Direct and convenient method of regioselective benzylation of methyl α-D-glucopyranoside

Article abstract of DOI:10.1080/00397910701397326

A facile and convenient method for the direct preparation of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2) by the regioselective benzylation of methyl α-D-glucopyranoside (1) with benzyl bromide in the presence of mild bases K2CO3 and KOH (1:1) withou

Full text of DOI:10.1080/00397910701397326

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Direct and Convenient Method of
Regioselective Benzylation of Methyl
α‐D‐Glucopyranoside
a
a
a
a
a
Xiaoliu Li , Zhiwei Li , Pingzhu Zhang , Hua Chen & Shiro Ikegami
a
Department of Chemistry, Hebei University, Baoding, China
Version of record first published: 03 Jul 2007.
To cite this article: Xiaoliu Li , Zhiwei Li , Pingzhu Zhang , Hua Chen & Shiro Ikegami (2007): Direct and
Convenient Method of Regioselective Benzylation of Methyl α‐D‐Glucopyranoside, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:13, 2195-2202
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Synthetic Communications , 37: 2195–2202, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701397326
Direct and Convenient Method of
Regioselective Benzylation of Methyl
a-D-Glucopyranoside
Xiaoliu Li, Zhiwei Li, Pingzhu Zhang, Hua Chen,
and Shiro Ikegami
Department of Chemistry, Hebei University, Baoding, China
Abstract: A facile and convenient method for the direct preparation of methyl
2,3,6-tri-O-benzyl-a-D-glucopyranoside (2) by the regioselective benzylation of
methyl a-D-glucopyranoside (1) with benzyl bromide in the presence of mild bases
K CO and KOH (1:1) without solvents is reported.
2
3
Keywords: benzylation, glucopyranoside, regioselectivity, selective protection
INTRODUCTION
The syntheses of carbohydrate derivatives and mimics have attracted a great
attention because of their important biological significance and potential che-
motherapeutic value, and many methodologies for the syntheses have been
[
1]
developed in recent years. One of the most important jobs in carbohydrate
synthesis is to get a suitably protected intermediate that always involves the
[
2]
protection of the hydroxyl group.
[
Among the variety of protecting
one of the most useful techniques is benzylation protection,
3,4]
methods,
because the benzyl ether group has the advantages of good stability to a
wide range of acidic and basic conditions and easy removal under mild hydro-
genation conditions.
Benzylation has been readily achieved by the reaction of carbohydrate
[5]
and benzyl halides in the presence of a base such as potassium hydroxide
Received June 28, 2006
Address correspondence to Xiaoliu Li, Department of Chemistry, Hebei University,
No. 180 Wusi East Road, Baoding, Hebei 071002, China. E-mail: lixl@mail.hbu.cn
2
195

