Efficient formation and cleavage of benzylidene acetals by sodium hydrogen sulfate supported on silica gel

Article abstract of DOI:10.1055/s-2007-984903

NaHSO₄SiO₂ was used as an efficient heterogeneous catalyst for both the formation and the cleavage of benzylidene acetals. This catalyst is compatible with many functional or protective groups. Under different solvent systems, either the formation or the cleavage of benzylidene acetals was carried out smoothly in excellent yields and with good chemoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984903

2116
LETTER
Efficient Formation and Cleavage of Benzylidene Acetals by Sodium
Hydrogen Sulfate Supported on Silica Gel
F
ormationandCle
o
avage of
B
en
u
z
ylidene
A
c
h
etals ong Niu,a,b Ning Wang,a Xiaoping Cao,b Xin-Shan Ye*a
a
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd 38,
Beijing 100083, P. R. of China
Fax +86(10)62014949; E-mail: xinshan@bjmu.edu.cn
b
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received 13 April 2007
regioselective removal of isopropylidene acetals, N-Boc,
methoxymethyl ether (MOM-), trityl, TBDMS, and other
groups.15 It can also catalyze formation of some protecting
groups16 and other transformations.17 Herein we report
Abstract: NaHSO4·SiO2 was used as an efficient heterogeneous
catalyst for both the formation and the cleavage of benzylidene
acetals. This catalyst is compatible with many functional or protec-
tive groups. Under different solvent systems, either the formation or
the cleavage of benzylidene acetals was carried out smoothly in that as a mild reagent NaHSO4·SiO2 can efficiently
excellent yields and with good chemoselectivity.
catalyze both the formation and cleavage of benzylidene
acetals in different solvents (Scheme 1).
Key words: sodium hydrogen sulfate supported on silica gel, pro-
tection, deprotection, benzylidene acetals, carbohydrate
Ph
OH
O
O
HO
R1O
PhCH(OMe)2
O
Protecting-group manipulation is still an essential element
in preparative carbohydrate and oligosaccharide synthe-
sis. Numerous methods and reagents are now available for
this purpose. Among them, benzylidene acetals have been
widely used for the protection of 1,2- and 1,3-diols in
carbohydrate chemistry due to its stability in neutral and
basic conditions.1 Furthermore, benzylidene acetals are
important for the functional-group transformations. Regio-
selective reductive opening of benzylidene acetals with
different reagents can lead to saccharides with one hy-
droxyl O-benzylated and one hydroxyl-free.2 Benzylidene
acetals can be also oxidatively cleaved with NBS to yield
6-bromo-4-benzoylhexopyranosides.3 Formation of ben-
zylidene acetals can be achieved with benzaldehyde in the
presence of ZnCl2,4 H2SO4 (concd),5 or TsOH.6 The for-
mation can be also realized with PhCHBr2 in pyridine7 or
PhCH(OMe)2 promoted by HBF4, TsOH, CSA,8 SnCl2,9
and other reagents.10 The benzylidene acetals can be
cleaved under neutral conditions, for example by hydro-
genolysis,11 by acid hydrolysis,12 or by other methods.13
However, most of these methods are associated with some
drawbacks such as use of strong acid conditions, unsatis-
factory yields, and incompatibility with other functional
groups. Therefore, the development of mild and efficient
conversion conditions both for the formation and for the
cleavage of benzylidene acetals is still in demand.
NaHSO4·SiO2
R3
89–99%
X = O, N
O
R1O
R3
MeCN
XR2
XR2
Ph
O
OH
HO
R1O
O
NaHSO4·SiO2
95–99%
X = O, N
O
R3
O
R1O
R3
CH2Cl2, MeOH
XR2
XR2
Scheme 1
The formation reaction of benzylidene acetals proceeded
in acetonitrile under mild conditions at room temperature.
