Efficient iodine-catalyzed preparation of benzylidene acetals of carbohydrate derivatives

Article abstract of DOI:10.1080/07328300802030837

An efficient preparation of benzylidene acetals of carbohydrate derivatives catalyzed by iodine has been developed. Yields were excellent in every case. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328300802030837

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Efficient Iodine‐Catalyzed Preparation
of Benzylidene Acetals of Carbohydrate
Derivatives
Rajib Panchadhayee a & Anup Kumar Misra a
a Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, UP, India
Version of record first published: 12 Jun 2008.
To cite this article: Rajib Panchadhayee & Anup Kumar Misra (2008): Efficient Iodine‐Catalyzed Preparation of
Benzylidene Acetals of Carbohydrate Derivatives , Journal of Carbohydrate Chemistry, 27:3, 148-155
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Journal of Carbohydrate Chemistry, 27:148–155, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802030837
Efficient Iodine-Catalyzed
Preparation of Benzylidene
Acetals of Carbohydrate
Derivatives
Rajib Panchadhayee and Anup Kumar Misra
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, UP, India
An efficient preparation of benzylidene acetals of carbohydrate derivatives catalyzed by
iodine has been developed. Yields were excellent in every case.
Keywords Carbohydrate, Benzylidene acetal, Iodine, Protecting group
INTRODUCTION
Preparation of suitably functionalized monosaccharide derivatives are the basic
requirements in the synthesis of oligosaccharides. Benzylidene acetal is one of
the frequently used protecting groups in the oligosaccharide synthesis for the
temporary protection of C-4/C-6 hydroxyl groups in carbohydrate derivatives.[1]
It can be removed easily under acidic hydrolysis[2] or under neutral condition by
hydrogenolysis.[3] One of the two C-O bonds of the benzylidene acetal can be
regioselectively opened under reductive conditions for its application in oligosac-
charide synthesis.[4] For these reasons several methods have appeared in the lit-
erature for the introduction of benzylidene acetal moiety in carbohydrates. Most
of the methods are based on the original report using benzaldehyde and zinc
chloride.[5] As a modification a transacetalation reaction condition has been
adopted using benzaldehyde dimethylacetal replacing benzaldehyde in the
presence of several Lewis acids (e.g., p-toluenesulfonic acid,[6] camphorsulfonic
acid,[7] etc.) and heterogeneous catalysts.[8,9] Benzylidene acetal formation has
Received October 3, 2007; accepted November 19, 2007.
C.D.R.I. communication no. 7374.
Address correspondence to Anup Kumar Misra, Medicinal and Process Chemistry
Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001,
UP, India. E-mail: akmisra69@rediffmail.com
148

Preparation of Benzylidene Acetals of Carbohydrate Derivatives
149
also been carried out under a basic condition using dibromotoluene and
pyridine.[10] However, most of these methods are time consuming, often requir-
ing reaction periods in excess of 24 h for completion as well as a large excess of
reagent and tedious workup followed by chromatographic purification. There-
fore, there is a need for a practical synthetic strategy, which renders the
access to the benzylidene acetal-containing carbohydrate derivatives using stoi-
chiometric reagents in a short reaction time. In recent years, molecular iodine
has been used as an inexpensive, nonmetallic, nontoxic bench-top catalyst in
several functional group transformations in carbohydrate chemistry.[11] It has
been applied to activate thioglycosides,[12] glycosyl sulfoxides,[13] and glycosyl
halides[14] in the oligosaccharide synthesis. In this communication we describe
a rapid preparation of benzylidene acetals of carbohydrate derivatives using ben-
zaldehyde dimethylacetal in the presence of molecular iodine as catalyst (Sch. 1).
RESULTS AND DISCUSSION
In a set of initial experiments, treatment of methyl a-D-glucopyranoside (1)
with benzaldehyde dimethylacetal (1.1 mol equiv.) in the presence of molecu-
lar iodine (0.5 equiv.) in dry acetonitrile at rt led to the corresponding 4,6-O-
benzylidene acetal (3) within 1 h (TLC; EtOAc-hexane 4:1). After optimization
of the reaction conditions it was observed that treatment of compound 1 with
benzaldehyde dimethylacetal (1.1 equiv.) in the presence of iodine (0.1 equiv.)
could furnish compound 3 in almost quantitative yield in 1 h at rt. Iodine was
removed during the removal of solvents under reduced pressure and the
compound collected proved to be pure by NMR and mass spectrometry. Fol-
lowing similar reaction conditions, a series of benzylidene acetal-containing
carbohydrate derivatives were prepared in excellent yield (Table 1). A 50-
mmol scale benzylidenation of methyl a-D-glucopyranoside using the opti-
mized reaction protocol furnished the desired product without affecting the
overall yield, indicating that the reagent system is equally viable in a scale-
up preparation. The reaction condition has been successfully applied for the
preparation of 4-methoxybenzylidene acetal of carbohydrate derivatives
(Table 1, entry 13–16). All known products gave acceptable spectral data
that matched with the cited references.
In conclusion, an efficient protocol has been demonstrated for the preparation
of 4,6-O-benzylidene derivatives of carbohydrate derivatives using benzaldehyde
Scheme 1: Molecular iodine-catalyzed benzylidene acetal formation in carbohydrate
derivatives.