2
196
X. Li et al.
[6]
or sodium hydride in anhydrous DMF or potassium hydroxide in H O-
2
[7]
CH Cl solution using crown ether as the phase-transfer catalyst. The
2
2
benzylation could also be completed under an acidic condition using benzyl
trichloroacetimidate in the presence of catalytic amounts of trifluoromethane-
[
8]
sulfonic acid. However, the selective benzyl protection of the hydroxyl
groups was not so easy to achieve because of the very slight difference of
reactivity between the hydroxyl groups. Conventionally, the selective protec-
[9]
tion could be realized by using multistep reactions, including the application
[11]
[
10]
of temporary protective groups such as trityl
some special protocols, for instance, the selective activation of cyclic stanny-
or silyl ether
or by using
[2,12]
lene acetal or stannyl ether intermediates
and the regioselective reductive
Only a few achievements in the direct
and regioselective benzylations of some carbohydrate diols have been
[2,13]
opening of O-benzylidene acetals.
[14]
reported using benzyl halides and a mild base of Ag O
and very recently
by utilizing the adjacent azido group activation under the conventional benzy-
2
[
15]
lation conditions (NaH/BnBr in DMF at rt).
venient method of direct and selective benzylation of the hydroxyl groups still
To develop a simple and con-
[
2,4,16]
remains a great challenge.
Solvent-free organic synthesis has been recently recognized as one of
the more promising green synthetic techniques because of its considerable
synthetic advantages in terms of yield, selectivity, and simplicity of the
[
17–22]
reaction procedure.
In a solvent-free reaction, the interaction between
the dissimilar reactants under grinding becomes more sensitive and direct
than those in a solution because of the absence of solvation and associated
[23]
shielding by solvent molecules.
Consequently, a slightly difference of
the reactivity between similar functional groups, such as the hydroxyl
groups in carbohydrates, may result in good reaction selectivity in the
solvent-free state. With this point of view, we conceived that the application
to the solvent-free reaction may provide a certain possibility for the direct and
selective protection of the hydroxyl groups in carbohydrates. In this article, we
describe a new approach to the direct and selective multibenzylation of methyl
a-D-glucopyranoside with benzyl bromide in the presence of a mild base in a
solvent-free state, which provided a facile and convenient preparation of the
selectively protected methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside (2).
RESULTS AND DISCUSSION
The reaction was performed by grinding a mixture of methyl a-D-glucopyra-
noside (1), benzyl bromide (8.0 eq.), and KOH (4.0 eq.)/K CO (4.0 eq.) in a
2
3
mortar for 20 min. Then the mixture was transferred into a flask and kept in an
oil bath at 1208C for 1h. After workup and purification by silica-gel column
chromatography (petroleum ether–ethyl acetate ¼ 3:1), the partially benzy-
lated product of methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside (2) was
isolated in 58% yield as the main product, and the per-benzylated methyl

Regioselective Benzylation of Methyl a-D-Glucopyranoside
2197
Scheme 1. Benzylation of 1.
a-D-glucopyranoside (3) (8%) and a mixture of the other partially benzyl
protected (such as 2,6-di-O-benzyl-, 3,6-di-O-benzyl-, and 6-O-benzyl-)
methyl a-D-glucopyranosides (in total 10%) were also obtained (Scheme 1)
(Table 1, entry 5).
As shown in Table 1, the reaction exhibited good regioselectivity and
afforded the partially protected product of methyl 2,3,6-tri-O-benzyl-a-D-
glucopyranoside (2) as the predominant product in all cases. The reaction
selectivity was remarkably influenced by the reaction temperature and base.
For instance, as the reaction temperature went up from 608C to 1208C, the
regioselectivity in the ratio of 2:3 increased from 2.47 to 3.81 in the
presence of 4.0 equivalents of KOH (entries 1–3). However, the reaction
selectivity decreased when 6.0 equivalents of KOH were used under the
a
Table 1. Selective benzylation of methyl a-D-glucopyranoside (1)
b
Yield (%)
Temp. (8C)/
time (h)
Entry
Base
2
3
2:3
1
2
3
4
4.0 eq. KOH
4.0 eq. KOH
4.0 eq. KOH
6.0 eq. KOH
60/1
90/1
120/1
120/1
28.6
41.7
52.6
50.6
11.6
14.7
13.8
20.2
2.47
2.84
3.81
2.50
4
4
4
4
.0 eq. KOH
5
120/1
120/2
57.9
56.8
7.7
7.52
3.05
.0 eq. K CO
2
3
3
.0 eq. KOH
.0 eq. K CO
6
18.6
2
c
7
6.0 eq. KOH
8.0 eq. KOH
120/1
120/3
15.7
51.0
4.6
14.3
3.41
3.57
c
8
4
4
.0 eq. KOH
.0 eq. K CO
c
9
120/3
36.8
8.5
4.33
2
3
a
The reaction was carried out with 10.0 mmol of 1 and 80.0 mmol (8.0 eq.) of benzyl
bromide.
b
The other partially protected (2,6-di-O-benzyl-, 3,6-di-O-benzyl-, and 6-O-benzyl-)
methyl a-D-glucopyranosides were also separated, and in the transformation of the
reaction mixture from mortar to flask, a small amount of the reaction mixture was lost.
c
Using benzyl chloride as the benzylating reagent instead of benzyl bromide under
similar reaction conditions to entry1. The reactant (1) was partially recovered.