Firstly, p-methylphenyl 2-deoxy-2-phthalimido-1-thio-b-
D-glucopyranoside (1) was chosen as the substrate. Treat-
ment of 1 with NaHSO4·SiO2 in the presence of benzalde-
hyde dimethyl acetal in acetonitrile provided the 4,6-O-
protected saccharide 2 in a very clean manner.18 In order
to test the reaction protocol, a series of sugar building
blocks were investigated. As displayed in Table 1, gluco-
sides and galactosides were furnished with benzylidene
acetals in excellent yields. In most cases, pure products
were obtained by removal of the heterogeneous catalyst
just by simple filtration and evaporation of the solvent. A
variety of functional groups such as azido, STol, OPh,
oxazolidinone, and general protective groups including
OMe, OBz, OAll, NPhth were unaffected. It is noteworthy
that the acid-labile protective groups p-methoxybenzyl
(PMB, entry 10) and epoxide (entry 11)19 were kept intact
during the protection operation. This method also worked
in the mannose case. Thiomannoside 25 provided the 4,6-
O-benzylidene-protected product 26 in 67% isolated yield
(entry 13), the dibenzylidenated side product was also
gained (the ratio of mono- to diprotected product is about
3:1 to 4:1). This result is better than that reported in the
literature (around 50% yield, even 38% yield).20
Recently, heterogeneous catalysts have been developed
for various chemical transformations. Among numerous
heterogeneous catalysts, sodium hydrogen sulfate sup-
ported on silica gel (NaHSO4·SiO2) especially attracted
our attention. This reagent can be easily prepared from
NaHSO4 and silica gel.14 It can promote chemo- and
SYNLETT 2007, No. 13, pp 2116–2120
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8
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Advanced online publication: 17.07.2007
DOI: 10.1055/s-2007-984903; Art ID: W07507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formation and Cleavage of Benzylidene Acetals
2117
Having achieved satisfactory results in the formation of labile protective group, survived the reaction conditions
benzylidene acetals, we turned our attention to the appli- (entry 6). On the other hand, epoxides, which frequently
cation of this catalyst to the reversed transformation– occur in natural products with the wide range of biological
deprotection of benzylidene acetals. Cleavage of ben- activities23 and are also synthetic precursors of many 1,2-
zylidene acetals was performed in a mixed solvent of functional groups,24 are normally unstable in acidic condi-
methanol (or isopropanol) and dichloromethane (v/v 1:4) tions. Interestingly, by the use of our method, we success-
in the presence of NaHSO4·SiO2 at room temperature.21 fully achieved the deprotection of the benzylidene acetal
As shown in Table 2, various benzylidene acetals under- 22 in quantitative yield with the epoxide intact (entry 7).
went deprotection smoothly to give the corresponding This yield is much higher than the reported19 yield (78%)
diols in good to excellent yields. For example, thiomanno- by hydrogenolysis cleavage. The benzylidene functional
side 3122 was treated with NaHSO4·SiO2 to obtain diol group in disaccharide derivative 33 was also smoothly
3222 in 96% yield (entry 5). Like the formation of and selectively deprotected in almost quantitative yield
benzylidene acetals, all of the functional groups in sub- (entry 8).
strates were not affected even after a long reaction time.
Especially, the PMB functional group, known as an acid-
Table 1 Formation of Benzylidene Acetals Catalyzed by NaHSO4·SiO2
Entry
Substrate
Time (h)
Product
Isolated yield (%)
99
HO
HO
HO
O
Ph
O
O
O
STol
STol
1
1
HO
NPhth
NPhth
2
1
HO
HO
O
O
Ph
O
O
OPh
OPh
HO
2
3
4
4
95
99
99
HO
OH
OH
3
4
HO
O
O
HO
Ph
O
O
HO
STol
2
STol
HO
OH
OH
6
5
HO
HO
HO
O
O
HO
Ph
O
O
1.5
OH
OH
OMe
OMe
7
8
HO
HO
HO
O
O
Ph
O
O
N3
5
6
1.5
4
99
99
N3
HO
OH
OH
9
10
HO
HO
HO
O
O
HO
Ph
O
O
STol
STol
N3
N3
11
12
Ph
OH
HO
OH
O
O
O
7
8
2
99
99
O
O
N3
O
HO
N3
13
14
Ph
OH
OH
O
O
O
BzO
1.5
O
O
N3
O
BzO
N3
15
16
Synlett 2007, No. 13, 2116–2120 © Thieme Stuttgart · New York