R. Panchadhayee and A. K. Misra
150
Table 1: Preparation of benzylidene acetals of carbohydrate derivatives using
benzaldehyde dimethylacetal in the presence of iodinea.
Time Yield
Entry
Substrates
Products
(h)
(%) Ref.
1
1
90
92
90
[6]
2
3
1
1
[6]
[15]
4
5
6
1
88
85
85
[8]
[8]
[8]
1
1.5
(continued)

Preparation of Benzylidene Acetals of Carbohydrate Derivatives
151
Table 1: Continued.
Time Yield
Entry
Substrates
Products
(h)
(%) Ref.
7
1.5
80
[16]
8
9
1
90
85
[17]
—
1.25
10
1
90
[18]
11
12
13
14
1.5
85
88
80
82
[19]
[20]
[8]
1
1.25
1.25
[21]
(continued)

R. Panchadhayee and A. K. Misra
Table 1: Continued.
Products
152
Time Yield
Entry
Substrates
(h)
(%) Ref.
15
1.25
80 [22]
16
1
78
[23]
aReaction condition: substrate (1 mmol), benzaldehyde dimethylacetal (1.1 mmol), CH3CN,
iodine (0.1 mmol), rt.
Mp: 4-methoxyphenyl; SE: 2-trimethylsilylethyl.
dimethyl acetal in the presence of a catalytic amount of molecular iodine. Use of
iodine, a cheap bench-top chemical, will certainly attract synthetic carbohydrate
chemists as a practical alternative to the currently used hazardous, moisture-
sensitive acidic catalysts for the preparation of benzylidene derivatives.
EXPERIMENTAL
General Methods
All the reactions were monitored by thin layer chromatography over silica
gel-coated TLC plates. The spots on the TLC were visualized by warming the
ceric sulphate [2% Ce(SO4)2 in 2N H2SO4]-sprayed plates on a hot plate.
1
Silica gel 230 to 400 mesh was used for column chromatography. H and 13C
NMR were recorded on a Bruker Advance DPX 300 MHz using TMS as
internal reference. Chemical shift value is expressed in ppm. Elementary
analysis was carried out on a Carlo ERBA-1108 analyzer. Optical rotations
were measured at 258C on a Rudolf Autopol III polarimeter. Commercially
available grades of organic solvents of adequate purity were used in all
reactions.
General Procedure for the Benzylidenation of Carbohydrate Derivatives
To a solution of the sugar substrate (1 mmol) in dry acetonitrile (2 mL) was
added benzaldehyde dimethylacetal (1.1 mmol) followed by iodine (25 mg,

Preparation of Benzylidene Acetals of Carbohydrate Derivatives
153
0.1 mmol). The mixture was stirred at rt until TLC revealed complete con-
sumption of the starting material to a faster-moving component (Table 1).
Evaporation under reduced pressure to remove the solvents and the catalyst
yielded the desired product in .95% purity, which was characterized by
spectral analysis.
4-Methoxyphenyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-b-D-
galactopyranoside (22)
1
Yellow oil; H NMR (CDCl3, 300 MHz): d 8.08–7.43 (m, 9H, Ar-H), 6.95
(d, J ¼ 9.0 Hz, 2H, Ar-H), 6.77 (d, J ¼ 9.0 Hz, 2H, Ar-H), 5.85 (d, J ¼ 9.0 Hz,
1 H, H-1), 5.65 (s, 1H, PhCH), 4.73 (t, J ¼ 9.0 Hz, 1H, H-2), 4.62 (dd, J ¼ 9.6,
3.0 Hz, 1H, H-3), 4.42 (d, J ¼ 12.0 Hz, 1H, H-6a), 4.36 (d, J ¼ 3.0 Hz, 1H,
H-4), 4.12 (d, J ¼ 12 Hz, 1H, H-6b), 3.74 (s, 3 H, OCH3), 3.72–3.70 (m, 1H,
H-5); ESI-MS: m/z 526.2 [M þ Na]þ; Anal. Calcd. for C28H25NO8 (503.16): C,
66.79; H, 5.0; found: C, 66.55; H, 5.22.
ACKNOWLEDGMENTS
Instrumentation facilities from SAIF, CDRI, is gratefully acknowledged. R.P.
thanks CSIR, New Delhi, for providing a Junior Research Fellowship. AKM
thanks the Department of Science Technology, New Delhi, for financial
support through Ramanna Fellowship.
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