An efficient method for the silylation of hydroxyl groups with hexamethyldisilazane (HMDS) catalyzed by aluminum tris(dihydrogen phosphate) under solvent-free and ambient conditions

Article abstract of DOI:10.1139/V08-086

A highly efficient and mild procedure for the trimethylsilylation of a wide variety of alcohols, including primary, benzylic, secondary, hindered secondary, tertiary, phenols, and oximes with hexamethyldisilazane (HMDS), using Al(H₂PO₄)₃ as a recyclable heterogeneous catalyst at room temperature in a few minutes with excellent yields under solvent-free conditions is described.

Full text of DOI:10.1139/V08-086

841
An efficient method for the silylation of hydroxyl
groups with hexamethyldisilazane (HMDS)
catalyzed by aluminum tris(dihydrogen phosphate)
under solvent-free and ambient conditions
Hamid Reza Shaterian, Majid Ghashang, Nassrin Tajbakhsh Riki, and
Manijeh Asadi
Abstract: A highly efficient and mild procedure for the trimethylsilylation of a wide variety of alcohols, including pri-
mary, benzylic, secondary, hindered secondary, tertiary, phenols, and oximes with hexamethyldisilazane (HMDS), using
Al(H2PO4)3 as a recyclable heterogeneous catalyst at room temperature in a few minutes with excellent yields under
solvent-free conditions is described.
Key words: trimethylsilylation, hexamethyldisilazane, aluminum tris(dihydrogen phosphate) [Al(H2PO4)3], solvent-free,
hydroxyl groups.
Résumé : On a mis au point une méthode douce et très efficace de triméthylsilylation d’une grande variété d’alcools, y
compris les alcools primaires, benzyliques, secondaires, secondaires empêchés et tertiaires, ainsi que des phénols et des
oximes, qui implique l’utilization de l’hexaméthyldisilazane (HMDS) en présence de Al(H2PO4)3 comme catalyseur hé-
térogène réutilizable et qui s’effectue en quelques minutes à la température ambiante, avec d’excellents rendements et
des conditions sans solvant.
Mots-clés : triméthylsilylation, hexaméthyldisilazane, tris(phosphate diacide) d’aluminium [Al(H2PO4)3], sans solvant,
groupements hydroxyles.
[Traduit par la Rédaction] Shaterian et al 845
Introduction
disilazane (HMDS) is frequently used for the trimethyl-
silylation of hydroxyl groups. HMDS is an inexpensive and
commercially available reagent. Its handling does not re-
quire special precautions and the workup is not time-
consuming because the by-product of the reaction is ammo-
nia, which is simple to remove from the reaction medium.
The low silylation power of HMDS is the main drawback to
its application. Therefore, there are a variety of catalysts for
activating this reagent, such as (CH3)3SiCl (8), K-10
montmorillionite (9), sulfonic acids (10), zirconium sulfo-
phenyl phosphonate (11), ZnCl2 (12), Envirocat EPZGO
(13), tungstophosphoric acid (14), iodine (15), lithium per-
chlorate (16), cupric sulfate pentahydrate (17), H–β Zeolite
(18), MgBr2 (19), lithium perchlorate supported on silica gel
(20), Al(HSO4)3 (21), Al(OTF)3 (22), magnesium triflate
(23), copper triflate (24), ZrCl4 (25), silica-HClO4 (26), lan-
thanum trichloride (27), trichloroisocyanuric acid (28), and
sulfonic acid-functionalized ordered nanoporous silica (29).
However, in most cases a long reaction time, drastic reaction
conditions, or tedious workup is needed. In addition,
trimethylsilyl azide is expensive and toxic. We now show
that O-trimethylsilylated compounds can be produced using
Al(H2PO4)3 (30) as an efficient, recyclable heterogeneous
catalyst at room temperature under solvent-free conditions
(Scheme 1).
Trimethylsilylation of organic compounds having labile
hydrogen atoms is an important organic transformation. It is
a frequently used protection method in multi-step sequence
synthesis of natural products due to the enhanced stability
under a variety of conditions, solubility in nonpolar solvents,
thermal stability, and the ease of removal, which is simply
accomplished by acid- or base-induced hydrolysis giving
only unreactive siloxane as the by-product (1). It is also used
extensively for the hydroxyl compounds to increase their
volatility for gas chromatography and mass spectrometry (1,
2). Several methods have been reported for this conversion,
including the reaction of an alcohol with trimethylsilyl-
halides in the presence of a stoichiometric amount of a
tertiary amine (3), with trimethylsilyl triflate and trimethyl-
silylmethallylsulfinates, which are more reactive than the
chloride (4), allylsilanes in the presence of a catalytic
amount of p-toluenesulfonic acid (4) iodine (5), trifluoro-
methanesulfonic acid (6), and Sc(OTf)3 (7). Hexamethyl-
Received 2 February 2008. Accepted 1 May 2008. Published
on NRC Research Press Web site at canjchem.nrc.ca at
9 July 2008.
H.R. Shaterian,1 M. Ghashang, N.T. Riki, and M. Asadi.
Department of Chemistry, Faculty of Sciences, University of
Sistan and Baluchestan, Zahedan, Iran.
This catalyst is safe, easy to handle, environmentally benign,
presents fewer disposal problems, and is stable in reaction
media.
1Corresponding author (e-mail: hrshaterian@hamoon.usb.ac.ir).
Can. J. Chem. 86: 841–845 (2008)
doi:10.1139/V08-086
© 2008 NRC Canada