2118
Y. Niu et al.
LETTER
Table 1 Formation of Benzylidene Acetals Catalyzed by NaHSO4·SiO2 (continued)
Entry
9
Substrate
Time (h)
Product
Isolated yield (%)
Ph
OH OH
O
O
O
2
99
90
HO
STol
O
HO
STol
OH
OH
17
18
Ph
OH
HO
O
O
10a
1.5
O
PMBO
STol
OPMB
O
PMBO
STol
OPMB
19
20
HO
HO
O
O
Ph
O
O
O
O
11a
12a
1
95
90
O
OMe
OMe
21
22
OH
Ph
O
O
STol
O
O
HO
O
STol
NBn
1.5
NBn
O
O
24
23
OH
O
OH
Ph
O
OH
O
O
HO
HO
HO
13
2.0
67
STol
STol
26
25
a 2 Equiv of PhCH(OMe)2 were used.
In conclusion, we have developed an efficient and facile
method for both the formation and the cleavage of ben-
zylidene acetals using NaHSO4·SiO2 as a heterogeneous
catalyst. By changing different solvents, either the ben-
zylidene-protected or deprotected saccharides can be ob-
tained in excellent yields and with high chemoselectivity.
All the reactions can be performed under very mild condi-
tions without any effects on other functional groups in-
cluding the acid-labile PMB and epoxide functionalities.
Moreover, the catalyst is inexpensive and environmental-
ly benign. Due to its simplicity, mild conditions, and com-
patibility with other functional groups, this method may
find wide application in carbohydrate chemistry and other
synthetic organic transformations.
References and Notes
(1) (a) Wuts, P. G. M. Greene’s Protecting Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: New York, 2007.
(b) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.;
Huang, Y.-W.; Lee, C.-C.; Chang, K.-L.; Hung, S.-C.
Nature (London) 2007, 446, 896. (c) Wang, P. G. Nat.
Chem. Biol. 2007, 3, 309.
(2) (a) Bhattacharjee, S. S.; Gorin, P. A. J. Can. J. Chem. 1969,
47, 1195. (b) Garegg, P. J. Pure Appl. Chem. 1984, 56, 845.
(c) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987,
2033. (d) de Ninno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36, 669. (e) Liptak, A.; Imre, J.;
Hangi, J.; Nanasi, P.; Neszmelyi, A. Tetrahedron 1982, 38,
3721. (f) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang,
B.-J.; Hsu, C.-Y.; Hung, S.-C. Angew. Chem. Int. Ed. 2005,
44, 1665; and references therein.
(3) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34,
1035. (b) Banaszek, A.; Pakulski, Z.; Zamojski, A.
Carbohydr. Res. 1995, 279, 173. (c) Boivin, J.; Monneret,
C.; Pais, M. Tetrahedron 1981, 37, 4219. (d) Hanessian, S.
Adv. Chem. Ser. 1968, 74, 159.
(4) Fletcher, H. G. Methods Carbohydr. Chem. 1963, 2, 307.
(5) Carman, R. M.; Kibby, J. J. Aust. J. Chem. 1976, 29, 1761.
(6) McGowan, D. A.; Berchtold, G. A. J. Am. Chem. Soc. 1982,
104, 7036.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China, ‘973’ and ‘863’ grants from the Ministry
of Science and Technology of China.
