Novel and highly effective method for the trimethylsilylation of alcohols and phenols with hexamethyldisilazane (HMDS), catalyzed by I2 generated in situ using Fe(NO3)3 · 9 H 2O/NaI under heterogeneous and neutral conditions

Article abstract of DOI:10.1002/hlca.200900002

Structurally diverse alcohols and phenols were trimethylsilylated in a clean and efficient reaction with hexamethyldisilazane (HMDS) based on the use of I₂ generated in situ from Fe(NO₃)₃ · 9 H₂O/NaI. The reaction occurs very rapid in good-to-high yield in CH₂Cl₂ at room temperature, and the use of toxic and corrosive molecular I₂ is avoided.

Full text of DOI:10.1002/hlca.200900002

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Helvetica Chimica Acta – Vol. 92 (2009)
Novel and Highly Effective Method for the Trimethylsilylation of Alcohols
and Phenols with Hexamethyldisilazane (HMDS), Catalyzed by I2 Generated
in situ Using Fe(NO3)3 · 9 H2O/NaI under Heterogeneous and Neutral
Conditions
by Ardeshir Khazaei*a), Sadegh Rahmatia), and Amin Rostamib)
a) Faculty of Chemistry, Bu-Ali Sina University, P.O. Box 651783868, Hamadan, Iran
(e-mail: khazaei_1326@yahoo.com)
b) Department of Chemistry, Faculty of Science, University of Kurdistan, P.O. Box 6617715143, Sanandaj,
Iran
Structurally diverse alcohols and phenols were trimethylsilylated in a clean and efficient reaction
with hexamethyldisilazane (HMDS) based on the use of I2 generated in situ from Fe(NO3)3 · 9 H2O/NaI.
The reaction occurs very rapid in good-to-high yield in CH2Cl2 at room temperature, and the use of toxic
and corrosive molecular I2 is avoided.
Introduction. – Protection of OH groups through the formation of silyl ethers has
been extensively utilized in organic synthesis [1][2]. HMDS is a stable, inexpensive,
and commercially available compound that can be used for the preparation of
trimethylsilyl ethers from OH compounds, 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 [3]. Therefore, for the
activation of HMDS, a variety of catalysts have been reported [4 – 15]. Although these
catalysts provide an improvement, they are not suitable for trimethylsilylation of
hindered and acid-sensitive alcohols.
Recently, the highly efficient method for trimethylsilylation of alcohols (no
phenols) using HMDS catalyzed by I2 in CH2Cl2 has been reported [9]. Although I2 is a
versatile reagent in organic synthesis [16], it is highly corrosive and toxic, making its use
somewhat unattractive. In order to overcome these disadvantages of I2, Bailey et al.
reported a convenient method for in situ generation of I2 using CuSO4/NaI [17].
Results and Discussion. – In continuation of our studies on using N-halo
compounds for the protection of OH functional groups [18 – 22], we report here the
use of readily available HMDS for trimethylsilylation of a wide range of alcohols and
phenols in the presence of I2 generated in situ from Fe(NO3)3 · 9 H2O/NaI under mild
and heterogeneous conditions (Scheme).
In the beginning, the trimethylsilylation of adamantan-1-ol with HMDS in the
presence of various salts and NaI in CH2Cl2 at room temperature was studied; the
results and reaction conditions are given in Table 1. Among the presented salts,
Fe(NO3)3 · 9 H2O is the best one (Table 1, Entry 1). Therefore, we choose it for
accomplishing the desired trimethylsilylation.
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme
Table 1. Trimethylsilylation of Adamantan-1-ol (10 mmol) with HMDS (10 mmol) in the Presence of
Various Salts (0.1 mmol) and NaI (0.2 mmol) in CH2Cl2 at r.t.
Entry
Mineral salts
Time
Yield [%]
1
2
3
4
5
6
7
8
Fe(NO3)3 · 9 H2O
Fe2(SO4)3 · 5 H2O
FeCl3 · 6 H2O
CuCl2 · 2 H2O
Cu(AcO)2 · H2O
CuSO4 · 5 H2O
20 min
4 h
30 min
6 h
6 h
3 h
100
95
100
trace
NRa)
100
100
NR
Cu(NO3)2 · 3 H2O
CuCO3 · Cu(OH)2
4 h
6 h
a) NR ¼ no reaction.
Treatment of benzylic, primary, propargylic, hindered, and unhindered secondary,
tertiary, and acid-sensitive tertiary alcohols with HMDS and the catalyst in CH2Cl2 at
room temperature produced the corresponding trimethylsilyl ethers in good to high
yields (Table 2).
As shown in Table 2, in the cases of primary and secondary alcohols, the reactions
were completed very quickly. Interestingly, different types of highly hindered tertiary
alcohols were successfully converted to the corresponding trimethylsilyl ethers in
almost quantitative yields at room temperature (Table 2, Entries 19 – 22). Under these
reaction conditions, no side products were observed.
The data in Table 3 clearly show that different types of phenols were successfully
converted to the corresponding silyl ethers in short time and in almost quantitative
yields. We observed that amines and thiols were not converted under this reaction even
after prolonged reaction times (Table 3, Entries 5 and 6).
It should be mentioned that molecular I2 was generated in situ by oxidation of NaI
using Fe(NO3)3 · 9 H2O. We measured the amount of I2 generated in situ in CH2Cl2 by
UV/VIS spectrophotometry. It was found that 0.142 mmol of I2 is produced for every
mmol of NaI. In order to prove that I2 is the actual catalyst, we conducted the
trimethylsilylation of benzyl alcohol with HMDS in the presence of catalytic amounts
of Fe(NO3)3 · 9 H2O (0.1 mmol) instead of the system of Fe(NO3)3 · 9 H2O/NaI. The
reaction was completed after 3 h, while benzyl alcohol was trimethylsilylated with
HMDS and Fe(NO3)3 · 9 H2O/NaI in a very short reaction time (Table 2, Entry 1).
We have found that iron residues generated through the reaction with Fe(NO3)3 ·
9 H2O and NaI have some positive effect on the silylation of alcohols with
hexamethyldisilazane (as Lewis acid). We compared the trimethylsilylation of benzyl
alcohol with I2 and with FeSO4/I2 at ꢀ 158. The reactions were completed after 15 min

