Rapid, acid-mediated deprotection of silyl ethers using microwave heating

Article abstract of DOI:10.1080/00397910500466488

Microwave heating of triethylsilyl (TES)- and tert-butyldimethylsilyl (TBS)-protected 1° and 2° alcohols in a mixture of equal parts acetic acid, tetrahydrofuran (THF), and water allows deprotection in as little as 5 min. tert-butyldiphenylsilyl (TBDPS)- and triisopropylsilyl (TIPS)-protected alcohols and silyl-protected phenols are stable in these conditions. Thus, selective deprotection of TES- and TBS-protected alcohols in the presence of TIPS or TBDPS ethers is possible. Similarly, alkyl silyl ethers can be deprotected in the presence of aryl silyl ethers. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500466488

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Rapid, Acid‐Mediated Deprotection of Silyl
Ethers Using Microwave Heating
R. David Crouch a & Anna B. Williams a
a Department of Chemistry , Dickinson College , Carlisle, Pennsylvania, USA
Published online: 16 Aug 2006.
To cite this article: R. David Crouch & Anna B. Williams (2006) Rapid, Acid‐Mediated Deprotection of
Silyl Ethers Using Microwave Heating, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:7, 959-964, DOI: 10.1080/00397910500466488
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Synthetic Communicationsw, 36: 959–964, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500466488
Rapid, Acid-Mediated Deprotection of Silyl
Ethers Using Microwave Heating
R. David Crouch and Anna B. Williams
Department of Chemistry, Dickinson College, Carlisle,
Pennsylvania, USA
Abstract: Microwave heating of triethylsilyl (TES)- and tert-butyldimethylsilyl
(TBS)-protected 18 and 28 alcohols in a mixture of equal parts acetic acid, tetrahydro-
furan (THF), and water allows deprotection in as little as 5 min. tert-butyldiphenylsilyl
(TBDPS)- and triisopropylsilyl (TIPS)-protected alcohols and silyl-protected phenols
are stable in these conditions. Thus, selective deprotection of TES- and TBS-
protected alcohols in the presence of TIPS or TBDPS ethers is possible. Similarly,
alkyl silyl ethers can be deprotected in the presence of aryl silyl ethers.
Keywords: Deprotection, protecting group, silyl ether, silyl protecting group
The increasing complexity of synthetic targets often requires the use of
protection/deprotection protocols,[1,2] and the development of techniques
for the manipulation of protecting groups remains an active field of study.[3]
Silyl protecting groups can be especially useful in protecting hydroxyl
groups in synthetic intermediates.[1–4] Many methods for removal of these
groups have been reported including acid-catalyzed and fluoride-mediated
techniques. One of the drawbacks to the use of acid-catalyzed methods is
the extended reactions times sometimes required for desilylation to occur.
Recent reports of the use of microwave irradiation to increase reaction
rates[5–8] prompted us to consider the use of this technique to accelerate desi-
lylation reactions. Although a number of recent publications describe the use
of microwave irradiation to accelerate desilylation,[9–20] most involve unusual
reagents that require special purchase or preparation[9–19] and/or oxidative
conditions that lead to the conversion of the protected alcohol to a carbonyl
Received in the USA October 12, 2005
Address correspondence to R. David Crouch, Department of Chemistry, Dickinson
College, Carlisle, Pennsylvania 17013, USA. E-mail: crouch@dickinson.edu
959