2
198
X. Li et al.
same conditions (entry 4), which indicated that the amount of 6.0 equivalents
of KOH was too strong in the selective reaction. A combined mild base of
K CO and KOH (4.0 equiv. in 1:1) was used in the reaction, and the
2
3
reaction regioselectivity was improved obviously with the ratio of 2:3 up to
7
2
.5:1 (entry 5). However, heating was prolonged to 2 h, the yield of methyl
,3,6-tri-O-benzyl-a-D-glucopyranoside (2) decreased and that of the per-ben-
zylated product (3) increased after heating for 2 h under the same conditions
entry 6).
Similarly, the benzylation of methyl a-D-glucopyranoside (1) with benzyl
(
chloride was examined, which was supposed to give a better regioselectivity
because of its lower alkylating reactivity than benzyl bromide. However, as
shown in Table 1 (entries 7–9), the results were not so good as the case of
using benzyl bromide as the benzylating reagent under similar conditions.
Methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside (2) is a very important
intermediate in the synthesis of carbohydrate derivatives. It was commonly
prepared from methyl a-D-glucopyranoside by the successive three-step
reactions of 4,6-O-benzylidenation and 2,3-O-dibenzylation and the
selective reductive opening of the acetal moiety of 4,6-O-benzylidene-2,3-
di-O-benzyl-a-D-glucopyranoside with the combinations of NaCNBH þ HCl
3
[2]
.
(
or AlCl ) or BH NMe þ AlCl in THF solution. Although each reaction
3
3
3
3
in the three steps gave a good to excellent yield, the overall yield of the
preparation was moderate. This one-step tribenzylation of methyl a-D-gluco-
pyranoside provided a simple and convenient method of direct preparation of
methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside (2).
On the basis of this achievement of selective protection, the benzylation
of methyl 4,6-O-benzylidene-a-D-glucopyranoside (4) was further examined
under similar reaction conditions as shown in Scheme 2 and Table 2. The
monobenzylation of the diol (4) exhibited slight regioselectivity, which
preferred the 2-OH-benzylated product 6 to the 3-OH benzylated product 7.
[
15]
The result was similar to that reported by Ye.
1
The products 2, 3, 5, 6,
13
and 7 were characterized by the H NMR, C NMR, and/or HH COSY
spectra or by comparing those with authentic samples.
The regioselectivity of tribenzylation of 1 may be attributed to the
different reactivities between the primary 6-OH and the secondary hydroxyl
groups, and the different acidities of the secondary hydroxyl groups (2-, 3-
and 4-OH), which may connect with the internal hydrogen bonding (IHB)
[
16,24]
interaction (Scheme 3). At first, the primary 6-OH in 1 was deprotonated
by a base to form the intermediate A, followed by benzylation to afford the
Scheme 2. Benzylation of 4.

