
methyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-D-glucopyr-
anoside (4) in 93% yield. The formation of 2 mol equiv
of methanol, during the benzylidene reaction using
1 mol equiv of benzaldehyde dimethylacetal, justified
the necessity of 4 mol equiv of acetic anhydride for acet-
ylation. The compatibility of H2SO4–silica with the rel-
atively less robust cis-decalin system was confirmed
when p-methoxyphenyl b-D-galactopyranoside (5) gave
p-methoxyphenyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-
D-galactopyranoside (6) in 89% yield. This example also
confirmed that H2SO4–silica is compatible with the rela-
tively acid labile p-methoxyphenyl glycosides. Other O-
glycosides, for example, n-octyl, trimethylsilyl, and thio-
glycosides, also gave satisfactory results under these
conditions (Table 1). The applicability of this reagent
system was further extended with the formation of
per-O-acetylated 4-methoxylbenzylidene, 4-nitrobenzyl-
idene, and 3-chlorobenzylidene derivatives using 4-
methoxy, 4-nitro, and 3-chlorobenzaldehydes, respec-
tively20 (Table 1 entries 5, 6, and 7).
After the successful execution of the one-pot strategy for
making per-O-acetylated benzylidene acetals, the appli-
cability of the reagent system was assessed for isopropyl-
idene ketals. Treatment of a mixture of methyl
a-L-rhamnopyranoside (17) in dry acetonitrile with
1 mol equiv of 2,2-dimethoxypropane in the presence of
H2SO4–silica afforded the corresponding isopropylidene
1
ketal in >95% purity, as confirmed by H NMR and
mass spectrometry after filtration and evaporation of
the solvents. A sequential acetylation reaction was also
performed successfully in the same pot using 3 mol
Table 1. H2SO4–silica promoted one-pot benzylidenation/isopropylidenation–acetylation of different glycosides
Entry
Starting material
Product
Timea (min)
Yield (%)
93
Ref.
22
OH
Ph
O
O
1
60
O
O
OMe
HO
AcO
OMe
HO
OAc
OH
4
1
Ph
O
OH
O
HO
O
O
OMP
OSE
2
3
60
60
89
90
23
24
HO
OMP
AcO
OH
OAc
6
5
O
OH
O
Ph
AcO
HO
HO
O
O
OSE
OH
OAc
7
8
Ph
HO
HO
HO
O
O
O
O
AcO
4
5
60
60
82
87
25
26
AcNH
AcNH
OC8H17
OC8H17
9
10
R
O
OH
O
O
O
OMe
AcO
HO
HO
OMe
OAc
R = 4-methoxyphenyl
OH
1
11
O
R
OH
O
O
O
AcO
HO
HO
6
7
AcO
90
90
75
78
27
28
OMe
HO
OMe
R = 4-nitrophenyl
12
13
O
R
OH
O
O
O
AcO
HO
HO
AcO
OMe
HO
OMe
12
R = 3-chlorophenyl
14

B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 4337–4341
4339
Table 1 (continued)
Entry
Starting material
Product
Ph
Timea (min)
60
Yield (%)
88
Ref.
29
OH
O
O
O
O
STol
HO
8
9
AcO
STol
HO
OAc
OH
16
15
OMe
OMe
Me
O
Me
AcO
O
HO
45
95
30
O
O
HO
OH
17
18
Me
O
SEt
OAc
O
O
Me
SEt
OH
O
10
11
12
45
30
45
93
91
92
31
15
32
OH
HO
19
20
O
HO
HO
O
O
OBn
O
AcO
OBn
OH
21
22
HO
HO
OH
O
O
O
O
O
O
HO
OMe
OMe
23
24
MP: 4-methoxyphenyl and SE: 2-trimethylsilylethyl.
a Total time required for acetalation/ketalation and acetylation.
equiv of acetic anhydride to give methyl 4-O-acetyl-2,3-
O-isopropylidene-a-L-rhamnopyranoside (18) in 95%
yield.21 Similarly other O-glycosides, such as benzyl
and thioglycosides also led to the desired products in
excellent yield (Table 1). It is worth noting that methyl
a-D-mannopyranoside (23) gave only 2,3;4,6-di-O-iso-
propylidene ketal (24) when treated with 2 mol equiv
of 2,2-dimethoxypropane under the same conditions.
The use of 1 mol equiv of 2,2-dimethoxypropane led to
an incomplete conversion of the starting material.
Acknowledgements
Instrumentation facilities from SAIF, CDRI are grate-
fully acknowledged. I thank Dr. Raja Roy for useful dis-
cussions during the course of this work, and Mr.
Abhijeet Deb Roy for assistance with acquiring NMR
spectra.
References and notes
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Kartha, K. P. R.; Russell, D. A.; Field, R. A. J. Org.
