BiOClO4-mediated deprotection of silyl ethers

Article abstract of DOI:10.1016/j.tetlet.2003.11.134

TES- and TBS-protected alcohols undergo deprotection in good to excellent yield upon heating with 1equiv of BiOClO₄-xH₂O in CH ₂Cl₂. TBDPS- and TIPS-protected 2°alcohols are more resistant to deprotection. The use of this method for selective desilylation is, however, limited to the deprotection of alkyl silyl ethers in the presence of TBDPS-protected phenols.

Full text of DOI:10.1016/j.tetlet.2003.11.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1279–1281
BiOClO4-mediated deprotection of silyl ethers
R. David Crouch,* Candice A. Romany, Anna C. Kreshock, Karina A. Menconi and
Jennifer L. Zile
Department of Chemistry, Dickinson College, Box 1773, Carlisle, PA 17013, USA
Received 30 October 2003; revised 21 November 2003; accepted 24 November 2003
Abstract—TES- and TBS-protected alcohols undergo deprotection in good to excellent yield upon heating with 1 equiv of BiOClO4-
xH2O in CH2Cl2. TBDPS- and TIPS-protected 2° alcohols are more resistant to deprotection. The use of this method in selective
desilylation is, however, limited to the deprotection of alkyl silyl ethers in the presence of TBDPS-protected phenols.
Ó 2003 Elsevier Ltd. All rights reserved.
As synthetic targets grow increasingly complex, protec-
tion/deprotection protocols continue to be of critical
importance1;2 and the development of methods for the
manipulation of protecting groups remains an active
area of investigation.3 Silyl protecting groups are espe-
cially valuable when the molecule contains hydroxyl
groups. Although protic acids and fluoride sources
continue to be widely used for the removal of silyl pro-
tecting groups, a number of Lewis acids have been
introduced to mediate desilylation reactions. Some
recent examples from the literature include: BF3–OEt2,4
BCl3,5 decaborane,6 Sc(OTf)3,7 InCl3,8 ZnBr2,9
Zn(BF4)2,10 Ce(OTf)4,11 and CeCl3–7H2O/NaI.12 Of
particular interest to us was the report that BiBr3 in wet
CH3CN could effect deprotection of silyl ethers.13 Bis-
muth reagents are noted for their relatively low cost and
their low toxicity14 and could serve as environmentally
friendly reagents for desilylation.
ethers and Bi(OTf)3 is a robust Lewis acid, showing no
selectivity among several silyl groups.21 And, the pre-
ferred solvent in Lewis acid-mediated desilylations has
been acetonitrile. We sought to investigate the use of
inexpensive and mild bismuth reagents using common
organic solvents and wish to report our findings.
Our initial work focused on the use of BiCl3 and
Bi(NO3)3 in CH2Cl2 in the desilylation of TBS-protected
3-phenyl-1-propanol. Even with the addition of NaI,
which is known to increase the Lewis acidity of these
salts,22;23 only unreacted silyl ether was recovered.
However, BiOClO4-xH2O24 proved to produce excellent
yields of deprotected alcohol in as little as 1 h. The results
of our preliminary studies are summarized in Table 1.
Based on our previous work in using ZnBr2 as a desilyl-
ation agent,9 we chose to focus on CH2Cl2 as the solvent
of choice. We subjected a series of silyl-protected
alcohols to our optimal reaction conditions of 1 equiv of
BiOClO4-xH2O in CH2Cl2 at 45 °C for 1 h and the results
of these reactions are summarized in Table 2.
A survey of the literature reveals a number of instances in
which bismuth salts have served as Lewis acids including
the hydrolysis of acetals,15;16 ketals,15;16 THP ethers,17
acetonides,18 and the opening of epoxides.19 Recent
reports of examples in which bismuth reagents have been
used to remove silyl protecting groups include the use of
BiCl3/NaI in CH3CN to selectively deprotect alkyl silyl
ethers in the presence of aryl silyl ethers20 and the
deprotection of silyl ethers with BiCl3, bismuth (III) tri-
fluoroacetate and Bi(OTf)3.21 The drawbacks of the latter
report are that most of the reactions are limited to TMS
Our results show that BiOClO4-xH2O in CH2Cl2 is an
effective reagent for the deprotection of 1° silyl ethers as
well as TES- and TBS-protected 2° alcohols. Longer
reaction times were required to achieve useful yields in
the deprotection of TIPS- and TBDPS-protected 2°
alcohols. TES- and TBS-protected phenols underwent
desilylation in 1 h but TBDPS-protected phenols were
largely unreactive under these conditions.
The reactivity of silyl protected alcohols is such that
selective removal of one of these groups in the presence of
* Corresponding author. Tel.: +1-717-245-1351; fax: +1-717-245-1995;
e-mail: crouch@dickinson.edu
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.134