842
Can. J. Chem. Vol. 86, 2008
Table 1. Preparation of benzyl trimethylsilyl ether using alumi-
num tris(dihydrogen phosphate) (0.05 g) as the catalyst under
solvent and solvent-free conditions at room temperature.
Scheme 1. Preparation of trimethylsilyl ethers.
Time
(min)
GC yield
(%)
Yield
(%)a
Entry
Solvent
1
2
3
4
5
6
Dichloromethane
Chloroform
Ethyl acetate
n-Hexane
Acetonitrile
Solvent-free
27
20
35
35
15
5
100
100
100
100
100
100
89
93
91
92
89
98
Results and discussion
First, silylation of benzyl alcohols with HMDS in the
presence of solid aluminum tris(dihydrogen phosphate) as
catalyst in various solvents and also under solvent-free con-
ditions at room temperature was investigated. The results
were summarized in Table 1. As shown in Table 1, the sol-
vent-free condition is obviously the best choice for these re-
actions. Solvent-free reactions promise to be an essential
facet of ‘Green Chemistry’. This type of organic reaction
possesses some advantages over traditional reactions in or-
ganic solvents. Solvent-free reactions make it possible to
reduce the consumption of environmentally unfriendly sol-
vents and lead to new environmentally benign procedures to
save resources and energy.
To determine the optimum quantity of Al(H2PO4)3, the re-
action of benzyl alcohol (1 equiv.) and HMDS (0.8 equiv.)
was carried out under the solvent-free conditions using dif-
ferent quantities of catalyst at room temperature. The use of
50 mg of catalyst resulted in the highest yield in 5 min (Ta-
ble 2).
Thus, we prepared a range of O-trimethylsilylated com-
pounds under the optimized reaction conditions (Table 3).
A wide range of structurally diverse and functionalized
phenols, alcohols, and oximes underwent silylation by this
procedure to provide the corresponding TMS ethers
(trimethysilyl ethers) in good to excellent isolated yields as
shown in Table 3 (entries 1–24, 26, 28). Primary alcohols
mostly reacted faster than secondary and tertiary alcohols.
Generally, in all cases of benzyl, primary, secondary, and
tertiary alcohols the reactions were completed within less
than 65 min in solvent-free conditions accompanied by evo-
lution of NH3 gas from the reaction mixture. Inspection of
the data in Table 3 clearly shows that different types of hin-
dered secondary and tertiary alcohols were successfully con-
verted to the corresponding silyl ethers at ambient
conditions (Table 3). Amines (Table 3, entries 26, 27) and
thiols (Table 3, entry 25) remained unaffected under the re-
action conditions. To examine the functional group compati-
bility, we tested some more alcohols having other functional
groups such as carbonyl group, amino group, alkene, and
ethers. Alcohols were successfully converted to the corre-
sponding silyl ethers, whereas, other functional groups were
intact (Table 3, entries 2, 16, 26, 28).
aIsolated yield and the product gave satisfactory IR and NMR spectra.
Table 2. Optimization of the catalyst in the synthesis of benzyl
trimethylsilyl ether.
Catalyst
(g)
Time
(min)
Isolated
yield (%)
Entry
1
2
3
4
0.1
3
5
50
75
94
98
90
86
0.05
0.025
0.01
HMDS to produce a reactive silylating agent (I). A rapid re-
action with alcohol then ensues, leading to the ammonium
silylating species (II) with concomitant release of the corre-
sponding silyl ether. Irreversible cleavage of (II) with alco-
hol leading to the fast evolution of ROTMS (trimethysilyl
ethers) and also formation of the unstable complexes of
Al(H2PO4)3 with ammonia (III). Cleavage of this complex
with HMDS leads to the fast evolution of NH3. Release of
Al(H2PO4)3 as catalyst from the intermediate (III) re-enters
the catalytic cycle (Scheme 2).
Al(H2PO4)3 is an inexpensive and nonhazardous solid acid
catalyst, which can be handled easily and removed from the
reaction mixtures by simple filtration. The recovered catalyst
was reused five times without any loss of activity (Table 4).
To show the merit of the present work in comparison with
reported results in the literature, we compared reactions of
Al(H2PO4)3 with iodine (15), lithium perchlorate (16), cu-
pric sulfate pentahydrate (17), magnesium triflate (23), and
copper triflate (24) in the synthesis of trimethylsilyl ethers.
As shown in Table 5, Al(H2PO4)3 is a better catalyst with re-
spect to reaction times and yields of the obtained products.
Thus, the present protocol with Al(H2PO4)3 as catalyst is
convincingly superior to the reported catalytic methods.
The catalyst stability was assessed to evaluate if the cata-
lyst could be disturbed by solvent or not. In a controlled ex-
periment, preparation of 2-naphthyl trimethylsilyl ether in
CH2Cl2 as solvent was examined (Table 3, entry 20), after
7 min, the catalyst was removed by simple filtration. The re-
action was continued further and it was observed that the re-
action stopped (GC monitoring) in absence of solid catalyst
particles (Fig. 1). This suggests to us that the catalyst is het-
erogeneous and stable in reaction medium. When the sepa-
rated catalyst was transferred to this media, the reaction was
progressed and completed. To reconfirm that there were no
active catalyst species in solution or to show that the process
The suggested mechanism of the Al(H2PO4)3 catalyzed
silylation of hydroxyl groups is shown in Scheme 2.
Al(H2PO4)3 can act as Brønsted acid and also Lewis acid
owing to the empty aluminum p-orbital. Thus, in this mecha-
nism, the operation process chart (OPC) of the catalyst in
this works is unknown but according to observations such as
the evolution of NH3 in the reaction conditions, we have
suggested that an acid–base interaction in Al(H2PO4)3 as
catalyst and nitrogen in HMDS polarizes the N–Si bond of
© 2008 NRC Canada