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3. Greene, T. W.; Wuts, P. G. M. Protective Groups in
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4. (a) de Belder, A. N. Adv. Carbohydr. Chem. Biochem.
1965, 20, 219–302; (b) de Belder, A. N. Adv. Carbohydr.
Chem. Biochem. 1977, 34, 179–241.
5. Kihlberg, J.; Frejd, T.; Jansson, K.; Magnusson, G.
Carbohydr. Res. 1986, 152, 113–130.
6. Barili, P. L.; Berti, G.; Catelani, G.; Colonna, F.; Marra,
A. Tetrahedron Lett. 1986, 27, 2307–2310.
7. Hung, S.-C.; Chen, C.-S. J. Chin. Chem. Soc. 2000, 47,
1257–1262.
A 25 mmol scale benzylidenation–acetylation reaction
with methyl-b-D-glucopyranoside (1) using stoichio-
metric reagents gave the desired product without affect-
ing the overall yield, which suggested that the reagent
system is equally viable on a large scale. After filtration
of the product, the H2SO4–silica was recovered and used
again after drying. Five recycles showed almost no
change in the reactivity or the yield of the desired
product.
In conclusion, a sequential one-pot strategy for making
per-O-acetylated benzylidene acetals or isopropylidene
ketals of O- and S-glycosides under stoichiometric con-
ditions has been developed using safe and easy to handle
H2SO4–silica. This strategy is compatible with various
glycosides, including acid labile p-methoxyphenyl glyco-
sides, and is equally applicable to large-scale synthesis.

4340
B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 4337–4341
8. Winnik, F. M.; Carver, J. P.; Krepinsky, J. J. J. Org.
Chem. 1982, 47, 2701–2707.
3.53 (m, 1H, H-5); 2.09, 2.05 (2s, 6H, 2 · COCH3). ESI
MS m/z 481.1 [M+Na].
9. Ault, R. G.; Howarth, W. N.; Hirst, E. L. J. Chem. Soc.
1935, 1012.
10. Wood, H. B., Jr.; Diehl, H. W.; Fletcher, H. G., Jr. J. Am.
Chem. Soc. 1957, 79, 1986–1988.
24. 2-Trimethylsilylethyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-
D-galactopyranoside (8). 1H NMR (300 MHz, CDCl3) d:
7.65–7.39 (m, 5H, ArH); 5.55 (s, 1H, CHPh); 5.15 (dd, 1H,
J1,2 = 7.8 Hz, J2,3 = 10.2 Hz, H-2); 5.04 (dd, 1H, J2,3
,
´
´
11. Liptak, A.; Imre, J.; Nanasi, P. Carbohydr. Res. 1981, 92,
J3,4 = 3.6 Hz, H-3); 4.45 (d, 1H, J1,2 = 7.8 Hz, H-1); 4.00
[m, 1H, O–CH2–CH2–Si(CH3)3]; 3.78–3.53 (m, 3H, H-5,
H-6a, H-6b); 3.50 [m, 2H, O–CH2–CH2–Si(CH3)3]; 2.03,
2.00 (2s, 6H, 2 · COCH3); 0.89 [m, 2H, O–CH2–CH2–
Si(CH3)3]; 0.02 [s, 9H, O–CH2–CH2–Si(CH3)3]. ESI MS
m/z 475.1 [M+Na].
154–156.
12. Boulineau, F. P.; Wei, A. Carbohydr. Res. 2001, 334, 271–
279.
13. Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415–
3416.
14. (a) Garegg, P. J.; Swahn, C.-G. Methods Carbohydr.
Chem. 1980, 8, 317; (b) Hoffmann, B.; Bernet, B.; Vasella,
A. Helv. Chim. Acta. 2002, 85, 265–286.
15. Mukhopadhyay, B.; Russell, D. A.; Field, R. A. Carbo-
hydr. Res. 2005, 340, 1075–1080.
25. n-Octyl
2-acetamido-3-O-acetyl-2-deoxy-4,6-O-benzyli-
dene-a-D-glucopyranoside (10). 1H NMR (300 MHz,
CDCl3) d: 7.44–7.31 (m, 5H, Ar.H); 5.86 (d, 1H,
J2,NH = 9.6 Hz, NH); 5.50 (s, 1H, CHPh); 5.29 (t, 1H,
J2,3 = J3,4 = 9.6 Hz, H-3); 4.79 (d, 1H, J1,2 = 3.2 Hz, H-1);
4.34 (dt, 1H, J2,3, J3,4, J2,NH = 9.6 Hz, H-2); 4.26 (dd, 1H,
J5,6 = 4.8 Hz, J6a,6b = 10.4 Hz, H-6a); 3.88 (m, 1H, H-5);
3.79 (t, 1H, J3,4 = J4,5 = 9.6 Hz, H-4); 3.68 (m, 2H, H-6b,
OCH2); 3.38 (m, 1H, OCH2); 2.03 (s, 3H, COCH3); 1.92 (s,
3H, NHCOCH3); 1.58 (m, 2H, OCH2CH2); 1.29 (m, 10H,
5 · octyl CH2); 0.87 (t, 3H, J = 5.7 Hz, octyl–CH3). ESI
MS m/z 486.3 [M+Na].
