A mild and highly efficient method for the preparation of silyl ethers using Fe(HSO4)3/Et3N by chlorosilanes

Article abstract of DOI:10.1002/jccs.201100701

Avery efficient and mild procedure for preparation of silyl ethers from benzylic, allylic, propargilic alcohols, phenols, naphtoles and some of phenolic drugs with trimethylsilylchloride (TMSCl), triethylsilylchloride (TESCl) and t-buthyldimethylsilyl chloride (TDSCl) ethers in the presence of Fe(HSO ₄)₃/Et₃N in roomtemperature in excellent yields is reported. This procedure also allows the excellent selectivity for silylation of alcohols and phenols.

Full text of DOI:10.1002/jccs.201100701

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
A Mild and Highly Efficient Method for the Preparation of Silyl Ethers using
Fe(HSO4)3/Et3N by Chlorosilanes
Abdolreza Abri,* Mohammad Galeh Assadi and Samira Pourreza
Chemistry Department, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran
(Received: Dec. 3, 2011; Accepted: Mar. 22, 2012; Published Online: ??; DOI: 10.1002/jccs.201100701)
A very efficient and mild procedure for preparation of silyl ethers from benzylic, allylic, propargilic alco-
hols, phenols, naphtoles and some of phenolic drugs with trimethylsilylchloride (TMSCl), triethyl-
silylchloride (TESCl) and t-buthyldimethylsilyl chloride (TDSCl) ethers in the presence of Fe(HSO4)3/
Et3N in room temperature in excellent yields is reported. This procedure also allows the excellent selectiv-
ity for silylation of alcohols and phenols.
Keywords: Silyl ethers; Phenolic drugs; TMSC; TESCl; TDSCl; Fe (HSO4)3.
INTRODUCTION
The protection of hydroxyl groups in the synthesis of
method for the synthesis of silyl ethers by alcohols and
phenols with chlorosilanes in the presence of Fe(HSO4)3/
Et3N, both in solution and under solvent-free conditions
(Scheme I).
poly functional compounds, and several chemical conver-
sions and multiple sequence synthesis is important process,
which is under considerable attention of organic chemists.1
Trimethylsilylation is used extensively for the protection
and derivatization of functional groups to increase volatil-
ity for gas chromatography and mass spectroscopy.2 And as
a silyl ether is widely used in the chemistry of drugs, ste-
roids, sugars and natural product synthesis.3-6 A large num-
ber of reagents and methods have been reported for the
preparation of trimethylsilyl ethers e.g. hexamethyldisil-
oxane,7 allylsilanes,8-9 chlorotrimethylsilane/lithium disul-
fide,10 N-trimethyl-2-oxazolidinone,11 TMSCl/K2CO3/
phase transfer catalyst,12 trimethylsilylazid,13 allyltrimeth-
ylsilane,14 and trimethylacetate,15 are examples.
Preparation of silyl ethers with Fe(HSO4)3/
Et3N reagent in solution and under solvent-
free condition
Scheme I
EXPERIMENTAL
Synthesis of silyl ethers were carried out under dry ar-
gon to exclude oxygen and moisture from the reaction sys-
tems.
1,1,1,3,3,3-Hexamethyldisilazane (HMDS) is fre-
quently used for the trimethylsilylation of hydroxyl groups.
HMDS is a stable, commercially available, and cheap re-
agent,16 and in workup does not require special precau-
tions, because the byproduct of the reaction is ammonia.
However, the low silylation power of HMDS is a main
drawback for its application which needs forceful condi-
tions and long reaction times in many instances. Therefore,
a variety of catalysts have been reported for activating of
this reagent.17
Materials
Chemicals were purchased from Fluka, Merk and
Aldrich chemical companies. All of trimethylsilyl ethers
and some of triethylsilyl ethers and tert-buthyldimethyl-
silyl ethers are known compounds, and were characterized
by spectra analyses, comparisons with authentic samples
(IR and NMR), and also by regeneration of the correspond-
ing alcohols. All yields refer to the isolated products. The
purity determination of the substrate and reaction monitor-
ing were accompanied by TLC on silica-gel Polygram
SILG/UV 254 plates.
