Protection of hydroxyl groups as a trimethylsilyl ether by 1,1,1,3,3,3-hexamethyldisilazane promoted by aspartic acid as an efficient organocatalyst

Article abstract of DOI:10.1016/S1872-2067(10)60210-0

A wide variety of alcohols and phenols were protected as trimethylsilyl ethers using 1,1,1,3,3,3-hexamethyl disilazane catalyzed by aspartic acid as a non-toxic, metal-free, and green organocatalyst at room temperature in acetonitrile under mild and heterogeneous conditions. The procedure is operationally simple and the silylated product was obtained in high yield and purity.

Full text of DOI:10.1016/S1872-2067(10)60210-0

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 4, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 595–598.
RESEARCH PAPER
Protection of Hydroxyl Groups as a Trimethylsilyl Ether by
1,1,1,3,3,3-Hexamethyldisilazane Promoted by Aspartic
Acid as an Efficient Organocatalyst
Arash GHORBANI-CHOGHAMARANI*, Masoomeh NOROUZI
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
Abstract: A wide variety of alcohols and phenols were protected as trimethylsilyl ethers using 1,1,1,3,3,3-hexamethyl disilazane catalyzed
by aspartic acid as a non-toxic, metal-free, and green organocatalyst at room temperature in acetonitrile under mild and heterogeneous
conditions. The procedure is operationally simple and the silylated product was obtained in high yield and purity.
Key words: alcohol; phenol; 1,1,1,3,3,3-hexamethyldisilazane; trimethylsilylation; protection
The search for molecules that are able to catalyze reactions
between other molecules is important to increase the efficiency
of chemical reactions and to provide ecological and economi-
cal viable options for the consumption of chemicals [1]. When
a chemical reaction is to be carried out selectively at one reac-
tive site in a multifunctional compound the other reactive sites
must be temporarily blocked [2]. Silyl ethers are a popular and
promising protecting group of hydroxy functions in synthetic
organic chemistry and a variety of silyl ethers have been de-
veloped to date [3–7]. However, the use of these silylating
agents is limited by disadvantages such as harsh reaction con-
ditions, scarcity and tedious purification processes. 1,1,1,3,3,3-
Hexamethyldisilazane (HMDS) is a cost-effective and stable
reagent and is one of the most widely used silylating agents for
the trimethylsilylation of hydroxyl groups. The best advantage
of this reagent is the quick isolation of the products from the
reaction media because the by-product of the reaction is am-
monia, which is easily removed from the reaction media.
However, the low silylating power of HMDS is its main
drawback. Therefore, to activate this reagent an appropriate
catalyst should be used. Over the last decade many catalysts
[8–15] have been used for this purpose but some of these
procedures suffer from long reaction times, low product yields,
heavy metal contamination, and catalyst toxicity.
1 Experimental
All chemicals and solvents were purchased from Fluka,
Merck, or Aldrich and used without further purification. All the
products are known and were characterized by a comparison of
1
their spectral (IR, H NMR, or 13C NMR) and physical data
with authentic samples.
To a mixture of 4-bromobenzyl alcohol (0.187 g, 1 mmol)
and hexamethyldisilazane (0.129 g, 0.8 mmol) in CH3CN (10
ml), aspartic acid (0.003 g, 0.02 mmol) was added and the
mixture was stirred at room temperature for 7 min (reaction
progress monitored by TLC). The reaction was then quenched
with water (10 ml) and 20 ml of CH2Cl2 was added. The or-
ganic phase was then dried over Na2SO4 (3 g). Evaporation of
the solvent gave pure (4-bromobenzyloxy)trimethylsilane in a
90% yield.
2 Results and discussion
In a continuation of our studies into the application of new
catalysts in organic functional group transformations [16–22],
we disclose here a new, efficient, and mild procedure for the
trimethylsilylation of a wide variety of hydroxyl groups using
HMDS in the presence of a catalytic amount of aspartic acid as
Received 24 November 2010. Accepted 6 February 2011.
*Corresponding author. Tel: +98-841-2227022; Fax: +98-841-2227022; E-mail: arashghch58@yahoo.com, a.ghorbani@mail.ilam.ac.ir
This work was supported by the research facilities of Ilam University, Ilam, Iran for financially supporting this research project.
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60210-0