(7) (a) Kenne, L.; Lindberg, B. Methods Carbohydr. Chem.
1980, 8, 317. (b) Russell, R. N.; Weigel, T. M.; Han, O.; Liu,
H.-W. Carbohydr. Res. 1990, 201, 95.
Synlett 2007, No. 13, 2116–2120 © Thieme Stuttgart · New York

LETTER
Formation and Cleavage of Benzylidene Acetals
2119
Table 2 Cleavage of Benzylidene Acetals Catalyzed by NaHSO4·SiO2
Entry
Substrate
Time (h)
Product
Isolated yield (%)
Ph
O
HO
HO
BzO
O
O
O
1
16
95
95
BzO
BzO
BzO
OMe
OMe
27
28
Ph
O
O
HO
HO
BnO
O
O
2
20
15
BnO
BnO
BnO
OMe
OMe
29
30
OH
O
Ph
O
O
O
O
STol
HO
O
3a
89
NBn
STol
NBn
O
O
24
23
OH
Ph
HO
O
O
O
O
4
25
18
17
99
96
93
BzO
O
N3
O
BzO
15
N3
16
N3
O
N3
O
O
HO
HO
N3
Ph
5
O
STol
STol
N3
31
32
Ph
O
OH
HO
O
O
6a
PMBO
STol
OPMB
O
PMBO
STol
19
OPMB
20
HO
HO
O
Ph
O
O
O
O
7a
11
10
99
99
O
OMe
OMe
21
22
Ph
O
OBn
O
OBn
BnO
BnO
O
OH
O
HO
O
BnO
BnO
O
8
BnO
O
OBz
BnO
STol
O
STol
OBz
34
33
a Solvent (i-PrOH–CH2Cl2, 1:4) was used.
(8) (a) Albert, R.; Dax, K.; Pleschko, R.; Stütz, A. Carbohydr.
Res. 1985, 137, 282. (b) Yamanoi, T.; Akiyama, T.; Ishida,
E.; Abe, H.; Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335.
(c) Crimmins, M. T.; Hollis, J. W. G.; Lever, G. J.
Tetrahedron Lett. 1987, 28, 3647. (d) Morimoto, Y.;
Mikami, A.; Kuwabe, S.-I.; Shirahama, H. Tetrahedron Lett.
1991, 32, 2909.
(9) Han, S. Y.; Joullié, M. M.; Petasis, N. A.; Bigorra, J.;
Cobera, J.; Font, J.; Ortuño, R. M. Tetrahedron 1993, 49,
349.
(11) (a) Peat, S.; Wiggins, L. F. J. Chem. Soc. 1938, 1088.
(b) Smith, A. B.; Hale, K. J. Tetrahedron Lett. 1989, 30,
1037. (c) Hartung, W. H.; Simonoff, R. Org. React. 1953, 7,
263.
(12) (a) Hann, R. M.; Richtmyer, N. K.; Diehl, H. W.; Hudson, C.
S. J. Am. Chem. Soc. 1950, 72, 561. (b) Smith, M.;
Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. J. Am.
Chem. Soc. 1962, 84, 430. (c) Bonner, T. G.; Bourne, E. J.;
McNally, S. J. Chem. Soc. 1960, 2929. (d) Szarek, W. A.;
Zamojski, A.; Tiwari, K. N.; Ison, E. R. Tetrahedron Lett.
1986, 27, 3827. (e) Park, M. H.; Takeda, R.; Nakanishi, K.
Tetrahedron Lett. 1987, 28, 3823.
(10) (a) Mukhopadhyay, B.; Russell, D. A.; Field, R. A.
Carbohydr. Res. 2005, 340, 1075. (b) Mukhopadhyay, B.
Tetrahedron Lett. 2006, 47, 4337.