16. (a) Zolfigol, M. A.; Bamoniri, A. Synlett 2002, 1621–1623;
(b) Zolfigol, M. A. Tetrahedron 2001, 57, 9509; (c)
Zolfigol, M. A.; Shirini, F.; Ghorbani Choghamarani,
A.; Mohammadpoor-Baltork, I. Green Chem. 2002, 4, 562.
17. Shirini, F.; Zolfigol, M. A.; Mohammadi, K. Bull. Korean
Chem. Soc. 2004, 25, 325–327.
18. Preparation of H2SO4 immobilized on silica: To a slurry of
silica gel (5 g, mesh 60–120, Spectrochem, India) in diethyl
ether (20 mL) was added commercially available concd
H2SO4 (250 lL), and the solvents were evaporated under
vacuum. The free flowing silica thus obtained was heated
at 110 ꢁC for 2 h and kept in a desiccator over P2O5 for
further use.
26. Methyl 2,3-di-O-acetyl-4,6-O-(4-methoxybenzylidene)-b-D-
glucopyranoside (11). 1H NMR (300 MHz, CDCl3) d: 7.35,
6.87 (2d, 4H, J = 6.9 Hz, ArH); 5.46 (s, 1H, CHPh); 5.30
(t, 1H, J2,3 = J3,4 = 9.3 Hz, H-3); 4.95 (dd, 1H,
J1,2 = 7.8 Hz, J2,3, H-2); 4.50 (d, 1H, J1,2, H-1); 4.36 (dd,
1H, J5,6 = 4.8 Hz, J6a,6b = 10.5 Hz, H-6a); 3.80 (s, 3H,
C6H4OCH3); 3.75 (m, 1H, H-6b); 3.68 (t, 1H,
J3,4 = J4,5 = 9.3 Hz, H-4); 3.51 (s, 3H, OCH3); 3.47 (m,
1H, H-5); 2.06, 2.03 (2s, 6H, 2 · COCH3). ESI MS m/z
419.2 [M+Na].
19. General procedure for benzylidenation–acetylation: To a
mixture of sugar glycoside (1 mmol) in dry acetonitrile
(5 mL), benzaldehyde dimethylacetal (1 mmol) was added,
followed by H2SO4–silica (50 mg). The mixture was stirred
at room temperature until TLC revealed complete con-
version of the starting material to a faster moving
component. Acetic anhydride (4 mmol) was added and
stirring continued until TLC showed complete conversion
to the diacetates. Filtration through a pad of Celiteꢂ and
evaporation of the solvent under vacuum yielded the
27. Methyl 2,3-di-O-acetyl-4,6-O-(4-nitrobenzylidene)-a-D-gluco-
pyranoside (13). 1H NMR (300 MHz, CDCl3) d: 8.12,
7.56 (2d, 4H, J = 7.0 Hz, ArH); 5.54 (s, 1H, CHPh); 5.49
(t, 1H, J2,3 = J3,4 = 9.6 Hz, H-3); 4.90 (d, 1H, J1,2
=
5.1 Hz, H-1); 4.84 (dd, 1H, J1,2 = 5.1 Hz, J2,3 = 9.6 Hz, H-
2); 4.27 (dd, 1H, J5,6 = 4.5 Hz, J6a,6b = 9.6 Hz, H-6a);
3.90 (m, 1H, H-5); 3.75 (t, 1H, J6a,6b = 9.6 Hz, H-6b); 3.63
(t, 1H, J3,4 = J4,5 = 9.6 Hz, H-4); 3.36 (s, 3H, OCH3);
2.04, 2.02 (2s, 6H, 2 · COCH3). ESI MS m/z 434.1
[M+Na].
1
desired products in >95% purity, as judged by H NMR.
20. For the synthesis of compounds 10, 11, and 13, 4-methoxy-
benzaldehyde, 3-chlorobenzaldehyde, and 4-nitrobenz-
aldehyde were used instead of benzaldehyde dimethy-
lacetal. The remainder of the procedure was the same as
before.