Regioselective Benzylation of Methyl a-D-Glucopyranoside
2199
Table 2. Selective benzylation of methyl 4,6-O-benzylidene-a-D-glucopyranoside
a
(4)
b
Yield (%)
Entry
1
Base
BnBr
5
6
7
4.0 eq. KOH þ
8.0 eq.
48.5
19.1
4.8
4
.0 eq. K CO
2 3
2
3
2.0 eq. KOH þ
.0 eq. K CO
4.0 eq. KOH þ
.0 eq. K CO
4.0 eq.
4.0 eq.
6.8
21.3
39.6
13.0
16.5
2
2
3
26.2
4
2
3
a
The reaction was carried out with 10.0 mmol of 4.
b
In the transformation of the reaction mixture from mortar to flask, a small amount of
the reaction mixture, was lost.
methyl 6-O-benzyl-a-D-glucopyranoside (B). In both A and B, the stronger
4
IHB will further decrease the acidity of the 4-OH (H ). On the other hand,
the steric factor of the 6-O-benzyl group may also influence the regioselectiv-
ity by blocking the base attacking 4-OH. The IHB and the steric effect
enhanced the reactive discrimination of the three secondary hydroxyl
groups and resulted in a high level of regioselectivity.
Similarly, the selectivity of the monobenzylation of 4 may also depend
upon the steric factor of the 4,6-O-benzylidene group and the different
acidities between 2- and 3-hydroxyl groups that may result from the IHB
3
(
Scheme 4). The hydrogen atom H involved in the IHB became less acidic
2
than H . Thus, the monobenzylation would preferably occur on 2-OH to
provide methyl 4,6-O-benzylidene-2-O-benzyl-a-D-glucopyranoside (6) as
the main monobenzylated product.
In summary, the benzylation of methyl a-D-glucopyranosides with benzyl
bromide and a base without solvent was investigated. In the presence of the
mild base of K CO and KOH (1:1), the regioselective benzylation of
2
3
methyl a-D-glucopyranoside (1) was carried out and predominantly afforded
methyl 2,3,6-tri-O-benzyl-a-D-glucopyranoside (2), providing a facile and
convenient method for preparing 2 by a direct and simple benzylation.
Scheme 3. Internal hydrogen bonding (IHB) interaction in 1 and its benzylation
intermediate.

2
200
X. Li et al.
Scheme 4. Internal hydrogen bonding (IHB) interaction in 4.
EXPERIMENTAL
1
13
H NMR, C NMR, and COSY spectra were measured on a FT-NMR
Bruker Avance 400 (400-MHz) NMR spectrometer using tetramethylsilane
Me Si) as an internal standard. Mass spectra (MS) were carried out on a
(
4
VG-7070E mass spectrometer with FAB (fast atomic bombardment) using
-nitrobenzyl alcohol (NBA) as the matrix. Thin-layer chromatography
TLC) was performed on precoated plates (Qingdao GF254) with detection
3
(
by UV light or with phosphomolybdic acid in EtOH/H O followed by
2
heating. Column chromatography was performed using SiO2 (Qingdao
200–300 mesh).
General Procedure for Benzylation without Solvent
The mixture of methyl a-D-glucopyranoside (1) (1.94 g, 10.0 mmol), KOH
(
(
40.0 mmol), K CO (40.0 mmol), and new distillated benzyl bromide
2 3
9.5 mL, 80.0 mmol) was ground in a mortar in N atmosphere for 20 min;
2
then the mixture was transferred into a flask and kept in an oil bath at
208C for 1 h. The reaction mixture was separated with H O and AcOEt.
1
2
The organic phase was dried over anhydrous MgSO4 and concentrated
under reduced pressure, and the residue was applied on silica-gel chromato-
graphy (petroleum ether–ethyl acetate ¼ 3:1, then 1:1) to get the per-benzy-
lated methyl a-D-glucopyranoside (3) (0.427 g, 7.7%), tribenzylated methyl
2,3,6-tri-O-benzyl-a-D-glucopyranoside (2) (2.69 g, 57.9%), and a mixture
of the dibenzyl-protected (such as 2,6-di-O-benzyl-, 3,6-di-O-benzyl-) and
the monobenzyl-protected methyl 6-O-benzyl-a-D-glucopyranosides.
ACKNOWLEDGMENT
The financial support from the National Natural Science Foundation of China
(
(
20472015), the Program of Science and Technology (S&T) of Hebei
3276414), the Natural Science Foundation of Hebei (2005000106), and the
Open Research Fund Program of Key Laboratory of Marine Drugs of Ministry
of Education of China (KLMD[OUC]200407) are gratefully acknowledged.

Regioselective Benzylation of Methyl a-D-Glucopyranoside
2201
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