Synlett 2007, No. 13, 2116–2120 © Thieme Stuttgart · New York

2120
Y. Niu et al.
LETTER
(13) (a) Mairanovsky, V. G. Angew. Chem., Int. Ed. Engl. 1976,
15, 281. (b) Agnihotri, G.; Misra, A. K. Tetrahetron Lett.
2006, 47, 3653.
(14) (a) Breton, G. W. J. Org. Chem. 1997, 62, 8952.
(b) Method for Preparation of NaHSO4·SiO2
crude reaction product through a short column of silica gel
using PE–EtOAc as eluent.
Compound 16: colorless solids, mp 108–109 °C. 1H NMR
(500 MHz, CDCl3): d = 8.10–8.08 (m, 2 H), 7.61–7.57 (m, 1
H), 7.49–7.44 (m, 4 H), 7.37–7.33 (m, 3 H), 6.02–5.94 (m, 1
H), 5.53 (s, 1 H), 5.39–5.35 (m, 1 H), 5.26–5.23 (m, 1 H),
4.98 (dd, J = 3.5, 10.5 Hz, 1 H), 4.52–4.46 (m, 3 H), 4.38–
4.35 (dd, J = 2.0, 12.5 Hz, 1 H), 4.22–4.17 (m, 1 H), 4.13–
4.08 (m, 2 H), 3.55 (d, J = 1.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d = 166.0, 137.5, 133.50, 133.45, 130.0, 129.3,
128.9, 128.5, 128.1, 126.1, 117.9, 101.0, 100.7, 72.8, 72.7,
70.3, 68.9, 66.4, 60.6. LRMS–FAB: m/z calcd for
To a solution of 4.14 g (0.03 mol) of NaHSO4·H2O in 20 mL
of H2O in a 100 mL round-bottomed flask was added 10.0 g
of SiO2 (column chromatographic grade, 60 Å, 200–300
mesh). Then, H2O was removed under reduced pressure, and
a free-flowing white solid was obtained. This reagent was
further dried by placing the beaker in an oven maintained at
105 °C for at least 10 h prior to use.
+
(15) (a) Mahender, G.; Ramu, R.; Ramesh, C.; Das, B. Chem.
Lett. 2003, 32, 734. (b) Ramesh, C.; Ravindranath, N.; Das,
B. J. Org. Chem. 2003, 68, 7101. (c) Ramesh, C.;
Mahender, G.; Ravindranath, N.; Das, B. Tetrahedron Lett.
2003, 44, 1465. (d) Ravindranath, N.; Ramesh, C.; Reddy,
M.; Das, B. Adv. Synth. Catal. 2003, 345, 1207. (e) Das, B.;
Mahender, G.; Kumar, V. S.; Chowdhury, N. Tetrahedron
Lett. 2004, 45, 6709. (f) Das, B.; Reddy, K. R.; Thirupathi,
P. Tetrahedron Lett. 2006, 47, 5855.
C23H27N4O6 [M + NH4 ]: 455; found: 455. Anal. Calcd for
C23H23N3O6: 63.15; H, 5.30; N, 9.61, Found: C, 62.80; H,
5.47; N, 9.57.
(19) Rehnberg, N.; Magnusson, G. J. Org. Chem. 1990, 55, 5467.
(20) Cumpstey, I.; Chayajarus, K.; Fairbanks, A. J.; Redgrave, A.
J.; Seward, C. M. P. Tetrahedron: Asymmetry 2004, 15,
3207.
(21) General Procedure for the Cleavage of Benzylidene
Acetals
(16) Ramu, R.; Nath, N.; Reddy, M.; Das, B. Synth. Commun.
2004, 34, 3135.
To a stirred solution of the 4,6-O-benzylidene-glycopyrano-
side (100 mg) in a mixed solvent of CH2Cl2 and MeOH (or
i-PrOH; v/v 4:1, 10 mL) was added activated NaHSO4·SiO2
(200 mg, dried at 105 °C for 10 h prior to use) at r.t. After
completion of the reaction (monitored by TLC), the mixture
was filtered through a Celite bed and the filtrate was con-
centrated. The residue was purified by column chromatog-
raphy on silica gel using PE–EtOAc as eluent to afford the
pure product. If the acid-sensitive functional groups exist, it
is necessary to quench the reaction with Et3N (0.2 mL) after
completion of the reaction.
