An efficient method for the protection of alcohols and phenols by using hexamethyldisilazane in the presence of cupric sulfate pentahydrate under neutral reaction conditions

Article abstract of DOI:10.1055/s-2005-865318

Alcohols and phenols are protected with hexamethyldisilazane in the presence of cupric sulfate pentahydrate in good to excellent yields in acetonitrile. The method is highly selective for the conversion of primary alcohols in the presence of secondary and tertiary alcohols as well as phenols. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865318

PAPER
1775
An Efficient Method for the Protection of Alcohols and Phenols by Using
Hexamethyldisilazane in the Presence of Cupric Sulfate Pentahydrate under
Neutral Reaction Conditions
An
Efficient Meth
a
od for the
t
Protec
t
o
ion of Alcoh
o
ols and Phe
n
l
ols under
Ne
A
utra
l
Reaction Con
k
ditions hlaghinia,* Sedigheh Tavakoli
Department of Chemistry, Damghan University of Basic Sciences, Damghan, Iran
Fax +98(232)5244787; E-mail: b_akhlaghinia@dubs.ac.ir
Received 31 January 2005
benzyl alcohol with HMDS using a catalytic amount of
Abstract: Alcohols and phenols are protected with hexamethyldi-
silazane in the presence of cupric sulfate pentahydrate in good to ex-
cellent yields in acetonitrile. The method is highly selective for the
conversion of primary alcohols in the presence of secondary and
tertiary alcohols as well as phenols.
CuSO4·5H2O was studied. Benzyl trimethylsilylether was
produced after 12 minutes in quantitative yield. We then
applied these conditions for the protection of structurally
different alcohols and phenols (Scheme 1).
Keywords: cupric sulfate pentahydrate , HMDS, alcohol, phenol,
trimethylsilylether
In order to optimize the reaction conditions, we first ex-
amined the effect of different molar ratios of ROH/
HMDS/catalyst. Employing the ratios which are shown in
Table 1 gave the best results and produced trimethylsi-
lylethers in quantitative yields.
Protection of the hydroxy functional group is an important
process in multi-step synthesis. One of the popular meth-
ods for this purpose is to convert hydroxy groups to their
corresponding silylethers. HMDS is a stable, cheap, and
commercially available compound that can be used for the
preparation of trimethylsilylethers from hydroxy com-
pounds, giving ammonia as the only by product. Even
though the handling of this reagent is easy, its main draw-
back is its poor silylating ability; forceful conditions and
long reaction times are required.1 A variety of catalysts
have been reported for the activation of HMDS.2–12 Re-
cently iodine13 and tungstophosphoric acid14 have also
been used as effective catalysts for the activation of
HMDS in silylation reactions.
Primary, secondary, and tertiary alcohols and phenols
were trimethylsilylated in this way. Generally, in the case
of primary and secondary alcohols the reactions took
place at room temperature accompanied by evolution of
ammonia gas from the reaction mixture.
Me3SiNHSiMe3
CuII
CuII
As a part of our ongoing research program to develop new
synthetic methodologies involving various new re-
agents,15 we perceived that cupric sulfate pentahydrate,
which is readily available, might be a useful catalyst for
trimethylsilylation because of its mild Lewis acidity. In
this paper we disclose that cupric sulfate pentahydrate can
be used as an efficient catalyst for trimethylsilylation of
alcohols and phenols.
Me3SiNHSiMe3
CuII
1
3
H3N
RCH2OH
RCH2OSiMe3
CuII
Me3SiNH2
RCH2OSiMe3
RCH2OH
2
In the present study trimethylsilylation of alcohols and
phenols in the presence of catalytic amount of
CuSO4·5H2O was investigated. Initially, the protection of
Scheme 2
CH3
H
CH3
Si
CH3
CuSO4⋅5H2O
CH3
CH3
2 ROSi
CH3
NH3
Si
N
+
2 ROH
H3C
+
MeCN
CH3
CH3
R: primary, secondary, tertiary alkyl and phenyl
Scheme 1
SYNTHESIS 2005, No. 11, pp 1775–1778
x
x.
x
x
.
2
0
0
5
Advanced online publication: 18.04.2005
DOI: 10.1055/s-2005-865318; Art ID: P01604SS
© Georg Thieme Verlag Stuttgart · New York

