Melamine-trisulfonic-acid-catalyzed trimethylsilylation of alcohols and phenols

Article abstract of DOI:10.1080/10426507.2010.544272

A highly convenient method for the trimethylsilylation of alcohols and phenols via treatment by hexamethyldisilazane in the presence ofmelamine trisulfonic acid as a catalyst has been developed. A wide variety of hydroxyl groups were selectively protected under solvent-free conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.544272

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Melamine-Trisulfonic-Acid-Catalyzed
Trimethylsilylation of Alcohols and
Phenols
Liqiang Wu a , Pengli Sun a & Fulin Yan a
a School of Pharmacy , Xinxiang Medical University , Xinxiang,
Henan, China
Published online: 14 Oct 2011.
To cite this article: Liqiang Wu , Pengli Sun & Fulin Yan (2011) Melamine-Trisulfonic-Acid-Catalyzed
Trimethylsilylation of Alcohols and Phenols, Phosphorus, Sulfur, and Silicon and the Related Elements,
186:10, 2055-2060, DOI: 10.1080/10426507.2010.544272
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Phosphorus, Sulfur, and Silicon, 186:2055–2060, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.544272
MELAMINE-TRISULFONIC-ACID-CATALYZED
TRIMETHYLSILYLATION OF ALCOHOLS AND PHENOLS
Liqiang Wu, Pengli Sun, and Fulin Yan
School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China
GRAPHICAL ABSTRACT
Abstract A highly convenient method for the trimethylsilylation of alcohols and phenols via
treatment by hexamethyldisilazane in the presence of melamine trisulfonic acid as a catalyst has
been developed. A wide variety of hydroxyl groups were selectively protected under solvent-free
conditions.
Keywords trimethylsilylation; hexamethyldisilazane; melamine trisulfonic acid; solvent-free
INTRODUCTION
The protection of hydroxyl groups by the formation of silyl ethers has been extensively
used in organic synthesis.1 Among many reagents which have been used for the protection,
hexamethyldisilazane (HMDS), a cheap, stable, and commercially available reagent, is
selected as one of the best candidates for this purpose. Its handling does not require special
precautions and the workup is not facile because the by-product of the reaction is ammonia,
which is simple to remove from the reaction medium.2 However, the low silylating power
of HMDS is the main drawback to its application. Therefore, there are a variety of catalysts
for the activation of this reagent, such as SnIV(TPP)(BF4)2,3 SiO2–ZnCl2,4 La(NO3)3,5
TiCl2(OTf)–SiO2,6 Fe(ClO4)3,7 1,3-dichloro-5,5-dimethylhydantoin,8 ZrCl4,9 trichloroiso-
cyanuric acid,10 LaCl3,11 NaHSO4–SiO2,12 NBS,13 H3PW12O40,14 alumina-supported het-
eropolyoxometalates,15 InBr3,16 CuSO4,17 ZnO,18 Fe(HSO4)3,19 HClO4–SiO2,20 ferric
chloride,21 I2,22 and tribromomelamine.23 However, many of these methodologies are asso-
ciated with one or more disadvantages such as (i) harsh reaction conditions, e.g., treatment
with air sensitive agents such as trichloroisocyanuric acid at CH2Cl2 for 4 h,10 heating
◦
at 85 C in PhMe catalyzed by alumina-supported heteropolyoxometalates,15 heating in
Received 10 September 2010; accepted 29 November 2010.
We are pleased to acknowledge the financial support from the Xinxiang Medical University.
Address correspondence to Liqiang Wu, School of Pharmacy, Xinxiang Medical University, Xinxiang,
Henan 453003, China. E-mail: wliq1974@sohu.com
2055

