N-Bromosuccinimide (NBS) - Selective and effective catalyst for trimethylsilylation of alcohols and phenols using hexamethyldisilazane and their regeneration under mild and neutral reaction conditions

Article abstract of DOI:10.1139/V07-029

Structurally diverse alcohols and phenols were trimethylsilylated in a clean and efficient reaction with hexamethyldisilazane (HMDS) based on the use of a catalytic amount of N-bromosuccinimide under both dichloromethane and solvent-free conditions at roo

Full text of DOI:10.1139/V07-029

336
N-Bromosuccinimide (NBS) — Selective and
effective catalyst for trimethylsilylation of alcohols
and phenols using hexamethyldisilazane and their
regeneration under mild and neutral reaction
conditions
Ardeshir Khazaei, Amin Rostami, Ayeh Raiatzadeh, and Marjan Mahboubifar
Abstract: Structurally diverse alcohols and phenols were trimethylsilylated in a clean and efficient reaction with
hexamethyldisilazane (HMDS) based on the use of a catalytic amount of N-bromosuccinimide under both dichloro-
methane and solvent-free conditions at room temperature. Deprotection of trimethylsilyl ethers was also be achieved ef-
ficiently in the presence of a catalytic amount of NBS in methanol at ambient temperature.
Key words: N-bromosuccinimide, solvent-free, alcohols, phenols, hexamethyldisilazane, trimethylsilyl ether, catalyst,
detrimethylsilylation.
Résumé : Opérant à la température ambiante, on a effectué d’une façon propre et efficace la triméthylsilylation
d’alcools et de phénols de structures différentes par réaction avec de l’hexaméthyldisilazane (HMDS), dans du dichlo-
rométhane ou sans solvant, en présence d’une quantité catalytique de N-bromosuccinimide (NBS). La déprotection des
éthers triméthylsilyles peut aussi se faire d’une façon efficace en présence d’une quantité catalytique de NBS, dans le
méthanol, à la température ambiante.
Mots clés : N-bromosuccinimide, sans solvant, alcools, phénols, hexaméthyldisilazane, éther triméthylsilyle, catalyseur,
détriméthylsilylation.
[Traduit par la Rédaction] Khazaei et al. 340
Introduction
giving ammonia as the only by-product. Even though the
handling of this reagent is easy, its main drawback is its
poor silylating ability; forceful conditions and long reaction
times are required (5). Therefore, for the activation of
HMDS a variety of catalysts have been reported such as
(CH3)3SiCl (6), ZnCl2 (7), zirconium sulfophenyl
phosphonate (8), montmorillonite K-10 (9), I2 (10), LiClO4
(11), H3PW12O40 (12), Al(OTf)3 (13), CuSO4·5H2O (14),
KBr (15), and LiClO4–SiO2 (16). Although these methods
produce good results in many instances, few of these cata-
lysts can do both protection and deprotection of alcohols and
phenols as trimethylsilyl ethers. Therefore, there is still a de-
mand to develop new mild methods for the trimethyl-
silylation of hydroxyl compounds and their regeneration in
the presence of inexpensive and benchtop catalysts.
The protection of hydroxy groups through the formation
of silyl ethers has been extensively utilized in organic syn-
thesis (1). Silyl ethers are easily prepared, show resistance to
oxidation, have good thermal stability and low viscosity, and
are easily recoverable from their parent compounds. More-
over, numerous silylating methods can be utilized today;
among them, trimethylsilylation is one of the most often
used. Generally, the formation of trimethylsilyl ethers is car-
ried out by the treatment of alcohols with trimethylsilyl
chlorides or trimethylsilyl triflates in the presence of a base
(2), Li2S (3), and sometimes a nonionic super base catalyst
(4). However, some of these methods frequently suffer from
drawbacks such as a lack of reactivity or a difficulty remov-
ing amine salts derived from the reaction during the
silylation reaction. HMDS is a stable, cheap, and commer-
cially available compound that can be used for the prepara-
tion of trimethylsilyl ethers from hydroxy compounds,
Similar to protection, deprotection of the trimethylsilyl
ethers constitutes an important process in the synthetic
chemistry of polyfunctional molecules, including the total
synthesis of natural products. Although several methods
Received 1 January 2007. Accepted 21 March 2007. Published on the NRC Research Press Web site at canjchem.nrc.ca on
5 May 2007.
A. Khazaei1, A. Raiatzadeh, and M. Mahboubifar. Faculty of Chemistry, Bu-Ali Sina University, Hamadan, Post Box No. 4119,
Iran, 6517838683.
A. Rostami. Department of Chemistry, Faculty of Science, Kurdistan University, Sanandaj, Iran.
1Corresponding author (e-mail: khazaei_1326@yahoo.com or a_rostami372@yahoo.com).
Can. J. Chem. 85: 336–340 (2007)
doi:10.1139/V07-029
© 2007 NRC Canada

