Efficient and practical protocol for silylation of hydroxyl groups using reusable lithium perchlorate dispread in silica gel under neutral condition

Article abstract of DOI:10.1016/j.jorganchem.2005.11.005

A very efficient and mild procedure for the trimethylsilylation of a wide variety of alcohols, including primary, allylic, benzylic, secondary, hindered secondary, tertiary, and phenols with hexamethyldisilazane on the surface of silica gel dispersed with LiClO₄ in room temperature at few minutes in excellent yields under neutral conditions is reported. This procedure also allows the excellent selectivity under LP-SiO₂ system for silylation of alcohols in the presence of amine and phenolic hydroxy groups.

Full text of DOI:10.1016/j.jorganchem.2005.11.005

Journal of Organometallic Chemistry 691 (2006) 817–820
www.elsevier.com/locate/jorganchem
Communication
Efficient and practical protocol for silylation of hydroxyl
groups using reusable lithium perchlorate dispread
in silica gel under neutral condition
*
Najmedin Azizi, Rozbeh Yousefi, Mohammad R. Saidi
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran
Received 27 September 2005; received in revised form 7 November 2005; accepted 7 November 2005
Available online 13 December 2005
Abstract
A very efficient and mild procedure for the trimethylsilylation of a wide variety of alcohols, including primary, allylic, benzylic, sec-
ondary, hindered secondary, tertiary, and phenols with hexamethyldisilazane on the surface of silica gel dispersed with LiClO4 in room
temperature at few minutes in excellent yields under neutral conditions is reported. This procedure also allows the excellent selectivity
under LP-SiO2 system for silylation of alcohols in the presence of amine and phenolic hydroxy groups.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: LP-SiO2; Silylation; Hexamethyldisilazane; Recycling; Hydroxyl group; Regioselective; Alcohol; Phenol; Lithium perchlorate; Silica gel
1. Introduction
[7], and tungstophosphoric acid [7c]. Hexamethyldisilaz-
ane (HMDS) is frequently used for the trimethylsilylation
of hydroxyl groups. HMDS is an inexpensive and com-
mercially available reagent. Its handling does not require
special precautions, and the workup is not time-consum-
ing, because the byproduct of the reaction is ammonia,
which is simple to remove from the reaction medium.
The low silylation power of HMDS is the main draw-
back to its application. Therefore, there are variety of
catalysts for activating of this reagent, such as I2 [8],
(CH3)3SiCl [9] and K-10 montmorillionite [10]. Recently,
trimethylsilyl azide used as an efficient reagent for the
silylation of hydroxyl group in neat conditions [11].
However, in most case a long reaction time, drastic reac-
tion conditions, or tedious workup is needed. In addi-
tion, trimethylsilyl azide is expensive and toxic. The
lack of a simple and general synthetic methodology for
the silylation of hydroxyl group in alcohols and phenols
under essentially neutral conditions, prompted us to
develop an efficient, convenient, and practical procedure
for the protection of hydroxyl groups at room
temperature.
Protection and deprotection of functional groups are
indispensable in gradients of the synthesis of poly func-
tional compounds, and several chemical conversions and
multiple sequence syntheses often require protection of
hydroxyl groups. The trimethylsilyl group is one of the
most popular and widely used groups for protecting the
hydroxyl function in synthetic organic chemistry and often
is used in analytical chemistry to prepare silyl ethers as vol-
atile derivatives of alcohols and phenols [1].
Several methods have been reported for this conver-
sion, including the reaction of an alcohol with trimethyl-
silyl halides in the presence of a stoichiometric amount of
a tertiary amine [2], with trimethylsilyl triflate and trim-
ethylsilyl methallylsulfinates, which are more reactive
than the chloride [3], allylsilanes in the presence of a cat-
alytic amount of p-toluenesulfonic acid [3], iodine [4], tri-
fluoromethanesulfonic acid [5], Sc(OTf)3 [6], zinc chloride
*
Corresponding author. Fax: +98 21 601 2983.
E-mail address: saidi@sharif.edu (M.R. Saidi).
0022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.11.005