28. Methyl
2,3-di-O-acetyl-4,6-O-(3-chlorobenzylidene)-a-D-
glucopyranoside (14). 1H NMR (300 MHz, CDCl3) d:
7.42–7.23 (m, 4H, ArH); 5.56 (t, 1H, J2,3 = J3,4 = 9.6 Hz,
H-3); 5.45 (s, 1H, CHPh); 4.92 (d, 1H, J1,2 = 3.6 Hz, H-1);
4.90 (dd, 1H, J1,2 = 3.6 Hz, J2,3 = 9.6 Hz, H-2); 4.30–4.28
(m, 1H), 4.27 (dd, 1H, J5,6 = 4.8 Hz, J6a,6b = 10.2 Hz, H-
6a); 3.91 (m, 1H, H-5); 3.74 (t, 1H, J6a,6b = 10.2 Hz, H-
6b); 3.62 (t, 1H, J3,4 = J4,5 = 9.6 Hz, H-4); 3.39 (s, 3H,
OCH3); 2.07, 2.04 (2s, 6H, 2 · COCH3). ESI MS m/z 423.1
[M+Na].
21. General procedure for isopropylidenation–acetylation: To a
mixture of sugar glycoside (1 mmol) in dry acetonitrile
(5 mL), 2,2-dimethoxypropane (1 mmol) was added, fol-
lowed by H2SO4–silica (50 mg). The mixture was stirred at
room temperature until TLC revealed complete conver-
sion of the starting material to a faster moving compo-
nent. Acetic anhydride (3 mmol) was added and stirring
continued until TLC showed complete conversion to the
acetates. Filtration through a pad of celiteꢂ and evapo-
ration of the solvent under vacuum yielded the desired
29. p-Tolyl 2,3-di-O-acetyl-4,6-O-benzylidene-1-thio-b-D-gluco-
pyranoside (16). 1H NMR (300 MHz, CDCl3) d: 7.45–7.14
(m, 9H, ArH); 5.48 (s, 1H, CHPh); 5.33 (t, 1H,
1
products in >95% purity, as judged by H NMR. For the
mannose derivative (23), 2 mmol of 2,2-dimethoxypro-
pane was added and the di-isopropylidene derivative (24)
was isolated by filtration and evaporation of the solvents.
22. Mathers, D. S.; Robertson, G. J. J. Chem. Soc. 1933, 696–
698.
23. 4-Methoxyphenyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-D-
galactopyranoside (6). 1H NMR (300 MHz, CDCl3) d:
7.51–6.76 (m, 9 H, ArH); 5.57 (dd, 1H, J1,2 = 8.1 Hz,
J2,3 = 10.2 Hz, H-2); 5.45 (s, 1H, CHPh); 5.04 (dd, 1H,
J2,3, J3,4 = 3.3 Hz, H-3); 4.89 (d, 1H, J1,2 = 8.1 Hz, H-1);
4.35 (d, 1H, J3,4 = 3.3 Hz, H-4); 4.29, 4.20 (2bd, 2H,
J6a,6b = 12.3 Hz, H-6a, H-6b); 3.71 (s, 3H, C6H4OCH3),
J2,3 = J3,4 = 9.2 Hz, H-3); 4.98 (t, 1H, J1,2 = 9.2 Hz, J2,3,
H-2); 4.74 (d, 1H, J1,2 = 9.2 Hz, H-1); 4.37 (dd, 1H,
J5,6 = 4.4 Hz, J6a,6b = 10.2 Hz, H-6a); 3.78 (t, 1H,
J3,4 = J4,5 = 9.2 Hz, H-4); 3.64 (t, 1H, J6a,6b = 10.2 Hz,
H-6b); 3.53 (m, 1H, H-5); 2.36 (s, 3H, SC6H4CH3), 2.12,
2.03 (2s, 6H, 2 · COCH3). ESI MS m/z 481.1 [M+Na].
30. Ashton, P. R.; Brown, C. L.; Menzer, S.; Nepogodiev, S.
A.; Stoddart, J. F.; Williams, D. J. Chem. Eur. J. 1996, 2,
580–591.
31. Ethyl 2-O-acetyl-3,4-di-O-isopropylidene-1-thio-b-L-fuco-
pyranoside (20). 1H NMR (300 MHz, CDCl3) d: 4.93
(dd, 1H, J1,2 = 10.2 Hz, J2,3 = 7.2 Hz, H-2); 4.25 (d, 1H,

B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 4337–4341
4341
J1,2 = 10.2 Hz, H-1); 4.15 (dd, 1H, J2,3, J3,4 = 1.8 Hz, H-
3); 4.01 (dd, 1H, J3,4, J4,5 = 5.1 Hz, H-4); 3.81 (m, 1H, H-
5); 2.65 (m, 2H, S–CH2–CH3); 2.04 (s, 3H, COCH3); 1.50,
1.29 (2s, 6H, isopropylidene–CH3), 1.35 (d, 3H,
J5,6 = 6.6 Hz, H-6); 1.19 (t, 3H, J = 7.5 Hz, S–CH2–
CH3). ESI MS m/z 313.1 [M+Na].
32. Gigg, J.; Gigg, R.; Payne, S.; Conat, R. Carbohydr. Res.
1985, 141, 91.