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R. D. Crouch et al. / Tetrahedron Letters 45 (2004) 1279–1281
Table 1. Deprotection of TES-protected 3-phenyl-1-propanol
BiOClO4-xH2O
CH2Cl2
OTBS
OH
Entry
Equivalent of BiOClO4
Temperature (°C)
Reaction time
Yielda (%)
1
2
3
4
5
6
1.0
2.0
2.0
2.0
1.0
0.5
25
25
25
25
45
45
1 h
1 h
26
87
67
94
92
45
5 h
2 days
1 h
2 days
a Yields of isolated products were spectrally identical to authentic 3-phenyl-1-propanol.
Table 2. Deprotection of silyl ethers with BiOClO4-xH2O
unreacted bis-silyl ether 1 and the product of bis-desilyla-
tion with the former being predominant. Longer reaction
times, however, led to the formation of more doubly de-
protected product.
Substrate
Product
Ph
OR
Ph
OH
R ¼ TES
TBS
TIPS
79%
92
A typical procedure follows: To a stirring solution of
1 equiv of silyl ether in reagent grade CH2Cl2 (approx-
imately 3 mL of solvent/mmol of substrate) was added
1.0 equiv of BiOClO4-xH2O. A reflux condenser was
attached and the heterogeneous mixture was stirred at
45 °C until disappearance of silyl ether was observed by
TLC (typically 1 h). The flask was cooled to room
temperature, CH2Cl2 was added for volume and the
reaction mixture was transferred to a separatory funnel.
The organic layer was washed successively with H2O,
saturated NaHCO3 (which made the organic layer
cloudy) and brine. The organic layer was dried with
MgSO4, filtered and concentrated in vacuo. Column
chromatography afforded the deprotected alcohol.
77
66
TBDPS
OR
OH
Ph
Ph
R ¼ TES
TBS
TIPS
85%
81
32 (52)a
65 (94)a
TBDPS
OR
OH
tBu
tBu
BiOClO4-xH2O is described as an oxidant25 but no
evidence of the product of oxidation of the alcohol was
observed. In a control experiment, 3-phenyl-1-propanol
was heated with BiOClO4-xH2O in CH2Cl2 overnight
and the alcohol was recovered unchanged. Although we
experienced no difficulties in handling this reagent, care
should always be exercised when handling perchlorate
salts.24
R ¼ TES
77%
85
TBS
TBDPS
<12
a Reaction time ¼ overnight.
another is unlikely to be synthetically useful. But the sta-
bility of TBDPS-protected phenols to these conditions
prompted us to investigate the selective deprotection of
alkyl silyl ethers in the presence of TBDPS aryl ethers.
Thus, a differentially protected bis-silyl ether 1 was pre-
pared and heated for 3 h in the presence of 1 equiv of
BiOClO4-xH2O to yield aryl silyl ether 2 in 65% yield (Eq.
1). The remainder of the product mixture included both
In summary, we have developed an easy-to-perform
method for deprotecting silyl-protected alcohols that
uses CH2Cl2, a readily available solvent. The method
allows for deprotection of most alkyl silyl ethers. If a
phenol is protected as a TBDPS ether, it may remain
intact as an alkyl silyl ether is deprotected.
TBDPSO
Acknowledgements
BiOClO4-xH2O
OTBS
CH2Cl2
1
This research was partially supported by an award to
Dickinson College under the Undergraduate Biological
Science Education Program of the Howard Hughes
Medical Institute and by the Arnold and Mabel Beck-
man Foundation through the Beckman Scholars Pro-
gram.
TBDPSO
OH
2, 65%

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