2056
L. WU ET AL.
CH3CN in the presence of 25 mol% Fe(HSO4)3 at reflux for 1.7 h;19 (ii) prolonged reac-
tion time;10,14,16 (iii) requirement for hazardous and carcinogenic organic solvents such as
CH3CN,3,9,12,17,19,20,21,23 CH2Cl2,7,8,10,11,16,22 PhMe;15 (iv) use of toxic, costly, or air sensi-
tive catalysts.3,8,10,13,18,23 Thus, the development of environmentally benign, high-yielding,
and clean approaches for the silylation of hydroxyl groups in demand.
Recently, melamine trisulfonic acid (MTSA) has emerged as a promising solid acid
catalyst for acid-catalyzed reactions, such as acetylation of alcohols, phenols, and amines;24
oxathioacetalyzation of aldehydes;25 and methoxymethylation of alcohols.26 This catalyst is
safe, easy to handle, environmentally benign, and presents fewer disposal problems. MTSA
as a solid acid catalyst was prepared from the reaction of melamine with neat chlorosulfonic
acid at room temperature (see Scheme 1).
NHSO3H
N
NH2
N
neat
r.t.
N
+ 3HCl
N
ClSO3H (3 eq.)
+
HO3SHN
N
NHSO3H
H2N
N
NH2
Scheme 1
In this article, we wish to report a rapid and highly efficient method for trimethylsi-
lylation of alcohols and phenols with HMDS catalyzed by MTSA at room temperature
(Scheme 2).
MTSA
neat, r.t.
ROH +
(Me3Si)2NH
ROSiMe3
1
2
Scheme 2
RESULTS AND DISCUSSION
Initially, we screened different solvents for the trimethylsilylation of benzyl alcohol
with HMDS in the presence of a catalytic amount of MTSA. As can be seen from Table 1,
Table 1 Solvent optimization for the synthesis of benzyl trimethylsilyl ethera
Entry
Solvent
CHCl3
CH2Cl2
EtOAc
n-Hexane
THF
CH3CN
Solvent-free
Yield (%)b
1
2
3
4
5
6
7
83
90
82
74
90
92
95
aReaction conditions: benzyl alcohol (1 mmol); HMDS (1 mmol); MTSA (0.05 mmol) r.t.; 15 min.
bIsolated yield.

TRIMETHYLSILYLATION OF ALCOHOLS AND PHENOLS
2057
Table 2 The amount of catalyst optimization for the synthesis of benzyl trimethylsilyl ethera
Entry
MTSA (mol%)
Time (min)b
Yield (%)b
1
2
3
4
5
6
7
0
1
2
3
4
5
6
60
25
20
15
15
15
15
0
71
83
96
96
95
95
aReaction conditions: benzyl alcohol (1 mmol); HMDS (1 mmol); r.t.
bBased on 3 runs.
benzyl alcohol was silylated in the solvent-free conditions faster than the other solvents.
Thus, solvent-free conditions were used throughout the work due to its high reaction rate
and easy workup procedures.
To optimize the catalyst loading, 0, 1, 2, 3, 4, and 5 mol% of MTSA was tested,
respectively. The results are summarized in Table 2. A 3 mol% loading of MTSA was
sufficient to push the reaction forward and 2 mol% of MTSA was not enough. Higher
amounts of MTSA did not lead to significant change in the reaction yields.
Table 3 Trimethylsilylation of alcohols and phenols catalyzed by MTSAa
Entry
Substrate
Benzyl alcohol
Time (min) Products
Yield (%)b
Ref.
1
2
3
4
5
6
7
8
9
15
10
15
10
15
15
20
25
20
15
2a
2b
2c
2d
2e
2f
2g
2h
2i
96 (90, 87, 88, 85, 82, 80)c
23
23
27
23
28
27
23
29
4-Chlorobenzyl alcohol
3-Nitrobenzyl alcohol
4-Nitrobenzyl alcohol
4-Methylbenzyl alcohol
4-Methoxylbenzyl alcohol
2,4-Dichlorobenzyl alcohol
3,4-Methylenedioxybenzyl alcohol
1-(3-Bromophenyl)ethanol
(4-Chlorocyclohexa-2,4-dienyl)
(4-chlorophenyl)methanol
Cyclohexanol
Menthol
Cholesterol
2-Adamantanol
(4-(4-methoxyphenyl)butoxy)
trimethylsilane
97
90
94
89
91
93
88
91
90
The work
The work
10
2j
11
12
13
14
15
20
30
30
25
20
2k
2l
2m
2n
2o
93
86
85
88
86
23
23
23
23
The work
16
17
18
19
20
21
22
23
Lauryl alcohol
2,2-Dimethylpropan-1-ol
Pentan-1-ol
Phenol
4-Chlorophenol
4-Nitrophenol
4-Methylphenol
4-Methoxylphenol
20
15
10
10
10
10
15
15
2p
2q
2r
2s
89
87
94
98
98
95
92
90
28
28
23
23
29
29
20
23
2t
2u
2v
2w
aReaction conditions: alcohol or phenol (1 mmol); HMDS (1 mmol); MTSA (0.03 mmol); neat; r.t.
bIsolated yield.
cYields after three times of catalyst recovery.