(17) (a) Zolfigol, M. A.; Madrakian, E.; Ghaemi, E. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2001, 40,
1191. (b) Zolfigol, M. A.; Madrakian, E.; Ghaemi, E.
Molecules 2001, 6, 614. (c) Zolfigol, M. A.; Madrakian, E.;
Ghaemi, E.; Kiani, M. Synth. Commun. 2000, 11, 2057.
(d) Shirini, F.; Zolfigol, M. A.; Torabi, S. Lett. Org. Chem.
2005, 2, 544. (e) Damavandi, J. A.; Zolfigol, M. A.; Karimi,
B. Synth. Commun. 2001, 31, 3183. (f) Zolfigol, M. A.;
Sadeghi, M. M.; Mohammadpoor-Baltork, I.; Ghorbani
Choghamarani, A.; Taqian-nasab, A. Asian J. Chem. 2001,
13, 887. (g) Das, B.; Venkateswarlu, K.; Mahender, G.;
Mahender, L. Tetrahedron Lett. 2005, 46, 3041. (h) Das,
B.; Banerjee, J.; Ravindranath, N. Tetrahedron 2004, 60,
8357. (i) Ramesh, C.; Banerjee, J.; Pal, R.; Das, B. Adv.
Synth. Catal. 2003, 345, 557. (j) Das, B.; Banerjee, J. Chem.
Lett. 2004, 33, 960. (k) Zhuang, W.; Jørgensen, K. A. Chem.
Commun. 2002, 1336.
Compound 19: white solids, mp 135–136 °C. 1H NMR (300
MHz, CDCl3): d = 7.45 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 8.7
Hz, 2 H), 7.27–7.24 (m, 2 H), 7.10 (d, J = 8.1 Hz, 2 H), 6.91–
6.85 (m, 4 H), 4.76 (d, J = 10.2 Hz, 1 H), 4.65 (d, J = 12.6
Hz, 3 H), 4.56 (d, J = 12.9 Hz, 1 H), 3.99–3.93 (m, 2 H), 3.81
(s, 3 H), 3.80 (s, 3 H), 3.79–3.72 (m, 1 H), 3.67 (t, J = 9.3 Hz,
1 H), 3.54 (dd, J = 3.3, 9.3 Hz, 1 H), 3.46–3.44 (m, 1 H), 2.58
(br s, 1 H), 2.32 (s, 3 H), 2.01 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 137.8, 132.6, 130.3, 129.9, 129.7, 129.6, 113.9,
113.8, 87.8, 82.1, 77.9, 75.4, 72.0, 69.4, 67.4, 62.8, 55.3.
21.1. ESI-HRMS: m/z calcd for C29H35O7S [M + H+]:
527.2098; found: 527.2104.
(18) General Procedure for the Formation of Benzylidene
Acetals
To a stirred solution of the glycoside substrate (100 mg) and
benzaldehyde dimethyl acetal (1.5 mmol) in MeCN (10 mL)
was added activated NaHSO4·SiO2 (200 mg, dried at 105 °C
for 10 h prior to use) at r.t. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched
with Et3N (0.2 mL). The catalyst was filtered off through a
plug of Celite, and the filtrate was removed under reduced
pressure to yield the product. Although the product was pure
enough, analytical samples were prepared by passing the
(22) Fan, Q.-H.; Ni, N.-T.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Org.
Lett. 2006, 8, 1007.
(23) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev.
2004, 104, 2857.
(24) Larock, R. C. Comprehensive Organic Transformations, 2rd
ed.; John Wiley and Sons: New York, 1999, 1019.
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