A new and efficient method for the protection of alcohols and phenols by using hexamethyldisilazane in the presence of anhydrous ferric chloride under mild reaction conditions

Article abstract of DOI:10.1080/10426500601047487

Alcohols and phenols are protected with hexamethyldisilazane in the presence of anhydrous ferric chloride in good to excellent yields in acetonitrile. This method is highly selective for the conversion of primary alcohols in the presence of secondary and

Full text of DOI:10.1080/10426500601047487

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Phosphorus, Sulfur, and Silicon
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A New and Efficient Method
for the Protection of Alcohols
and Phenols by Using
Hexamethyldisilazane in the
Presence of Anhydrous Ferric
Chloride under Mild Reaction
Conditions
Batool Akhlaghinia a
a Department of Chemistry , Damghan University of
Basic Sciences , Damghan, Iran
Published online: 30 Jan 2007.
To cite this article: Batool Akhlaghinia (2007) A New and Efficient Method for the
Protection of Alcohols and Phenols by Using Hexamethyldisilazane in the Presence of
Anhydrous Ferric Chloride under Mild Reaction Conditions, Phosphorus, Sulfur, and
Silicon and the Related Elements, 182:3, 687-694, DOI: 10.1080/10426500601047487
To link to this article: http://dx.doi.org/10.1080/10426500601047487
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Phosphorus, Sulfur, and Silicon, 182:687–694, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601047487
A New and Efficient Method for the Protection
of Alcohols and Phenols by Using Hexamethyldisilazane
in the Presence of Anhydrous Ferric Chloride under Mild
Reaction Conditions
Batool Akhlaghinia
Department of Chemistry, Damghan University of Basic Sciences,
Damghan, Iran
Alcohols and phenols are protected with hexamethyldisilazane in the presence of
anhydrous ferric chloride in good to excellent yields in acetonitrile. This method is
highly selective for the conversion of primary alcohols in the presence of secondary
and tertiary alcohols and also for conversion phenols.
Keywords Alcohol; ferric chloride; hexamethyldisilazane HMDS; phenol; trimethylsi-
lylether
INTRODUCTION
The importance of hydroxyl-group functionality in organic chemistry is
reflected by the continuous appearance in the literature of methods for
developing complex structures based on the chemical interconversion
of this functional group. A limiting factor in some cases is the pres-
ence of more than one oxygen function of comparable reactivity in the
molecule to be transformed. This difficulty is circumvented by the use
of protective groups, which is a practice that in theory allows free ma-
nipulation of the desired functionality. However, it is only in a few cases
that this practice reaches an acceptable practical level, mostly due to
the difficulties involved in the selectivity of protecting and of regener-
ating specific hydroxyl groups. The role of silyl groups has already been
recognized as an important part of organic chemistry from both ana-
lytical and synthetic points of view, especially as a protecting group in
many syntheses of reasonable complexity.1 Generally the formation of
Received July 29, 2005; accepted August 21, 2006.
The authors gratefully acknowledge the partial support of this study by the Damghan
University Research Council.
Address correspondence to Batool Akhlaghinia, Department of Chemistry, Damghan
University of Basic Sciences, Damghan, Iran. E-mail: b akhlaghinia@dubs.ac.ir
687

688
B. Akhlaghinia and S. Tavakoli
silyl ethers is carried out by treatment of alcohols with silyl chlorides or
silyl 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 difficulty in the removal
of amine salts derived from the reaction of byproduced acids and co-
bases during the silylation reaction. 1,1,1,3,3,3-Hexamethyldisilazane
(HMDS) is a stable, commercially available, and cheap reagent for
trimethylsilylation of hydrogen-labile substrates,1a giving ammonia as
the only byproduct. On the other hand, silylation using this silazan-
type reagent is nearly neutral and does not need precautions. However,
the low silylating power of HMDS is the main drawback for its ap-
plication, which needs forceful conditions and long reaction times in
many cases. A variety of catalysts, such as (CH3)3SiCl,5 sulfonic acids6
ZnCl2,7 complexes of metal chlorideswithnitrogen ligands,8 zirconium
sulfophenyl phosphonate,9 K-10 montmorilonite,10 and a special type
of catalyst having the general formula X1-NH-X2 in which at least one
of the groups X1, X2, is electron-withdrawing, such as an ester or amide
group, has also been reported for the silylation of a wide range of func-
tional groups using HMDS.11
As part of our ongoing research to develop new synthetic method-
ologies involving various new reagents,12 we perceived that anhydrous
ferric chloride, which is readily available, might be a useful catalyst for
trimethylsilylation because of its mild Lewis acidity. In this article we
report that anhydrous ferric chloride can be used as an efficient catalyst
for the trimethylsilylation of alcohols and phenols.
RESULTS AND DISCUSSION
In the present study the trimethylsilylation of alcohols and phenols in
the presence of a catalytic amount of FeCl3 was investigated. The pro-
tection of benzyl alcohol under the catalytic effect of FeCl3 was studied.
Benzyl trimethylsilylether was produced immediately in a quantitative
yield. We applied these reaction conditions for the protection of struc-
turally different alcohols and phenols (Scheme 1).
R: primary, secondary, tertiary alkyl and phenyl
SCHEME 1