Recently, the use of metal hydrogensulfates in or-
ganic reactions became an important part of our research
program.18-22 In continuation of these studies, we were in-
terested to investigate the applicability of Fe(HSO4)3 in or-
ganic synthesis.23 Here in we wish to report an efficient
Measurements
1H-NMR spectra were recorded on a Brucker 400 AC
spectrometer in CDCl3. The Infrared spectra were recorded
* Corresponding author. Tel: +98 412 432 7541; E-mail: ar.abri@yahoo.com, ar.abri@azaruniv.edu
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1

Article
Abri et al.
on a Shimadzu FT IR-408 spectrophotometer.
General procedure for the preparation of silyl ethers
under solvent-free conditions
General procedure for the preparation of silyl ethers
in CH3CN
A mixture of the substrate (1 mmol), triethylamine (1
mmol) and Fe(HSO4)3 (0.03 mmol), chlorosilane (1 mmol)
was stirred at room temperature. The progress of the reac-
tion was monitored by TLC. Water (10 mL) was added and
the mixture extracted with diethyl ether (3 × 7 mL). The or-
ganic layer was separated and dried (MgSO4). Evaporation
of the solvent gave almost pure product(s). Further purifi-
cation was proceeded by vacuum distillation or recrystal-
lization to afford pure silyl ether.
To a mixture of the substrate (1 mmol), triethylamine
(1 mmol) and Fe(HSO4)3 (0.03 mmol) in CH3CN (5 mL),
chlorosilane (1 mmol) was added dropwise within 10 min
with stirring at room temperature. After completion of the
reaction, (TLC or GC), water was added (10 mL) and the
organic layer was separated, dried (MgSO4) and filtered.
Evaporation of the solvent gave under reduced pressure
afforded the silylated compounds in high purity. Further
purification was proceeded by vacuum distillation or
recrystallization to afford the pure silyl ethers in good
high yields.
RESULTS AND DISCUSSION
In our development of new methods for functional
Table 1. Trimethylsilylation of alcohols and phenols in solution and under solvent-free conditionsa
Silylation in CH3CN Solvent-free silylation
Time (min)
Yield (%)b
20 98
Entry
Substrate
Time (min)
Yield (%)b
1
C6H5CH2OH
2-BrC6H4CH2OH
2-ClC6H4CH2OH
4-ClC6H4CH2OH
2-NO2C6H4CH2OH
3-NO2C6H4CH2OH
4-NO2C6H4CH2OH
4-NH2C6H4CH2OH
C6H5OH
15
16
15
15
5
98
95
90
95
95
90
95
85
95
80
85
85
2
25
20
20
10
12
8
95
90
95
90
90
95
85
90
80
85
80
3
4
5
6
5
7
4
8
20
20
40
10
20
15
17
30
5
9
10
11
12
4-NH2C6H4OH
4-NO2C6H4OH
4-ClC6H4OH
OH
20
13
14
10
50
70
70
8
75
70
OH
40
OH
CH2=CHCH2OHc
CH=CCH2OHc
15
16
30
15
70
65
20
10
70
70
HO
17
18
19
20
10
45
12
10
95
80
90
75
10
30
5
90
90
95
75
CHO
CH2OH
O
COOH
HO
CH3CONH
OH
OH
10
21
22
23
24
20
50
55
20
70
30
40
35
10
30
30
20
80
30
45
40
COOCH3
OH
O
HOOC
HO
NH2
OH
O
O
a Products were characterized by their physical constant, IR, NMR and Mass spectroscopy.
b Isolated yield. c Triethylsilylation was performed at reflux and 80 oC, respectively.