Khazaei et al.
337
Scheme 1.
have been reported for the deprotection of trimethylsilyl
ethers (17), the development of mild, efficient, ecofriendly,
and selective reagents for the deprotection of trimethylsilyl
ethers continues to be desirable.
Solvent-free reactions have attracted considerable atten-
tion in chemical processes for different reasons. They are
valuable due to environmental safety, economic viewpoint,
easy workup, high yields of the products, and (usually) fast
reaction times (18). This is why we tried to develop a sol-
vent-free version of this new reaction.
HMDS–catalyst. The 1:2:0.01 ratio for alcohols and phenols
gave the best results and produced trimethylsilyl ethers in
quantitative yields. As shown in Table 1, using a mixture of
HMDS (2 mmol) and a catalytic amount of NBS (0.01 mmol),
primary (alkyl and benzylic), secondary (hindered and un-
hindered), and tertiary alcohols and a variety of phenols
(with electron-withdrawing and electron-releasing groups)
were transformed into the corresponding trimethylsilyl
ethers in good to high yield under both dichloromethane (I)
and solvent-free (II) conditions at room temperature (RT).
We observed that amines and thiols were not converted to
the corresponding silyl ethers under these reaction condi-
tions, even after prolonged reaction times.
Results and discussion
Because of the nearly neutral nature of the reaction me-
dium, no elimination by-products were observed at all. Sub-
sequently, we discovered that the desilylation of the
trimethylsilyl ethers can be carried out to obtain the corre-
sponding alcohols and phenols in good to excellent yields by
using the same catalyst in methanol at RT (Scheme 1 and
Table 2).
In continuation of our interest in the application of N-halo
compounds (19) in organic synthesis, we have found that
NBS is an inexpensive commercially available reagent that
has been used as an effective catalyst for the acetalization of
carbonyl compounds (20a, 20b), the conversion of aldehydes
to 1,1-diacetates (20c), and the acylation of alcohols (20d)
under mild and nearly neutral reaction conditions.
We used this procedure for the selective trimethylsilyl-
ation of n-octanol (as a model for primary alcohols) or 2-
pentanol (as a model for secondary alcohols) in the presence
of 1-adamantanol (as a model for tertiary alcohols). The
only observed products were n-octyl trimethylsilyl ether or
2-pentyl trimethylsilyl ether in 100% conversion (Scheme 2).
In this present work, the catalytic application of NBS has
been investigated as a selective reagent for the efficient
trimethylsilylation of a wide range of alcohols and phenols
under both solution and solvent-free conditions as well as
the desilylation of the corresponding TMS ethers in metha-
nol (Scheme 1).
We first examined the effect of different ratios of ROH–
Similarly, in a binary mixture of 4-methoxyphenol and
© 2007 NRC Canada