Protection of Alcohols and Phenols
689
SCHEME 2
In order to optimize reaction conditions, we first examined the ef-
fect of different molar ratios of the alcohol/HMDS/catalyst. The best
results were obtained using the ratio 1:0.7:0.07. Trimethylsilylethers
were produced in quantitative yields (Table I).
Compounds that were trimethylsilylated in this way are primary,
secondary, and tertiary alcohols and phenols. Generally, the reactions
were completed at r.t. and were accompanied by the evolution of NH3
gas from the reaction mixture.
The mechanism of these transformations is unclear. One hypothesis
may be that FeCl3acts as a Lewis acid, which may polarize the Si-N
bond in HMDS to produce the effective silylating agent 1 (Scheme 2). A
rapid reaction of 1 with alcohol yields 2 with a concomitant release of
the corresponding silylether. The reaction of 2 with a second molecule of
alcohol produces the corresponding silylether and the Fe(III) ammine
complex 3. The cleavage of 3 leads to the fast evolution of NH3 and
release of the catalyst, which re-enters the catalytic cycle (Scheme 2).
This method was found to be highly selective. In a binary mixture
of benzyl alcohol and 3-phenyl-1-propanol, benzylic alcohol was com-
pletely converted to the corresponding silylether, while only a 5% con-
version was observed for the propanol derivative (Table II). Excellent

690
B. Akhlaghinia and S. Tavakoli
TABLE I Trimethylsilylation of Alcohols and Phenols Catalyzed by
FeCl3 in Dry Acetonitrile
ROH
Reaction time Conversion (%)a Isolated yield (%)
Immediately
2.5 h2
100
100
92
90
Immediately
10 min
100
100
93
96
Immediately
100
98
5 h
3 h
100
100
97
96
3 h
100
100
98
97
3.5 h
20 min
100
91
10 min
100
100
92
98
Immediately
Immediately
100
95

Protection of Alcohols and Phenols
691
TABLE I Trimethylsilylation of Alcohols and Phenols Catalyzed by
FeCl3 in Dry Acetonitrile (Continued)
ROH
Reaction time
Immediately
Conversion (%)a
100
Isolated yield (%)
95
Immediately
100
99
Immediately
46 h
100
100
90
94
32 h
80
60
95
10 min
100
30 min
70 min
25 min
100
100
100
97
90
94
2 h
100
95
75 min
1.5 h
90
65
85
58
aYields were determined by GC using an internal standard.

692
B. Akhlaghinia and S. Tavakoli
TABLE II The Selective Reaction of Different Binary Mixtures with
HMDS/FeCl3
Binary mixture
Products
Reaction time
Yield (%)a
Immediately
100
95
Immediately
Immediately
100
100
100
96
4.5 h
100
100
100
Immediately
Immediately
100
100
95
Immediately
100
97

Protection of Alcohols and Phenols
693
TABLE II The Selective Reaction of Different Binary Mixtures
with HMDS/FeCl3
Binary mixture
Products
Reaction time
Yield (%)a
6.5 h
100
97
Immediately
100
97
aYields were determined by an GC using internal standard.
selectivity was also observed for the conversion of primary alcohols in
the presence of a secondary alcohol as well as of secondary alcohols in
the presence of tertiary ones (Table II). Selectivity was observed in the
conversion of benzyl alcohol in the presence of phenol (Table II).
In conclusion, the methodology described in this article shows that
FeCl3 is an effective catalyst for the trimethylsilylation of alcohols and
phenols. Advantages of our protocol are simplicity, short reaction times,
mild reaction conditions, as well as good yields. We expect this method
to be a useful addition to modern synthetic methodologies.
EXPERIMENTAL
Chemicals were obtained from Merck (Darmstadt, Germany) or Fluka
(Buchs, Switzerland). FTIR spectra were recorded on a Perkin Elmer
(Norwalk, Connecticut, USA) RXI spectrometer.NMR spectra were
recorded on a Bruker Avance DPX 250 MHz instrument. Products
were purified by column chromatography, and purity determination of
the products was accomplished by GLC on a Shimadzu model GC 10-
A instrument using n-octane as an internal standard or by TLC on a
silica-gel polygram on SIL G/UV 254 plates.
Typical Procedure for the Protection of Benzyl Alcohol
To a mixture of benzyl alcohol (0.108 g, 1 mmol) and HMDS (0.112 g,
0.7 mmol) in dry CH3CN (3–5 mL), FeCl3 (0.011 g, 0.07 mmol) was
added, and the reaction mixture was stirred at room temperature. GC

694
B. Akhlaghinia and S. Tavakoli
analysis showed that the reaction was completed immediately. The re-
action mixture was filtered. Column chromatography of the filtrate on
silica gel using n-hexane as an eluent gave benzyl trimethylsilylether
in a 98% yield.
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