2
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Preparation of Silyl Ethers using Fe(HSO4)3/Et3N by Chlorosilanes
Table 2. Triethylsilylation of alcohols and phenols in solution and under solvent-free conditionsa
Silylation in CH3CN
Solvent-free silylation
Substrate
Entry
Time (h)
Yield (%)b
Time (h)
Yield (%)b
1
C6H5CH2OH
2-BrC6H4CH2OH
2-ClC6H4CH2OH
4-ClC6H4CH2OH
2-NO2C6H4CH2OH
3-NO2C6H4CH2OH
4-NO2C6H4CH2OH
4-NH2C6H4CH2OH
C6H5OH
25
30
26
25
10
12
8
95
95
95
95
90
90
95
80
95
80
85
75
20
20
20
22
5
95
95
95
95
95
95
95
85
95
80
85
80
2
3
4
5
6
5
7
3
8
30
10
30
20
30
25
7
9
10
11
12
4-NH2C6H4OH
4-NO2C6H4OH
4-ClC6H4OH
25
18
25
OH
13
14
30
80
60
15
90
80
65
OH
100
OH
CH2=CHCH2OHc
CH=CCH2OHc
15
16
50
30
70
60
40
20
70
70
HO
17
15
90
10
90
CHO
18
19
20
15
10
80
80
90
95
13
5
90
95
98
CH2OH
O
COOH
HO
CH3CONH
OH
60
OH
21
22
60
40
70
30
20
30
80
30
COOCH3
OH
O
HOOC
HO
23
24
90
30
45
30
20
30
45
30
NH2
OH
O
O
a Products were characterized by their physical constant, IR, NMR and Mass spectroscopy.
b Isolated yield. c Triethylsilylation was performed at reflux and 80 oC, respectively.
group transformation, we have already introduced ferric
hindered silylethers such as triethylsilyl and tert-buthyldi-
methylsilyl ethers are synthesized. In order to optimized
the reaction conditions, we first examined the effect of dif-
ferent ratios of ROH/TMSCl or TESCl/Fe(HSO4)3/Et3N,
employing the 1/1/0.03/1 mmol ratio gave the best result
and produced trimethylsilyl, triethylsilyl and tert-buthyldi-
methylsilyl ethers in quantitative yields. The reactions
were completed within 20-150 min in acetonitrile or sol-
vent-free conditions in room temperature.
hydrogensulfate as new reagent system for the silylation of
hydroxyl groups with HMDS.23 Even though the activity of
HMDS has been increased drastically in the presence of
this reagent, the method suffer from limitations. With
Fe(HSO4)/HMDS, trimethylsilylation of alcohols and phe-
nols in solution and under solvent-free conditions were
performed at reflux and 90-100 oC, respectively.
In view of this, we decided to overcome these limita-
tions by conducting the silylation reactions in the presence
of Fe(HSO4)3/Et3N with chlorosilanes instead of silazanes.
In this method not only trimethylsilylether but also other
Trimethylsily, triethylsilyl and tert-buthyldimethyl-
silyl ethers of benzylic alcohols including acid sensitive
and electron-donating or-with drawing groups were pro-
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Article
Abri et al.
Table 3. Tert-buthyldimethyl silylation of alcohols and phenols in solution and under solvent-free
conditionsa
Silylation in CH3CN
Time (h)
Yield (%)b
60 100
Solvent-free silylation
Entry
Substrate
Time (h)
Yield (%)b
1
C6H5CH2OH
2-BrC6H4CH2OH
2-ClC6H4CH2OH
4-ClC6H4CH2OH
2-NO2C6H4CH2OH
3-NO2C6H4CH2OH
4-NO2C6H4CH2OH
4-NH2C6H4CH2OH
C6H5OH
20
20
20
19
5
95
95
95
95
95
95
95
90
95
80
85
80
2
33
25
20
30
18
13
22
80
30
30
80
95
95
95
100
95
95
90
90
80
85
70
3
4
5
6
5
7
3
8
22
7
9
10
11
12
4-NH2C6H4OH
25
18
25
4-NO2C6H4OH
4-ClC6H4OH
OH
13
14
60
90
60
25
90
85
OH
150
110
OH
CH2=CHCH2OHc
CH=CCH2OHc
15
16
60
50
70
60
40
20
70
75
HO
17
120
90
20
90
CHO
18
19
20
CH2OH
O
80
45
70
100
95
15
30
60
95
COOH
HO
100
100
CH3CONH
OH
OH
180
21
22
23
120
60
70
25
60
30
20
20
80
40
60
COOCH3
OH
O
HOOC
HO
100
NH2
OH
24
80
30
40
40
O
O
a Products were characterized by their physical constant, IR, NMR and Mass spectroscopy.