818
N. Azizi et al. / Journal of Organometallic Chemistry 691 (2006) 817–820
Table 2
2. Results and discussion
Silylation of sec., tert., and acid-sensitive alcohol
Entry
ROH
Yield (%)a
Time (min)
20
In recent years, the use of lithium perchlorate in diethyl
ether (LPDE) as a medium has attracted attention due to
the enhanced rate and selectivity to various organic trans-
formations [12]. The LPDE provides a convenient medium
to carry out reactions under neutral and easy work-up con-
ditions. In continuation of our interest on the application
of lithium perchlorate for various organic transformations
[13], in this paper, we explore a very efficient, simple and
practical method for the silylation of phenols and alcohols
under neutral conditions. By using different reaction condi-
tions for the silylation of an alcohol with HMDS, we found
out that lithium perchlorate dispersed on silica gel (chro-
matography grade) in CH2Cl2 in ratio of LP-SiO2 (1:2
ratio, 1.0 g), HMDS (6 mmol), and ROH (10 mmol) at
room temperature, is the best reaction conditions. Interest-
ingly, reactions catalyzed by LiClO4 alone in the absence of
silica in CH2Cl2 or on the silica surface without LiClO4 are
not complete and the yields are very low. On the other
hand, in the case of solid alcohols, when the reaction is car-
ried out under neat conditions, the mixture becomes extre-
mely viscous and difficult to stir. Therefore, the reaction
with silica gel and under solvent-free condition was not
complete after long reaction time. Lithium perchlorate dis-
persed on silica gel in CH2Cl2 (in the case of simple alco-
hols petroleum ether can be used) was used for the
silylation of hydroxyl function for a variety of alcohols
and phenols with simple and highly efficient reaction condi-
tions. The results are summarized in Tables 1 and 2. Pri-
mary, secondary, tertiary, allylic, benzylic, hindered, acid
sensitive alcohols and phenols can be converted to the cor-
OH
94
97
1
2
Me
Ph
HO
Ph
20
O
OH
3
4
96
97
30
15
Me
Me
OH
OH
5
88
97
40
15
Ph
Ph
6
7
8
OH
96
89
15
30
OH
OH
Ph
Me
96b
6
9
HO
HO
Ph
OH
OH
96c
95c
95c
40d
40d
40d
10
11
12
n=1
n=2
n=3
n
Ph
OH
Table 1
13
87
50
Silylation of alcohols and phenols with HMDS
4–SiO2
ROH HMDSð0:6 eq.Þ;LiClO
ROSiMe
a
b,c
d
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒ!
3
Isolated yield.
1.5 equiv. HMDS was used.
The yield of bis(tirmethysilyl) ether.
CH2Cl2 r.t.,
;
Entry
ROH
Yeild (%)a
Time (min)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
1-Hexanol
96
96
96
95
98
97
92
95
96
94
96
96
96
95
96
90
84
90
90
84
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
Cyclohexanol
tret-Butanol
Allyl alcohol
Benzyl alcohol
responding ethers under these conditions. The reactions are
very fast and even bulky and acid-sensitive alcohols, which
required long reaction time (few days) by other conven-
tional reported methods, are found to give high yields in
few minutes at room temperature. In the case of simple
alcohols, silylation occurs quantitatively in a few minutes
(Table 1). Due to the mild and neutral reaction conditions,
no isomerization of double or triple bond and elimination
product were observed. The LP-SiO2 can also be used as a
catalyst for phenol derivatives. In general phenols give
lower yield and have longer reaction time in comparison
with alcohols.
4-Chlorobenzyl alcohol
4-Methoxy benzyl alcohol
Cinnamyl alcohol
1-Octanol
2-Octanol
Proparygylic alcohol
2-Propanol
Furfuryl alcohol
Cetyl alcohol
Isoamyl alcohol
1-Naphtol
2-Naphtol
Phenol
120
120
120
120
120
We also explored the chemoselectivity of LP-SiO2 sys-
tem. Table 3 clearly shows that in the presence of an
amine, and phenol the reaction with alcohol is completely
selective and the corresponding silylated alcohol is the
4-Methyl phenol
4-Chloro phenol
Isolated yeilds.

N. Azizi et al. / Journal of Organometallic Chemistry 691 (2006) 817–820
819
Table 3
Selective O-trimethylsilylation of alcohol in the presence of amine, and phenolic hydroxyl
HMDS (2 equi.), CH2Cl2
LP-SiO2, r.t, 10 min
OH
OSiMe3
PhCH2OSiMe3
100%
+
PhCH2OH
+
0%
HMDS (2 equi.), CH2Cl2
LP-SiO2, r.t, 10 min
H2N
H2N
OH
H2N
OSiMe3
100%
HMDS (2 equi.), CH2Cl2
LP-SiO2, r.t, 40 min
H2N
OH
OSiMe3
96%
sole product. Also, in the presence of an amino group,
only phenol reacts with HMDS to form the correspond-
ing silylated product. In the case of diol and dihydoxy
phenol (Table 2, entries 9–12), only bis(silylated) diol is
formed. Although the mechanism of this reaction is not
clear, silica gel has an important role and its presence
was found to be essential for the high efficiency of the
reaction.
In summery LiClO4–SiO2, is found to be superior, effi-
cient and novel catalyst for the silylation of various
hydroxy substrates with HMDS under mild and neutral
conditions. This procedure provides a novel, efficient and
general methodology for the preparation of trimethylsilyl
ether in high yields. In addition, LP-SiO2 is cheap, stable,
easy to handle and non-toxic with very simple work-up
procedure, which consists of filtration and removal of sol-
vent. The LP-SiO2 can be re-used several times after activa-
tion. Furthermore, HMDS exhibit excellent selectivity
under LP-SiO2 system for silylation of alcohols in the pres-
ence of amine, acid and phenol. Further investigation to
broaden the scope and synthetic applications of LP-SiO2
under solvent-free conditions is under way in our
laboratory.
Acknowledgments
We are grateful to the Research Council of Sharif Uni-
versity of Technology for financial support. We also thank
‘‘Volkswagen-Stiftung, Federal Republic of Germany’’ for
financial support towards the purchase of chemicals. The
author thanks the Islamic Development Bank (IDB) for
granting loan in 1993 to purchase 500-MHz Bruker
NMR spectrometer.
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