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Helvetica Chimica Acta – Vol. 92 (2009)
Table 2. Trimethylsilylation of Alcohols (10 mmol) using HMDS (10 mmol) Catalyzed with I2 Generated
in situ from Fe(NO3)3 · 9 H2O (0.1 mmol)/NaI (0.2 mmol) in CH2Cl2 at r.t.
Entry Substrate
Time [min] Producta)
Yield [%]b)
1
2
3
4
5
6
PhCH2OH
immediately PhCH2OSiMe3
immediately 4-MeO-C6H4CH2OSiMe3
90
95
95
94
96
93
4-MeO-C6H4CH2OH
4-Cl-C6H4CH2OH
2-Br-C6H4CH2OH
2,4-(Cl)2C6H3CH2OH
4
4-Cl-C6H4CH2OSiMe3
immediately 2-Br-C6H4CH2OSiMe3
immediately 2,4-(Cl)2C6H3CH2OSiMe3
immediately
7
8
9
10
11
12
Me(CH2)6CH2OH
Me(CH2)14CH2OH
HꢀC ꢁ CꢀCH2OH
PhCH2CH2OH
immediately Me(CH2)6CH2OSiMe3
immediately Me(CH2)14CH2OSiMe3
92
90
75
93
90
95
2
HꢀC ꢁ CꢀCH2OSiMe3
immediately PhCH2CH2OSiMe3
PhCH(OH)Ph
3.5
PhCH(OSiMe3)Ph
immediately
13
14
immediately
immediately
95
94
15
3.5
96
16
immediately
93
17
18
Me(CH2)4CH(OH)Me
immediately Me(CH2)4CH(OSiMe3)Me
2.5
92
90
19
20
21
55
20
60
75
93
90
22
3
95
a) All products were characterized by comparison of their spectral data (1H-NMR and IR) with those of
authentic samples. b) Yield of isolated TMS ether.

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Table 3. Trimethylsilylation of Phenols (10 mmol) using HMDS (10 mmol) Catalyzed with I2 Generated
in situ from Fe(NO3)3 · 9 H2O (0.1 mmol)/NaI (0.2 mmol) in CH2Cl2 at r.t.
Entry
1
Substrate
Time [min]
6
Producta)
Yield [%]b)
93
2
immediately
90
3
4
8
8
95
94
5
6
C6H5NH2
C6H5SH
NR
NR
–
–
–
–
a) All products were characterized by comparison of their spectral data (1H-NMR and IR) with those of
authentic samples. b) Yield of isolated TMS ether.
and 9 min, respectively, indicating that some cooperative catalysis between a FeII
complex and molecular I2 is operative.
Conclusions. – In summary, a mild method for the in situ generation of I2 from
inexpensive starting materials, Fe(NO3)3 · 9 H2O/NaI, has been developed. The I2
generated in situ has been shown to be an effective promoter of trimethylsilylation
of a variety of alcohols and phenols using HMDS under mild, heterogeneous, and
neutral conditions.
The authors acknowledge to Bu-Ali Sina University Research Councils, Center of Excellence in
Development of Chemistry Methods (CEBCM) and National Foundation of elites (BMN) for support of
this work.
Experimental Part
General Procedure for Trimethylsilylation of Alcohols and Phenols Using HMDS Catalyzed with I2
Generated in situ from Fe(NO3)3 · 9 H2O/NaI in CH2Cl2. The alcohol or phenol (10 mmol) was added to a
mixture of Fe(NO3)3 · 9 H2O (0.1 mmol) and NaI (0.2 mmol) in CH2Cl2 (3 ml). Then, HMDS (10 mmol
in 5 ml CH2Cl2) was added dropwise to this mixture within 5 min. The mixture was stirred vigorously at
r.t. for the specified time (Table 2). After completion of the reaction (TLC), the mixture was filtered,
and the solids were washed with CH2Cl2 (5 ml). Powdered Na2S2O3 (ca. 2 g; portion wise) was added, the
mixture was stirred for additional 5 min, and the resulting mixture was filtered. Finally, H2O (10 ml) was
added to destroy the extra amount of HMDS, the org. layer was separated, and the filtrate was dried
(Na2SO4). Evaporation of the solvent under reduce pressure gave almost pure product.

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Received January 3, 2009