1776
B. Akhlaghinia, S. Tavakoli
PAPER
The mechanism of these transformations is unclear. One This method was found to be highly selective for primary
idea may be that CuSO4·5H2O acts as a Lewis acid, which alcohols. In a binary mixture of 3-phenyl-1-propanol and
may polarize the Si–N bond in HMDS to produce silylat- 2-octanol, the primary alcohol was completely converted
ing agent 1 (Scheme 2). A rapid reaction with alcohol then to the corresponding silylether, while only a 5% conver-
ensues, leading to 2 with concomitant release of the corre- sion was observed for the secondary alcohol (Table 2, en-
sponding silylether which results in the formation of the tries 1, 2). Excellent selectivity was also observed for the
ammonia–Cu(II) complex 3. Cleavage of 3, leads to the conversion of primary and secondary alcohols in the pres-
fast evolution of ammonia and release of catalyst, which ence of a tertiary alcohol (Table 2, entries 3, 4). Similarly,
re-enters to the catalytic cycle (Scheme 2). Nevertheless, this method showed excellent selectivity for the conver-
at this time there is no experimental evidence for 1 acting sion of benzyl alcohol in the presence of phenol (Table 2,
in this manner, and the actual role of this reagent will have entry 5).
to be studied in more detail.
Table 1 Trimethylsilylation of Alcohols and Phenols Catalyzed by CuSO4·5H2O in Anhydrous Acetonitrile
Entry
1
ROH
Molar ratio
ROH/HMDS/Catalyst
Time
1.5 h
Conversion (%)a Isolated yield (%)
1:0.7:0.01
100
92
OH
2
3
1:0.7:0.01
1:0.7:0.01
3.5 h
2 h
100
100
90
93
OH
OH
4
5
6
7
1:0.7:0.01
1:0.7:0.01
1:0.7:0.01
1:0.7:0.01
2.5 h
2.5 h
100
100
100
100
96
98
96
98
OH
OH
24.5 h
24.5 h
OH
OH
OH
8
9
1:0.7:0.01
1:0.8:0.01
30 h
100
100
97
91
OH
7.5 h
O2N
Cl
10
1:0.8:0.01
7.5 h
100
92
OH
11
12
1:0.7:0.01
1:0.7:0.01
12 min
4 h
100
100
98
95
OH
OH
O
O
13
14
1:0.7:0.01
1:0.7:0.01
20 min
20 min
100
100
95
99
OH
OH
Synthesis 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York

PAPER
An Efficient Method for the Protection of Alcohols and Phenols under Neutral Reaction Conditions
1777
Table 1 Trimethylsilylation of Alcohols and Phenols Catalyzed by CuSO4·5H2O in Anhydrous Acetonitrile (continued)
Entry
15b
ROH
Molar ratio
ROH/HMDS/Catalyst
Time
38 h
Conversion (%)a Isolated yield (%)
1:0.8:0.01
100
90
OH
16b
17b
18b
1:0.8:0.01
1:0.8:0.01
1:0.7:0.01
45.5 h
38 h
100
80
94
60
95
OH
OH
OH
1.5 h
100
19b
1:0.7:0.01
5.5 h
100
97
OH
O
20
21
1:0.7:0.01
1:0.7:0.01
4 h
3 h
100
100
90
94
OH
OH
22b
23b
1:0.9:0.01
1:0.9:0.01
4.5 h
3.5 h
100
100
95
98
OH
Cl
OH
O2N
24b
25b
1:0.7:0.1
38 h
38 h
65
50
50
40
OH
1:0.7:0.01
OH
a GC yield using internal standard.
b The reaction was performed under reflux.
Table 2 Selective Reaction of Different Binary Mixtures with HMDS/CuSO4·5H2O
Entry
1
Binary mixture
Products
Time (h)
11
Yield (%)a
100
OH
OH
OSiMe3
95
OH
OSiMe3
2
8
100
98
OH
OH
OH
Synthesis 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York

1778
B. Akhlaghinia, S. Tavakoli
PAPER
Table 2 Selective Reaction of Different Binary Mixtures with HMDS/CuSO4·5H2O (continued)
Entry
3
Binary mixture
Products
Time (h)
6.5
Yield (%)a
100
OH
OSiMe3
97
OH
OH
OH
4
5
7.5
0.5
100
OSiMe3
98
OH
OH
100
OSiMe3
OH
OH
97
OH
a GC yield using internal standard.
In conclusion, the present methodology demonstrates References
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To a mixture of benzyl alcohol (1 mmol, 0.108 g) and HMDS (0.7
mmol, 0.056 g) in anhyd CH3CN (3–5 mL), CuSO4·5H2O (0.01
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Acknowledgment
We gratefully acknowledge the partial support of this study by
Damghan University Research Council.
Synthesis 2005, No. 11, 1775–1778 © Thieme Stuttgart · New York