960
R. D. Crouch and A. B. Williams
functional group.[9–17] Many of these reports also focus on the trimethylsilyl
(TMS) group,[9–19] the most labile of all silyl groups, which is not as widely
used in total synthesis as other, more stable, silyl groups. We sought a rapid
deprotection method that preserved the alcohol, used readily available
reagents, and could be used on silyl groups more typically employed in
synthetic chemistry. We report our initial findings.
Among the oldest methods for acid-catalyzed deprotection of silyl ethers
is the use of mixtures of acetic acid, THF, and water.[21,22] Many examples of
this reaction utilize lengthy reaction times often approaching 72 h.[23–26]
Elevated temperatures can reduce reaction times to as little as 1 h.[27] So,
we chose this as our system to test the use of microwave irradiation in desilyla-
tion reactions using a Discover microwave system (from CEM), allowing both
temperature and pressure in the reaction vessel to be carefully monitored. Our
early attempts focused on limiting the quantity of acetic acid in the mixture.
But these attempts failed to produce useful quantities of alcohol in the 5–
10-min time span we wished to use. Longer reactions times and higher temp-
eratures did not produce alcohol in useful yields. One attempt to replace THF
with DMF in hopes of increasing the solubility of the TBS ether in the reaction
mixture produced a yield of 69% of deprotected alcohol. Subsequently, we
found that the use of a 1 : 2 : 2 mixture of HOAc, THF, and H2O with an
irradiation time of 5 min to a temperature of 1258C produced an 87%
isolated yield of alcohol. By contrast, stirring the same substrate in 1 : 1 : 1
HOAc, THF, and H2O at room temperature for 1 h produced a yield of
,49% deprotected alcohol. The results of these experiments are summarized
in Table 1. For subsequent experiments on other silyl ethers, we found that a
1 : 1 : 1 mixture of HOAc, THF, and H2O produced the most reliable results.
Table 1. Microwave-mediated deprotection of 18 TBS ether
Ratios
Entry
HOAc
THF
H2O
Temp. 8C
Yielda
1
2
3
4
5
6
7
1
1
1
1
1
1
1
5
5
7
4
3
2
1
1
1
7
4
3
2
1
125
150
125
150
125
125
125
n.r.b
n.r.
n.r.
79%
69%
87%
85%
aIsolated yields.
bNo reaction was observed by TLC.

Acid-Mediated Deprotection of Silyl Ethers
961
Scheme 1. Deprotection of 18 and 28 silyl ethers. Top: reaction conditions: 5 min at
1258C then 15 min at 1508C; bottom: reaction conditions: 15 min at 1508C.
A series of silyl-protected 18 and 28 alcohols was prepared and subjected
to these deprotection conditions. The results are shown in Scheme 1. Although
TES and TBS groups were readily removed in 5 min of irradiation at 1258C,
TIPS and TBDPS proved to be stable to these conditions. When the TIPS-
protected 18 alcohol was irradiated for an additional 15 min at 1508C,
alcohol was isolated in less than 15% yield. Neither TIPS- nor TBDPS-
protected 18 alcohol showed evidence of desilylation at 1258C over 5 min.
Silyl-protected 28 alcohols required 10 min at 1258C but otherwise showed
similar results, with the TIPS group being largely inert to the reaction
conditions.
These results, along with our inability to deprotect the TBS ether of
4-t-butylphenol using these conditions, pointed to the possibility of
selective deprotection of silyl protected alcohols bearing different silyl
groups and the deprotection of alkyl silyl ethers in the presence of aryl silyl
ethers.[3,4] To test this possibility, bis-silyl ethers 1 and 3 were prepared
using standard methods and subjected to microwave irradiation at 1258C for
5 min. The results are summarized in Scheme 2.
This method is especially rapid, clean, and easy to perform using readily
available reagents and modern focused microwave technology. The stability
of aryl silyl ethers allows them to remain untouched as alkyl silyl ether
undergoes selective desilylation. Similarly, careful selection of protecting
groups (i.e., one is a TBDPS group) permits deprotection of one alkyl silyl
ether in the presence of another with good yields and in 10 min.

962
R. D. Crouch and A. B. Williams
Scheme 2.
EXPERIMENTAL
Silyl ethers were prepared using published procedures.[21] THF was purchased
from Aldrich and used as received. Glacial acetic acid was purchased from
1
Acros and used as received. H NMR spectra of all products of desilylation
were recorded at 300 MHz on a Bruker DPX-300 spectrometer and
compared to spectra of authentic alcohol.
General Method for Deprotection of Silyl Ethers
A 10-mL reaction vessel was charged with a magnetic stir bar, 1 mmol of silyl
ether, and 1 mL each of glacial acetic acid, THF, and H2O. A septum cap was
affixed, the vessel was placed in the microwave cavity of a CEM Discover
microwave reactor, and the pressure sensor was attached. The stirring
reaction mixture was irradiated at 1258C (power ¼ 60 W) for 5 min for 18
alkyl silyl ethers (10 min for 28 alkyl silyl ethers). After cooling to room temp-
erature, TLC indicated disappearance of starting material, and the mixture was
diluted with Et2O and water. The layers were separated, and the aqueous phase
was extracted with Et2O. The combined organic phase was washed three ꢀ
with saturated NaHCO3 and three ꢀ with water, dried over MgSO4, filtered,
and concentrated. Column chromatography afforded the pure alcohol. All
products were spectrally identical to authentic alcohols.
ACKNOWLEDGMENTS
Support of this work by a grant from the Research Corporation is gratefully
acknowledged. Dickinson College is also acknowledged for support of this
project.

Acid-Mediated Deprotection of Silyl Ethers
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