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Direct and Convenient Method ofRegioselective Benzylation of Methylα‐D‐GlucopyranosideXiaoliu Li a , Zhiwei Li a , Pingzhu Zhang a , Hua Chen a & Shiro Ikegami aa Department of Chemistry, Hebei University, Baoding, ChinaVersion of record first published: 03 Jul 2007.

To cite this article: Xiaoliu Li , Zhiwei Li , Pingzhu Zhang , Hua Chen & Shiro Ikegami (2007): Direct andConvenient 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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Direct and Convenient Method ofRegioselective 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

K2CO3 and KOH (1:1) without solvents is reported.

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

developed in recent years.[1] One of the most important jobs in carbohydrate

synthesis is to get a suitably protected intermediate that always involves the

protection of the hydroxyl group.[2] Among the variety of protecting

methods,[3,4] one of the most useful techniques is benzylation protection,

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

and benzyl halides in the presence of a base such as potassium hydroxide[5]

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

Synthetic Communicationsw, 37: 2195–2202, 2007

Copyright # Taylor & Francis Group, LLC

ISSN 0039-7911 print/1532-2432 online

DOI: 10.1080/00397910701397326

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or sodium hydride[6] in anhydrous DMF or potassium hydroxide in H2O-

CH2Cl2 solution using crown ether as the phase-transfer catalyst.[7] The

benzylation could also be completed under an acidic condition using benzyl

trichloroacetimidate in the presence of catalytic amounts of trifluoromethane-

sulfonic acid.[8] 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-

tion could be realized by using multistep reactions,[9] including the application

of temporary protective groups such as trityl[10] or silyl ether[11] or by using

some special protocols, for instance, the selective activation of cyclic stanny-

lene acetal or stannyl ether intermediates[2,12] and the regioselective reductive

opening of O-benzylidene acetals.[2,13] Only a few achievements in the direct

and regioselective benzylations of some carbohydrate diols have been

reported using benzyl halides and a mild base of Ag2O[14] and very recently

by utilizing the adjacent azido group activation under the conventional benzy-

lation conditions (NaH/BnBr in DMF at rt).[15] To develop a simple and con-

venient method of direct and selective benzylation of the hydroxyl groups still

remains a great challenge.[2,4,16]

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

reaction procedure.[17–22] 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

shielding by solvent molecules.[23] 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.)/K2CO3 (4.0 eq.) in a

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

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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, theregioselectivity 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

Table 1. Selective benzylation of methyl a-D-glucopyranoside (1)a

Entry Base

Temp. (8C)/time (h)

Yield (%)b

2 3 2:3

1 4.0 eq. KOH 60/1 28.6 11.6 2.47

2 4.0 eq. KOH 90/1 41.7 14.7 2.84

3 4.0 eq. KOH 120/1 52.6 13.8 3.81

4 6.0 eq. KOH 120/1 50.6 20.2 2.50

54.0 eq. KOH

120/1 57.9 7.7 7.524.0 eq. K2CO3

64.0 eq. KOH

120/2 56.8 18.6 3.054.0 eq. K2CO3

7c 6.0 eq. KOH 120/1 15.7 4.6 3.41

8c 8.0 eq. KOH 120/3 51.0 14.3 3.57

9c4.0 eq. KOH

120/3 36.8 8.5 4.334.0 eq. K2CO3

aThe reaction was carried out with 10.0 mmol of 1 and 80.0 mmol (8.0 eq.) of benzyl

bromide.bThe 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.cUsing benzyl chloride as the benzylating reagent instead of benzyl bromide under

similar reaction conditions to entry1. The reactant (1) was partially recovered.

Scheme 1. Benzylation of 1.

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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

K2CO3 and KOH (4.0 equiv. in 1:1) was used in the reaction, and the

reaction regioselectivity was improved obviously with the ratio of 2:3 up to

7.5:1 (entry 5). However, heating was prolonged to 2 h, the yield of methyl

2,3,6-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 NaCNBH3þHCl

(or AlCl3) or BH3.NMe3þAlCl3 in THF solution.[2] Although each reaction

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.

The result was similar to that reported by Ye.[15] The products 2, 3, 5, 6,

and 7 were characterized by the 1H NMR, 13C 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)

interaction (Scheme 3).[16,24] 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.

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methyl 6-O-benzyl-a-D-glucopyranoside (B). In both A and B, the stronger

IHB will further decrease the acidity of the 4-OH (H4). 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

(Scheme 4). The hydrogen atom H3 involved in the IHB became less acidic

than H2. 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 K2CO3 and KOH (1:1), the regioselective benzylation of

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.

Table 2. Selective benzylation of methyl 4,6-O-benzylidene-a-D-glucopyranoside

(4)a

Entry Base BnBr

Yield (%)b

5 6 7

1 4.0 eq. KOHþ 8.0 eq. 48.5 19.1 4.8

4.0 eq. K2CO3

2 2.0 eq. KOHþ 4.0 eq. 6.8 21.3 13.0

2.0 eq. K2CO3

3 4.0 eq. KOHþ 4.0 eq. 26.2 39.6 16.5

4.0 eq. K2CO3

aThe reaction was carried out with 10.0 mmol of 4.bIn the transformation of the reaction mixture from mortar to flask, a small amount of

the reaction mixture, was lost.

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EXPERIMENTAL

1H NMR, 13C NMR, and COSY spectra were measured on a FT-NMR

Bruker Avance 400 (400-MHz) NMR spectrometer using tetramethylsilane

(Me4Si) as an internal standard. Mass spectra (MS) were carried out on a

VG-7070E mass spectrometer with FAB (fast atomic bombardment) using

3-nitrobenzyl alcohol (NBA) as the matrix. Thin-layer chromatography

(TLC) was performed on precoated plates (Qingdao GF254) with detection

by UV light or with phosphomolybdic acid in EtOH/H2O followed by

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), K2CO3 (40.0 mmol), and new distillated benzyl bromide

(9.5 mL, 80.0 mmol) was ground in a mortar in N2 atmosphere for 20 min;

then the mixture was transferred into a flask and kept in an oil bath at

1208C for 1 h. The reaction mixture was separated with H2O and AcOEt.

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.

Scheme 4. Internal hydrogen bonding (IHB) interaction in 4.

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