Shaterian et al
843
Table 3. Silylation of alcohols, phenols, naphthols, and oximes with HMDS in the presence of
solid aluminum tris(dihydrogen phosphate) as the catalyst (0.05 g) under solvent-free conditions
at room temperature.
Time
(min)
Yield
(%)a
Entry
Substrate
1
2
3
4
5
6
7
8
Benzyl alcohol
5
4
7
9
8
6
8
19
65
12
9
7
56
9
11
10
6
6
7
6
6
6
5
6
7
7
7
98
96
98
93
92
83
87
94
89
96
96
91
97
94
95
98
97
96
94
95
96
95
93
90
—
92
—
80
4-Methoxybenzyl alcohol
2-Phenyl ethanol
Diphenyl methanol
1-Phenyl ethanol
1-Butanol
3-Methyl-1-butanol
Cyclohexanol
tert-Butanol
Tetrahydro-2-furylmethanol
5-Methyl-2-(1-ethylmethyl) cyclohexanol
1,4-Butandiol
Tricyclo[3,3,1,13,7] doc-1-ol
1-Octanol
2-Octanol
(3β)-Choest-4-en-3-ol
Phenol
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4-Methylphenol
1-Naphthol
2-Naphthol
4,4′-Biphenol
Acetophenone oxime
Benzaldehyde oxime
4-Methyl acetophenone oxime
1,3-Propanditiol
4-Aminophenol
Aniline
Benzoin
21
aThe pure isolated products were characterized by comparison of their physical data with those of known
compounds (8–30).
Table 4. Reusability of the catalyst based on the preparation of
Scheme 2. The suggested mechanism of the Al(H2PO4)3 cata-
benzyl trimethylsilyl ether.
lyzed silylation of hydroxyl groups.
Entry
Run no.
Yield (%)
1
2
3
4
5
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
97
96
96
95
94
heterogeneity of the catalyst in the reaction conditions. This
evidence showed that the process is heterogeneous and no
leaching occurs.
Conclusion
In conclusion, a reliable, rapid, and environmentally be-
nign method for the preparation of trimethylsilyl ethers in a
high to excellent yield under solvent-free and ambient condi-
tions has been developed, which involves the use of recycla-
ble Al(H2PO4)3. In addition to the purity of the products, the
short reaction times and ease of work-up make the method
is truly heterogeneous, the catalyst was subjected to vigor-
ous stripping in CH2Cl2 for 30 min. The catalyst was filtered
and the filtrate was used as reaction medium. No noticeable
transformation of 2-naphthyl trimethylsilyl ether confirmed
© 2008 NRC Canada