338
Can. J. Chem. Vol. 85, 2007
Table 1. Trimethylsilylation of alcohols and phenols using
HMDS catalyzed with NBS under both dichloromethane (I) and
solvent-free (II) conditions at RT.
Table 2. Deprotection of trimethylsilyl ethers in the presence of
catalytic NBS (0.2 mmol) in methanol at RT.
Time
(h)
Yield
(%)a
Yield
(%)b
Time
(h)
Yield
(%)a
Yield
(%)b
Entry
Substrate
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1.17
1.00
0.84
0.84
1.33
2.50
4.00
2.00
6.00
14.00
8.00
3.50
5.00
24.00
0.42
0.75
0.42
0.84
1.00
1.00
0.84
5.00
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
100
100
100
100
80
100
90
100
30
100
100
100
100
100
95
94
95
95
96
76
94
83
96
23
95
93
95
94
96
89
89
94
95
90
91
95
95
Entry Substrate Productc
I
II
1.10
1.00 93 100
95 100
1.00 95 100
1.50 95 95
I
II
I
II
1
2
3
4
5
2.10
2.35
2.35 0.84
2.30
1.46
1.00
2.10
0.75
5.11
8.00
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
90 100
84 95
85 95
91 96
89 93
89 90
80 96
78 94
87 77
90 86
79 74
91 76
90 95
74 93
6
0.50 85 100
1.50 81 100
7
8
9
1g
1h
1i
2g
2h
2i
1.50 90
5.00 95
8.00 83
80
90
80
80
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
12.00 10.00 95
6.00
2.50
5.00 94 100
5.00 80 100
48.00 30.00 95 100d 92 96d
95
100
100
95
95
100
100
0.75
2.00
0.50
2.10
2.21
3.00
2.30
5.00
0.50 96 100
0.75 90 100
0.58 90 100
0.84 99 100
1.00 97 100
91 95
85 93
83 95
95 95
91 95
93 85
80 92
23 94
2t
2u
2v
1t
1u
1v
1t
2t
1.50 99
90
aConversion yields.
1u
1v
1w
1x
2u
2v
2w
2x
1.00 85 100
5.50 30 100
bIsolated yields.
15.00 15.00
15.00 15.00
0
0
0
0
0
0
0
0
to produce the reactive silylating agent (as a Lewis acid).
Therefore, the mechanism shown in Scheme 4 is proposed.
aConversion yields.
bIsolated yields.
cAll products were characterized by comparison of their spectral
data (1H NMR and IR spectroscopy) with those of authentic samples.
dIn this case the ratio of substrate–HMDS–NBS was 1:8:0.2.
Conclusion
In summary, we have shown that NBS is an efficient and
selective catalyst for the protection of a variety of alcohols
and phenols as TMS ethers using HMDS and their
deprotection under very mild conditions. The product yields
are good to high and the procedure is easy and clean. There-
fore, this procedure could be utilized in transformations that
need mild reaction conditions.
2,6-diisopropylphenol (as a model for hindered phenol), 4-
methoxyphenol was completely converted to the correspond-
ing silyl ether, while 0% conversion was observed for 2,6-
diisopropylphenol (Scheme 3).
To assess the catalytic activity of NBS for trimethyl-
silylation, we compared our results for the trimethyl-
silylation of 1-naphtol with the best of the well-known
procedures from the literature (Table 3). The advantages and
the characteristic aspects of the described method in this
communication, in comparison with other previously re-
ported catalysts, are the following: a variety of phenols (6,
10, 12) can be trimethylsilylated in good to high yields (11,
14) at RT (12, 14). In addition, the catalyst NBS is inexpen-
sive, has no sensitivity to moisture (11), does not require a
large amount of catalyst (11), and no special efforts are re-
quired for the reaction (14).
On the basis of the previously reported mechanism for the
application of I2 for the trimethylsilylation of alcohols (10)
and the catalytic application of NBS for the protection of
carbonyl and hydroxyl functional groups (18), one explana-
tion for this process is that NBS may act as a source for the
formation of Br+, which polarizes the Si–N bond in HMDS
Experimental
General procedure for the trimethyisilylation of
alcohols and phenols using HMDS catalyzed with NBS
in solution
Alcohols or phenols (1 mmol) were added to a mixture of
HMDS (2 mmol) and NBS (0.01 mmol) in CH2Cl2 (7 mL),
and the mixture was then stirred at RT for the specified time
(Table 1). The progress was monitored by TLC. After com-
pletion of the reaction, water (10 mL) was added to destroy
the extra amounts of HMDS for alcohols and 5% aq. NaOH
(10 mL) for phenols, then the organic layer was separated
and dried over anhydr. Na2SO4. The solvent was evaporated,
and n-hexane (20 mL) was added to the residual mixture. In-
soluble catalyst was removed by filtration. Evaporation of
the n-hexane under reduced pressure gave pure product with-
out further purification.
© 2007 NRC Canada

Khazaei et al.
339
Scheme 2.
Scheme 3.
Table 3. Comparison of the activity of various catalysts in the trimethylsilylation of 1-naphtol with HMDS.
Entry
Catalyst
Conditions
HMDS–Cat
Time (h)
1.50
3.00
38.00
0.33
—
Yield (%)
Reference
1
2
NBS
NBS
Solvent-free, RT
CH2Cl2, RT
2.0:0.01
2.0:0.01
85
93
This work
This work
3
CuSO4·5H2O
LiClO4
CH3CN, reflux
Solvent-free, RT
Solvent-free, 55–60 °C
CH2Cl2, RT
0.7:0.10
0.7:0.50
0.8:0.01
0.8:0.01
0.8:2 drops
—
50
80
—
—
—
92
85
90
14
11
12
10
6
4
6
H3PW12O40
I2
7
—
8
Si(CH3)3Cl
Montmorillonite K-10
KBr
Solvent-free, 125 °C
CH2Cl2, RT
—
9
—
9
10
11
CH3CN, RT
0.7:0.10
0.7:0.10 g
0.13
2.00
15
16
LiClO4-SiO2
CH2Cl2, RT
Scheme 4.
© 2007 NRC Canada

340
Can. J. Chem. Vol. 85, 2007
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reaction was monitored by TLC. On completion of the reac-
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product was purified through a short column of silica gel to
obtain pure alcohol or phenol.
Acknowledgments
We are thankful to the Bu-Ali Sina University Research
Councils for partial support of this work.
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© 2007 NRC Canada