b Isolated yield. c Triethylsilylation was performed at reflux and 80 oC, respectively.
ceed efficiently with high isolated yields (Table 1, 2, 3 en-
tries 1-8). Phenols also undergo silylation easily using this
method and their corresponding silyl ethers isolated in
good to high yields (Table 1, 2, 3 entries 9-12). Some of
phenolic drugs were, also, successfully converted to their
corresponding silyl ethers in almost quantitative yields at
room temperature (Table 1, 2, 3 entries 20, 21) in solution
and solvent-free conditions. This method is not useful for
the silylation of ibuprofen, mesalazine and naproxen (Ta-
ble 1, 2, 3 entries 22, 23 and 24 respectively) because the
protection of hydroxyl group in carboxylic acid is very
difficult.
buthyldimethylsilyl ethers derivatives were isolated in high
yields (60-98%), and the reactions were completed in a rel-
atively short time (8-100 min).
Although by omitting of the solvent the reaction
times and the yields of the products were not changed con-
siderably, the need for the solvent is avoided and the work-
up procedure become easier.
We have found that Fe(HSO4)3 is a reusable catalyst
and even after five runs for the condensation reactions the
activity of the reagent was almost the same as that of the
freshly used reagent.
In order to show the efficiency of this method Table 4
compares some of the results with some those reported in
In all case the trimethylsilyl, triethylsilyl and tert-
4
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Preparation of Silyl Ethers using Fe(HSO4)3/Et3N by Chlorosilanes
Table 4. Comparison of some of the results obtained by the present method
(t/min)
(Yield %)
Entry
R1
Silylation in CH3CN
Solvent-free silylation
(1)
(2)
(1)
(2)
1
2
3
C6H5CH2OH
2-BrC6H4CH2OH
2-ClC6H4CH2OH
(20)(98)
(25)(95)
(20)(90)
(102)(70)
(120)(60)
(114)(60)
(15)(98)
(16)(95)
(15)(90)
(15)(90)
(12)(90)
(15)(95)
(1) (Trimethylsilylation) with some of those reported by Fe(HSO4)3/HMDS (2)23
the literature.23
Although the mechanism for these transformations is
The selective and competitive silylation
of phenols in the presence of allyl and
propargyl alcohols
Scheme III
unclear, but it seems that the Et3N acts as a base, and polar-
ize the O-H bond in ROH. Then chlorosilane react with
Fe(HSO4)3 as a Lewis acid to produce the silylating agent.
A rapid reaction with RO-, and the concomitant release of
the corresponding silyl ether, is a feature of this mechanism
that is shown in Scheme II.
Scheme II The mechanism of preparation of silyl
ethers with Fe(HSO4)3/Et3N reagent
easy and clean work-up procedure, short reaction times and
good to high yields of the products, which make it a useful
addition to the present methodologies for the synthesis of
chlorosilanes.
This method was also found to be useful for trimeth-
yl, triethyl and tert-buthyldimethyl silylions of allyl and
propargyl alcohols, but at the reflux conditions (Table 1, 2,
3 entries 15). Therefore we observed the selective and com-
petitive silylation of phenols in the presence of allyl and
propargyl alcohols.
ACKNOWLEDGMENTS
The authors are thankful to Azarbaijan University of
Tarbiat Moalem Research Council for the partial support of
this work.
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allyl alcohol or propargyl alcohol remained intact (Scheme
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