844
Can. J. Chem. Vol. 86, 2008
Table 5. Comparison of our results with results obtained by some metal salts.
Entry
Catalyst
Conditions [molar ratio of catalyst]
Time, yield (%)
1
Iodine
CH2Cl2, RT [0.01]
—
2
LiClO4
Solvent-free, RT [0.5]
CH3CN, RT [0.01]
20 min, 96
1.5 h, 95
120 min, 70
60 min, 70
6 min, 97
3
Cupric sulfate pentahydrate
Cu(OTf)2
4
CH3CN, RT [0.01]
5
Mg(OTf)2
Solvent-free, RT [0.01]
Solvent-free, RT [0.16]
10
Al(H2PO4)3
Note: Based on phenol/HMDS (1:0.8 equiv.).
Heat
Fig. 1. Evaluation of the catalyst stability in the preparation of
2-naphthyl trimethylsilyl ether.
Al2O3 + H3PO4 → Al(H2PO4)3 + H2O ↑
General procedure for silylation of alcohols using
HMDS catalyzed with Al(H2PO4)3
Al(H2PO4)3 (0.05 g) was added to a stirred solution of al-
cohol (1 mmol) and HMDS (0.7 mmol) and the mixture was
stirred at room temperature for the time specified in Table 3.
The reaction was followed by GC and TLC (n-hexane–
EtOAc, 9:1). After completion of the reaction, n-hexane was
added and the heterogeneous catalyst was filtered and the re-
sulting mixture was passed through a short pad of silica gel.
Then, the pad column was washed with n-hexane (2 ×
10 mL). Evaporation of the solvent under reduced pressure
gave pure product(s) (Table 3). The separated catalyst was
washed by ethyl acetate and dried in oven at 100 °C for 3 h.
The desired pure product(s) was characterized by compari-
son of their physical data with those of known compounds
(8–30).
advantageous. We are currently exploring further applica-
tions of Al(H2PO4)3 for other types of functional group
transformations in our laboratories.
Experimental
General
Acknowledgements
All reagents were purchased from Merck and Sigma-
Aldrich and used without further purification. Al(H2PO4)3
was prepared according to the reported procedure (30). All
yields refer to isolated products after purification. Products
were characterized by comparison with authentic samples
We are thankful to the Sistan and Baluchestan University
Research Council for the partial support of this work.
1
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© 2008 NRC Canada