2058
L. WU ET AL.
Table 4 MTSA-catalyzed trimethylsilylation of benzyl alcohol in comparison with other literatures
Entry
Catalyst and conditions
Solvent
CH3CN
Neat
CH3CN
CH3CN
CH2Cl2
CH2Cl2/CH3CN
CH3CN
CH2Cl2/CH3CN
Neat
Time (min)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
Fe(HSO4)3 (25 mol%); refiux
TiCl2(OTf)–SiO2 (1 mol%)
SnIV(TPP)(BF4)2 (1 mol%)
ZrCl4 (2 mol%)
Trichloroisocyanuric acid (6 mol%)
Trichloromelamine (3 mol%)
HClO4–SiO2 (2.5 mol%)
Tribromomelamine (3 mol%)
MTSA (3 mol%)
100
10
1
70
87
100
95
90
92
93
98
96
[19]
[6]
[3]
[9]
[10]
[8]
[20]
[23]
This work
1
240
30
10
10
15
On the basis of 3 runs, the reaction conditions were optimized. As shown in Table 3,
benzylic alcohols, cyclic alcohols, and aliphatic alcohols were silylated with HMDS at
room temperature within 30 min in excellent yields after the addition of the acid catalyst
MTSA. We were then interested in whether the same catalyst could be employed for
trimethysilylation of phenolic compounds. Under the same conditions as above, all of the
tested phenols were smoothly converted into the corresponding silyl ethers in good yields.
No elimination and rearrangement by-products were observed at all.
The reusability of the catalyst was tested in the synthesis of benzyl trimethylsilyl
ether. The catalyst was recovered after each run, washed with CH2Cl2, dried in an oven at
100 ◦C for 30 min prior to use, and tested for its activity in the subsequent run and fresh
catalyst was not added. The catalyst was tested for 6 runs. It was seen that the catalyst
displayed very good reusability (Table 3, entry 1).
To illustrate the efficiency of the proposed method, Table 4 compares some of our
results with some of those reported for relevant reagents in the literature, which demonstrates
its significant superiority. Compared with some of the reported methods in Table 4, the
present method has a short reaction time, good yield, and solvent-free conditions. In
addition, MTSA is a stable, cost effective, recyclable, and noncorrosive catalyst with high
efficiency.
CONCLUSION
In conclusion, we have developed a simple, mild, and environmentally benign method
for trimethylsilylation of alcohols and phenols with HMDS catalyzed by MTSA at room
temperature. This method offers the advantage of shorter reaction times, high chemoselec-
tivity, and easy workup. We believe that this methodology could be an important addition
to the existing methodologies.
EXPERIMENTAL
NMR spectra were determined on Bruker AV-400 spectrometer at room temperature
using tetramethylsilane (TMS) as internal standard, coupling constants (J) were measured
in Hz; elemental analysis were performed by a Vario-III elemental analyzer; melting points
were determined on a XT-4 binocular microscope and were uncorrected; and MTSA was
prepared according to reference [24]; Commercially available reagents were used through-
out without further purification unless otherwise stated.

TRIMETHYLSILYLATION OF ALCOHOLS AND PHENOLS
2059
General Procedure for Trimethylsilylation of Alcohols and Phenols
A mixture of alcohol or phenol (1 mmol), MTSA (0.03 mmol), and HMDS (1
mmol) was prepared and stirred at room temperature for appropriate time (Table 3). After
completion of the reaction (TLC), 10-mL water was added and the mixture was extracted
with diethyl ether (3 × 10 mL). The organic layer was separated, dried (MgSO4), and
filtered. Evaporation of the solvent under reduced pressure gave the highly pure product
without further purification. The desired pure products were characterized by comparison
of their NMR data with those of known compounds. The spectral data of some new
trimethylsilylethers are given below.
1
(1-(3-Bromophenyl)ethoxy)trimethylsilane (2i). H NMR (400 MHz,
CDCl3): δ 7.40–7.31 (m, 4H), 4.82 (q, J = 8.4, 1H), 1.49 (d, J = 4.4, 3H), 0.15 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 149.3, 135.1, 130.2, 127.4, 125.8, 124.2, 68.9, 26.9, 0.08;
Anal. Calcd. for C11H17BrSi: C 48.35, H 6.27; found: C 48.28, H 6.35.
(4-chlorocyclohexa-2,4-dienyl)(4-chlorophenyl)methoxy)trimethylsilane
1
(2j). H NMR (400 MHz, CDCl3): δ 7.60–7.53 (m, 4H), 7.28–7.20 (m, 4H), 5.89 (s, 1H),
0.28 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 164.8, 158.2, 141.2, 140.2, 116.3, 115.0,
76.2, 0.10; Anal. Calcd. for C16H18Cl2OSi: C 59.07, H 5.58; found: C 59.01, H 5.63.
1
(4-(4-methoxyphenyl)butoxy)trimethylsilane (2o). H NMR (400 MHz,
CDCl3): δ 7.10 (d, J = 8.4, 2H), 6.82 (d, J = 8.4, 2H), 3.72 (s, 3H), 3.70–3.67 (m, 2H),
2.58–2.54 (m, 2H), 1.65–1.60 (m, 2H), 1.47–1.40 (m, 2H), 0.19 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 158.2, 132.1, 130.4, 114.2, 65.2, 55.9, 36.8, 33.1, 26.9, 0.12; Anal. Calcd.
for C14H24O2Si: C 66.61, H 9.58; found: C 66.72, H 9.48.
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