Arash GHORBANI-CHOGHAMARANI et al. / Chinese Journal of Catalysis, 2011, 32: 595–598
Table 1 Trimethylsilylation of 4-bromobenzyl alcohol using HMDS and
an efficient organocatalyst under mild and heterogeneous
conditions at room temperature.
catalytic amounts of aspartic acid at room temperature in different sol-
vents
Initially, to find an appropriate solvent for this procedure we
screened different solvents for the trimethylsilylation of
4-bromobenzyl alcohol with HMDS in the presence of a cata-
lytic amount of aspartic acid. As is evident from Table 1,
4-bromobenzyl alcohol was silylated in acetonitrile faster than
in the other solvents. Consequently, we decided to use ace-
tonitrile as a solvent for the protection of the hydroxyl group by
HMDS and aspartic acid.
Entry
Solvent
acetonitrile
chloroform
dichloromethane
n-hexane
Time (h)
0.12
24
Yielda (%)
1
2
3
4
5
6
90
66
87
12
b
24
—
ethyl acetate
acetone
20
77
87
24
Reaction conditions: substrate 1 mmol, HMDS 0.8 mmol, aspartic acid
0.02 mmol. aIsolated yield. bTrace conversion.
With optimal conditions in hand, we report here the protec-
tion of alcohols as trimethylsilyl ethers using HMDS in the
presence of a catalytic amount of aspartic acid in acetonitrile at
room temperature with good to excellent yields (Table 2).
The trimethylsilylated product was obtained in good to high
yield and the work-up procedure is very simple. Aspartic acid
is easily isolated by filtration and the pure product can be
obtained by a simple distillation of the reaction solvent. As
shown in Table 2, the amount of HMDS and catalyst depends
on the nature of the alcohol.
Table 2 Trimethylsilylation of alcohols 1a–1v to the corresponding trimethylsilyl ethers 2a–2v using HMDS in the presence of a catalytic amount of
aspartic acid in CH3CN at room temperature
R
OH
R
OSiMe3
1
2
Catalyst Time Yielda
(mmol) (min) (%)
HMDS Catalyst Time Yielda
(mmol) (mmol) (min) (%)
Entry
1
Substrate
HMDS (mmol)
0.8
Entry
13
Substrate
0.02
0.02
—
8
95
0.8
0.8
0.8
0.02
0.02
0.02
3
88
1a
1b
1b
1l
1m
1n
CHCH OH
H3CO
CH2OH
CH2OH
CH2OH
2
CH
3
2
3
0.8
0.8
50
91
14
15
4
98
O2N
O2N
CHOH
CH CH
2
3
300
72b
25 84
60 96
HO
OH O
4
0.8
0.02
7
90
16
0.8
0.02
1c
1o
Br
F
CH OH
2
5
6
0.8
0.8
0.02
0.02
3
6
91
98
17
18
1.6
1.0
0.02
0.02
10 80
17 97
1d
1e
1p
1q
CH2OH
OH
H
OH
H
H
H C
Me HC
2
CH OH
3
2
CH
3
H C
3
H
H
HO
OH
7
8
0.8
0.8
0.8
0.8
0.02
0.02
0.02
0.02
10
3
88
97
94
92
19
20
21
22
0.8
0.8
1.0
0.8
0.02
0.02
0.02
0.02
60 90
1f
1g
1h
1i
1r
1s
1t
CH OH
2
Cl
OH
3
96
CH2OH
F
Cl
OH
9
50
5
25 94
90 85
Cl
CH2OH
Cl
F
F
10
1u
F
CH OH
2
OH
F
F
OH
11
12
0.8
0.8
0.02
0.02
3
5
98
86
23
2.0
0.20
840 87
1j
1v
CH2CH2OH
CH2CCH3
CH3
1k
CH OH
2
O
aIsolated yield. bIn the absence of catalyst.

Arash GHORBANI-CHOGHAMARANI et al. / Chinese Journal of Catalysis, 2011, 32: 595–598
OH
OTMS
OH
CH CCH
OTMS
CH CCH
HMDS (1 mmol)
+
+
2
3
2
3
Aspartic acid (0.02 mmol)
CH
CH
3
CH CN, rt, 25 min
3
3
100%
Trace
Scheme 1. Selectivity in the silylation reaction.
To investigate the role of aspartic acid as catalyst,
4-nitrobenzyl alcohol was subjected to the trimethylsilylation
reaction without the catalyst. However, the reaction was not
complete and the silylated product was obtained in 72% yield
after 300 min (Table 2, entry 3).
H3N
O
O
O
OH
O
O
O
NH3 O
Also, our results show that unhindered alcohols are more
reactive than hindered alcohols and this selectivity is shown
emphatically in Scheme 1.
R
OH + Me3SiNHSiMe3
H
H
O
N
R
SiMe3
Me3Si
H
To demonstrate the reactivity of the described system some
hydrogen-labile substrates (in addition to alcohols) such as
phenols, amines, and thiols were subjected to trimethylsilyla-
tion with HMDS in the presence of a catalytic amount of as-
partic acid (Table 3).
NH3
O
O
O
O
H
O
R
OH
O
R
OSiMe3 + NH2SiMe3
+
HO
H
NH3 O
As shown in Table 3 the phenolic and alcoholic compounds
were protected as trimethylsilyl ethers but the thiols and
amines did not react with HMDS. Therefore, this procedure
may be used for the silylation of hydroxyl groups in the pres-
ence of amino and thio functions.
O
N
R
H
Me3Si
H
O
OH
O
R
OSiMe3
+
+ NH3
NH3 O
A plausible mechanism for the silylation reaction is outlined
in Scheme 2. Aspartic acid polarizes the Si–N bond by hy-
drogen bonding. Polarization of the Si–N bond converts
HMDS to an activated silylating agent. On the other hand,
hydrogen bonding between the hydroxyl group and the car-
boxylate moiety activates the hydroxyl group. The same se-
quence is apparent for the second alcohol molecule. Finally,
the hydroxyl group silylate and ammonia is released as a
by-product.
Scheme 2. Mechanism of the silylation of hydroxyl groups upon cataly-
sis by aspartic acid.
3 Conclusions
We developed a new catalytic protocol for the efficient
trimethylsilylation of alcohol and phenol derivatives under
metal-free, mild, and heterogeneous conditions. Short reaction
times, metal-free content, good reaction yields, no environ-
mental pollution, and simple work-up procedures make this
method an excellent alternative for the protection of hydroxyl
groups.
Table 3 Trimethylsilylation of phenols, amines, and thiols to the cor-
responding trimethylsilylated products using HMDS in the presence of a
catalytic amount of aspartic acid in acetonitrile at room temperature
Time Yieldb
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